Role of toxicological analysis in the

management of poisonings with cardiotoxicants

Bruno Meacutegarbane

Reacuteanimation Meacutedicale et Toxicologique INSERM U705 Universiteacute Paris - Diderot

Hocircpital Lariboisiegravere Paris France

bull One among the first causes of hospital admission and death

bull Increasing incidence

bull In the USA 10th cause of exposures (37) but 4th cause of death (fatality rate 027)

Poisonings with cardiovascular agents

Poisoned patients

Cardiovascular failure

1554 60 (4 )

164 (11 ) 37 (22 )

January 1998 to October 2002 3922 patients

N Mortality rate

Lariboisiegravere Hospital ICU Paris France

Cardiotoxicants

ndash Cardiovascular pharmaceuticals

ndash Sodium-channel blockers (Class I)

ndash Beta-blockers (class II)

ndash Potassium channel blockers (sotalol) (class III)

ndash Calcium-channel antagonists (class IV)

ndash Cardioglycosides (class V)

ndash Non-cardiovascular pharmaceuticals

antipsychotics antidepressants antihistamines hellip

ndash Drugs cocaine amphetamines hellip

ndash Rural toxicants organophosphates pesticides hellip

ndash Industrial toxicants alumine phosphide hellip

ndash Household toxicants trichloroethylene hellip

ndash Plants digitalis aconit colchicine yew Taxus baccatahellip

ndash Over-the-counter laquo Best life raquo (sibutramine)

A larger entity than cardiovascular drugs

Definition of ldquosevere poisoningrdquo with cardiotoxicant requiring ICU admission

A poisoning should be considered as ldquosevererdquo if bull Life-threatening symptoms occur including hemodynamic instability cardiac arrhythmia or conduction disturbances coma seizures respiratory failure or alveolar hypoventilation bull The patient has been exposed to a large amount of toxicant requiring a close monitoring bull The patient is vulnerable (co-morbidities elderly or infants)

French Society of Critical Care Medicine Reacuteanimation 2006

Signal

measurement

Interpretation

- Diagnostic

- Prognostic

- Theacuterapeutical

Is toxicological

analysis useful

in cardiotoxicant

poisonings

Sampling

Bloodplasma

Urine

Gastric liquid

But also

Saliva

Sweat

Hair

Detection

Separation +

Detection

Quantification

Principle of a toxicological analysis

x

x x x

x

Urine Blood

Management of cardiotoxicant poisoning

bull Initial ABC assessment and resuscitation

bull History determination

bull Clinical examination ECG and laboratory features

bull Therapeutic indications

- Supportive treatments

- Gastrointestinal decontamination

- Elimination enhancement

- Antidotes

bull Toxicological analysis

Clinical approach and laboratory findings are more important

than toxicological analysis results for emergent decisions

2006

2012

Why does not the clinician need any toxicological analysis to manage his

patient with cardiotoxicant poisoning

ProCon debate

The prognostic value of the ingested dose

Example of ajmaline poisoning

Ingested tablets N Cardiac arrest

1 g 7 0

2 g 13 1

3 g 16 8

Delay for symptom occurrence 1 - 3 h All patients in cardiac arrest died

Conso F Press Med 1980

Acebutolol gt 15 g

Amitritptyline gt 2 g

Carbamazepine gt 10 g

Chloroquine gt 4 g

Clomipramine gt 2 g

Dextropropoxyphen gt 500 mg

Dosulepine gt 125 g

Flecainide gt 15 g

Maprotiline gt 3 g

Propranolol gt 2 g

Baud FJ Crit Care 2007

Doses resulting in severe cardiovascular failure

Simulated probability over time for having an epinephrine infusion rate gt3 mgh

Meacutegarbane B Clin Tox 2011

The prognostic value of the ingested dose Example of chloroquine poisoning

Assessment of patientrsquos low risk if none present in the ED

- Systolic pressure lt100 mm Hg - Seizures - Unresponsiveness to verbal stimuli - Need for intubation - Any rhythm except sinus - Second- or third-degree atrioventricular block - QRS ge 012 s - PaO2 ge45 mmHg

Among the 151 low-risk patients none developed a high-risk condition after admission and none required ICU intervention These predictive criteria eliminated over 50 ICU days without compromising quality of care

Excessive admission in the ICU may also result in non-useful expenses and limited bed availability

Predicting the clinical course in intentional drug overdose in the emergency room

Brett AS Arch Intern Med 1987

Echocardiography coupled with Doppler allows a direct visualization of the heart contractility and aspects (ventricle dilatation myocardium thickness valve diseases) However it remains operator-dependent

Echocardiography

Hypovolemia or vasoplegia Cardiogenic shock

Echocardiography aspects

Severe dysrhythmia

- VO2 110 mLminm2

- SaO2 95

- Hb 11 gdl

40

90

SvO2 ()

1

Cardiac index (Lminm2)

2 3

57

70

5 6 7

80

83

SvO2 versus cardiac index relationships

SvO2 = SaO2 - VO2

IC x Hb x 134

Manini AF ClinTox 2010

- Despite of absence of specificity he serum lactate concentration had an excellent prognostic utility to predict drug-overdose fatality - The optimal lactate cut-point was 30 mmolL (84 sensitivity 75 specificity) which conferred a 158-fold increase in odds of fatality (p lt 0001)

Serum lactate is an excellent prognosticator

ROC-AUC 087 (95 CI 081ndash094)

Lactate is a marker of all types of SHOCK

1048707 A marker of inadequate perfusion or cellular O2 consumption

1048707 A marker of inadequate resuscitation and management

1048707 A predictor of patient bad outcome and development of organ

dysfunction

Beta-blocker poisonings Prognostic value of lactate concentration on admission

0

3

6

9

12

15

18

21

24

27

30

Survivors Fatalities

plt 00008S

eru

m l

acta

te c

on

cen

trati

on

s (

mm

ol

L)

0

3

6

9

12

15

18

21

24

27

30

On admissionvalues

plt 00001

Peakvalues

Seru

m l

acta

te c

on

cen

trati

on

s (

mm

ol

L)

The ROC-AUC of initial lactate for predicting mortality was 084 (074-094)

The cutoff point maximizing the sum of sensitivity and specificity was 27 mmolL

For the 30 mmolL selected lactate cutoff point 55 sensitivity 80 specificity

Meacutegarbane B Clin Tox 2010

Boehnert MT N Engl J Med 1985

Poisonings with tricyclic antidepressants Prognostic value of QRS to predict seizures and arrhythmias

Serum glucose as biomarker in calcium channel blocker poisonings

Levine M Crit Care Med 2007

Initial glucose level Peak glucose level

Increase in blood glucose +71 vs 0 p=00067

Serum potassium as biomarker in digitalis poisoning

Female

Male

lt 55

gt 55

lt 55

gt 55

Yes

No

Yes

No

Yes

No

Yes

No

K + gt45

Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No

Death rate

17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23

AV block Age

Dally S Press Med 1981

0 8 16 24 32 40 48 56

0

40

80

120

160

200

240

280

Plasma Lactate (mmolL)

Blo

od

Cyan

ide (

microm

ol

l)

Lactate as biomarker in cyanide poisoning

Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002

Chloroquine poisoning prognosis assessment

Supposed

ingested dose

Systolic BP QRS

duration

Severe gt 4 g or lt 100 mmHg or gt 010 s

Moderate 2 - 4 g and

gt 100 mmHg and

lt 010 s

Mild

lt 2 g and

gt 100 mmHg and

lt 010 s

Clemessy JL et al Crit Care Med 1996

Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg

Intubation and mechanical ventilation

Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h

Riou B N Engl J Med 1988

Macrocirculation level

- Measurement of blood pressure and cardiac index Microcirculation level

- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain

- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)

Hemodynamic monitoring of cardiotoxicant poisonings

Poisonings with tricyclic antidepressants Value of serum concentrations

Boehnert MT N Engl J Med 1985

Prognostic value of serum theophylline concentration

Sessler CN Am J Med 1990

Why does the clinician need toxicological analysis to manage his

patient with cardiotoxicant poisoning

ProCon debate

- Positive diagnosis assessment to confirm a toxic hypothesis

- Differential diagnosis to exclude a toxic hypothesis

- Prognosis evaluation

- Help for treatment indications monitoring and re-evaluation

- Retrospective evaluation medico-legal issue or scientific studies

What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings

t

Severity C blood

t

Severity C blood

Confirm severity Supportive treatments

Prognostic factors Antidotes

Interest of analysis according to drug effects

Injury-inducing drugs

Functional drugs

Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues

Prerequisite availability of toxicological analysis

- Complexity and requirements of the assays

- Dialogue between biologists and clinicians

Importance of conservative plasma and urine sampling (initial and repetitive)

Expert opinion on appropriateness of disposal according to availability of drug screening

Fabbri A Emerg Med J 2003

Does a comprehensive drug screening add to decision making for poisonings in the ED

improve agreement on patient disposal Save potentially hospital resources

Meprobamate poisonings Is serum concentration useful to indicate the

mechanism of shock

Charron C Intensive Care Med 2005

Dose-dependent hypotension with narrowed QRS

- hypovolemia

- vasoplegia if concentrations le 150 mgl

- cardiogenic if concentrations gt 150 mgl

Plasma chloroquine concentration le 12 M No death

12-25 microM death rate 2

gt 25 microM death rate 22

gt 50 microM death rate 60

Chloroquine poisoning In-hospital prognosis assessment using

blood concentrations

Clemessy JL Crit Care Med 1996

TKTD using blood concentrations TKTD using plasma concentrations

Chloroquine poisoning blood vs plasma concentrations

0 25 50 75 100 125 15000

05

10

15

20

25

30

35

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 096

0 10 20 30 40 5000

05

10

15

20

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 091

0 1 2 3 4 5 6 7 8 900

05

10

15

20

Plasma chloroquine concentration (micromolL)

Ep

inep

hri

ne

infu

sio

n r

ate

(mg

h)

0 5 10 15 20 250

1

2

3

4

Plasma chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh)

R2 = 005

R2 = 017

Patient 1

Patient 2

PKPD population modeling in chloroquine poisonings

Meacutegarbane B Clin Tox2010

Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings

Relationship Between PlasmaFlecainide Concentration and

Outcome

Survivors Fatalities

0

1

2

3

4

5

6

7

8

9

10

Outcome of Acute Poisonings

Pla

sm

a F

lecain

ide

Co

ncen

trati

on

s (

mg

L)

Meacutegarbane B Clin Tox 2007

Meacutegarbane B BCPT 2010

Verapamil poisonings

Flecainide poisonings

Meacutegarbane B Clin Tox 2002 (abstract)

0

5

10

15

20

25P

red

icte

d c

on

cen

trati

on

s (n

gm

l)

0

10

0

20

0

30

0

40

0

Time since ingestion (hours)

Predicted concentration profiles

Non suvivors C(t) = 242 exp (-0003t)

Survivors C(t) = 177 exp (-0019t)

Cut-off C(t) = 207 exp (-0011t)

0

20

40

60

80

Co

lch

icin

e p

lasm

a c

on

cen

tra

tion

on

ad

mis

sio

n(n

gm

l)

Alive patients (N = 18)

Dead patients(N = 5)

Colchicine poisonings prognostic value of the time-course of serum concentrations

Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments

Q = body load of glycoside to neutralize

Estimation using ingested amount of digitalis

Estimation using serum glycoside concentration

Q = Weight

(kg)

volume of distribution

digoxin 56 lkg

digitoxin 056 lkg

Serum glycoside concentration

(ngml) x x

Q = x Ingested amount (mg) digoxin bioavailability (60 )

digitoxin bioavailability (100 ) or

One vial of digibind (40 mg) neutralizes 06 mg of digoxin

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

bull One among the first causes of hospital admission and death

bull Increasing incidence

bull In the USA 10th cause of exposures (37) but 4th cause of death (fatality rate 027)

Poisonings with cardiovascular agents

Poisoned patients

Cardiovascular failure

1554 60 (4 )

164 (11 ) 37 (22 )

January 1998 to October 2002 3922 patients

N Mortality rate

Lariboisiegravere Hospital ICU Paris France

Cardiotoxicants

ndash Cardiovascular pharmaceuticals

ndash Sodium-channel blockers (Class I)

ndash Beta-blockers (class II)

ndash Potassium channel blockers (sotalol) (class III)

ndash Calcium-channel antagonists (class IV)

ndash Cardioglycosides (class V)

ndash Non-cardiovascular pharmaceuticals

antipsychotics antidepressants antihistamines hellip

ndash Drugs cocaine amphetamines hellip

ndash Rural toxicants organophosphates pesticides hellip

ndash Industrial toxicants alumine phosphide hellip

ndash Household toxicants trichloroethylene hellip

ndash Plants digitalis aconit colchicine yew Taxus baccatahellip

ndash Over-the-counter laquo Best life raquo (sibutramine)

A larger entity than cardiovascular drugs

Definition of ldquosevere poisoningrdquo with cardiotoxicant requiring ICU admission

A poisoning should be considered as ldquosevererdquo if bull Life-threatening symptoms occur including hemodynamic instability cardiac arrhythmia or conduction disturbances coma seizures respiratory failure or alveolar hypoventilation bull The patient has been exposed to a large amount of toxicant requiring a close monitoring bull The patient is vulnerable (co-morbidities elderly or infants)

French Society of Critical Care Medicine Reacuteanimation 2006

Signal

measurement

Interpretation

- Diagnostic

- Prognostic

- Theacuterapeutical

Is toxicological

analysis useful

in cardiotoxicant

poisonings

Sampling

Bloodplasma

Urine

Gastric liquid

But also

Saliva

Sweat

Hair

Detection

Separation +

Detection

Quantification

Principle of a toxicological analysis

x

x x x

x

Urine Blood

Management of cardiotoxicant poisoning

bull Initial ABC assessment and resuscitation

bull History determination

bull Clinical examination ECG and laboratory features

bull Therapeutic indications

- Supportive treatments

- Gastrointestinal decontamination

- Elimination enhancement

- Antidotes

bull Toxicological analysis

Clinical approach and laboratory findings are more important

than toxicological analysis results for emergent decisions

2006

2012

Why does not the clinician need any toxicological analysis to manage his

patient with cardiotoxicant poisoning

ProCon debate

The prognostic value of the ingested dose

Example of ajmaline poisoning

Ingested tablets N Cardiac arrest

1 g 7 0

2 g 13 1

3 g 16 8

Delay for symptom occurrence 1 - 3 h All patients in cardiac arrest died

Conso F Press Med 1980

Acebutolol gt 15 g

Amitritptyline gt 2 g

Carbamazepine gt 10 g

Chloroquine gt 4 g

Clomipramine gt 2 g

Dextropropoxyphen gt 500 mg

Dosulepine gt 125 g

Flecainide gt 15 g

Maprotiline gt 3 g

Propranolol gt 2 g

Baud FJ Crit Care 2007

Doses resulting in severe cardiovascular failure

Simulated probability over time for having an epinephrine infusion rate gt3 mgh

Meacutegarbane B Clin Tox 2011

The prognostic value of the ingested dose Example of chloroquine poisoning

Assessment of patientrsquos low risk if none present in the ED

- Systolic pressure lt100 mm Hg - Seizures - Unresponsiveness to verbal stimuli - Need for intubation - Any rhythm except sinus - Second- or third-degree atrioventricular block - QRS ge 012 s - PaO2 ge45 mmHg

Among the 151 low-risk patients none developed a high-risk condition after admission and none required ICU intervention These predictive criteria eliminated over 50 ICU days without compromising quality of care

Excessive admission in the ICU may also result in non-useful expenses and limited bed availability

Predicting the clinical course in intentional drug overdose in the emergency room

Brett AS Arch Intern Med 1987

Echocardiography coupled with Doppler allows a direct visualization of the heart contractility and aspects (ventricle dilatation myocardium thickness valve diseases) However it remains operator-dependent

Echocardiography

Hypovolemia or vasoplegia Cardiogenic shock

Echocardiography aspects

Severe dysrhythmia

- VO2 110 mLminm2

- SaO2 95

- Hb 11 gdl

40

90

SvO2 ()

1

Cardiac index (Lminm2)

2 3

57

70

5 6 7

80

83

SvO2 versus cardiac index relationships

SvO2 = SaO2 - VO2

IC x Hb x 134

Manini AF ClinTox 2010

- Despite of absence of specificity he serum lactate concentration had an excellent prognostic utility to predict drug-overdose fatality - The optimal lactate cut-point was 30 mmolL (84 sensitivity 75 specificity) which conferred a 158-fold increase in odds of fatality (p lt 0001)

Serum lactate is an excellent prognosticator

ROC-AUC 087 (95 CI 081ndash094)

Lactate is a marker of all types of SHOCK

1048707 A marker of inadequate perfusion or cellular O2 consumption

1048707 A marker of inadequate resuscitation and management

1048707 A predictor of patient bad outcome and development of organ

dysfunction

Beta-blocker poisonings Prognostic value of lactate concentration on admission

0

3

6

9

12

15

18

21

24

27

30

Survivors Fatalities

plt 00008S

eru

m l

acta

te c

on

cen

trati

on

s (

mm

ol

L)

0

3

6

9

12

15

18

21

24

27

30

On admissionvalues

plt 00001

Peakvalues

Seru

m l

acta

te c

on

cen

trati

on

s (

mm

ol

L)

The ROC-AUC of initial lactate for predicting mortality was 084 (074-094)

The cutoff point maximizing the sum of sensitivity and specificity was 27 mmolL

For the 30 mmolL selected lactate cutoff point 55 sensitivity 80 specificity

Meacutegarbane B Clin Tox 2010

Boehnert MT N Engl J Med 1985

Poisonings with tricyclic antidepressants Prognostic value of QRS to predict seizures and arrhythmias

Serum glucose as biomarker in calcium channel blocker poisonings

Levine M Crit Care Med 2007

Initial glucose level Peak glucose level

Increase in blood glucose +71 vs 0 p=00067

Serum potassium as biomarker in digitalis poisoning

Female

Male

lt 55

gt 55

lt 55

gt 55

Yes

No

Yes

No

Yes

No

Yes

No

K + gt45

Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No

Death rate

17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23

AV block Age

Dally S Press Med 1981

0 8 16 24 32 40 48 56

0

40

80

120

160

200

240

280

Plasma Lactate (mmolL)

Blo

od

Cyan

ide (

microm

ol

l)

Lactate as biomarker in cyanide poisoning

Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002

Chloroquine poisoning prognosis assessment

Supposed

ingested dose

Systolic BP QRS

duration

Severe gt 4 g or lt 100 mmHg or gt 010 s

Moderate 2 - 4 g and

gt 100 mmHg and

lt 010 s

Mild

lt 2 g and

gt 100 mmHg and

lt 010 s

Clemessy JL et al Crit Care Med 1996

Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg

Intubation and mechanical ventilation

Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h

Riou B N Engl J Med 1988

Macrocirculation level

- Measurement of blood pressure and cardiac index Microcirculation level

- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain

- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)

Hemodynamic monitoring of cardiotoxicant poisonings

Poisonings with tricyclic antidepressants Value of serum concentrations

Boehnert MT N Engl J Med 1985

Prognostic value of serum theophylline concentration

Sessler CN Am J Med 1990

Why does the clinician need toxicological analysis to manage his

patient with cardiotoxicant poisoning

ProCon debate

- Positive diagnosis assessment to confirm a toxic hypothesis

- Differential diagnosis to exclude a toxic hypothesis

- Prognosis evaluation

- Help for treatment indications monitoring and re-evaluation

- Retrospective evaluation medico-legal issue or scientific studies

What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings

t

Severity C blood

t

Severity C blood

Confirm severity Supportive treatments

Prognostic factors Antidotes

Interest of analysis according to drug effects

Injury-inducing drugs

Functional drugs

Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues

Prerequisite availability of toxicological analysis

- Complexity and requirements of the assays

- Dialogue between biologists and clinicians

Importance of conservative plasma and urine sampling (initial and repetitive)

Expert opinion on appropriateness of disposal according to availability of drug screening

Fabbri A Emerg Med J 2003

Does a comprehensive drug screening add to decision making for poisonings in the ED

improve agreement on patient disposal Save potentially hospital resources

Meprobamate poisonings Is serum concentration useful to indicate the

mechanism of shock

Charron C Intensive Care Med 2005

Dose-dependent hypotension with narrowed QRS

- hypovolemia

- vasoplegia if concentrations le 150 mgl

- cardiogenic if concentrations gt 150 mgl

Plasma chloroquine concentration le 12 M No death

12-25 microM death rate 2

gt 25 microM death rate 22

gt 50 microM death rate 60

Chloroquine poisoning In-hospital prognosis assessment using

blood concentrations

Clemessy JL Crit Care Med 1996

TKTD using blood concentrations TKTD using plasma concentrations

Chloroquine poisoning blood vs plasma concentrations

0 25 50 75 100 125 15000

05

10

15

20

25

30

35

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 096

0 10 20 30 40 5000

05

10

15

20

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 091

0 1 2 3 4 5 6 7 8 900

05

10

15

20

Plasma chloroquine concentration (micromolL)

Ep

inep

hri

ne

infu

sio

n r

ate

(mg

h)

0 5 10 15 20 250

1

2

3

4

Plasma chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh)

R2 = 005

R2 = 017

Patient 1

Patient 2

PKPD population modeling in chloroquine poisonings

Meacutegarbane B Clin Tox2010

Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings

Relationship Between PlasmaFlecainide Concentration and

Outcome

Survivors Fatalities

0

1

2

3

4

5

6

7

8

9

10

Outcome of Acute Poisonings

Pla

sm

a F

lecain

ide

Co

ncen

trati

on

s (

mg

L)

Meacutegarbane B Clin Tox 2007

Meacutegarbane B BCPT 2010

Verapamil poisonings

Flecainide poisonings

Meacutegarbane B Clin Tox 2002 (abstract)

0

5

10

15

20

25P

red

icte

d c

on

cen

trati

on

s (n

gm

l)

0

10

0

20

0

30

0

40

0

Time since ingestion (hours)

Predicted concentration profiles

Non suvivors C(t) = 242 exp (-0003t)

Survivors C(t) = 177 exp (-0019t)

Cut-off C(t) = 207 exp (-0011t)

0

20

40

60

80

Co

lch

icin

e p

lasm

a c

on

cen

tra

tion

on

ad

mis

sio

n(n

gm

l)

Alive patients (N = 18)

Dead patients(N = 5)

Colchicine poisonings prognostic value of the time-course of serum concentrations

Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments

Q = body load of glycoside to neutralize

Estimation using ingested amount of digitalis

Estimation using serum glycoside concentration

Q = Weight

(kg)

volume of distribution

digoxin 56 lkg

digitoxin 056 lkg

Serum glycoside concentration

(ngml) x x

Q = x Ingested amount (mg) digoxin bioavailability (60 )

digitoxin bioavailability (100 ) or

One vial of digibind (40 mg) neutralizes 06 mg of digoxin

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

Cardiotoxicants

ndash Cardiovascular pharmaceuticals

ndash Sodium-channel blockers (Class I)

ndash Beta-blockers (class II)

ndash Potassium channel blockers (sotalol) (class III)

ndash Calcium-channel antagonists (class IV)

ndash Cardioglycosides (class V)

ndash Non-cardiovascular pharmaceuticals

antipsychotics antidepressants antihistamines hellip

ndash Drugs cocaine amphetamines hellip

ndash Rural toxicants organophosphates pesticides hellip

ndash Industrial toxicants alumine phosphide hellip

ndash Household toxicants trichloroethylene hellip

ndash Plants digitalis aconit colchicine yew Taxus baccatahellip

ndash Over-the-counter laquo Best life raquo (sibutramine)

A larger entity than cardiovascular drugs

Definition of ldquosevere poisoningrdquo with cardiotoxicant requiring ICU admission

A poisoning should be considered as ldquosevererdquo if bull Life-threatening symptoms occur including hemodynamic instability cardiac arrhythmia or conduction disturbances coma seizures respiratory failure or alveolar hypoventilation bull The patient has been exposed to a large amount of toxicant requiring a close monitoring bull The patient is vulnerable (co-morbidities elderly or infants)

French Society of Critical Care Medicine Reacuteanimation 2006

Signal

measurement

Interpretation

- Diagnostic

- Prognostic

- Theacuterapeutical

Is toxicological

analysis useful

in cardiotoxicant

poisonings

Sampling

Bloodplasma

Urine

Gastric liquid

But also

Saliva

Sweat

Hair

Detection

Separation +

Detection

Quantification

Principle of a toxicological analysis

x

x x x

x

Urine Blood

Management of cardiotoxicant poisoning

bull Initial ABC assessment and resuscitation

bull History determination

bull Clinical examination ECG and laboratory features

bull Therapeutic indications

- Supportive treatments

- Gastrointestinal decontamination

- Elimination enhancement

- Antidotes

bull Toxicological analysis

Clinical approach and laboratory findings are more important

than toxicological analysis results for emergent decisions

2006

2012

Why does not the clinician need any toxicological analysis to manage his

patient with cardiotoxicant poisoning

ProCon debate

The prognostic value of the ingested dose

Example of ajmaline poisoning

Ingested tablets N Cardiac arrest

1 g 7 0

2 g 13 1

3 g 16 8

Delay for symptom occurrence 1 - 3 h All patients in cardiac arrest died

Conso F Press Med 1980

Acebutolol gt 15 g

Amitritptyline gt 2 g

Carbamazepine gt 10 g

Chloroquine gt 4 g

Clomipramine gt 2 g

Dextropropoxyphen gt 500 mg

Dosulepine gt 125 g

Flecainide gt 15 g

Maprotiline gt 3 g

Propranolol gt 2 g

Baud FJ Crit Care 2007

Doses resulting in severe cardiovascular failure

Simulated probability over time for having an epinephrine infusion rate gt3 mgh

Meacutegarbane B Clin Tox 2011

The prognostic value of the ingested dose Example of chloroquine poisoning

Assessment of patientrsquos low risk if none present in the ED

- Systolic pressure lt100 mm Hg - Seizures - Unresponsiveness to verbal stimuli - Need for intubation - Any rhythm except sinus - Second- or third-degree atrioventricular block - QRS ge 012 s - PaO2 ge45 mmHg

Among the 151 low-risk patients none developed a high-risk condition after admission and none required ICU intervention These predictive criteria eliminated over 50 ICU days without compromising quality of care

Excessive admission in the ICU may also result in non-useful expenses and limited bed availability

Predicting the clinical course in intentional drug overdose in the emergency room

Brett AS Arch Intern Med 1987

Echocardiography coupled with Doppler allows a direct visualization of the heart contractility and aspects (ventricle dilatation myocardium thickness valve diseases) However it remains operator-dependent

Echocardiography

Hypovolemia or vasoplegia Cardiogenic shock

Echocardiography aspects

Severe dysrhythmia

- VO2 110 mLminm2

- SaO2 95

- Hb 11 gdl

40

90

SvO2 ()

1

Cardiac index (Lminm2)

2 3

57

70

5 6 7

80

83

SvO2 versus cardiac index relationships

SvO2 = SaO2 - VO2

IC x Hb x 134

Manini AF ClinTox 2010

- Despite of absence of specificity he serum lactate concentration had an excellent prognostic utility to predict drug-overdose fatality - The optimal lactate cut-point was 30 mmolL (84 sensitivity 75 specificity) which conferred a 158-fold increase in odds of fatality (p lt 0001)

Serum lactate is an excellent prognosticator

ROC-AUC 087 (95 CI 081ndash094)

Lactate is a marker of all types of SHOCK

1048707 A marker of inadequate perfusion or cellular O2 consumption

1048707 A marker of inadequate resuscitation and management

1048707 A predictor of patient bad outcome and development of organ

dysfunction

Beta-blocker poisonings Prognostic value of lactate concentration on admission

0

3

6

9

12

15

18

21

24

27

30

Survivors Fatalities

plt 00008S

eru

m l

acta

te c

on

cen

trati

on

s (

mm

ol

L)

0

3

6

9

12

15

18

21

24

27

30

On admissionvalues

plt 00001

Peakvalues

Seru

m l

acta

te c

on

cen

trati

on

s (

mm

ol

L)

The ROC-AUC of initial lactate for predicting mortality was 084 (074-094)

The cutoff point maximizing the sum of sensitivity and specificity was 27 mmolL

For the 30 mmolL selected lactate cutoff point 55 sensitivity 80 specificity

Meacutegarbane B Clin Tox 2010

Boehnert MT N Engl J Med 1985

Poisonings with tricyclic antidepressants Prognostic value of QRS to predict seizures and arrhythmias

Serum glucose as biomarker in calcium channel blocker poisonings

Levine M Crit Care Med 2007

Initial glucose level Peak glucose level

Increase in blood glucose +71 vs 0 p=00067

Serum potassium as biomarker in digitalis poisoning

Female

Male

lt 55

gt 55

lt 55

gt 55

Yes

No

Yes

No

Yes

No

Yes

No

K + gt45

Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No

Death rate

17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23

AV block Age

Dally S Press Med 1981

0 8 16 24 32 40 48 56

0

40

80

120

160

200

240

280

Plasma Lactate (mmolL)

Blo

od

Cyan

ide (

microm

ol

l)

Lactate as biomarker in cyanide poisoning

Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002

Chloroquine poisoning prognosis assessment

Supposed

ingested dose

Systolic BP QRS

duration

Severe gt 4 g or lt 100 mmHg or gt 010 s

Moderate 2 - 4 g and

gt 100 mmHg and

lt 010 s

Mild

lt 2 g and

gt 100 mmHg and

lt 010 s

Clemessy JL et al Crit Care Med 1996

Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg

Intubation and mechanical ventilation

Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h

Riou B N Engl J Med 1988

Macrocirculation level

- Measurement of blood pressure and cardiac index Microcirculation level

- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain

- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)

Hemodynamic monitoring of cardiotoxicant poisonings

Poisonings with tricyclic antidepressants Value of serum concentrations

Boehnert MT N Engl J Med 1985

Prognostic value of serum theophylline concentration

Sessler CN Am J Med 1990

Why does the clinician need toxicological analysis to manage his

patient with cardiotoxicant poisoning

ProCon debate

- Positive diagnosis assessment to confirm a toxic hypothesis

- Differential diagnosis to exclude a toxic hypothesis

- Prognosis evaluation

- Help for treatment indications monitoring and re-evaluation

- Retrospective evaluation medico-legal issue or scientific studies

What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings

t

Severity C blood

t

Severity C blood

Confirm severity Supportive treatments

Prognostic factors Antidotes

Interest of analysis according to drug effects

Injury-inducing drugs

Functional drugs

Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues

Prerequisite availability of toxicological analysis

- Complexity and requirements of the assays

- Dialogue between biologists and clinicians

Importance of conservative plasma and urine sampling (initial and repetitive)

Expert opinion on appropriateness of disposal according to availability of drug screening

Fabbri A Emerg Med J 2003

Does a comprehensive drug screening add to decision making for poisonings in the ED

improve agreement on patient disposal Save potentially hospital resources

Meprobamate poisonings Is serum concentration useful to indicate the

mechanism of shock

Charron C Intensive Care Med 2005

Dose-dependent hypotension with narrowed QRS

- hypovolemia

- vasoplegia if concentrations le 150 mgl

- cardiogenic if concentrations gt 150 mgl

Plasma chloroquine concentration le 12 M No death

12-25 microM death rate 2

gt 25 microM death rate 22

gt 50 microM death rate 60

Chloroquine poisoning In-hospital prognosis assessment using

blood concentrations

Clemessy JL Crit Care Med 1996

TKTD using blood concentrations TKTD using plasma concentrations

Chloroquine poisoning blood vs plasma concentrations

0 25 50 75 100 125 15000

05

10

15

20

25

30

35

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 096

0 10 20 30 40 5000

05

10

15

20

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 091

0 1 2 3 4 5 6 7 8 900

05

10

15

20

Plasma chloroquine concentration (micromolL)

Ep

inep

hri

ne

infu

sio

n r

ate

(mg

h)

0 5 10 15 20 250

1

2

3

4

Plasma chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh)

R2 = 005

R2 = 017

Patient 1

Patient 2

PKPD population modeling in chloroquine poisonings

Meacutegarbane B Clin Tox2010

Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings

Relationship Between PlasmaFlecainide Concentration and

Outcome

Survivors Fatalities

0

1

2

3

4

5

6

7

8

9

10

Outcome of Acute Poisonings

Pla

sm

a F

lecain

ide

Co

ncen

trati

on

s (

mg

L)

Meacutegarbane B Clin Tox 2007

Meacutegarbane B BCPT 2010

Verapamil poisonings

Flecainide poisonings

Meacutegarbane B Clin Tox 2002 (abstract)

0

5

10

15

20

25P

red

icte

d c

on

cen

trati

on

s (n

gm

l)

0

10

0

20

0

30

0

40

0

Time since ingestion (hours)

Predicted concentration profiles

Non suvivors C(t) = 242 exp (-0003t)

Survivors C(t) = 177 exp (-0019t)

Cut-off C(t) = 207 exp (-0011t)

0

20

40

60

80

Co

lch

icin

e p

lasm

a c

on

cen

tra

tion

on

ad

mis

sio

n(n

gm

l)

Alive patients (N = 18)

Dead patients(N = 5)

Colchicine poisonings prognostic value of the time-course of serum concentrations

Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments

Q = body load of glycoside to neutralize

Estimation using ingested amount of digitalis

Estimation using serum glycoside concentration

Q = Weight

(kg)

volume of distribution

digoxin 56 lkg

digitoxin 056 lkg

Serum glycoside concentration

(ngml) x x

Q = x Ingested amount (mg) digoxin bioavailability (60 )

digitoxin bioavailability (100 ) or

One vial of digibind (40 mg) neutralizes 06 mg of digoxin

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

Definition of ldquosevere poisoningrdquo with cardiotoxicant requiring ICU admission

A poisoning should be considered as ldquosevererdquo if bull Life-threatening symptoms occur including hemodynamic instability cardiac arrhythmia or conduction disturbances coma seizures respiratory failure or alveolar hypoventilation bull The patient has been exposed to a large amount of toxicant requiring a close monitoring bull The patient is vulnerable (co-morbidities elderly or infants)

French Society of Critical Care Medicine Reacuteanimation 2006

Signal

measurement

Interpretation

- Diagnostic

- Prognostic

- Theacuterapeutical

Is toxicological

analysis useful

in cardiotoxicant

poisonings

Sampling

Bloodplasma

Urine

Gastric liquid

But also

Saliva

Sweat

Hair

Detection

Separation +

Detection

Quantification

Principle of a toxicological analysis

x

x x x

x

Urine Blood

Management of cardiotoxicant poisoning

bull Initial ABC assessment and resuscitation

bull History determination

bull Clinical examination ECG and laboratory features

bull Therapeutic indications

- Supportive treatments

- Gastrointestinal decontamination

- Elimination enhancement

- Antidotes

bull Toxicological analysis

Clinical approach and laboratory findings are more important

than toxicological analysis results for emergent decisions

2006

2012

Why does not the clinician need any toxicological analysis to manage his

patient with cardiotoxicant poisoning

ProCon debate

The prognostic value of the ingested dose

Example of ajmaline poisoning

Ingested tablets N Cardiac arrest

1 g 7 0

2 g 13 1

3 g 16 8

Delay for symptom occurrence 1 - 3 h All patients in cardiac arrest died

Conso F Press Med 1980

Acebutolol gt 15 g

Amitritptyline gt 2 g

Carbamazepine gt 10 g

Chloroquine gt 4 g

Clomipramine gt 2 g

Dextropropoxyphen gt 500 mg

Dosulepine gt 125 g

Flecainide gt 15 g

Maprotiline gt 3 g

Propranolol gt 2 g

Baud FJ Crit Care 2007

Doses resulting in severe cardiovascular failure

Simulated probability over time for having an epinephrine infusion rate gt3 mgh

Meacutegarbane B Clin Tox 2011

The prognostic value of the ingested dose Example of chloroquine poisoning

Assessment of patientrsquos low risk if none present in the ED

- Systolic pressure lt100 mm Hg - Seizures - Unresponsiveness to verbal stimuli - Need for intubation - Any rhythm except sinus - Second- or third-degree atrioventricular block - QRS ge 012 s - PaO2 ge45 mmHg

Among the 151 low-risk patients none developed a high-risk condition after admission and none required ICU intervention These predictive criteria eliminated over 50 ICU days without compromising quality of care

Excessive admission in the ICU may also result in non-useful expenses and limited bed availability

Predicting the clinical course in intentional drug overdose in the emergency room

Brett AS Arch Intern Med 1987

Echocardiography coupled with Doppler allows a direct visualization of the heart contractility and aspects (ventricle dilatation myocardium thickness valve diseases) However it remains operator-dependent

Echocardiography

Hypovolemia or vasoplegia Cardiogenic shock

Echocardiography aspects

Severe dysrhythmia

- VO2 110 mLminm2

- SaO2 95

- Hb 11 gdl

40

90

SvO2 ()

1

Cardiac index (Lminm2)

2 3

57

70

5 6 7

80

83

SvO2 versus cardiac index relationships

SvO2 = SaO2 - VO2

IC x Hb x 134

Manini AF ClinTox 2010

- Despite of absence of specificity he serum lactate concentration had an excellent prognostic utility to predict drug-overdose fatality - The optimal lactate cut-point was 30 mmolL (84 sensitivity 75 specificity) which conferred a 158-fold increase in odds of fatality (p lt 0001)

Serum lactate is an excellent prognosticator

ROC-AUC 087 (95 CI 081ndash094)

Lactate is a marker of all types of SHOCK

1048707 A marker of inadequate perfusion or cellular O2 consumption

1048707 A marker of inadequate resuscitation and management

1048707 A predictor of patient bad outcome and development of organ

dysfunction

Beta-blocker poisonings Prognostic value of lactate concentration on admission

0

3

6

9

12

15

18

21

24

27

30

Survivors Fatalities

plt 00008S

eru

m l

acta

te c

on

cen

trati

on

s (

mm

ol

L)

0

3

6

9

12

15

18

21

24

27

30

On admissionvalues

plt 00001

Peakvalues

Seru

m l

acta

te c

on

cen

trati

on

s (

mm

ol

L)

The ROC-AUC of initial lactate for predicting mortality was 084 (074-094)

The cutoff point maximizing the sum of sensitivity and specificity was 27 mmolL

For the 30 mmolL selected lactate cutoff point 55 sensitivity 80 specificity

Meacutegarbane B Clin Tox 2010

Boehnert MT N Engl J Med 1985

Poisonings with tricyclic antidepressants Prognostic value of QRS to predict seizures and arrhythmias

Serum glucose as biomarker in calcium channel blocker poisonings

Levine M Crit Care Med 2007

Initial glucose level Peak glucose level

Increase in blood glucose +71 vs 0 p=00067

Serum potassium as biomarker in digitalis poisoning

Female

Male

lt 55

gt 55

lt 55

gt 55

Yes

No

Yes

No

Yes

No

Yes

No

K + gt45

Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No

Death rate

17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23

AV block Age

Dally S Press Med 1981

0 8 16 24 32 40 48 56

0

40

80

120

160

200

240

280

Plasma Lactate (mmolL)

Blo

od

Cyan

ide (

microm

ol

l)

Lactate as biomarker in cyanide poisoning

Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002

Chloroquine poisoning prognosis assessment

Supposed

ingested dose

Systolic BP QRS

duration

Severe gt 4 g or lt 100 mmHg or gt 010 s

Moderate 2 - 4 g and

gt 100 mmHg and

lt 010 s

Mild

lt 2 g and

gt 100 mmHg and

lt 010 s

Clemessy JL et al Crit Care Med 1996

Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg

Intubation and mechanical ventilation

Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h

Riou B N Engl J Med 1988

Macrocirculation level

- Measurement of blood pressure and cardiac index Microcirculation level

- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain

- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)

Hemodynamic monitoring of cardiotoxicant poisonings

Poisonings with tricyclic antidepressants Value of serum concentrations

Boehnert MT N Engl J Med 1985

Prognostic value of serum theophylline concentration

Sessler CN Am J Med 1990

Why does the clinician need toxicological analysis to manage his

patient with cardiotoxicant poisoning

ProCon debate

- Positive diagnosis assessment to confirm a toxic hypothesis

- Differential diagnosis to exclude a toxic hypothesis

- Prognosis evaluation

- Help for treatment indications monitoring and re-evaluation

- Retrospective evaluation medico-legal issue or scientific studies

What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings

t

Severity C blood

t

Severity C blood

Confirm severity Supportive treatments

Prognostic factors Antidotes

Interest of analysis according to drug effects

Injury-inducing drugs

Functional drugs

Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues

Prerequisite availability of toxicological analysis

- Complexity and requirements of the assays

- Dialogue between biologists and clinicians

Importance of conservative plasma and urine sampling (initial and repetitive)

Expert opinion on appropriateness of disposal according to availability of drug screening

Fabbri A Emerg Med J 2003

Does a comprehensive drug screening add to decision making for poisonings in the ED

improve agreement on patient disposal Save potentially hospital resources

Meprobamate poisonings Is serum concentration useful to indicate the

mechanism of shock

Charron C Intensive Care Med 2005

Dose-dependent hypotension with narrowed QRS

- hypovolemia

- vasoplegia if concentrations le 150 mgl

- cardiogenic if concentrations gt 150 mgl

Plasma chloroquine concentration le 12 M No death

12-25 microM death rate 2

gt 25 microM death rate 22

gt 50 microM death rate 60

Chloroquine poisoning In-hospital prognosis assessment using

blood concentrations

Clemessy JL Crit Care Med 1996

TKTD using blood concentrations TKTD using plasma concentrations

Chloroquine poisoning blood vs plasma concentrations

0 25 50 75 100 125 15000

05

10

15

20

25

30

35

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 096

0 10 20 30 40 5000

05

10

15

20

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 091

0 1 2 3 4 5 6 7 8 900

05

10

15

20

Plasma chloroquine concentration (micromolL)

Ep

inep

hri

ne

infu

sio

n r

ate

(mg

h)

0 5 10 15 20 250

1

2

3

4

Plasma chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh)

R2 = 005

R2 = 017

Patient 1

Patient 2

PKPD population modeling in chloroquine poisonings

Meacutegarbane B Clin Tox2010

Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings

Relationship Between PlasmaFlecainide Concentration and

Outcome

Survivors Fatalities

0

1

2

3

4

5

6

7

8

9

10

Outcome of Acute Poisonings

Pla

sm

a F

lecain

ide

Co

ncen

trati

on

s (

mg

L)

Meacutegarbane B Clin Tox 2007

Meacutegarbane B BCPT 2010

Verapamil poisonings

Flecainide poisonings

Meacutegarbane B Clin Tox 2002 (abstract)

0

5

10

15

20

25P

red

icte

d c

on

cen

trati

on

s (n

gm

l)

0

10

0

20

0

30

0

40

0

Time since ingestion (hours)

Predicted concentration profiles

Non suvivors C(t) = 242 exp (-0003t)

Survivors C(t) = 177 exp (-0019t)

Cut-off C(t) = 207 exp (-0011t)

0

20

40

60

80

Co

lch

icin

e p

lasm

a c

on

cen

tra

tion

on

ad

mis

sio

n(n

gm

l)

Alive patients (N = 18)

Dead patients(N = 5)

Colchicine poisonings prognostic value of the time-course of serum concentrations

Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments

Q = body load of glycoside to neutralize

Estimation using ingested amount of digitalis

Estimation using serum glycoside concentration

Q = Weight

(kg)

volume of distribution

digoxin 56 lkg

digitoxin 056 lkg

Serum glycoside concentration

(ngml) x x

Q = x Ingested amount (mg) digoxin bioavailability (60 )

digitoxin bioavailability (100 ) or

One vial of digibind (40 mg) neutralizes 06 mg of digoxin

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

Signal

measurement

Interpretation

- Diagnostic

- Prognostic

- Theacuterapeutical

Is toxicological

analysis useful

in cardiotoxicant

poisonings

Sampling

Bloodplasma

Urine

Gastric liquid

But also

Saliva

Sweat

Hair

Detection

Separation +

Detection

Quantification

Principle of a toxicological analysis

x

x x x

x

Urine Blood

Management of cardiotoxicant poisoning

bull Initial ABC assessment and resuscitation

bull History determination

bull Clinical examination ECG and laboratory features

bull Therapeutic indications

- Supportive treatments

- Gastrointestinal decontamination

- Elimination enhancement

- Antidotes

bull Toxicological analysis

Clinical approach and laboratory findings are more important

than toxicological analysis results for emergent decisions

2006

2012

Why does not the clinician need any toxicological analysis to manage his

patient with cardiotoxicant poisoning

ProCon debate

The prognostic value of the ingested dose

Example of ajmaline poisoning

Ingested tablets N Cardiac arrest

1 g 7 0

2 g 13 1

3 g 16 8

Delay for symptom occurrence 1 - 3 h All patients in cardiac arrest died

Conso F Press Med 1980

Acebutolol gt 15 g

Amitritptyline gt 2 g

Carbamazepine gt 10 g

Chloroquine gt 4 g

Clomipramine gt 2 g

Dextropropoxyphen gt 500 mg

Dosulepine gt 125 g

Flecainide gt 15 g

Maprotiline gt 3 g

Propranolol gt 2 g

Baud FJ Crit Care 2007

Doses resulting in severe cardiovascular failure

Simulated probability over time for having an epinephrine infusion rate gt3 mgh

Meacutegarbane B Clin Tox 2011

The prognostic value of the ingested dose Example of chloroquine poisoning

Assessment of patientrsquos low risk if none present in the ED

- Systolic pressure lt100 mm Hg - Seizures - Unresponsiveness to verbal stimuli - Need for intubation - Any rhythm except sinus - Second- or third-degree atrioventricular block - QRS ge 012 s - PaO2 ge45 mmHg

Among the 151 low-risk patients none developed a high-risk condition after admission and none required ICU intervention These predictive criteria eliminated over 50 ICU days without compromising quality of care

Excessive admission in the ICU may also result in non-useful expenses and limited bed availability

Predicting the clinical course in intentional drug overdose in the emergency room

Brett AS Arch Intern Med 1987

Echocardiography coupled with Doppler allows a direct visualization of the heart contractility and aspects (ventricle dilatation myocardium thickness valve diseases) However it remains operator-dependent

Echocardiography

Hypovolemia or vasoplegia Cardiogenic shock

Echocardiography aspects

Severe dysrhythmia

- VO2 110 mLminm2

- SaO2 95

- Hb 11 gdl

40

90

SvO2 ()

1

Cardiac index (Lminm2)

2 3

57

70

5 6 7

80

83

SvO2 versus cardiac index relationships

SvO2 = SaO2 - VO2

IC x Hb x 134

Manini AF ClinTox 2010

- Despite of absence of specificity he serum lactate concentration had an excellent prognostic utility to predict drug-overdose fatality - The optimal lactate cut-point was 30 mmolL (84 sensitivity 75 specificity) which conferred a 158-fold increase in odds of fatality (p lt 0001)

Serum lactate is an excellent prognosticator

ROC-AUC 087 (95 CI 081ndash094)

Lactate is a marker of all types of SHOCK

1048707 A marker of inadequate perfusion or cellular O2 consumption

1048707 A marker of inadequate resuscitation and management

1048707 A predictor of patient bad outcome and development of organ

dysfunction

Beta-blocker poisonings Prognostic value of lactate concentration on admission

0

3

6

9

12

15

18

21

24

27

30

Survivors Fatalities

plt 00008S

eru

m l

acta

te c

on

cen

trati

on

s (

mm

ol

L)

0

3

6

9

12

15

18

21

24

27

30

On admissionvalues

plt 00001

Peakvalues

Seru

m l

acta

te c

on

cen

trati

on

s (

mm

ol

L)

The ROC-AUC of initial lactate for predicting mortality was 084 (074-094)

The cutoff point maximizing the sum of sensitivity and specificity was 27 mmolL

For the 30 mmolL selected lactate cutoff point 55 sensitivity 80 specificity

Meacutegarbane B Clin Tox 2010

Boehnert MT N Engl J Med 1985

Poisonings with tricyclic antidepressants Prognostic value of QRS to predict seizures and arrhythmias

Serum glucose as biomarker in calcium channel blocker poisonings

Levine M Crit Care Med 2007

Initial glucose level Peak glucose level

Increase in blood glucose +71 vs 0 p=00067

Serum potassium as biomarker in digitalis poisoning

Female

Male

lt 55

gt 55

lt 55

gt 55

Yes

No

Yes

No

Yes

No

Yes

No

K + gt45

Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No

Death rate

17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23

AV block Age

Dally S Press Med 1981

0 8 16 24 32 40 48 56

0

40

80

120

160

200

240

280

Plasma Lactate (mmolL)

Blo

od

Cyan

ide (

microm

ol

l)

Lactate as biomarker in cyanide poisoning

Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002

Chloroquine poisoning prognosis assessment

Supposed

ingested dose

Systolic BP QRS

duration

Severe gt 4 g or lt 100 mmHg or gt 010 s

Moderate 2 - 4 g and

gt 100 mmHg and

lt 010 s

Mild

lt 2 g and

gt 100 mmHg and

lt 010 s

Clemessy JL et al Crit Care Med 1996

Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg

Intubation and mechanical ventilation

Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h

Riou B N Engl J Med 1988

Macrocirculation level

- Measurement of blood pressure and cardiac index Microcirculation level

- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain

- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)

Hemodynamic monitoring of cardiotoxicant poisonings

Poisonings with tricyclic antidepressants Value of serum concentrations

Boehnert MT N Engl J Med 1985

Prognostic value of serum theophylline concentration

Sessler CN Am J Med 1990

Why does the clinician need toxicological analysis to manage his

patient with cardiotoxicant poisoning

ProCon debate

- Positive diagnosis assessment to confirm a toxic hypothesis

- Differential diagnosis to exclude a toxic hypothesis

- Prognosis evaluation

- Help for treatment indications monitoring and re-evaluation

- Retrospective evaluation medico-legal issue or scientific studies

What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings

t

Severity C blood

t

Severity C blood

Confirm severity Supportive treatments

Prognostic factors Antidotes

Interest of analysis according to drug effects

Injury-inducing drugs

Functional drugs

Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues

Prerequisite availability of toxicological analysis

- Complexity and requirements of the assays

- Dialogue between biologists and clinicians

Importance of conservative plasma and urine sampling (initial and repetitive)

Expert opinion on appropriateness of disposal according to availability of drug screening

Fabbri A Emerg Med J 2003

Does a comprehensive drug screening add to decision making for poisonings in the ED

improve agreement on patient disposal Save potentially hospital resources

Meprobamate poisonings Is serum concentration useful to indicate the

mechanism of shock

Charron C Intensive Care Med 2005

Dose-dependent hypotension with narrowed QRS

- hypovolemia

- vasoplegia if concentrations le 150 mgl

- cardiogenic if concentrations gt 150 mgl

Plasma chloroquine concentration le 12 M No death

12-25 microM death rate 2

gt 25 microM death rate 22

gt 50 microM death rate 60

Chloroquine poisoning In-hospital prognosis assessment using

blood concentrations

Clemessy JL Crit Care Med 1996

TKTD using blood concentrations TKTD using plasma concentrations

Chloroquine poisoning blood vs plasma concentrations

0 25 50 75 100 125 15000

05

10

15

20

25

30

35

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 096

0 10 20 30 40 5000

05

10

15

20

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 091

0 1 2 3 4 5 6 7 8 900

05

10

15

20

Plasma chloroquine concentration (micromolL)

Ep

inep

hri

ne

infu

sio

n r

ate

(mg

h)

0 5 10 15 20 250

1

2

3

4

Plasma chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh)

R2 = 005

R2 = 017

Patient 1

Patient 2

PKPD population modeling in chloroquine poisonings

Meacutegarbane B Clin Tox2010

Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings

Relationship Between PlasmaFlecainide Concentration and

Outcome

Survivors Fatalities

0

1

2

3

4

5

6

7

8

9

10

Outcome of Acute Poisonings

Pla

sm

a F

lecain

ide

Co

ncen

trati

on

s (

mg

L)

Meacutegarbane B Clin Tox 2007

Meacutegarbane B BCPT 2010

Verapamil poisonings

Flecainide poisonings

Meacutegarbane B Clin Tox 2002 (abstract)

0

5

10

15

20

25P

red

icte

d c

on

cen

trati

on

s (n

gm

l)

0

10

0

20

0

30

0

40

0

Time since ingestion (hours)

Predicted concentration profiles

Non suvivors C(t) = 242 exp (-0003t)

Survivors C(t) = 177 exp (-0019t)

Cut-off C(t) = 207 exp (-0011t)

0

20

40

60

80

Co

lch

icin

e p

lasm

a c

on

cen

tra

tion

on

ad

mis

sio

n(n

gm

l)

Alive patients (N = 18)

Dead patients(N = 5)

Colchicine poisonings prognostic value of the time-course of serum concentrations

Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments

Q = body load of glycoside to neutralize

Estimation using ingested amount of digitalis

Estimation using serum glycoside concentration

Q = Weight

(kg)

volume of distribution

digoxin 56 lkg

digitoxin 056 lkg

Serum glycoside concentration

(ngml) x x

Q = x Ingested amount (mg) digoxin bioavailability (60 )

digitoxin bioavailability (100 ) or

One vial of digibind (40 mg) neutralizes 06 mg of digoxin

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

Management of cardiotoxicant poisoning

bull Initial ABC assessment and resuscitation

bull History determination

bull Clinical examination ECG and laboratory features

bull Therapeutic indications

- Supportive treatments

- Gastrointestinal decontamination

- Elimination enhancement

- Antidotes

bull Toxicological analysis

Clinical approach and laboratory findings are more important

than toxicological analysis results for emergent decisions

2006

2012

Why does not the clinician need any toxicological analysis to manage his

patient with cardiotoxicant poisoning

ProCon debate

The prognostic value of the ingested dose

Example of ajmaline poisoning

Ingested tablets N Cardiac arrest

1 g 7 0

2 g 13 1

3 g 16 8

Delay for symptom occurrence 1 - 3 h All patients in cardiac arrest died

Conso F Press Med 1980

Acebutolol gt 15 g

Amitritptyline gt 2 g

Carbamazepine gt 10 g

Chloroquine gt 4 g

Clomipramine gt 2 g

Dextropropoxyphen gt 500 mg

Dosulepine gt 125 g

Flecainide gt 15 g

Maprotiline gt 3 g

Propranolol gt 2 g

Baud FJ Crit Care 2007

Doses resulting in severe cardiovascular failure

Simulated probability over time for having an epinephrine infusion rate gt3 mgh

Meacutegarbane B Clin Tox 2011

The prognostic value of the ingested dose Example of chloroquine poisoning

Assessment of patientrsquos low risk if none present in the ED

- Systolic pressure lt100 mm Hg - Seizures - Unresponsiveness to verbal stimuli - Need for intubation - Any rhythm except sinus - Second- or third-degree atrioventricular block - QRS ge 012 s - PaO2 ge45 mmHg

Among the 151 low-risk patients none developed a high-risk condition after admission and none required ICU intervention These predictive criteria eliminated over 50 ICU days without compromising quality of care

Excessive admission in the ICU may also result in non-useful expenses and limited bed availability

Predicting the clinical course in intentional drug overdose in the emergency room

Brett AS Arch Intern Med 1987

Echocardiography coupled with Doppler allows a direct visualization of the heart contractility and aspects (ventricle dilatation myocardium thickness valve diseases) However it remains operator-dependent

Echocardiography

Hypovolemia or vasoplegia Cardiogenic shock

Echocardiography aspects

Severe dysrhythmia

- VO2 110 mLminm2

- SaO2 95

- Hb 11 gdl

40

90

SvO2 ()

1

Cardiac index (Lminm2)

2 3

57

70

5 6 7

80

83

SvO2 versus cardiac index relationships

SvO2 = SaO2 - VO2

IC x Hb x 134

Manini AF ClinTox 2010

- Despite of absence of specificity he serum lactate concentration had an excellent prognostic utility to predict drug-overdose fatality - The optimal lactate cut-point was 30 mmolL (84 sensitivity 75 specificity) which conferred a 158-fold increase in odds of fatality (p lt 0001)

Serum lactate is an excellent prognosticator

ROC-AUC 087 (95 CI 081ndash094)

Lactate is a marker of all types of SHOCK

1048707 A marker of inadequate perfusion or cellular O2 consumption

1048707 A marker of inadequate resuscitation and management

1048707 A predictor of patient bad outcome and development of organ

dysfunction

Beta-blocker poisonings Prognostic value of lactate concentration on admission

0

3

6

9

12

15

18

21

24

27

30

Survivors Fatalities

plt 00008S

eru

m l

acta

te c

on

cen

trati

on

s (

mm

ol

L)

0

3

6

9

12

15

18

21

24

27

30

On admissionvalues

plt 00001

Peakvalues

Seru

m l

acta

te c

on

cen

trati

on

s (

mm

ol

L)

The ROC-AUC of initial lactate for predicting mortality was 084 (074-094)

The cutoff point maximizing the sum of sensitivity and specificity was 27 mmolL

For the 30 mmolL selected lactate cutoff point 55 sensitivity 80 specificity

Meacutegarbane B Clin Tox 2010

Boehnert MT N Engl J Med 1985

Poisonings with tricyclic antidepressants Prognostic value of QRS to predict seizures and arrhythmias

Serum glucose as biomarker in calcium channel blocker poisonings

Levine M Crit Care Med 2007

Initial glucose level Peak glucose level

Increase in blood glucose +71 vs 0 p=00067

Serum potassium as biomarker in digitalis poisoning

Female

Male

lt 55

gt 55

lt 55

gt 55

Yes

No

Yes

No

Yes

No

Yes

No

K + gt45

Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No

Death rate

17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23

AV block Age

Dally S Press Med 1981

0 8 16 24 32 40 48 56

0

40

80

120

160

200

240

280

Plasma Lactate (mmolL)

Blo

od

Cyan

ide (

microm

ol

l)

Lactate as biomarker in cyanide poisoning

Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002

Chloroquine poisoning prognosis assessment

Supposed

ingested dose

Systolic BP QRS

duration

Severe gt 4 g or lt 100 mmHg or gt 010 s

Moderate 2 - 4 g and

gt 100 mmHg and

lt 010 s

Mild

lt 2 g and

gt 100 mmHg and

lt 010 s

Clemessy JL et al Crit Care Med 1996

Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg

Intubation and mechanical ventilation

Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h

Riou B N Engl J Med 1988

Macrocirculation level

- Measurement of blood pressure and cardiac index Microcirculation level

- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain

- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)

Hemodynamic monitoring of cardiotoxicant poisonings

Poisonings with tricyclic antidepressants Value of serum concentrations

Boehnert MT N Engl J Med 1985

Prognostic value of serum theophylline concentration

Sessler CN Am J Med 1990

Why does the clinician need toxicological analysis to manage his

patient with cardiotoxicant poisoning

ProCon debate

- Positive diagnosis assessment to confirm a toxic hypothesis

- Differential diagnosis to exclude a toxic hypothesis

- Prognosis evaluation

- Help for treatment indications monitoring and re-evaluation

- Retrospective evaluation medico-legal issue or scientific studies

What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings

t

Severity C blood

t

Severity C blood

Confirm severity Supportive treatments

Prognostic factors Antidotes

Interest of analysis according to drug effects

Injury-inducing drugs

Functional drugs

Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues

Prerequisite availability of toxicological analysis

- Complexity and requirements of the assays

- Dialogue between biologists and clinicians

Importance of conservative plasma and urine sampling (initial and repetitive)

Expert opinion on appropriateness of disposal according to availability of drug screening

Fabbri A Emerg Med J 2003

Does a comprehensive drug screening add to decision making for poisonings in the ED

improve agreement on patient disposal Save potentially hospital resources

Meprobamate poisonings Is serum concentration useful to indicate the

mechanism of shock

Charron C Intensive Care Med 2005

Dose-dependent hypotension with narrowed QRS

- hypovolemia

- vasoplegia if concentrations le 150 mgl

- cardiogenic if concentrations gt 150 mgl

Plasma chloroquine concentration le 12 M No death

12-25 microM death rate 2

gt 25 microM death rate 22

gt 50 microM death rate 60

Chloroquine poisoning In-hospital prognosis assessment using

blood concentrations

Clemessy JL Crit Care Med 1996

TKTD using blood concentrations TKTD using plasma concentrations

Chloroquine poisoning blood vs plasma concentrations

0 25 50 75 100 125 15000

05

10

15

20

25

30

35

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 096

0 10 20 30 40 5000

05

10

15

20

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 091

0 1 2 3 4 5 6 7 8 900

05

10

15

20

Plasma chloroquine concentration (micromolL)

Ep

inep

hri

ne

infu

sio

n r

ate

(mg

h)

0 5 10 15 20 250

1

2

3

4

Plasma chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh)

R2 = 005

R2 = 017

Patient 1

Patient 2

PKPD population modeling in chloroquine poisonings

Meacutegarbane B Clin Tox2010

Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings

Relationship Between PlasmaFlecainide Concentration and

Outcome

Survivors Fatalities

0

1

2

3

4

5

6

7

8

9

10

Outcome of Acute Poisonings

Pla

sm

a F

lecain

ide

Co

ncen

trati

on

s (

mg

L)

Meacutegarbane B Clin Tox 2007

Meacutegarbane B BCPT 2010

Verapamil poisonings

Flecainide poisonings

Meacutegarbane B Clin Tox 2002 (abstract)

0

5

10

15

20

25P

red

icte

d c

on

cen

trati

on

s (n

gm

l)

0

10

0

20

0

30

0

40

0

Time since ingestion (hours)

Predicted concentration profiles

Non suvivors C(t) = 242 exp (-0003t)

Survivors C(t) = 177 exp (-0019t)

Cut-off C(t) = 207 exp (-0011t)

0

20

40

60

80

Co

lch

icin

e p

lasm

a c

on

cen

tra

tion

on

ad

mis

sio

n(n

gm

l)

Alive patients (N = 18)

Dead patients(N = 5)

Colchicine poisonings prognostic value of the time-course of serum concentrations

Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments

Q = body load of glycoside to neutralize

Estimation using ingested amount of digitalis

Estimation using serum glycoside concentration

Q = Weight

(kg)

volume of distribution

digoxin 56 lkg

digitoxin 056 lkg

Serum glycoside concentration

(ngml) x x

Q = x Ingested amount (mg) digoxin bioavailability (60 )

digitoxin bioavailability (100 ) or

One vial of digibind (40 mg) neutralizes 06 mg of digoxin

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

Why does not the clinician need any toxicological analysis to manage his

patient with cardiotoxicant poisoning

ProCon debate

The prognostic value of the ingested dose

Example of ajmaline poisoning

Ingested tablets N Cardiac arrest

1 g 7 0

2 g 13 1

3 g 16 8

Delay for symptom occurrence 1 - 3 h All patients in cardiac arrest died

Conso F Press Med 1980

Acebutolol gt 15 g

Amitritptyline gt 2 g

Carbamazepine gt 10 g

Chloroquine gt 4 g

Clomipramine gt 2 g

Dextropropoxyphen gt 500 mg

Dosulepine gt 125 g

Flecainide gt 15 g

Maprotiline gt 3 g

Propranolol gt 2 g

Baud FJ Crit Care 2007

Doses resulting in severe cardiovascular failure

Simulated probability over time for having an epinephrine infusion rate gt3 mgh

Meacutegarbane B Clin Tox 2011

The prognostic value of the ingested dose Example of chloroquine poisoning

Assessment of patientrsquos low risk if none present in the ED

- Systolic pressure lt100 mm Hg - Seizures - Unresponsiveness to verbal stimuli - Need for intubation - Any rhythm except sinus - Second- or third-degree atrioventricular block - QRS ge 012 s - PaO2 ge45 mmHg

Among the 151 low-risk patients none developed a high-risk condition after admission and none required ICU intervention These predictive criteria eliminated over 50 ICU days without compromising quality of care

Excessive admission in the ICU may also result in non-useful expenses and limited bed availability

Predicting the clinical course in intentional drug overdose in the emergency room

Brett AS Arch Intern Med 1987

Echocardiography coupled with Doppler allows a direct visualization of the heart contractility and aspects (ventricle dilatation myocardium thickness valve diseases) However it remains operator-dependent

Echocardiography

Hypovolemia or vasoplegia Cardiogenic shock

Echocardiography aspects

Severe dysrhythmia

- VO2 110 mLminm2

- SaO2 95

- Hb 11 gdl

40

90

SvO2 ()

1

Cardiac index (Lminm2)

2 3

57

70

5 6 7

80

83

SvO2 versus cardiac index relationships

SvO2 = SaO2 - VO2

IC x Hb x 134

Manini AF ClinTox 2010

- Despite of absence of specificity he serum lactate concentration had an excellent prognostic utility to predict drug-overdose fatality - The optimal lactate cut-point was 30 mmolL (84 sensitivity 75 specificity) which conferred a 158-fold increase in odds of fatality (p lt 0001)

Serum lactate is an excellent prognosticator

ROC-AUC 087 (95 CI 081ndash094)

Lactate is a marker of all types of SHOCK

1048707 A marker of inadequate perfusion or cellular O2 consumption

1048707 A marker of inadequate resuscitation and management

1048707 A predictor of patient bad outcome and development of organ

dysfunction

Beta-blocker poisonings Prognostic value of lactate concentration on admission

0

3

6

9

12

15

18

21

24

27

30

Survivors Fatalities

plt 00008S

eru

m l

acta

te c

on

cen

trati

on

s (

mm

ol

L)

0

3

6

9

12

15

18

21

24

27

30

On admissionvalues

plt 00001

Peakvalues

Seru

m l

acta

te c

on

cen

trati

on

s (

mm

ol

L)

The ROC-AUC of initial lactate for predicting mortality was 084 (074-094)

The cutoff point maximizing the sum of sensitivity and specificity was 27 mmolL

For the 30 mmolL selected lactate cutoff point 55 sensitivity 80 specificity

Meacutegarbane B Clin Tox 2010

Boehnert MT N Engl J Med 1985

Poisonings with tricyclic antidepressants Prognostic value of QRS to predict seizures and arrhythmias

Serum glucose as biomarker in calcium channel blocker poisonings

Levine M Crit Care Med 2007

Initial glucose level Peak glucose level

Increase in blood glucose +71 vs 0 p=00067

Serum potassium as biomarker in digitalis poisoning

Female

Male

lt 55

gt 55

lt 55

gt 55

Yes

No

Yes

No

Yes

No

Yes

No

K + gt45

Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No

Death rate

17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23

AV block Age

Dally S Press Med 1981

0 8 16 24 32 40 48 56

0

40

80

120

160

200

240

280

Plasma Lactate (mmolL)

Blo

od

Cyan

ide (

microm

ol

l)

Lactate as biomarker in cyanide poisoning

Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002

Chloroquine poisoning prognosis assessment

Supposed

ingested dose

Systolic BP QRS

duration

Severe gt 4 g or lt 100 mmHg or gt 010 s

Moderate 2 - 4 g and

gt 100 mmHg and

lt 010 s

Mild

lt 2 g and

gt 100 mmHg and

lt 010 s

Clemessy JL et al Crit Care Med 1996

Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg

Intubation and mechanical ventilation

Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h

Riou B N Engl J Med 1988

Macrocirculation level

- Measurement of blood pressure and cardiac index Microcirculation level

- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain

- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)

Hemodynamic monitoring of cardiotoxicant poisonings

Poisonings with tricyclic antidepressants Value of serum concentrations

Boehnert MT N Engl J Med 1985

Prognostic value of serum theophylline concentration

Sessler CN Am J Med 1990

Why does the clinician need toxicological analysis to manage his

patient with cardiotoxicant poisoning

ProCon debate

- Positive diagnosis assessment to confirm a toxic hypothesis

- Differential diagnosis to exclude a toxic hypothesis

- Prognosis evaluation

- Help for treatment indications monitoring and re-evaluation

- Retrospective evaluation medico-legal issue or scientific studies

What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings

t

Severity C blood

t

Severity C blood

Confirm severity Supportive treatments

Prognostic factors Antidotes

Interest of analysis according to drug effects

Injury-inducing drugs

Functional drugs

Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues

Prerequisite availability of toxicological analysis

- Complexity and requirements of the assays

- Dialogue between biologists and clinicians

Importance of conservative plasma and urine sampling (initial and repetitive)

Expert opinion on appropriateness of disposal according to availability of drug screening

Fabbri A Emerg Med J 2003

Does a comprehensive drug screening add to decision making for poisonings in the ED

improve agreement on patient disposal Save potentially hospital resources

Meprobamate poisonings Is serum concentration useful to indicate the

mechanism of shock

Charron C Intensive Care Med 2005

Dose-dependent hypotension with narrowed QRS

- hypovolemia

- vasoplegia if concentrations le 150 mgl

- cardiogenic if concentrations gt 150 mgl

Plasma chloroquine concentration le 12 M No death

12-25 microM death rate 2

gt 25 microM death rate 22

gt 50 microM death rate 60

Chloroquine poisoning In-hospital prognosis assessment using

blood concentrations

Clemessy JL Crit Care Med 1996

TKTD using blood concentrations TKTD using plasma concentrations

Chloroquine poisoning blood vs plasma concentrations

0 25 50 75 100 125 15000

05

10

15

20

25

30

35

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 096

0 10 20 30 40 5000

05

10

15

20

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 091

0 1 2 3 4 5 6 7 8 900

05

10

15

20

Plasma chloroquine concentration (micromolL)

Ep

inep

hri

ne

infu

sio

n r

ate

(mg

h)

0 5 10 15 20 250

1

2

3

4

Plasma chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh)

R2 = 005

R2 = 017

Patient 1

Patient 2

PKPD population modeling in chloroquine poisonings

Meacutegarbane B Clin Tox2010

Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings

Relationship Between PlasmaFlecainide Concentration and

Outcome

Survivors Fatalities

0

1

2

3

4

5

6

7

8

9

10

Outcome of Acute Poisonings

Pla

sm

a F

lecain

ide

Co

ncen

trati

on

s (

mg

L)

Meacutegarbane B Clin Tox 2007

Meacutegarbane B BCPT 2010

Verapamil poisonings

Flecainide poisonings

Meacutegarbane B Clin Tox 2002 (abstract)

0

5

10

15

20

25P

red

icte

d c

on

cen

trati

on

s (n

gm

l)

0

10

0

20

0

30

0

40

0

Time since ingestion (hours)

Predicted concentration profiles

Non suvivors C(t) = 242 exp (-0003t)

Survivors C(t) = 177 exp (-0019t)

Cut-off C(t) = 207 exp (-0011t)

0

20

40

60

80

Co

lch

icin

e p

lasm

a c

on

cen

tra

tion

on

ad

mis

sio

n(n

gm

l)

Alive patients (N = 18)

Dead patients(N = 5)

Colchicine poisonings prognostic value of the time-course of serum concentrations

Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments

Q = body load of glycoside to neutralize

Estimation using ingested amount of digitalis

Estimation using serum glycoside concentration

Q = Weight

(kg)

volume of distribution

digoxin 56 lkg

digitoxin 056 lkg

Serum glycoside concentration

(ngml) x x

Q = x Ingested amount (mg) digoxin bioavailability (60 )

digitoxin bioavailability (100 ) or

One vial of digibind (40 mg) neutralizes 06 mg of digoxin

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

The prognostic value of the ingested dose

Example of ajmaline poisoning

Ingested tablets N Cardiac arrest

1 g 7 0

2 g 13 1

3 g 16 8

Delay for symptom occurrence 1 - 3 h All patients in cardiac arrest died

Conso F Press Med 1980

Acebutolol gt 15 g

Amitritptyline gt 2 g

Carbamazepine gt 10 g

Chloroquine gt 4 g

Clomipramine gt 2 g

Dextropropoxyphen gt 500 mg

Dosulepine gt 125 g

Flecainide gt 15 g

Maprotiline gt 3 g

Propranolol gt 2 g

Baud FJ Crit Care 2007

Doses resulting in severe cardiovascular failure

Simulated probability over time for having an epinephrine infusion rate gt3 mgh

Meacutegarbane B Clin Tox 2011

The prognostic value of the ingested dose Example of chloroquine poisoning

Assessment of patientrsquos low risk if none present in the ED

- Systolic pressure lt100 mm Hg - Seizures - Unresponsiveness to verbal stimuli - Need for intubation - Any rhythm except sinus - Second- or third-degree atrioventricular block - QRS ge 012 s - PaO2 ge45 mmHg

Among the 151 low-risk patients none developed a high-risk condition after admission and none required ICU intervention These predictive criteria eliminated over 50 ICU days without compromising quality of care

Excessive admission in the ICU may also result in non-useful expenses and limited bed availability

Predicting the clinical course in intentional drug overdose in the emergency room

Brett AS Arch Intern Med 1987

Echocardiography coupled with Doppler allows a direct visualization of the heart contractility and aspects (ventricle dilatation myocardium thickness valve diseases) However it remains operator-dependent

Echocardiography

Hypovolemia or vasoplegia Cardiogenic shock

Echocardiography aspects

Severe dysrhythmia

- VO2 110 mLminm2

- SaO2 95

- Hb 11 gdl

40

90

SvO2 ()

1

Cardiac index (Lminm2)

2 3

57

70

5 6 7

80

83

SvO2 versus cardiac index relationships

SvO2 = SaO2 - VO2

IC x Hb x 134

Manini AF ClinTox 2010

- Despite of absence of specificity he serum lactate concentration had an excellent prognostic utility to predict drug-overdose fatality - The optimal lactate cut-point was 30 mmolL (84 sensitivity 75 specificity) which conferred a 158-fold increase in odds of fatality (p lt 0001)

Serum lactate is an excellent prognosticator

ROC-AUC 087 (95 CI 081ndash094)

Lactate is a marker of all types of SHOCK

1048707 A marker of inadequate perfusion or cellular O2 consumption

1048707 A marker of inadequate resuscitation and management

1048707 A predictor of patient bad outcome and development of organ

dysfunction

Beta-blocker poisonings Prognostic value of lactate concentration on admission

0

3

6

9

12

15

18

21

24

27

30

Survivors Fatalities

plt 00008S

eru

m l

acta

te c

on

cen

trati

on

s (

mm

ol

L)

0

3

6

9

12

15

18

21

24

27

30

On admissionvalues

plt 00001

Peakvalues

Seru

m l

acta

te c

on

cen

trati

on

s (

mm

ol

L)

The ROC-AUC of initial lactate for predicting mortality was 084 (074-094)

The cutoff point maximizing the sum of sensitivity and specificity was 27 mmolL

For the 30 mmolL selected lactate cutoff point 55 sensitivity 80 specificity

Meacutegarbane B Clin Tox 2010

Boehnert MT N Engl J Med 1985

Poisonings with tricyclic antidepressants Prognostic value of QRS to predict seizures and arrhythmias

Serum glucose as biomarker in calcium channel blocker poisonings

Levine M Crit Care Med 2007

Initial glucose level Peak glucose level

Increase in blood glucose +71 vs 0 p=00067

Serum potassium as biomarker in digitalis poisoning

Female

Male

lt 55

gt 55

lt 55

gt 55

Yes

No

Yes

No

Yes

No

Yes

No

K + gt45

Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No

Death rate

17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23

AV block Age

Dally S Press Med 1981

0 8 16 24 32 40 48 56

0

40

80

120

160

200

240

280

Plasma Lactate (mmolL)

Blo

od

Cyan

ide (

microm

ol

l)

Lactate as biomarker in cyanide poisoning

Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002

Chloroquine poisoning prognosis assessment

Supposed

ingested dose

Systolic BP QRS

duration

Severe gt 4 g or lt 100 mmHg or gt 010 s

Moderate 2 - 4 g and

gt 100 mmHg and

lt 010 s

Mild

lt 2 g and

gt 100 mmHg and

lt 010 s

Clemessy JL et al Crit Care Med 1996

Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg

Intubation and mechanical ventilation

Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h

Riou B N Engl J Med 1988

Macrocirculation level

- Measurement of blood pressure and cardiac index Microcirculation level

- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain

- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)

Hemodynamic monitoring of cardiotoxicant poisonings

Poisonings with tricyclic antidepressants Value of serum concentrations

Boehnert MT N Engl J Med 1985

Prognostic value of serum theophylline concentration

Sessler CN Am J Med 1990

Why does the clinician need toxicological analysis to manage his

patient with cardiotoxicant poisoning

ProCon debate

- Positive diagnosis assessment to confirm a toxic hypothesis

- Differential diagnosis to exclude a toxic hypothesis

- Prognosis evaluation

- Help for treatment indications monitoring and re-evaluation

- Retrospective evaluation medico-legal issue or scientific studies

What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings

t

Severity C blood

t

Severity C blood

Confirm severity Supportive treatments

Prognostic factors Antidotes

Interest of analysis according to drug effects

Injury-inducing drugs

Functional drugs

Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues

Prerequisite availability of toxicological analysis

- Complexity and requirements of the assays

- Dialogue between biologists and clinicians

Importance of conservative plasma and urine sampling (initial and repetitive)

Expert opinion on appropriateness of disposal according to availability of drug screening

Fabbri A Emerg Med J 2003

Does a comprehensive drug screening add to decision making for poisonings in the ED

improve agreement on patient disposal Save potentially hospital resources

Meprobamate poisonings Is serum concentration useful to indicate the

mechanism of shock

Charron C Intensive Care Med 2005

Dose-dependent hypotension with narrowed QRS

- hypovolemia

- vasoplegia if concentrations le 150 mgl

- cardiogenic if concentrations gt 150 mgl

Plasma chloroquine concentration le 12 M No death

12-25 microM death rate 2

gt 25 microM death rate 22

gt 50 microM death rate 60

Chloroquine poisoning In-hospital prognosis assessment using

blood concentrations

Clemessy JL Crit Care Med 1996

TKTD using blood concentrations TKTD using plasma concentrations

Chloroquine poisoning blood vs plasma concentrations

0 25 50 75 100 125 15000

05

10

15

20

25

30

35

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 096

0 10 20 30 40 5000

05

10

15

20

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 091

0 1 2 3 4 5 6 7 8 900

05

10

15

20

Plasma chloroquine concentration (micromolL)

Ep

inep

hri

ne

infu

sio

n r

ate

(mg

h)

0 5 10 15 20 250

1

2

3

4

Plasma chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh)

R2 = 005

R2 = 017

Patient 1

Patient 2

PKPD population modeling in chloroquine poisonings

Meacutegarbane B Clin Tox2010

Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings

Relationship Between PlasmaFlecainide Concentration and

Outcome

Survivors Fatalities

0

1

2

3

4

5

6

7

8

9

10

Outcome of Acute Poisonings

Pla

sm

a F

lecain

ide

Co

ncen

trati

on

s (

mg

L)

Meacutegarbane B Clin Tox 2007

Meacutegarbane B BCPT 2010

Verapamil poisonings

Flecainide poisonings

Meacutegarbane B Clin Tox 2002 (abstract)

0

5

10

15

20

25P

red

icte

d c

on

cen

trati

on

s (n

gm

l)

0

10

0

20

0

30

0

40

0

Time since ingestion (hours)

Predicted concentration profiles

Non suvivors C(t) = 242 exp (-0003t)

Survivors C(t) = 177 exp (-0019t)

Cut-off C(t) = 207 exp (-0011t)

0

20

40

60

80

Co

lch

icin

e p

lasm

a c

on

cen

tra

tion

on

ad

mis

sio

n(n

gm

l)

Alive patients (N = 18)

Dead patients(N = 5)

Colchicine poisonings prognostic value of the time-course of serum concentrations

Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments

Q = body load of glycoside to neutralize

Estimation using ingested amount of digitalis

Estimation using serum glycoside concentration

Q = Weight

(kg)

volume of distribution

digoxin 56 lkg

digitoxin 056 lkg

Serum glycoside concentration

(ngml) x x

Q = x Ingested amount (mg) digoxin bioavailability (60 )

digitoxin bioavailability (100 ) or

One vial of digibind (40 mg) neutralizes 06 mg of digoxin

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

Acebutolol gt 15 g

Amitritptyline gt 2 g

Carbamazepine gt 10 g

Chloroquine gt 4 g

Clomipramine gt 2 g

Dextropropoxyphen gt 500 mg

Dosulepine gt 125 g

Flecainide gt 15 g

Maprotiline gt 3 g

Propranolol gt 2 g

Baud FJ Crit Care 2007

Doses resulting in severe cardiovascular failure

Simulated probability over time for having an epinephrine infusion rate gt3 mgh

Meacutegarbane B Clin Tox 2011

The prognostic value of the ingested dose Example of chloroquine poisoning

Assessment of patientrsquos low risk if none present in the ED

- Systolic pressure lt100 mm Hg - Seizures - Unresponsiveness to verbal stimuli - Need for intubation - Any rhythm except sinus - Second- or third-degree atrioventricular block - QRS ge 012 s - PaO2 ge45 mmHg

Among the 151 low-risk patients none developed a high-risk condition after admission and none required ICU intervention These predictive criteria eliminated over 50 ICU days without compromising quality of care

Excessive admission in the ICU may also result in non-useful expenses and limited bed availability

Predicting the clinical course in intentional drug overdose in the emergency room

Brett AS Arch Intern Med 1987

Echocardiography coupled with Doppler allows a direct visualization of the heart contractility and aspects (ventricle dilatation myocardium thickness valve diseases) However it remains operator-dependent

Echocardiography

Hypovolemia or vasoplegia Cardiogenic shock

Echocardiography aspects

Severe dysrhythmia

- VO2 110 mLminm2

- SaO2 95

- Hb 11 gdl

40

90

SvO2 ()

1

Cardiac index (Lminm2)

2 3

57

70

5 6 7

80

83

SvO2 versus cardiac index relationships

SvO2 = SaO2 - VO2

IC x Hb x 134

Manini AF ClinTox 2010

- Despite of absence of specificity he serum lactate concentration had an excellent prognostic utility to predict drug-overdose fatality - The optimal lactate cut-point was 30 mmolL (84 sensitivity 75 specificity) which conferred a 158-fold increase in odds of fatality (p lt 0001)

Serum lactate is an excellent prognosticator

ROC-AUC 087 (95 CI 081ndash094)

Lactate is a marker of all types of SHOCK

1048707 A marker of inadequate perfusion or cellular O2 consumption

1048707 A marker of inadequate resuscitation and management

1048707 A predictor of patient bad outcome and development of organ

dysfunction

Beta-blocker poisonings Prognostic value of lactate concentration on admission

0

3

6

9

12

15

18

21

24

27

30

Survivors Fatalities

plt 00008S

eru

m l

acta

te c

on

cen

trati

on

s (

mm

ol

L)

0

3

6

9

12

15

18

21

24

27

30

On admissionvalues

plt 00001

Peakvalues

Seru

m l

acta

te c

on

cen

trati

on

s (

mm

ol

L)

The ROC-AUC of initial lactate for predicting mortality was 084 (074-094)

The cutoff point maximizing the sum of sensitivity and specificity was 27 mmolL

For the 30 mmolL selected lactate cutoff point 55 sensitivity 80 specificity

Meacutegarbane B Clin Tox 2010

Boehnert MT N Engl J Med 1985

Poisonings with tricyclic antidepressants Prognostic value of QRS to predict seizures and arrhythmias

Serum glucose as biomarker in calcium channel blocker poisonings

Levine M Crit Care Med 2007

Initial glucose level Peak glucose level

Increase in blood glucose +71 vs 0 p=00067

Serum potassium as biomarker in digitalis poisoning

Female

Male

lt 55

gt 55

lt 55

gt 55

Yes

No

Yes

No

Yes

No

Yes

No

K + gt45

Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No

Death rate

17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23

AV block Age

Dally S Press Med 1981

0 8 16 24 32 40 48 56

0

40

80

120

160

200

240

280

Plasma Lactate (mmolL)

Blo

od

Cyan

ide (

microm

ol

l)

Lactate as biomarker in cyanide poisoning

Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002

Chloroquine poisoning prognosis assessment

Supposed

ingested dose

Systolic BP QRS

duration

Severe gt 4 g or lt 100 mmHg or gt 010 s

Moderate 2 - 4 g and

gt 100 mmHg and

lt 010 s

Mild

lt 2 g and

gt 100 mmHg and

lt 010 s

Clemessy JL et al Crit Care Med 1996

Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg

Intubation and mechanical ventilation

Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h

Riou B N Engl J Med 1988

Macrocirculation level

- Measurement of blood pressure and cardiac index Microcirculation level

- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain

- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)

Hemodynamic monitoring of cardiotoxicant poisonings

Poisonings with tricyclic antidepressants Value of serum concentrations

Boehnert MT N Engl J Med 1985

Prognostic value of serum theophylline concentration

Sessler CN Am J Med 1990

Why does the clinician need toxicological analysis to manage his

patient with cardiotoxicant poisoning

ProCon debate

- Positive diagnosis assessment to confirm a toxic hypothesis

- Differential diagnosis to exclude a toxic hypothesis

- Prognosis evaluation

- Help for treatment indications monitoring and re-evaluation

- Retrospective evaluation medico-legal issue or scientific studies

What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings

t

Severity C blood

t

Severity C blood

Confirm severity Supportive treatments

Prognostic factors Antidotes

Interest of analysis according to drug effects

Injury-inducing drugs

Functional drugs

Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues

Prerequisite availability of toxicological analysis

- Complexity and requirements of the assays

- Dialogue between biologists and clinicians

Importance of conservative plasma and urine sampling (initial and repetitive)

Expert opinion on appropriateness of disposal according to availability of drug screening

Fabbri A Emerg Med J 2003

Does a comprehensive drug screening add to decision making for poisonings in the ED

improve agreement on patient disposal Save potentially hospital resources

Meprobamate poisonings Is serum concentration useful to indicate the

mechanism of shock

Charron C Intensive Care Med 2005

Dose-dependent hypotension with narrowed QRS

- hypovolemia

- vasoplegia if concentrations le 150 mgl

- cardiogenic if concentrations gt 150 mgl

Plasma chloroquine concentration le 12 M No death

12-25 microM death rate 2

gt 25 microM death rate 22

gt 50 microM death rate 60

Chloroquine poisoning In-hospital prognosis assessment using

blood concentrations

Clemessy JL Crit Care Med 1996

TKTD using blood concentrations TKTD using plasma concentrations

Chloroquine poisoning blood vs plasma concentrations

0 25 50 75 100 125 15000

05

10

15

20

25

30

35

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 096

0 10 20 30 40 5000

05

10

15

20

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 091

0 1 2 3 4 5 6 7 8 900

05

10

15

20

Plasma chloroquine concentration (micromolL)

Ep

inep

hri

ne

infu

sio

n r

ate

(mg

h)

0 5 10 15 20 250

1

2

3

4

Plasma chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh)

R2 = 005

R2 = 017

Patient 1

Patient 2

PKPD population modeling in chloroquine poisonings

Meacutegarbane B Clin Tox2010

Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings

Relationship Between PlasmaFlecainide Concentration and

Outcome

Survivors Fatalities

0

1

2

3

4

5

6

7

8

9

10

Outcome of Acute Poisonings

Pla

sm

a F

lecain

ide

Co

ncen

trati

on

s (

mg

L)

Meacutegarbane B Clin Tox 2007

Meacutegarbane B BCPT 2010

Verapamil poisonings

Flecainide poisonings

Meacutegarbane B Clin Tox 2002 (abstract)

0

5

10

15

20

25P

red

icte

d c

on

cen

trati

on

s (n

gm

l)

0

10

0

20

0

30

0

40

0

Time since ingestion (hours)

Predicted concentration profiles

Non suvivors C(t) = 242 exp (-0003t)

Survivors C(t) = 177 exp (-0019t)

Cut-off C(t) = 207 exp (-0011t)

0

20

40

60

80

Co

lch

icin

e p

lasm

a c

on

cen

tra

tion

on

ad

mis

sio

n(n

gm

l)

Alive patients (N = 18)

Dead patients(N = 5)

Colchicine poisonings prognostic value of the time-course of serum concentrations

Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments

Q = body load of glycoside to neutralize

Estimation using ingested amount of digitalis

Estimation using serum glycoside concentration

Q = Weight

(kg)

volume of distribution

digoxin 56 lkg

digitoxin 056 lkg

Serum glycoside concentration

(ngml) x x

Q = x Ingested amount (mg) digoxin bioavailability (60 )

digitoxin bioavailability (100 ) or

One vial of digibind (40 mg) neutralizes 06 mg of digoxin

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

Simulated probability over time for having an epinephrine infusion rate gt3 mgh

Meacutegarbane B Clin Tox 2011

The prognostic value of the ingested dose Example of chloroquine poisoning

Assessment of patientrsquos low risk if none present in the ED

- Systolic pressure lt100 mm Hg - Seizures - Unresponsiveness to verbal stimuli - Need for intubation - Any rhythm except sinus - Second- or third-degree atrioventricular block - QRS ge 012 s - PaO2 ge45 mmHg

Among the 151 low-risk patients none developed a high-risk condition after admission and none required ICU intervention These predictive criteria eliminated over 50 ICU days without compromising quality of care

Excessive admission in the ICU may also result in non-useful expenses and limited bed availability

Predicting the clinical course in intentional drug overdose in the emergency room

Brett AS Arch Intern Med 1987

Echocardiography coupled with Doppler allows a direct visualization of the heart contractility and aspects (ventricle dilatation myocardium thickness valve diseases) However it remains operator-dependent

Echocardiography

Hypovolemia or vasoplegia Cardiogenic shock

Echocardiography aspects

Severe dysrhythmia

- VO2 110 mLminm2

- SaO2 95

- Hb 11 gdl

40

90

SvO2 ()

1

Cardiac index (Lminm2)

2 3

57

70

5 6 7

80

83

SvO2 versus cardiac index relationships

SvO2 = SaO2 - VO2

IC x Hb x 134

Manini AF ClinTox 2010

- Despite of absence of specificity he serum lactate concentration had an excellent prognostic utility to predict drug-overdose fatality - The optimal lactate cut-point was 30 mmolL (84 sensitivity 75 specificity) which conferred a 158-fold increase in odds of fatality (p lt 0001)

Serum lactate is an excellent prognosticator

ROC-AUC 087 (95 CI 081ndash094)

Lactate is a marker of all types of SHOCK

1048707 A marker of inadequate perfusion or cellular O2 consumption

1048707 A marker of inadequate resuscitation and management

1048707 A predictor of patient bad outcome and development of organ

dysfunction

Beta-blocker poisonings Prognostic value of lactate concentration on admission

0

3

6

9

12

15

18

21

24

27

30

Survivors Fatalities

plt 00008S

eru

m l

acta

te c

on

cen

trati

on

s (

mm

ol

L)

0

3

6

9

12

15

18

21

24

27

30

On admissionvalues

plt 00001

Peakvalues

Seru

m l

acta

te c

on

cen

trati

on

s (

mm

ol

L)

The ROC-AUC of initial lactate for predicting mortality was 084 (074-094)

The cutoff point maximizing the sum of sensitivity and specificity was 27 mmolL

For the 30 mmolL selected lactate cutoff point 55 sensitivity 80 specificity

Meacutegarbane B Clin Tox 2010

Boehnert MT N Engl J Med 1985

Poisonings with tricyclic antidepressants Prognostic value of QRS to predict seizures and arrhythmias

Serum glucose as biomarker in calcium channel blocker poisonings

Levine M Crit Care Med 2007

Initial glucose level Peak glucose level

Increase in blood glucose +71 vs 0 p=00067

Serum potassium as biomarker in digitalis poisoning

Female

Male

lt 55

gt 55

lt 55

gt 55

Yes

No

Yes

No

Yes

No

Yes

No

K + gt45

Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No

Death rate

17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23

AV block Age

Dally S Press Med 1981

0 8 16 24 32 40 48 56

0

40

80

120

160

200

240

280

Plasma Lactate (mmolL)

Blo

od

Cyan

ide (

microm

ol

l)

Lactate as biomarker in cyanide poisoning

Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002

Chloroquine poisoning prognosis assessment

Supposed

ingested dose

Systolic BP QRS

duration

Severe gt 4 g or lt 100 mmHg or gt 010 s

Moderate 2 - 4 g and

gt 100 mmHg and

lt 010 s

Mild

lt 2 g and

gt 100 mmHg and

lt 010 s

Clemessy JL et al Crit Care Med 1996

Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg

Intubation and mechanical ventilation

Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h

Riou B N Engl J Med 1988

Macrocirculation level

- Measurement of blood pressure and cardiac index Microcirculation level

- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain

- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)

Hemodynamic monitoring of cardiotoxicant poisonings

Poisonings with tricyclic antidepressants Value of serum concentrations

Boehnert MT N Engl J Med 1985

Prognostic value of serum theophylline concentration

Sessler CN Am J Med 1990

Why does the clinician need toxicological analysis to manage his

patient with cardiotoxicant poisoning

ProCon debate

- Positive diagnosis assessment to confirm a toxic hypothesis

- Differential diagnosis to exclude a toxic hypothesis

- Prognosis evaluation

- Help for treatment indications monitoring and re-evaluation

- Retrospective evaluation medico-legal issue or scientific studies

What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings

t

Severity C blood

t

Severity C blood

Confirm severity Supportive treatments

Prognostic factors Antidotes

Interest of analysis according to drug effects

Injury-inducing drugs

Functional drugs

Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues

Prerequisite availability of toxicological analysis

- Complexity and requirements of the assays

- Dialogue between biologists and clinicians

Importance of conservative plasma and urine sampling (initial and repetitive)

Expert opinion on appropriateness of disposal according to availability of drug screening

Fabbri A Emerg Med J 2003

Does a comprehensive drug screening add to decision making for poisonings in the ED

improve agreement on patient disposal Save potentially hospital resources

Meprobamate poisonings Is serum concentration useful to indicate the

mechanism of shock

Charron C Intensive Care Med 2005

Dose-dependent hypotension with narrowed QRS

- hypovolemia

- vasoplegia if concentrations le 150 mgl

- cardiogenic if concentrations gt 150 mgl

Plasma chloroquine concentration le 12 M No death

12-25 microM death rate 2

gt 25 microM death rate 22

gt 50 microM death rate 60

Chloroquine poisoning In-hospital prognosis assessment using

blood concentrations

Clemessy JL Crit Care Med 1996

TKTD using blood concentrations TKTD using plasma concentrations

Chloroquine poisoning blood vs plasma concentrations

0 25 50 75 100 125 15000

05

10

15

20

25

30

35

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 096

0 10 20 30 40 5000

05

10

15

20

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 091

0 1 2 3 4 5 6 7 8 900

05

10

15

20

Plasma chloroquine concentration (micromolL)

Ep

inep

hri

ne

infu

sio

n r

ate

(mg

h)

0 5 10 15 20 250

1

2

3

4

Plasma chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh)

R2 = 005

R2 = 017

Patient 1

Patient 2

PKPD population modeling in chloroquine poisonings

Meacutegarbane B Clin Tox2010

Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings

Relationship Between PlasmaFlecainide Concentration and

Outcome

Survivors Fatalities

0

1

2

3

4

5

6

7

8

9

10

Outcome of Acute Poisonings

Pla

sm

a F

lecain

ide

Co

ncen

trati

on

s (

mg

L)

Meacutegarbane B Clin Tox 2007

Meacutegarbane B BCPT 2010

Verapamil poisonings

Flecainide poisonings

Meacutegarbane B Clin Tox 2002 (abstract)

0

5

10

15

20

25P

red

icte

d c

on

cen

trati

on

s (n

gm

l)

0

10

0

20

0

30

0

40

0

Time since ingestion (hours)

Predicted concentration profiles

Non suvivors C(t) = 242 exp (-0003t)

Survivors C(t) = 177 exp (-0019t)

Cut-off C(t) = 207 exp (-0011t)

0

20

40

60

80

Co

lch

icin

e p

lasm

a c

on

cen

tra

tion

on

ad

mis

sio

n(n

gm

l)

Alive patients (N = 18)

Dead patients(N = 5)

Colchicine poisonings prognostic value of the time-course of serum concentrations

Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments

Q = body load of glycoside to neutralize

Estimation using ingested amount of digitalis

Estimation using serum glycoside concentration

Q = Weight

(kg)

volume of distribution

digoxin 56 lkg

digitoxin 056 lkg

Serum glycoside concentration

(ngml) x x

Q = x Ingested amount (mg) digoxin bioavailability (60 )

digitoxin bioavailability (100 ) or

One vial of digibind (40 mg) neutralizes 06 mg of digoxin

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

Assessment of patientrsquos low risk if none present in the ED

- Systolic pressure lt100 mm Hg - Seizures - Unresponsiveness to verbal stimuli - Need for intubation - Any rhythm except sinus - Second- or third-degree atrioventricular block - QRS ge 012 s - PaO2 ge45 mmHg

Among the 151 low-risk patients none developed a high-risk condition after admission and none required ICU intervention These predictive criteria eliminated over 50 ICU days without compromising quality of care

Excessive admission in the ICU may also result in non-useful expenses and limited bed availability

Predicting the clinical course in intentional drug overdose in the emergency room

Brett AS Arch Intern Med 1987

Echocardiography coupled with Doppler allows a direct visualization of the heart contractility and aspects (ventricle dilatation myocardium thickness valve diseases) However it remains operator-dependent

Echocardiography

Hypovolemia or vasoplegia Cardiogenic shock

Echocardiography aspects

Severe dysrhythmia

- VO2 110 mLminm2

- SaO2 95

- Hb 11 gdl

40

90

SvO2 ()

1

Cardiac index (Lminm2)

2 3

57

70

5 6 7

80

83

SvO2 versus cardiac index relationships

SvO2 = SaO2 - VO2

IC x Hb x 134

Manini AF ClinTox 2010

- Despite of absence of specificity he serum lactate concentration had an excellent prognostic utility to predict drug-overdose fatality - The optimal lactate cut-point was 30 mmolL (84 sensitivity 75 specificity) which conferred a 158-fold increase in odds of fatality (p lt 0001)

Serum lactate is an excellent prognosticator

ROC-AUC 087 (95 CI 081ndash094)

Lactate is a marker of all types of SHOCK

1048707 A marker of inadequate perfusion or cellular O2 consumption

1048707 A marker of inadequate resuscitation and management

1048707 A predictor of patient bad outcome and development of organ

dysfunction

Beta-blocker poisonings Prognostic value of lactate concentration on admission

0

3

6

9

12

15

18

21

24

27

30

Survivors Fatalities

plt 00008S

eru

m l

acta

te c

on

cen

trati

on

s (

mm

ol

L)

0

3

6

9

12

15

18

21

24

27

30

On admissionvalues

plt 00001

Peakvalues

Seru

m l

acta

te c

on

cen

trati

on

s (

mm

ol

L)

The ROC-AUC of initial lactate for predicting mortality was 084 (074-094)

The cutoff point maximizing the sum of sensitivity and specificity was 27 mmolL

For the 30 mmolL selected lactate cutoff point 55 sensitivity 80 specificity

Meacutegarbane B Clin Tox 2010

Boehnert MT N Engl J Med 1985

Poisonings with tricyclic antidepressants Prognostic value of QRS to predict seizures and arrhythmias

Serum glucose as biomarker in calcium channel blocker poisonings

Levine M Crit Care Med 2007

Initial glucose level Peak glucose level

Increase in blood glucose +71 vs 0 p=00067

Serum potassium as biomarker in digitalis poisoning

Female

Male

lt 55

gt 55

lt 55

gt 55

Yes

No

Yes

No

Yes

No

Yes

No

K + gt45

Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No

Death rate

17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23

AV block Age

Dally S Press Med 1981

0 8 16 24 32 40 48 56

0

40

80

120

160

200

240

280

Plasma Lactate (mmolL)

Blo

od

Cyan

ide (

microm

ol

l)

Lactate as biomarker in cyanide poisoning

Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002

Chloroquine poisoning prognosis assessment

Supposed

ingested dose

Systolic BP QRS

duration

Severe gt 4 g or lt 100 mmHg or gt 010 s

Moderate 2 - 4 g and

gt 100 mmHg and

lt 010 s

Mild

lt 2 g and

gt 100 mmHg and

lt 010 s

Clemessy JL et al Crit Care Med 1996

Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg

Intubation and mechanical ventilation

Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h

Riou B N Engl J Med 1988

Macrocirculation level

- Measurement of blood pressure and cardiac index Microcirculation level

- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain

- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)

Hemodynamic monitoring of cardiotoxicant poisonings

Poisonings with tricyclic antidepressants Value of serum concentrations

Boehnert MT N Engl J Med 1985

Prognostic value of serum theophylline concentration

Sessler CN Am J Med 1990

Why does the clinician need toxicological analysis to manage his

patient with cardiotoxicant poisoning

ProCon debate

- Positive diagnosis assessment to confirm a toxic hypothesis

- Differential diagnosis to exclude a toxic hypothesis

- Prognosis evaluation

- Help for treatment indications monitoring and re-evaluation

- Retrospective evaluation medico-legal issue or scientific studies

What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings

t

Severity C blood

t

Severity C blood

Confirm severity Supportive treatments

Prognostic factors Antidotes

Interest of analysis according to drug effects

Injury-inducing drugs

Functional drugs

Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues

Prerequisite availability of toxicological analysis

- Complexity and requirements of the assays

- Dialogue between biologists and clinicians

Importance of conservative plasma and urine sampling (initial and repetitive)

Expert opinion on appropriateness of disposal according to availability of drug screening

Fabbri A Emerg Med J 2003

Does a comprehensive drug screening add to decision making for poisonings in the ED

improve agreement on patient disposal Save potentially hospital resources

Meprobamate poisonings Is serum concentration useful to indicate the

mechanism of shock

Charron C Intensive Care Med 2005

Dose-dependent hypotension with narrowed QRS

- hypovolemia

- vasoplegia if concentrations le 150 mgl

- cardiogenic if concentrations gt 150 mgl

Plasma chloroquine concentration le 12 M No death

12-25 microM death rate 2

gt 25 microM death rate 22

gt 50 microM death rate 60

Chloroquine poisoning In-hospital prognosis assessment using

blood concentrations

Clemessy JL Crit Care Med 1996

TKTD using blood concentrations TKTD using plasma concentrations

Chloroquine poisoning blood vs plasma concentrations

0 25 50 75 100 125 15000

05

10

15

20

25

30

35

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 096

0 10 20 30 40 5000

05

10

15

20

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 091

0 1 2 3 4 5 6 7 8 900

05

10

15

20

Plasma chloroquine concentration (micromolL)

Ep

inep

hri

ne

infu

sio

n r

ate

(mg

h)

0 5 10 15 20 250

1

2

3

4

Plasma chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh)

R2 = 005

R2 = 017

Patient 1

Patient 2

PKPD population modeling in chloroquine poisonings

Meacutegarbane B Clin Tox2010

Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings

Relationship Between PlasmaFlecainide Concentration and

Outcome

Survivors Fatalities

0

1

2

3

4

5

6

7

8

9

10

Outcome of Acute Poisonings

Pla

sm

a F

lecain

ide

Co

ncen

trati

on

s (

mg

L)

Meacutegarbane B Clin Tox 2007

Meacutegarbane B BCPT 2010

Verapamil poisonings

Flecainide poisonings

Meacutegarbane B Clin Tox 2002 (abstract)

0

5

10

15

20

25P

red

icte

d c

on

cen

trati

on

s (n

gm

l)

0

10

0

20

0

30

0

40

0

Time since ingestion (hours)

Predicted concentration profiles

Non suvivors C(t) = 242 exp (-0003t)

Survivors C(t) = 177 exp (-0019t)

Cut-off C(t) = 207 exp (-0011t)

0

20

40

60

80

Co

lch

icin

e p

lasm

a c

on

cen

tra

tion

on

ad

mis

sio

n(n

gm

l)

Alive patients (N = 18)

Dead patients(N = 5)

Colchicine poisonings prognostic value of the time-course of serum concentrations

Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments

Q = body load of glycoside to neutralize

Estimation using ingested amount of digitalis

Estimation using serum glycoside concentration

Q = Weight

(kg)

volume of distribution

digoxin 56 lkg

digitoxin 056 lkg

Serum glycoside concentration

(ngml) x x

Q = x Ingested amount (mg) digoxin bioavailability (60 )

digitoxin bioavailability (100 ) or

One vial of digibind (40 mg) neutralizes 06 mg of digoxin

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

Echocardiography coupled with Doppler allows a direct visualization of the heart contractility and aspects (ventricle dilatation myocardium thickness valve diseases) However it remains operator-dependent

Echocardiography

Hypovolemia or vasoplegia Cardiogenic shock

Echocardiography aspects

Severe dysrhythmia

- VO2 110 mLminm2

- SaO2 95

- Hb 11 gdl

40

90

SvO2 ()

1

Cardiac index (Lminm2)

2 3

57

70

5 6 7

80

83

SvO2 versus cardiac index relationships

SvO2 = SaO2 - VO2

IC x Hb x 134

Manini AF ClinTox 2010

- Despite of absence of specificity he serum lactate concentration had an excellent prognostic utility to predict drug-overdose fatality - The optimal lactate cut-point was 30 mmolL (84 sensitivity 75 specificity) which conferred a 158-fold increase in odds of fatality (p lt 0001)

Serum lactate is an excellent prognosticator

ROC-AUC 087 (95 CI 081ndash094)

Lactate is a marker of all types of SHOCK

1048707 A marker of inadequate perfusion or cellular O2 consumption

1048707 A marker of inadequate resuscitation and management

1048707 A predictor of patient bad outcome and development of organ

dysfunction

Beta-blocker poisonings Prognostic value of lactate concentration on admission

0

3

6

9

12

15

18

21

24

27

30

Survivors Fatalities

plt 00008S

eru

m l

acta

te c

on

cen

trati

on

s (

mm

ol

L)

0

3

6

9

12

15

18

21

24

27

30

On admissionvalues

plt 00001

Peakvalues

Seru

m l

acta

te c

on

cen

trati

on

s (

mm

ol

L)

The ROC-AUC of initial lactate for predicting mortality was 084 (074-094)

The cutoff point maximizing the sum of sensitivity and specificity was 27 mmolL

For the 30 mmolL selected lactate cutoff point 55 sensitivity 80 specificity

Meacutegarbane B Clin Tox 2010

Boehnert MT N Engl J Med 1985

Poisonings with tricyclic antidepressants Prognostic value of QRS to predict seizures and arrhythmias

Serum glucose as biomarker in calcium channel blocker poisonings

Levine M Crit Care Med 2007

Initial glucose level Peak glucose level

Increase in blood glucose +71 vs 0 p=00067

Serum potassium as biomarker in digitalis poisoning

Female

Male

lt 55

gt 55

lt 55

gt 55

Yes

No

Yes

No

Yes

No

Yes

No

K + gt45

Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No

Death rate

17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23

AV block Age

Dally S Press Med 1981

0 8 16 24 32 40 48 56

0

40

80

120

160

200

240

280

Plasma Lactate (mmolL)

Blo

od

Cyan

ide (

microm

ol

l)

Lactate as biomarker in cyanide poisoning

Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002

Chloroquine poisoning prognosis assessment

Supposed

ingested dose

Systolic BP QRS

duration

Severe gt 4 g or lt 100 mmHg or gt 010 s

Moderate 2 - 4 g and

gt 100 mmHg and

lt 010 s

Mild

lt 2 g and

gt 100 mmHg and

lt 010 s

Clemessy JL et al Crit Care Med 1996

Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg

Intubation and mechanical ventilation

Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h

Riou B N Engl J Med 1988

Macrocirculation level

- Measurement of blood pressure and cardiac index Microcirculation level

- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain

- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)

Hemodynamic monitoring of cardiotoxicant poisonings

Poisonings with tricyclic antidepressants Value of serum concentrations

Boehnert MT N Engl J Med 1985

Prognostic value of serum theophylline concentration

Sessler CN Am J Med 1990

Why does the clinician need toxicological analysis to manage his

patient with cardiotoxicant poisoning

ProCon debate

- Positive diagnosis assessment to confirm a toxic hypothesis

- Differential diagnosis to exclude a toxic hypothesis

- Prognosis evaluation

- Help for treatment indications monitoring and re-evaluation

- Retrospective evaluation medico-legal issue or scientific studies

What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings

t

Severity C blood

t

Severity C blood

Confirm severity Supportive treatments

Prognostic factors Antidotes

Interest of analysis according to drug effects

Injury-inducing drugs

Functional drugs

Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues

Prerequisite availability of toxicological analysis

- Complexity and requirements of the assays

- Dialogue between biologists and clinicians

Importance of conservative plasma and urine sampling (initial and repetitive)

Expert opinion on appropriateness of disposal according to availability of drug screening

Fabbri A Emerg Med J 2003

Does a comprehensive drug screening add to decision making for poisonings in the ED

improve agreement on patient disposal Save potentially hospital resources

Meprobamate poisonings Is serum concentration useful to indicate the

mechanism of shock

Charron C Intensive Care Med 2005

Dose-dependent hypotension with narrowed QRS

- hypovolemia

- vasoplegia if concentrations le 150 mgl

- cardiogenic if concentrations gt 150 mgl

Plasma chloroquine concentration le 12 M No death

12-25 microM death rate 2

gt 25 microM death rate 22

gt 50 microM death rate 60

Chloroquine poisoning In-hospital prognosis assessment using

blood concentrations

Clemessy JL Crit Care Med 1996

TKTD using blood concentrations TKTD using plasma concentrations

Chloroquine poisoning blood vs plasma concentrations

0 25 50 75 100 125 15000

05

10

15

20

25

30

35

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 096

0 10 20 30 40 5000

05

10

15

20

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 091

0 1 2 3 4 5 6 7 8 900

05

10

15

20

Plasma chloroquine concentration (micromolL)

Ep

inep

hri

ne

infu

sio

n r

ate

(mg

h)

0 5 10 15 20 250

1

2

3

4

Plasma chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh)

R2 = 005

R2 = 017

Patient 1

Patient 2

PKPD population modeling in chloroquine poisonings

Meacutegarbane B Clin Tox2010

Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings

Relationship Between PlasmaFlecainide Concentration and

Outcome

Survivors Fatalities

0

1

2

3

4

5

6

7

8

9

10

Outcome of Acute Poisonings

Pla

sm

a F

lecain

ide

Co

ncen

trati

on

s (

mg

L)

Meacutegarbane B Clin Tox 2007

Meacutegarbane B BCPT 2010

Verapamil poisonings

Flecainide poisonings

Meacutegarbane B Clin Tox 2002 (abstract)

0

5

10

15

20

25P

red

icte

d c

on

cen

trati

on

s (n

gm

l)

0

10

0

20

0

30

0

40

0

Time since ingestion (hours)

Predicted concentration profiles

Non suvivors C(t) = 242 exp (-0003t)

Survivors C(t) = 177 exp (-0019t)

Cut-off C(t) = 207 exp (-0011t)

0

20

40

60

80

Co

lch

icin

e p

lasm

a c

on

cen

tra

tion

on

ad

mis

sio

n(n

gm

l)

Alive patients (N = 18)

Dead patients(N = 5)

Colchicine poisonings prognostic value of the time-course of serum concentrations

Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments

Q = body load of glycoside to neutralize

Estimation using ingested amount of digitalis

Estimation using serum glycoside concentration

Q = Weight

(kg)

volume of distribution

digoxin 56 lkg

digitoxin 056 lkg

Serum glycoside concentration

(ngml) x x

Q = x Ingested amount (mg) digoxin bioavailability (60 )

digitoxin bioavailability (100 ) or

One vial of digibind (40 mg) neutralizes 06 mg of digoxin

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

- VO2 110 mLminm2

- SaO2 95

- Hb 11 gdl

40

90

SvO2 ()

1

Cardiac index (Lminm2)

2 3

57

70

5 6 7

80

83

SvO2 versus cardiac index relationships

SvO2 = SaO2 - VO2

IC x Hb x 134

Manini AF ClinTox 2010

- Despite of absence of specificity he serum lactate concentration had an excellent prognostic utility to predict drug-overdose fatality - The optimal lactate cut-point was 30 mmolL (84 sensitivity 75 specificity) which conferred a 158-fold increase in odds of fatality (p lt 0001)

Serum lactate is an excellent prognosticator

ROC-AUC 087 (95 CI 081ndash094)

Lactate is a marker of all types of SHOCK

1048707 A marker of inadequate perfusion or cellular O2 consumption

1048707 A marker of inadequate resuscitation and management

1048707 A predictor of patient bad outcome and development of organ

dysfunction

Beta-blocker poisonings Prognostic value of lactate concentration on admission

0

3

6

9

12

15

18

21

24

27

30

Survivors Fatalities

plt 00008S

eru

m l

acta

te c

on

cen

trati

on

s (

mm

ol

L)

0

3

6

9

12

15

18

21

24

27

30

On admissionvalues

plt 00001

Peakvalues

Seru

m l

acta

te c

on

cen

trati

on

s (

mm

ol

L)

The ROC-AUC of initial lactate for predicting mortality was 084 (074-094)

The cutoff point maximizing the sum of sensitivity and specificity was 27 mmolL

For the 30 mmolL selected lactate cutoff point 55 sensitivity 80 specificity

Meacutegarbane B Clin Tox 2010

Boehnert MT N Engl J Med 1985

Poisonings with tricyclic antidepressants Prognostic value of QRS to predict seizures and arrhythmias

Serum glucose as biomarker in calcium channel blocker poisonings

Levine M Crit Care Med 2007

Initial glucose level Peak glucose level

Increase in blood glucose +71 vs 0 p=00067

Serum potassium as biomarker in digitalis poisoning

Female

Male

lt 55

gt 55

lt 55

gt 55

Yes

No

Yes

No

Yes

No

Yes

No

K + gt45

Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No

Death rate

17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23

AV block Age

Dally S Press Med 1981

0 8 16 24 32 40 48 56

0

40

80

120

160

200

240

280

Plasma Lactate (mmolL)

Blo

od

Cyan

ide (

microm

ol

l)

Lactate as biomarker in cyanide poisoning

Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002

Chloroquine poisoning prognosis assessment

Supposed

ingested dose

Systolic BP QRS

duration

Severe gt 4 g or lt 100 mmHg or gt 010 s

Moderate 2 - 4 g and

gt 100 mmHg and

lt 010 s

Mild

lt 2 g and

gt 100 mmHg and

lt 010 s

Clemessy JL et al Crit Care Med 1996

Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg

Intubation and mechanical ventilation

Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h

Riou B N Engl J Med 1988

Macrocirculation level

- Measurement of blood pressure and cardiac index Microcirculation level

- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain

- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)

Hemodynamic monitoring of cardiotoxicant poisonings

Poisonings with tricyclic antidepressants Value of serum concentrations

Boehnert MT N Engl J Med 1985

Prognostic value of serum theophylline concentration

Sessler CN Am J Med 1990

Why does the clinician need toxicological analysis to manage his

patient with cardiotoxicant poisoning

ProCon debate

- Positive diagnosis assessment to confirm a toxic hypothesis

- Differential diagnosis to exclude a toxic hypothesis

- Prognosis evaluation

- Help for treatment indications monitoring and re-evaluation

- Retrospective evaluation medico-legal issue or scientific studies

What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings

t

Severity C blood

t

Severity C blood

Confirm severity Supportive treatments

Prognostic factors Antidotes

Interest of analysis according to drug effects

Injury-inducing drugs

Functional drugs

Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues

Prerequisite availability of toxicological analysis

- Complexity and requirements of the assays

- Dialogue between biologists and clinicians

Importance of conservative plasma and urine sampling (initial and repetitive)

Expert opinion on appropriateness of disposal according to availability of drug screening

Fabbri A Emerg Med J 2003

Does a comprehensive drug screening add to decision making for poisonings in the ED

improve agreement on patient disposal Save potentially hospital resources

Meprobamate poisonings Is serum concentration useful to indicate the

mechanism of shock

Charron C Intensive Care Med 2005

Dose-dependent hypotension with narrowed QRS

- hypovolemia

- vasoplegia if concentrations le 150 mgl

- cardiogenic if concentrations gt 150 mgl

Plasma chloroquine concentration le 12 M No death

12-25 microM death rate 2

gt 25 microM death rate 22

gt 50 microM death rate 60

Chloroquine poisoning In-hospital prognosis assessment using

blood concentrations

Clemessy JL Crit Care Med 1996

TKTD using blood concentrations TKTD using plasma concentrations

Chloroquine poisoning blood vs plasma concentrations

0 25 50 75 100 125 15000

05

10

15

20

25

30

35

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 096

0 10 20 30 40 5000

05

10

15

20

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 091

0 1 2 3 4 5 6 7 8 900

05

10

15

20

Plasma chloroquine concentration (micromolL)

Ep

inep

hri

ne

infu

sio

n r

ate

(mg

h)

0 5 10 15 20 250

1

2

3

4

Plasma chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh)

R2 = 005

R2 = 017

Patient 1

Patient 2

PKPD population modeling in chloroquine poisonings

Meacutegarbane B Clin Tox2010

Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings

Relationship Between PlasmaFlecainide Concentration and

Outcome

Survivors Fatalities

0

1

2

3

4

5

6

7

8

9

10

Outcome of Acute Poisonings

Pla

sm

a F

lecain

ide

Co

ncen

trati

on

s (

mg

L)

Meacutegarbane B Clin Tox 2007

Meacutegarbane B BCPT 2010

Verapamil poisonings

Flecainide poisonings

Meacutegarbane B Clin Tox 2002 (abstract)

0

5

10

15

20

25P

red

icte

d c

on

cen

trati

on

s (n

gm

l)

0

10

0

20

0

30

0

40

0

Time since ingestion (hours)

Predicted concentration profiles

Non suvivors C(t) = 242 exp (-0003t)

Survivors C(t) = 177 exp (-0019t)

Cut-off C(t) = 207 exp (-0011t)

0

20

40

60

80

Co

lch

icin

e p

lasm

a c

on

cen

tra

tion

on

ad

mis

sio

n(n

gm

l)

Alive patients (N = 18)

Dead patients(N = 5)

Colchicine poisonings prognostic value of the time-course of serum concentrations

Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments

Q = body load of glycoside to neutralize

Estimation using ingested amount of digitalis

Estimation using serum glycoside concentration

Q = Weight

(kg)

volume of distribution

digoxin 56 lkg

digitoxin 056 lkg

Serum glycoside concentration

(ngml) x x

Q = x Ingested amount (mg) digoxin bioavailability (60 )

digitoxin bioavailability (100 ) or

One vial of digibind (40 mg) neutralizes 06 mg of digoxin

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

Manini AF ClinTox 2010

- Despite of absence of specificity he serum lactate concentration had an excellent prognostic utility to predict drug-overdose fatality - The optimal lactate cut-point was 30 mmolL (84 sensitivity 75 specificity) which conferred a 158-fold increase in odds of fatality (p lt 0001)

Serum lactate is an excellent prognosticator

ROC-AUC 087 (95 CI 081ndash094)

Lactate is a marker of all types of SHOCK

1048707 A marker of inadequate perfusion or cellular O2 consumption

1048707 A marker of inadequate resuscitation and management

1048707 A predictor of patient bad outcome and development of organ

dysfunction

Beta-blocker poisonings Prognostic value of lactate concentration on admission

0

3

6

9

12

15

18

21

24

27

30

Survivors Fatalities

plt 00008S

eru

m l

acta

te c

on

cen

trati

on

s (

mm

ol

L)

0

3

6

9

12

15

18

21

24

27

30

On admissionvalues

plt 00001

Peakvalues

Seru

m l

acta

te c

on

cen

trati

on

s (

mm

ol

L)

The ROC-AUC of initial lactate for predicting mortality was 084 (074-094)

The cutoff point maximizing the sum of sensitivity and specificity was 27 mmolL

For the 30 mmolL selected lactate cutoff point 55 sensitivity 80 specificity

Meacutegarbane B Clin Tox 2010

Boehnert MT N Engl J Med 1985

Poisonings with tricyclic antidepressants Prognostic value of QRS to predict seizures and arrhythmias

Serum glucose as biomarker in calcium channel blocker poisonings

Levine M Crit Care Med 2007

Initial glucose level Peak glucose level

Increase in blood glucose +71 vs 0 p=00067

Serum potassium as biomarker in digitalis poisoning

Female

Male

lt 55

gt 55

lt 55

gt 55

Yes

No

Yes

No

Yes

No

Yes

No

K + gt45

Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No

Death rate

17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23

AV block Age

Dally S Press Med 1981

0 8 16 24 32 40 48 56

0

40

80

120

160

200

240

280

Plasma Lactate (mmolL)

Blo

od

Cyan

ide (

microm

ol

l)

Lactate as biomarker in cyanide poisoning

Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002

Chloroquine poisoning prognosis assessment

Supposed

ingested dose

Systolic BP QRS

duration

Severe gt 4 g or lt 100 mmHg or gt 010 s

Moderate 2 - 4 g and

gt 100 mmHg and

lt 010 s

Mild

lt 2 g and

gt 100 mmHg and

lt 010 s

Clemessy JL et al Crit Care Med 1996

Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg

Intubation and mechanical ventilation

Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h

Riou B N Engl J Med 1988

Macrocirculation level

- Measurement of blood pressure and cardiac index Microcirculation level

- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain

- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)

Hemodynamic monitoring of cardiotoxicant poisonings

Poisonings with tricyclic antidepressants Value of serum concentrations

Boehnert MT N Engl J Med 1985

Prognostic value of serum theophylline concentration

Sessler CN Am J Med 1990

Why does the clinician need toxicological analysis to manage his

patient with cardiotoxicant poisoning

ProCon debate

- Positive diagnosis assessment to confirm a toxic hypothesis

- Differential diagnosis to exclude a toxic hypothesis

- Prognosis evaluation

- Help for treatment indications monitoring and re-evaluation

- Retrospective evaluation medico-legal issue or scientific studies

What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings

t

Severity C blood

t

Severity C blood

Confirm severity Supportive treatments

Prognostic factors Antidotes

Interest of analysis according to drug effects

Injury-inducing drugs

Functional drugs

Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues

Prerequisite availability of toxicological analysis

- Complexity and requirements of the assays

- Dialogue between biologists and clinicians

Importance of conservative plasma and urine sampling (initial and repetitive)

Expert opinion on appropriateness of disposal according to availability of drug screening

Fabbri A Emerg Med J 2003

Does a comprehensive drug screening add to decision making for poisonings in the ED

improve agreement on patient disposal Save potentially hospital resources

Meprobamate poisonings Is serum concentration useful to indicate the

mechanism of shock

Charron C Intensive Care Med 2005

Dose-dependent hypotension with narrowed QRS

- hypovolemia

- vasoplegia if concentrations le 150 mgl

- cardiogenic if concentrations gt 150 mgl

Plasma chloroquine concentration le 12 M No death

12-25 microM death rate 2

gt 25 microM death rate 22

gt 50 microM death rate 60

Chloroquine poisoning In-hospital prognosis assessment using

blood concentrations

Clemessy JL Crit Care Med 1996

TKTD using blood concentrations TKTD using plasma concentrations

Chloroquine poisoning blood vs plasma concentrations

0 25 50 75 100 125 15000

05

10

15

20

25

30

35

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 096

0 10 20 30 40 5000

05

10

15

20

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 091

0 1 2 3 4 5 6 7 8 900

05

10

15

20

Plasma chloroquine concentration (micromolL)

Ep

inep

hri

ne

infu

sio

n r

ate

(mg

h)

0 5 10 15 20 250

1

2

3

4

Plasma chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh)

R2 = 005

R2 = 017

Patient 1

Patient 2

PKPD population modeling in chloroquine poisonings

Meacutegarbane B Clin Tox2010

Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings

Relationship Between PlasmaFlecainide Concentration and

Outcome

Survivors Fatalities

0

1

2

3

4

5

6

7

8

9

10

Outcome of Acute Poisonings

Pla

sm

a F

lecain

ide

Co

ncen

trati

on

s (

mg

L)

Meacutegarbane B Clin Tox 2007

Meacutegarbane B BCPT 2010

Verapamil poisonings

Flecainide poisonings

Meacutegarbane B Clin Tox 2002 (abstract)

0

5

10

15

20

25P

red

icte

d c

on

cen

trati

on

s (n

gm

l)

0

10

0

20

0

30

0

40

0

Time since ingestion (hours)

Predicted concentration profiles

Non suvivors C(t) = 242 exp (-0003t)

Survivors C(t) = 177 exp (-0019t)

Cut-off C(t) = 207 exp (-0011t)

0

20

40

60

80

Co

lch

icin

e p

lasm

a c

on

cen

tra

tion

on

ad

mis

sio

n(n

gm

l)

Alive patients (N = 18)

Dead patients(N = 5)

Colchicine poisonings prognostic value of the time-course of serum concentrations

Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments

Q = body load of glycoside to neutralize

Estimation using ingested amount of digitalis

Estimation using serum glycoside concentration

Q = Weight

(kg)

volume of distribution

digoxin 56 lkg

digitoxin 056 lkg

Serum glycoside concentration

(ngml) x x

Q = x Ingested amount (mg) digoxin bioavailability (60 )

digitoxin bioavailability (100 ) or

One vial of digibind (40 mg) neutralizes 06 mg of digoxin

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

Beta-blocker poisonings Prognostic value of lactate concentration on admission

0

3

6

9

12

15

18

21

24

27

30

Survivors Fatalities

plt 00008S

eru

m l

acta

te c

on

cen

trati

on

s (

mm

ol

L)

0

3

6

9

12

15

18

21

24

27

30

On admissionvalues

plt 00001

Peakvalues

Seru

m l

acta

te c

on

cen

trati

on

s (

mm

ol

L)

The ROC-AUC of initial lactate for predicting mortality was 084 (074-094)

The cutoff point maximizing the sum of sensitivity and specificity was 27 mmolL

For the 30 mmolL selected lactate cutoff point 55 sensitivity 80 specificity

Meacutegarbane B Clin Tox 2010

Boehnert MT N Engl J Med 1985

Poisonings with tricyclic antidepressants Prognostic value of QRS to predict seizures and arrhythmias

Serum glucose as biomarker in calcium channel blocker poisonings

Levine M Crit Care Med 2007

Initial glucose level Peak glucose level

Increase in blood glucose +71 vs 0 p=00067

Serum potassium as biomarker in digitalis poisoning

Female

Male

lt 55

gt 55

lt 55

gt 55

Yes

No

Yes

No

Yes

No

Yes

No

K + gt45

Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No

Death rate

17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23

AV block Age

Dally S Press Med 1981

0 8 16 24 32 40 48 56

0

40

80

120

160

200

240

280

Plasma Lactate (mmolL)

Blo

od

Cyan

ide (

microm

ol

l)

Lactate as biomarker in cyanide poisoning

Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002

Chloroquine poisoning prognosis assessment

Supposed

ingested dose

Systolic BP QRS

duration

Severe gt 4 g or lt 100 mmHg or gt 010 s

Moderate 2 - 4 g and

gt 100 mmHg and

lt 010 s

Mild

lt 2 g and

gt 100 mmHg and

lt 010 s

Clemessy JL et al Crit Care Med 1996

Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg

Intubation and mechanical ventilation

Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h

Riou B N Engl J Med 1988

Macrocirculation level

- Measurement of blood pressure and cardiac index Microcirculation level

- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain

- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)

Hemodynamic monitoring of cardiotoxicant poisonings

Poisonings with tricyclic antidepressants Value of serum concentrations

Boehnert MT N Engl J Med 1985

Prognostic value of serum theophylline concentration

Sessler CN Am J Med 1990

Why does the clinician need toxicological analysis to manage his

patient with cardiotoxicant poisoning

ProCon debate

- Positive diagnosis assessment to confirm a toxic hypothesis

- Differential diagnosis to exclude a toxic hypothesis

- Prognosis evaluation

- Help for treatment indications monitoring and re-evaluation

- Retrospective evaluation medico-legal issue or scientific studies

What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings

t

Severity C blood

t

Severity C blood

Confirm severity Supportive treatments

Prognostic factors Antidotes

Interest of analysis according to drug effects

Injury-inducing drugs

Functional drugs

Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues

Prerequisite availability of toxicological analysis

- Complexity and requirements of the assays

- Dialogue between biologists and clinicians

Importance of conservative plasma and urine sampling (initial and repetitive)

Expert opinion on appropriateness of disposal according to availability of drug screening

Fabbri A Emerg Med J 2003

Does a comprehensive drug screening add to decision making for poisonings in the ED

improve agreement on patient disposal Save potentially hospital resources

Meprobamate poisonings Is serum concentration useful to indicate the

mechanism of shock

Charron C Intensive Care Med 2005

Dose-dependent hypotension with narrowed QRS

- hypovolemia

- vasoplegia if concentrations le 150 mgl

- cardiogenic if concentrations gt 150 mgl

Plasma chloroquine concentration le 12 M No death

12-25 microM death rate 2

gt 25 microM death rate 22

gt 50 microM death rate 60

Chloroquine poisoning In-hospital prognosis assessment using

blood concentrations

Clemessy JL Crit Care Med 1996

TKTD using blood concentrations TKTD using plasma concentrations

Chloroquine poisoning blood vs plasma concentrations

0 25 50 75 100 125 15000

05

10

15

20

25

30

35

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 096

0 10 20 30 40 5000

05

10

15

20

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 091

0 1 2 3 4 5 6 7 8 900

05

10

15

20

Plasma chloroquine concentration (micromolL)

Ep

inep

hri

ne

infu

sio

n r

ate

(mg

h)

0 5 10 15 20 250

1

2

3

4

Plasma chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh)

R2 = 005

R2 = 017

Patient 1

Patient 2

PKPD population modeling in chloroquine poisonings

Meacutegarbane B Clin Tox2010

Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings

Relationship Between PlasmaFlecainide Concentration and

Outcome

Survivors Fatalities

0

1

2

3

4

5

6

7

8

9

10

Outcome of Acute Poisonings

Pla

sm

a F

lecain

ide

Co

ncen

trati

on

s (

mg

L)

Meacutegarbane B Clin Tox 2007

Meacutegarbane B BCPT 2010

Verapamil poisonings

Flecainide poisonings

Meacutegarbane B Clin Tox 2002 (abstract)

0

5

10

15

20

25P

red

icte

d c

on

cen

trati

on

s (n

gm

l)

0

10

0

20

0

30

0

40

0

Time since ingestion (hours)

Predicted concentration profiles

Non suvivors C(t) = 242 exp (-0003t)

Survivors C(t) = 177 exp (-0019t)

Cut-off C(t) = 207 exp (-0011t)

0

20

40

60

80

Co

lch

icin

e p

lasm

a c

on

cen

tra

tion

on

ad

mis

sio

n(n

gm

l)

Alive patients (N = 18)

Dead patients(N = 5)

Colchicine poisonings prognostic value of the time-course of serum concentrations

Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments

Q = body load of glycoside to neutralize

Estimation using ingested amount of digitalis

Estimation using serum glycoside concentration

Q = Weight

(kg)

volume of distribution

digoxin 56 lkg

digitoxin 056 lkg

Serum glycoside concentration

(ngml) x x

Q = x Ingested amount (mg) digoxin bioavailability (60 )

digitoxin bioavailability (100 ) or

One vial of digibind (40 mg) neutralizes 06 mg of digoxin

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

Boehnert MT N Engl J Med 1985

Poisonings with tricyclic antidepressants Prognostic value of QRS to predict seizures and arrhythmias

Serum glucose as biomarker in calcium channel blocker poisonings

Levine M Crit Care Med 2007

Initial glucose level Peak glucose level

Increase in blood glucose +71 vs 0 p=00067

Serum potassium as biomarker in digitalis poisoning

Female

Male

lt 55

gt 55

lt 55

gt 55

Yes

No

Yes

No

Yes

No

Yes

No

K + gt45

Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No

Death rate

17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23

AV block Age

Dally S Press Med 1981

0 8 16 24 32 40 48 56

0

40

80

120

160

200

240

280

Plasma Lactate (mmolL)

Blo

od

Cyan

ide (

microm

ol

l)

Lactate as biomarker in cyanide poisoning

Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002

Chloroquine poisoning prognosis assessment

Supposed

ingested dose

Systolic BP QRS

duration

Severe gt 4 g or lt 100 mmHg or gt 010 s

Moderate 2 - 4 g and

gt 100 mmHg and

lt 010 s

Mild

lt 2 g and

gt 100 mmHg and

lt 010 s

Clemessy JL et al Crit Care Med 1996

Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg

Intubation and mechanical ventilation

Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h

Riou B N Engl J Med 1988

Macrocirculation level

- Measurement of blood pressure and cardiac index Microcirculation level

- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain

- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)

Hemodynamic monitoring of cardiotoxicant poisonings

Poisonings with tricyclic antidepressants Value of serum concentrations

Boehnert MT N Engl J Med 1985

Prognostic value of serum theophylline concentration

Sessler CN Am J Med 1990

Why does the clinician need toxicological analysis to manage his

patient with cardiotoxicant poisoning

ProCon debate

- Positive diagnosis assessment to confirm a toxic hypothesis

- Differential diagnosis to exclude a toxic hypothesis

- Prognosis evaluation

- Help for treatment indications monitoring and re-evaluation

- Retrospective evaluation medico-legal issue or scientific studies

What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings

t

Severity C blood

t

Severity C blood

Confirm severity Supportive treatments

Prognostic factors Antidotes

Interest of analysis according to drug effects

Injury-inducing drugs

Functional drugs

Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues

Prerequisite availability of toxicological analysis

- Complexity and requirements of the assays

- Dialogue between biologists and clinicians

Importance of conservative plasma and urine sampling (initial and repetitive)

Expert opinion on appropriateness of disposal according to availability of drug screening

Fabbri A Emerg Med J 2003

Does a comprehensive drug screening add to decision making for poisonings in the ED

improve agreement on patient disposal Save potentially hospital resources

Meprobamate poisonings Is serum concentration useful to indicate the

mechanism of shock

Charron C Intensive Care Med 2005

Dose-dependent hypotension with narrowed QRS

- hypovolemia

- vasoplegia if concentrations le 150 mgl

- cardiogenic if concentrations gt 150 mgl

Plasma chloroquine concentration le 12 M No death

12-25 microM death rate 2

gt 25 microM death rate 22

gt 50 microM death rate 60

Chloroquine poisoning In-hospital prognosis assessment using

blood concentrations

Clemessy JL Crit Care Med 1996

TKTD using blood concentrations TKTD using plasma concentrations

Chloroquine poisoning blood vs plasma concentrations

0 25 50 75 100 125 15000

05

10

15

20

25

30

35

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 096

0 10 20 30 40 5000

05

10

15

20

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 091

0 1 2 3 4 5 6 7 8 900

05

10

15

20

Plasma chloroquine concentration (micromolL)

Ep

inep

hri

ne

infu

sio

n r

ate

(mg

h)

0 5 10 15 20 250

1

2

3

4

Plasma chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh)

R2 = 005

R2 = 017

Patient 1

Patient 2

PKPD population modeling in chloroquine poisonings

Meacutegarbane B Clin Tox2010

Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings

Relationship Between PlasmaFlecainide Concentration and

Outcome

Survivors Fatalities

0

1

2

3

4

5

6

7

8

9

10

Outcome of Acute Poisonings

Pla

sm

a F

lecain

ide

Co

ncen

trati

on

s (

mg

L)

Meacutegarbane B Clin Tox 2007

Meacutegarbane B BCPT 2010

Verapamil poisonings

Flecainide poisonings

Meacutegarbane B Clin Tox 2002 (abstract)

0

5

10

15

20

25P

red

icte

d c

on

cen

trati

on

s (n

gm

l)

0

10

0

20

0

30

0

40

0

Time since ingestion (hours)

Predicted concentration profiles

Non suvivors C(t) = 242 exp (-0003t)

Survivors C(t) = 177 exp (-0019t)

Cut-off C(t) = 207 exp (-0011t)

0

20

40

60

80

Co

lch

icin

e p

lasm

a c

on

cen

tra

tion

on

ad

mis

sio

n(n

gm

l)

Alive patients (N = 18)

Dead patients(N = 5)

Colchicine poisonings prognostic value of the time-course of serum concentrations

Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments

Q = body load of glycoside to neutralize

Estimation using ingested amount of digitalis

Estimation using serum glycoside concentration

Q = Weight

(kg)

volume of distribution

digoxin 56 lkg

digitoxin 056 lkg

Serum glycoside concentration

(ngml) x x

Q = x Ingested amount (mg) digoxin bioavailability (60 )

digitoxin bioavailability (100 ) or

One vial of digibind (40 mg) neutralizes 06 mg of digoxin

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

Serum glucose as biomarker in calcium channel blocker poisonings

Levine M Crit Care Med 2007

Initial glucose level Peak glucose level

Increase in blood glucose +71 vs 0 p=00067

Serum potassium as biomarker in digitalis poisoning

Female

Male

lt 55

gt 55

lt 55

gt 55

Yes

No

Yes

No

Yes

No

Yes

No

K + gt45

Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No

Death rate

17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23

AV block Age

Dally S Press Med 1981

0 8 16 24 32 40 48 56

0

40

80

120

160

200

240

280

Plasma Lactate (mmolL)

Blo

od

Cyan

ide (

microm

ol

l)

Lactate as biomarker in cyanide poisoning

Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002

Chloroquine poisoning prognosis assessment

Supposed

ingested dose

Systolic BP QRS

duration

Severe gt 4 g or lt 100 mmHg or gt 010 s

Moderate 2 - 4 g and

gt 100 mmHg and

lt 010 s

Mild

lt 2 g and

gt 100 mmHg and

lt 010 s

Clemessy JL et al Crit Care Med 1996

Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg

Intubation and mechanical ventilation

Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h

Riou B N Engl J Med 1988

Macrocirculation level

- Measurement of blood pressure and cardiac index Microcirculation level

- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain

- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)

Hemodynamic monitoring of cardiotoxicant poisonings

Poisonings with tricyclic antidepressants Value of serum concentrations

Boehnert MT N Engl J Med 1985

Prognostic value of serum theophylline concentration

Sessler CN Am J Med 1990

Why does the clinician need toxicological analysis to manage his

patient with cardiotoxicant poisoning

ProCon debate

- Positive diagnosis assessment to confirm a toxic hypothesis

- Differential diagnosis to exclude a toxic hypothesis

- Prognosis evaluation

- Help for treatment indications monitoring and re-evaluation

- Retrospective evaluation medico-legal issue or scientific studies

What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings

t

Severity C blood

t

Severity C blood

Confirm severity Supportive treatments

Prognostic factors Antidotes

Interest of analysis according to drug effects

Injury-inducing drugs

Functional drugs

Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues

Prerequisite availability of toxicological analysis

- Complexity and requirements of the assays

- Dialogue between biologists and clinicians

Importance of conservative plasma and urine sampling (initial and repetitive)

Expert opinion on appropriateness of disposal according to availability of drug screening

Fabbri A Emerg Med J 2003

Does a comprehensive drug screening add to decision making for poisonings in the ED

improve agreement on patient disposal Save potentially hospital resources

Meprobamate poisonings Is serum concentration useful to indicate the

mechanism of shock

Charron C Intensive Care Med 2005

Dose-dependent hypotension with narrowed QRS

- hypovolemia

- vasoplegia if concentrations le 150 mgl

- cardiogenic if concentrations gt 150 mgl

Plasma chloroquine concentration le 12 M No death

12-25 microM death rate 2

gt 25 microM death rate 22

gt 50 microM death rate 60

Chloroquine poisoning In-hospital prognosis assessment using

blood concentrations

Clemessy JL Crit Care Med 1996

TKTD using blood concentrations TKTD using plasma concentrations

Chloroquine poisoning blood vs plasma concentrations

0 25 50 75 100 125 15000

05

10

15

20

25

30

35

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 096

0 10 20 30 40 5000

05

10

15

20

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 091

0 1 2 3 4 5 6 7 8 900

05

10

15

20

Plasma chloroquine concentration (micromolL)

Ep

inep

hri

ne

infu

sio

n r

ate

(mg

h)

0 5 10 15 20 250

1

2

3

4

Plasma chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh)

R2 = 005

R2 = 017

Patient 1

Patient 2

PKPD population modeling in chloroquine poisonings

Meacutegarbane B Clin Tox2010

Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings

Relationship Between PlasmaFlecainide Concentration and

Outcome

Survivors Fatalities

0

1

2

3

4

5

6

7

8

9

10

Outcome of Acute Poisonings

Pla

sm

a F

lecain

ide

Co

ncen

trati

on

s (

mg

L)

Meacutegarbane B Clin Tox 2007

Meacutegarbane B BCPT 2010

Verapamil poisonings

Flecainide poisonings

Meacutegarbane B Clin Tox 2002 (abstract)

0

5

10

15

20

25P

red

icte

d c

on

cen

trati

on

s (n

gm

l)

0

10

0

20

0

30

0

40

0

Time since ingestion (hours)

Predicted concentration profiles

Non suvivors C(t) = 242 exp (-0003t)

Survivors C(t) = 177 exp (-0019t)

Cut-off C(t) = 207 exp (-0011t)

0

20

40

60

80

Co

lch

icin

e p

lasm

a c

on

cen

tra

tion

on

ad

mis

sio

n(n

gm

l)

Alive patients (N = 18)

Dead patients(N = 5)

Colchicine poisonings prognostic value of the time-course of serum concentrations

Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments

Q = body load of glycoside to neutralize

Estimation using ingested amount of digitalis

Estimation using serum glycoside concentration

Q = Weight

(kg)

volume of distribution

digoxin 56 lkg

digitoxin 056 lkg

Serum glycoside concentration

(ngml) x x

Q = x Ingested amount (mg) digoxin bioavailability (60 )

digitoxin bioavailability (100 ) or

One vial of digibind (40 mg) neutralizes 06 mg of digoxin

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

Serum potassium as biomarker in digitalis poisoning

Female

Male

lt 55

gt 55

lt 55

gt 55

Yes

No

Yes

No

Yes

No

Yes

No

K + gt45

Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No

Death rate

17 4 8 2 49 18 29 9 38 11 20 6 74 35 50 23

AV block Age

Dally S Press Med 1981

0 8 16 24 32 40 48 56

0

40

80

120

160

200

240

280

Plasma Lactate (mmolL)

Blo

od

Cyan

ide (

microm

ol

l)

Lactate as biomarker in cyanide poisoning

Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002

Chloroquine poisoning prognosis assessment

Supposed

ingested dose

Systolic BP QRS

duration

Severe gt 4 g or lt 100 mmHg or gt 010 s

Moderate 2 - 4 g and

gt 100 mmHg and

lt 010 s

Mild

lt 2 g and

gt 100 mmHg and

lt 010 s

Clemessy JL et al Crit Care Med 1996

Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg

Intubation and mechanical ventilation

Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h

Riou B N Engl J Med 1988

Macrocirculation level

- Measurement of blood pressure and cardiac index Microcirculation level

- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain

- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)

Hemodynamic monitoring of cardiotoxicant poisonings

Poisonings with tricyclic antidepressants Value of serum concentrations

Boehnert MT N Engl J Med 1985

Prognostic value of serum theophylline concentration

Sessler CN Am J Med 1990

Why does the clinician need toxicological analysis to manage his

patient with cardiotoxicant poisoning

ProCon debate

- Positive diagnosis assessment to confirm a toxic hypothesis

- Differential diagnosis to exclude a toxic hypothesis

- Prognosis evaluation

- Help for treatment indications monitoring and re-evaluation

- Retrospective evaluation medico-legal issue or scientific studies

What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings

t

Severity C blood

t

Severity C blood

Confirm severity Supportive treatments

Prognostic factors Antidotes

Interest of analysis according to drug effects

Injury-inducing drugs

Functional drugs

Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues

Prerequisite availability of toxicological analysis

- Complexity and requirements of the assays

- Dialogue between biologists and clinicians

Importance of conservative plasma and urine sampling (initial and repetitive)

Expert opinion on appropriateness of disposal according to availability of drug screening

Fabbri A Emerg Med J 2003

Does a comprehensive drug screening add to decision making for poisonings in the ED

improve agreement on patient disposal Save potentially hospital resources

Meprobamate poisonings Is serum concentration useful to indicate the

mechanism of shock

Charron C Intensive Care Med 2005

Dose-dependent hypotension with narrowed QRS

- hypovolemia

- vasoplegia if concentrations le 150 mgl

- cardiogenic if concentrations gt 150 mgl

Plasma chloroquine concentration le 12 M No death

12-25 microM death rate 2

gt 25 microM death rate 22

gt 50 microM death rate 60

Chloroquine poisoning In-hospital prognosis assessment using

blood concentrations

Clemessy JL Crit Care Med 1996

TKTD using blood concentrations TKTD using plasma concentrations

Chloroquine poisoning blood vs plasma concentrations

0 25 50 75 100 125 15000

05

10

15

20

25

30

35

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 096

0 10 20 30 40 5000

05

10

15

20

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 091

0 1 2 3 4 5 6 7 8 900

05

10

15

20

Plasma chloroquine concentration (micromolL)

Ep

inep

hri

ne

infu

sio

n r

ate

(mg

h)

0 5 10 15 20 250

1

2

3

4

Plasma chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh)

R2 = 005

R2 = 017

Patient 1

Patient 2

PKPD population modeling in chloroquine poisonings

Meacutegarbane B Clin Tox2010

Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings

Relationship Between PlasmaFlecainide Concentration and

Outcome

Survivors Fatalities

0

1

2

3

4

5

6

7

8

9

10

Outcome of Acute Poisonings

Pla

sm

a F

lecain

ide

Co

ncen

trati

on

s (

mg

L)

Meacutegarbane B Clin Tox 2007

Meacutegarbane B BCPT 2010

Verapamil poisonings

Flecainide poisonings

Meacutegarbane B Clin Tox 2002 (abstract)

0

5

10

15

20

25P

red

icte

d c

on

cen

trati

on

s (n

gm

l)

0

10

0

20

0

30

0

40

0

Time since ingestion (hours)

Predicted concentration profiles

Non suvivors C(t) = 242 exp (-0003t)

Survivors C(t) = 177 exp (-0019t)

Cut-off C(t) = 207 exp (-0011t)

0

20

40

60

80

Co

lch

icin

e p

lasm

a c

on

cen

tra

tion

on

ad

mis

sio

n(n

gm

l)

Alive patients (N = 18)

Dead patients(N = 5)

Colchicine poisonings prognostic value of the time-course of serum concentrations

Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments

Q = body load of glycoside to neutralize

Estimation using ingested amount of digitalis

Estimation using serum glycoside concentration

Q = Weight

(kg)

volume of distribution

digoxin 56 lkg

digitoxin 056 lkg

Serum glycoside concentration

(ngml) x x

Q = x Ingested amount (mg) digoxin bioavailability (60 )

digitoxin bioavailability (100 ) or

One vial of digibind (40 mg) neutralizes 06 mg of digoxin

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

0 8 16 24 32 40 48 56

0

40

80

120

160

200

240

280

Plasma Lactate (mmolL)

Blo

od

Cyan

ide (

microm

ol

l)

Lactate as biomarker in cyanide poisoning

Sensitivity 94 Specificity 70 PPV 64 NPV 98 Baud FJ Crit Care Med 2002

Chloroquine poisoning prognosis assessment

Supposed

ingested dose

Systolic BP QRS

duration

Severe gt 4 g or lt 100 mmHg or gt 010 s

Moderate 2 - 4 g and

gt 100 mmHg and

lt 010 s

Mild

lt 2 g and

gt 100 mmHg and

lt 010 s

Clemessy JL et al Crit Care Med 1996

Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg

Intubation and mechanical ventilation

Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h

Riou B N Engl J Med 1988

Macrocirculation level

- Measurement of blood pressure and cardiac index Microcirculation level

- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain

- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)

Hemodynamic monitoring of cardiotoxicant poisonings

Poisonings with tricyclic antidepressants Value of serum concentrations

Boehnert MT N Engl J Med 1985

Prognostic value of serum theophylline concentration

Sessler CN Am J Med 1990

Why does the clinician need toxicological analysis to manage his

patient with cardiotoxicant poisoning

ProCon debate

- Positive diagnosis assessment to confirm a toxic hypothesis

- Differential diagnosis to exclude a toxic hypothesis

- Prognosis evaluation

- Help for treatment indications monitoring and re-evaluation

- Retrospective evaluation medico-legal issue or scientific studies

What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings

t

Severity C blood

t

Severity C blood

Confirm severity Supportive treatments

Prognostic factors Antidotes

Interest of analysis according to drug effects

Injury-inducing drugs

Functional drugs

Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues

Prerequisite availability of toxicological analysis

- Complexity and requirements of the assays

- Dialogue between biologists and clinicians

Importance of conservative plasma and urine sampling (initial and repetitive)

Expert opinion on appropriateness of disposal according to availability of drug screening

Fabbri A Emerg Med J 2003

Does a comprehensive drug screening add to decision making for poisonings in the ED

improve agreement on patient disposal Save potentially hospital resources

Meprobamate poisonings Is serum concentration useful to indicate the

mechanism of shock

Charron C Intensive Care Med 2005

Dose-dependent hypotension with narrowed QRS

- hypovolemia

- vasoplegia if concentrations le 150 mgl

- cardiogenic if concentrations gt 150 mgl

Plasma chloroquine concentration le 12 M No death

12-25 microM death rate 2

gt 25 microM death rate 22

gt 50 microM death rate 60

Chloroquine poisoning In-hospital prognosis assessment using

blood concentrations

Clemessy JL Crit Care Med 1996

TKTD using blood concentrations TKTD using plasma concentrations

Chloroquine poisoning blood vs plasma concentrations

0 25 50 75 100 125 15000

05

10

15

20

25

30

35

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 096

0 10 20 30 40 5000

05

10

15

20

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 091

0 1 2 3 4 5 6 7 8 900

05

10

15

20

Plasma chloroquine concentration (micromolL)

Ep

inep

hri

ne

infu

sio

n r

ate

(mg

h)

0 5 10 15 20 250

1

2

3

4

Plasma chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh)

R2 = 005

R2 = 017

Patient 1

Patient 2

PKPD population modeling in chloroquine poisonings

Meacutegarbane B Clin Tox2010

Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings

Relationship Between PlasmaFlecainide Concentration and

Outcome

Survivors Fatalities

0

1

2

3

4

5

6

7

8

9

10

Outcome of Acute Poisonings

Pla

sm

a F

lecain

ide

Co

ncen

trati

on

s (

mg

L)

Meacutegarbane B Clin Tox 2007

Meacutegarbane B BCPT 2010

Verapamil poisonings

Flecainide poisonings

Meacutegarbane B Clin Tox 2002 (abstract)

0

5

10

15

20

25P

red

icte

d c

on

cen

trati

on

s (n

gm

l)

0

10

0

20

0

30

0

40

0

Time since ingestion (hours)

Predicted concentration profiles

Non suvivors C(t) = 242 exp (-0003t)

Survivors C(t) = 177 exp (-0019t)

Cut-off C(t) = 207 exp (-0011t)

0

20

40

60

80

Co

lch

icin

e p

lasm

a c

on

cen

tra

tion

on

ad

mis

sio

n(n

gm

l)

Alive patients (N = 18)

Dead patients(N = 5)

Colchicine poisonings prognostic value of the time-course of serum concentrations

Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments

Q = body load of glycoside to neutralize

Estimation using ingested amount of digitalis

Estimation using serum glycoside concentration

Q = Weight

(kg)

volume of distribution

digoxin 56 lkg

digitoxin 056 lkg

Serum glycoside concentration

(ngml) x x

Q = x Ingested amount (mg) digoxin bioavailability (60 )

digitoxin bioavailability (100 ) or

One vial of digibind (40 mg) neutralizes 06 mg of digoxin

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

Chloroquine poisoning prognosis assessment

Supposed

ingested dose

Systolic BP QRS

duration

Severe gt 4 g or lt 100 mmHg or gt 010 s

Moderate 2 - 4 g and

gt 100 mmHg and

lt 010 s

Mild

lt 2 g and

gt 100 mmHg and

lt 010 s

Clemessy JL et al Crit Care Med 1996

Severe poisoning Epinephrine 025 microgkgmin with increasing 025 microgkgmin steps to obtain SBP ge 100 mmHg

Intubation and mechanical ventilation

Diazepam 2 mgkg in 30 min followed with 2-4 mgkg24h

Riou B N Engl J Med 1988

Macrocirculation level

- Measurement of blood pressure and cardiac index Microcirculation level

- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain

- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)

Hemodynamic monitoring of cardiotoxicant poisonings

Poisonings with tricyclic antidepressants Value of serum concentrations

Boehnert MT N Engl J Med 1985

Prognostic value of serum theophylline concentration

Sessler CN Am J Med 1990

Why does the clinician need toxicological analysis to manage his

patient with cardiotoxicant poisoning

ProCon debate

- Positive diagnosis assessment to confirm a toxic hypothesis

- Differential diagnosis to exclude a toxic hypothesis

- Prognosis evaluation

- Help for treatment indications monitoring and re-evaluation

- Retrospective evaluation medico-legal issue or scientific studies

What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings

t

Severity C blood

t

Severity C blood

Confirm severity Supportive treatments

Prognostic factors Antidotes

Interest of analysis according to drug effects

Injury-inducing drugs

Functional drugs

Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues

Prerequisite availability of toxicological analysis

- Complexity and requirements of the assays

- Dialogue between biologists and clinicians

Importance of conservative plasma and urine sampling (initial and repetitive)

Expert opinion on appropriateness of disposal according to availability of drug screening

Fabbri A Emerg Med J 2003

Does a comprehensive drug screening add to decision making for poisonings in the ED

improve agreement on patient disposal Save potentially hospital resources

Meprobamate poisonings Is serum concentration useful to indicate the

mechanism of shock

Charron C Intensive Care Med 2005

Dose-dependent hypotension with narrowed QRS

- hypovolemia

- vasoplegia if concentrations le 150 mgl

- cardiogenic if concentrations gt 150 mgl

Plasma chloroquine concentration le 12 M No death

12-25 microM death rate 2

gt 25 microM death rate 22

gt 50 microM death rate 60

Chloroquine poisoning In-hospital prognosis assessment using

blood concentrations

Clemessy JL Crit Care Med 1996

TKTD using blood concentrations TKTD using plasma concentrations

Chloroquine poisoning blood vs plasma concentrations

0 25 50 75 100 125 15000

05

10

15

20

25

30

35

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 096

0 10 20 30 40 5000

05

10

15

20

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 091

0 1 2 3 4 5 6 7 8 900

05

10

15

20

Plasma chloroquine concentration (micromolL)

Ep

inep

hri

ne

infu

sio

n r

ate

(mg

h)

0 5 10 15 20 250

1

2

3

4

Plasma chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh)

R2 = 005

R2 = 017

Patient 1

Patient 2

PKPD population modeling in chloroquine poisonings

Meacutegarbane B Clin Tox2010

Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings

Relationship Between PlasmaFlecainide Concentration and

Outcome

Survivors Fatalities

0

1

2

3

4

5

6

7

8

9

10

Outcome of Acute Poisonings

Pla

sm

a F

lecain

ide

Co

ncen

trati

on

s (

mg

L)

Meacutegarbane B Clin Tox 2007

Meacutegarbane B BCPT 2010

Verapamil poisonings

Flecainide poisonings

Meacutegarbane B Clin Tox 2002 (abstract)

0

5

10

15

20

25P

red

icte

d c

on

cen

trati

on

s (n

gm

l)

0

10

0

20

0

30

0

40

0

Time since ingestion (hours)

Predicted concentration profiles

Non suvivors C(t) = 242 exp (-0003t)

Survivors C(t) = 177 exp (-0019t)

Cut-off C(t) = 207 exp (-0011t)

0

20

40

60

80

Co

lch

icin

e p

lasm

a c

on

cen

tra

tion

on

ad

mis

sio

n(n

gm

l)

Alive patients (N = 18)

Dead patients(N = 5)

Colchicine poisonings prognostic value of the time-course of serum concentrations

Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments

Q = body load of glycoside to neutralize

Estimation using ingested amount of digitalis

Estimation using serum glycoside concentration

Q = Weight

(kg)

volume of distribution

digoxin 56 lkg

digitoxin 056 lkg

Serum glycoside concentration

(ngml) x x

Q = x Ingested amount (mg) digoxin bioavailability (60 )

digitoxin bioavailability (100 ) or

One vial of digibind (40 mg) neutralizes 06 mg of digoxin

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

Macrocirculation level

- Measurement of blood pressure and cardiac index Microcirculation level

- Simple signs dizziness transitory consciousness loss and collapse skin discoloration or even chest pain

- More sophisticated signs requiring a close and repeated assessment of any change in the mental status low urine output and routine clinical chemistry (lactate creatinine and liver function tests)

Hemodynamic monitoring of cardiotoxicant poisonings

Poisonings with tricyclic antidepressants Value of serum concentrations

Boehnert MT N Engl J Med 1985

Prognostic value of serum theophylline concentration

Sessler CN Am J Med 1990

Why does the clinician need toxicological analysis to manage his

patient with cardiotoxicant poisoning

ProCon debate

- Positive diagnosis assessment to confirm a toxic hypothesis

- Differential diagnosis to exclude a toxic hypothesis

- Prognosis evaluation

- Help for treatment indications monitoring and re-evaluation

- Retrospective evaluation medico-legal issue or scientific studies

What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings

t

Severity C blood

t

Severity C blood

Confirm severity Supportive treatments

Prognostic factors Antidotes

Interest of analysis according to drug effects

Injury-inducing drugs

Functional drugs

Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues

Prerequisite availability of toxicological analysis

- Complexity and requirements of the assays

- Dialogue between biologists and clinicians

Importance of conservative plasma and urine sampling (initial and repetitive)

Expert opinion on appropriateness of disposal according to availability of drug screening

Fabbri A Emerg Med J 2003

Does a comprehensive drug screening add to decision making for poisonings in the ED

improve agreement on patient disposal Save potentially hospital resources

Meprobamate poisonings Is serum concentration useful to indicate the

mechanism of shock

Charron C Intensive Care Med 2005

Dose-dependent hypotension with narrowed QRS

- hypovolemia

- vasoplegia if concentrations le 150 mgl

- cardiogenic if concentrations gt 150 mgl

Plasma chloroquine concentration le 12 M No death

12-25 microM death rate 2

gt 25 microM death rate 22

gt 50 microM death rate 60

Chloroquine poisoning In-hospital prognosis assessment using

blood concentrations

Clemessy JL Crit Care Med 1996

TKTD using blood concentrations TKTD using plasma concentrations

Chloroquine poisoning blood vs plasma concentrations

0 25 50 75 100 125 15000

05

10

15

20

25

30

35

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 096

0 10 20 30 40 5000

05

10

15

20

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 091

0 1 2 3 4 5 6 7 8 900

05

10

15

20

Plasma chloroquine concentration (micromolL)

Ep

inep

hri

ne

infu

sio

n r

ate

(mg

h)

0 5 10 15 20 250

1

2

3

4

Plasma chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh)

R2 = 005

R2 = 017

Patient 1

Patient 2

PKPD population modeling in chloroquine poisonings

Meacutegarbane B Clin Tox2010

Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings

Relationship Between PlasmaFlecainide Concentration and

Outcome

Survivors Fatalities

0

1

2

3

4

5

6

7

8

9

10

Outcome of Acute Poisonings

Pla

sm

a F

lecain

ide

Co

ncen

trati

on

s (

mg

L)

Meacutegarbane B Clin Tox 2007

Meacutegarbane B BCPT 2010

Verapamil poisonings

Flecainide poisonings

Meacutegarbane B Clin Tox 2002 (abstract)

0

5

10

15

20

25P

red

icte

d c

on

cen

trati

on

s (n

gm

l)

0

10

0

20

0

30

0

40

0

Time since ingestion (hours)

Predicted concentration profiles

Non suvivors C(t) = 242 exp (-0003t)

Survivors C(t) = 177 exp (-0019t)

Cut-off C(t) = 207 exp (-0011t)

0

20

40

60

80

Co

lch

icin

e p

lasm

a c

on

cen

tra

tion

on

ad

mis

sio

n(n

gm

l)

Alive patients (N = 18)

Dead patients(N = 5)

Colchicine poisonings prognostic value of the time-course of serum concentrations

Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments

Q = body load of glycoside to neutralize

Estimation using ingested amount of digitalis

Estimation using serum glycoside concentration

Q = Weight

(kg)

volume of distribution

digoxin 56 lkg

digitoxin 056 lkg

Serum glycoside concentration

(ngml) x x

Q = x Ingested amount (mg) digoxin bioavailability (60 )

digitoxin bioavailability (100 ) or

One vial of digibind (40 mg) neutralizes 06 mg of digoxin

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

Poisonings with tricyclic antidepressants Value of serum concentrations

Boehnert MT N Engl J Med 1985

Prognostic value of serum theophylline concentration

Sessler CN Am J Med 1990

Why does the clinician need toxicological analysis to manage his

patient with cardiotoxicant poisoning

ProCon debate

- Positive diagnosis assessment to confirm a toxic hypothesis

- Differential diagnosis to exclude a toxic hypothesis

- Prognosis evaluation

- Help for treatment indications monitoring and re-evaluation

- Retrospective evaluation medico-legal issue or scientific studies

What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings

t

Severity C blood

t

Severity C blood

Confirm severity Supportive treatments

Prognostic factors Antidotes

Interest of analysis according to drug effects

Injury-inducing drugs

Functional drugs

Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues

Prerequisite availability of toxicological analysis

- Complexity and requirements of the assays

- Dialogue between biologists and clinicians

Importance of conservative plasma and urine sampling (initial and repetitive)

Expert opinion on appropriateness of disposal according to availability of drug screening

Fabbri A Emerg Med J 2003

Does a comprehensive drug screening add to decision making for poisonings in the ED

improve agreement on patient disposal Save potentially hospital resources

Meprobamate poisonings Is serum concentration useful to indicate the

mechanism of shock

Charron C Intensive Care Med 2005

Dose-dependent hypotension with narrowed QRS

- hypovolemia

- vasoplegia if concentrations le 150 mgl

- cardiogenic if concentrations gt 150 mgl

Plasma chloroquine concentration le 12 M No death

12-25 microM death rate 2

gt 25 microM death rate 22

gt 50 microM death rate 60

Chloroquine poisoning In-hospital prognosis assessment using

blood concentrations

Clemessy JL Crit Care Med 1996

TKTD using blood concentrations TKTD using plasma concentrations

Chloroquine poisoning blood vs plasma concentrations

0 25 50 75 100 125 15000

05

10

15

20

25

30

35

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 096

0 10 20 30 40 5000

05

10

15

20

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 091

0 1 2 3 4 5 6 7 8 900

05

10

15

20

Plasma chloroquine concentration (micromolL)

Ep

inep

hri

ne

infu

sio

n r

ate

(mg

h)

0 5 10 15 20 250

1

2

3

4

Plasma chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh)

R2 = 005

R2 = 017

Patient 1

Patient 2

PKPD population modeling in chloroquine poisonings

Meacutegarbane B Clin Tox2010

Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings

Relationship Between PlasmaFlecainide Concentration and

Outcome

Survivors Fatalities

0

1

2

3

4

5

6

7

8

9

10

Outcome of Acute Poisonings

Pla

sm

a F

lecain

ide

Co

ncen

trati

on

s (

mg

L)

Meacutegarbane B Clin Tox 2007

Meacutegarbane B BCPT 2010

Verapamil poisonings

Flecainide poisonings

Meacutegarbane B Clin Tox 2002 (abstract)

0

5

10

15

20

25P

red

icte

d c

on

cen

trati

on

s (n

gm

l)

0

10

0

20

0

30

0

40

0

Time since ingestion (hours)

Predicted concentration profiles

Non suvivors C(t) = 242 exp (-0003t)

Survivors C(t) = 177 exp (-0019t)

Cut-off C(t) = 207 exp (-0011t)

0

20

40

60

80

Co

lch

icin

e p

lasm

a c

on

cen

tra

tion

on

ad

mis

sio

n(n

gm

l)

Alive patients (N = 18)

Dead patients(N = 5)

Colchicine poisonings prognostic value of the time-course of serum concentrations

Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments

Q = body load of glycoside to neutralize

Estimation using ingested amount of digitalis

Estimation using serum glycoside concentration

Q = Weight

(kg)

volume of distribution

digoxin 56 lkg

digitoxin 056 lkg

Serum glycoside concentration

(ngml) x x

Q = x Ingested amount (mg) digoxin bioavailability (60 )

digitoxin bioavailability (100 ) or

One vial of digibind (40 mg) neutralizes 06 mg of digoxin

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

Prognostic value of serum theophylline concentration

Sessler CN Am J Med 1990

Why does the clinician need toxicological analysis to manage his

patient with cardiotoxicant poisoning

ProCon debate

- Positive diagnosis assessment to confirm a toxic hypothesis

- Differential diagnosis to exclude a toxic hypothesis

- Prognosis evaluation

- Help for treatment indications monitoring and re-evaluation

- Retrospective evaluation medico-legal issue or scientific studies

What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings

t

Severity C blood

t

Severity C blood

Confirm severity Supportive treatments

Prognostic factors Antidotes

Interest of analysis according to drug effects

Injury-inducing drugs

Functional drugs

Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues

Prerequisite availability of toxicological analysis

- Complexity and requirements of the assays

- Dialogue between biologists and clinicians

Importance of conservative plasma and urine sampling (initial and repetitive)

Expert opinion on appropriateness of disposal according to availability of drug screening

Fabbri A Emerg Med J 2003

Does a comprehensive drug screening add to decision making for poisonings in the ED

improve agreement on patient disposal Save potentially hospital resources

Meprobamate poisonings Is serum concentration useful to indicate the

mechanism of shock

Charron C Intensive Care Med 2005

Dose-dependent hypotension with narrowed QRS

- hypovolemia

- vasoplegia if concentrations le 150 mgl

- cardiogenic if concentrations gt 150 mgl

Plasma chloroquine concentration le 12 M No death

12-25 microM death rate 2

gt 25 microM death rate 22

gt 50 microM death rate 60

Chloroquine poisoning In-hospital prognosis assessment using

blood concentrations

Clemessy JL Crit Care Med 1996

TKTD using blood concentrations TKTD using plasma concentrations

Chloroquine poisoning blood vs plasma concentrations

0 25 50 75 100 125 15000

05

10

15

20

25

30

35

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 096

0 10 20 30 40 5000

05

10

15

20

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 091

0 1 2 3 4 5 6 7 8 900

05

10

15

20

Plasma chloroquine concentration (micromolL)

Ep

inep

hri

ne

infu

sio

n r

ate

(mg

h)

0 5 10 15 20 250

1

2

3

4

Plasma chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh)

R2 = 005

R2 = 017

Patient 1

Patient 2

PKPD population modeling in chloroquine poisonings

Meacutegarbane B Clin Tox2010

Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings

Relationship Between PlasmaFlecainide Concentration and

Outcome

Survivors Fatalities

0

1

2

3

4

5

6

7

8

9

10

Outcome of Acute Poisonings

Pla

sm

a F

lecain

ide

Co

ncen

trati

on

s (

mg

L)

Meacutegarbane B Clin Tox 2007

Meacutegarbane B BCPT 2010

Verapamil poisonings

Flecainide poisonings

Meacutegarbane B Clin Tox 2002 (abstract)

0

5

10

15

20

25P

red

icte

d c

on

cen

trati

on

s (n

gm

l)

0

10

0

20

0

30

0

40

0

Time since ingestion (hours)

Predicted concentration profiles

Non suvivors C(t) = 242 exp (-0003t)

Survivors C(t) = 177 exp (-0019t)

Cut-off C(t) = 207 exp (-0011t)

0

20

40

60

80

Co

lch

icin

e p

lasm

a c

on

cen

tra

tion

on

ad

mis

sio

n(n

gm

l)

Alive patients (N = 18)

Dead patients(N = 5)

Colchicine poisonings prognostic value of the time-course of serum concentrations

Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments

Q = body load of glycoside to neutralize

Estimation using ingested amount of digitalis

Estimation using serum glycoside concentration

Q = Weight

(kg)

volume of distribution

digoxin 56 lkg

digitoxin 056 lkg

Serum glycoside concentration

(ngml) x x

Q = x Ingested amount (mg) digoxin bioavailability (60 )

digitoxin bioavailability (100 ) or

One vial of digibind (40 mg) neutralizes 06 mg of digoxin

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

Why does the clinician need toxicological analysis to manage his

patient with cardiotoxicant poisoning

ProCon debate

- Positive diagnosis assessment to confirm a toxic hypothesis

- Differential diagnosis to exclude a toxic hypothesis

- Prognosis evaluation

- Help for treatment indications monitoring and re-evaluation

- Retrospective evaluation medico-legal issue or scientific studies

What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings

t

Severity C blood

t

Severity C blood

Confirm severity Supportive treatments

Prognostic factors Antidotes

Interest of analysis according to drug effects

Injury-inducing drugs

Functional drugs

Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues

Prerequisite availability of toxicological analysis

- Complexity and requirements of the assays

- Dialogue between biologists and clinicians

Importance of conservative plasma and urine sampling (initial and repetitive)

Expert opinion on appropriateness of disposal according to availability of drug screening

Fabbri A Emerg Med J 2003

Does a comprehensive drug screening add to decision making for poisonings in the ED

improve agreement on patient disposal Save potentially hospital resources

Meprobamate poisonings Is serum concentration useful to indicate the

mechanism of shock

Charron C Intensive Care Med 2005

Dose-dependent hypotension with narrowed QRS

- hypovolemia

- vasoplegia if concentrations le 150 mgl

- cardiogenic if concentrations gt 150 mgl

Plasma chloroquine concentration le 12 M No death

12-25 microM death rate 2

gt 25 microM death rate 22

gt 50 microM death rate 60

Chloroquine poisoning In-hospital prognosis assessment using

blood concentrations

Clemessy JL Crit Care Med 1996

TKTD using blood concentrations TKTD using plasma concentrations

Chloroquine poisoning blood vs plasma concentrations

0 25 50 75 100 125 15000

05

10

15

20

25

30

35

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 096

0 10 20 30 40 5000

05

10

15

20

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 091

0 1 2 3 4 5 6 7 8 900

05

10

15

20

Plasma chloroquine concentration (micromolL)

Ep

inep

hri

ne

infu

sio

n r

ate

(mg

h)

0 5 10 15 20 250

1

2

3

4

Plasma chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh)

R2 = 005

R2 = 017

Patient 1

Patient 2

PKPD population modeling in chloroquine poisonings

Meacutegarbane B Clin Tox2010

Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings

Relationship Between PlasmaFlecainide Concentration and

Outcome

Survivors Fatalities

0

1

2

3

4

5

6

7

8

9

10

Outcome of Acute Poisonings

Pla

sm

a F

lecain

ide

Co

ncen

trati

on

s (

mg

L)

Meacutegarbane B Clin Tox 2007

Meacutegarbane B BCPT 2010

Verapamil poisonings

Flecainide poisonings

Meacutegarbane B Clin Tox 2002 (abstract)

0

5

10

15

20

25P

red

icte

d c

on

cen

trati

on

s (n

gm

l)

0

10

0

20

0

30

0

40

0

Time since ingestion (hours)

Predicted concentration profiles

Non suvivors C(t) = 242 exp (-0003t)

Survivors C(t) = 177 exp (-0019t)

Cut-off C(t) = 207 exp (-0011t)

0

20

40

60

80

Co

lch

icin

e p

lasm

a c

on

cen

tra

tion

on

ad

mis

sio

n(n

gm

l)

Alive patients (N = 18)

Dead patients(N = 5)

Colchicine poisonings prognostic value of the time-course of serum concentrations

Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments

Q = body load of glycoside to neutralize

Estimation using ingested amount of digitalis

Estimation using serum glycoside concentration

Q = Weight

(kg)

volume of distribution

digoxin 56 lkg

digitoxin 056 lkg

Serum glycoside concentration

(ngml) x x

Q = x Ingested amount (mg) digoxin bioavailability (60 )

digitoxin bioavailability (100 ) or

One vial of digibind (40 mg) neutralizes 06 mg of digoxin

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

- Positive diagnosis assessment to confirm a toxic hypothesis

- Differential diagnosis to exclude a toxic hypothesis

- Prognosis evaluation

- Help for treatment indications monitoring and re-evaluation

- Retrospective evaluation medico-legal issue or scientific studies

What does the clinician expect from the toxicological analysis for the management of cardiotoxicant poisonings

t

Severity C blood

t

Severity C blood

Confirm severity Supportive treatments

Prognostic factors Antidotes

Interest of analysis according to drug effects

Injury-inducing drugs

Functional drugs

Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues

Prerequisite availability of toxicological analysis

- Complexity and requirements of the assays

- Dialogue between biologists and clinicians

Importance of conservative plasma and urine sampling (initial and repetitive)

Expert opinion on appropriateness of disposal according to availability of drug screening

Fabbri A Emerg Med J 2003

Does a comprehensive drug screening add to decision making for poisonings in the ED

improve agreement on patient disposal Save potentially hospital resources

Meprobamate poisonings Is serum concentration useful to indicate the

mechanism of shock

Charron C Intensive Care Med 2005

Dose-dependent hypotension with narrowed QRS

- hypovolemia

- vasoplegia if concentrations le 150 mgl

- cardiogenic if concentrations gt 150 mgl

Plasma chloroquine concentration le 12 M No death

12-25 microM death rate 2

gt 25 microM death rate 22

gt 50 microM death rate 60

Chloroquine poisoning In-hospital prognosis assessment using

blood concentrations

Clemessy JL Crit Care Med 1996

TKTD using blood concentrations TKTD using plasma concentrations

Chloroquine poisoning blood vs plasma concentrations

0 25 50 75 100 125 15000

05

10

15

20

25

30

35

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 096

0 10 20 30 40 5000

05

10

15

20

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 091

0 1 2 3 4 5 6 7 8 900

05

10

15

20

Plasma chloroquine concentration (micromolL)

Ep

inep

hri

ne

infu

sio

n r

ate

(mg

h)

0 5 10 15 20 250

1

2

3

4

Plasma chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh)

R2 = 005

R2 = 017

Patient 1

Patient 2

PKPD population modeling in chloroquine poisonings

Meacutegarbane B Clin Tox2010

Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings

Relationship Between PlasmaFlecainide Concentration and

Outcome

Survivors Fatalities

0

1

2

3

4

5

6

7

8

9

10

Outcome of Acute Poisonings

Pla

sm

a F

lecain

ide

Co

ncen

trati

on

s (

mg

L)

Meacutegarbane B Clin Tox 2007

Meacutegarbane B BCPT 2010

Verapamil poisonings

Flecainide poisonings

Meacutegarbane B Clin Tox 2002 (abstract)

0

5

10

15

20

25P

red

icte

d c

on

cen

trati

on

s (n

gm

l)

0

10

0

20

0

30

0

40

0

Time since ingestion (hours)

Predicted concentration profiles

Non suvivors C(t) = 242 exp (-0003t)

Survivors C(t) = 177 exp (-0019t)

Cut-off C(t) = 207 exp (-0011t)

0

20

40

60

80

Co

lch

icin

e p

lasm

a c

on

cen

tra

tion

on

ad

mis

sio

n(n

gm

l)

Alive patients (N = 18)

Dead patients(N = 5)

Colchicine poisonings prognostic value of the time-course of serum concentrations

Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments

Q = body load of glycoside to neutralize

Estimation using ingested amount of digitalis

Estimation using serum glycoside concentration

Q = Weight

(kg)

volume of distribution

digoxin 56 lkg

digitoxin 056 lkg

Serum glycoside concentration

(ngml) x x

Q = x Ingested amount (mg) digoxin bioavailability (60 )

digitoxin bioavailability (100 ) or

One vial of digibind (40 mg) neutralizes 06 mg of digoxin

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

t

Severity C blood

t

Severity C blood

Confirm severity Supportive treatments

Prognostic factors Antidotes

Interest of analysis according to drug effects

Injury-inducing drugs

Functional drugs

Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues

Prerequisite availability of toxicological analysis

- Complexity and requirements of the assays

- Dialogue between biologists and clinicians

Importance of conservative plasma and urine sampling (initial and repetitive)

Expert opinion on appropriateness of disposal according to availability of drug screening

Fabbri A Emerg Med J 2003

Does a comprehensive drug screening add to decision making for poisonings in the ED

improve agreement on patient disposal Save potentially hospital resources

Meprobamate poisonings Is serum concentration useful to indicate the

mechanism of shock

Charron C Intensive Care Med 2005

Dose-dependent hypotension with narrowed QRS

- hypovolemia

- vasoplegia if concentrations le 150 mgl

- cardiogenic if concentrations gt 150 mgl

Plasma chloroquine concentration le 12 M No death

12-25 microM death rate 2

gt 25 microM death rate 22

gt 50 microM death rate 60

Chloroquine poisoning In-hospital prognosis assessment using

blood concentrations

Clemessy JL Crit Care Med 1996

TKTD using blood concentrations TKTD using plasma concentrations

Chloroquine poisoning blood vs plasma concentrations

0 25 50 75 100 125 15000

05

10

15

20

25

30

35

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 096

0 10 20 30 40 5000

05

10

15

20

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 091

0 1 2 3 4 5 6 7 8 900

05

10

15

20

Plasma chloroquine concentration (micromolL)

Ep

inep

hri

ne

infu

sio

n r

ate

(mg

h)

0 5 10 15 20 250

1

2

3

4

Plasma chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh)

R2 = 005

R2 = 017

Patient 1

Patient 2

PKPD population modeling in chloroquine poisonings

Meacutegarbane B Clin Tox2010

Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings

Relationship Between PlasmaFlecainide Concentration and

Outcome

Survivors Fatalities

0

1

2

3

4

5

6

7

8

9

10

Outcome of Acute Poisonings

Pla

sm

a F

lecain

ide

Co

ncen

trati

on

s (

mg

L)

Meacutegarbane B Clin Tox 2007

Meacutegarbane B BCPT 2010

Verapamil poisonings

Flecainide poisonings

Meacutegarbane B Clin Tox 2002 (abstract)

0

5

10

15

20

25P

red

icte

d c

on

cen

trati

on

s (n

gm

l)

0

10

0

20

0

30

0

40

0

Time since ingestion (hours)

Predicted concentration profiles

Non suvivors C(t) = 242 exp (-0003t)

Survivors C(t) = 177 exp (-0019t)

Cut-off C(t) = 207 exp (-0011t)

0

20

40

60

80

Co

lch

icin

e p

lasm

a c

on

cen

tra

tion

on

ad

mis

sio

n(n

gm

l)

Alive patients (N = 18)

Dead patients(N = 5)

Colchicine poisonings prognostic value of the time-course of serum concentrations

Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments

Q = body load of glycoside to neutralize

Estimation using ingested amount of digitalis

Estimation using serum glycoside concentration

Q = Weight

(kg)

volume of distribution

digoxin 56 lkg

digitoxin 056 lkg

Serum glycoside concentration

(ngml) x x

Q = x Ingested amount (mg) digoxin bioavailability (60 )

digitoxin bioavailability (100 ) or

One vial of digibind (40 mg) neutralizes 06 mg of digoxin

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

Level 1 30-60 min Useful for emergent decisions hospitalICU admission or discharge diagnosis treatment indications Level 2 4-24 h Useful for initial diagnosis correction and treatment adaptation Level 3 1-several days Useful for the definitive diagnosis or medico-legal issues

Prerequisite availability of toxicological analysis

- Complexity and requirements of the assays

- Dialogue between biologists and clinicians

Importance of conservative plasma and urine sampling (initial and repetitive)

Expert opinion on appropriateness of disposal according to availability of drug screening

Fabbri A Emerg Med J 2003

Does a comprehensive drug screening add to decision making for poisonings in the ED

improve agreement on patient disposal Save potentially hospital resources

Meprobamate poisonings Is serum concentration useful to indicate the

mechanism of shock

Charron C Intensive Care Med 2005

Dose-dependent hypotension with narrowed QRS

- hypovolemia

- vasoplegia if concentrations le 150 mgl

- cardiogenic if concentrations gt 150 mgl

Plasma chloroquine concentration le 12 M No death

12-25 microM death rate 2

gt 25 microM death rate 22

gt 50 microM death rate 60

Chloroquine poisoning In-hospital prognosis assessment using

blood concentrations

Clemessy JL Crit Care Med 1996

TKTD using blood concentrations TKTD using plasma concentrations

Chloroquine poisoning blood vs plasma concentrations

0 25 50 75 100 125 15000

05

10

15

20

25

30

35

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 096

0 10 20 30 40 5000

05

10

15

20

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 091

0 1 2 3 4 5 6 7 8 900

05

10

15

20

Plasma chloroquine concentration (micromolL)

Ep

inep

hri

ne

infu

sio

n r

ate

(mg

h)

0 5 10 15 20 250

1

2

3

4

Plasma chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh)

R2 = 005

R2 = 017

Patient 1

Patient 2

PKPD population modeling in chloroquine poisonings

Meacutegarbane B Clin Tox2010

Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings

Relationship Between PlasmaFlecainide Concentration and

Outcome

Survivors Fatalities

0

1

2

3

4

5

6

7

8

9

10

Outcome of Acute Poisonings

Pla

sm

a F

lecain

ide

Co

ncen

trati

on

s (

mg

L)

Meacutegarbane B Clin Tox 2007

Meacutegarbane B BCPT 2010

Verapamil poisonings

Flecainide poisonings

Meacutegarbane B Clin Tox 2002 (abstract)

0

5

10

15

20

25P

red

icte

d c

on

cen

trati

on

s (n

gm

l)

0

10

0

20

0

30

0

40

0

Time since ingestion (hours)

Predicted concentration profiles

Non suvivors C(t) = 242 exp (-0003t)

Survivors C(t) = 177 exp (-0019t)

Cut-off C(t) = 207 exp (-0011t)

0

20

40

60

80

Co

lch

icin

e p

lasm

a c

on

cen

tra

tion

on

ad

mis

sio

n(n

gm

l)

Alive patients (N = 18)

Dead patients(N = 5)

Colchicine poisonings prognostic value of the time-course of serum concentrations

Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments

Q = body load of glycoside to neutralize

Estimation using ingested amount of digitalis

Estimation using serum glycoside concentration

Q = Weight

(kg)

volume of distribution

digoxin 56 lkg

digitoxin 056 lkg

Serum glycoside concentration

(ngml) x x

Q = x Ingested amount (mg) digoxin bioavailability (60 )

digitoxin bioavailability (100 ) or

One vial of digibind (40 mg) neutralizes 06 mg of digoxin

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

Expert opinion on appropriateness of disposal according to availability of drug screening

Fabbri A Emerg Med J 2003

Does a comprehensive drug screening add to decision making for poisonings in the ED

improve agreement on patient disposal Save potentially hospital resources

Meprobamate poisonings Is serum concentration useful to indicate the

mechanism of shock

Charron C Intensive Care Med 2005

Dose-dependent hypotension with narrowed QRS

- hypovolemia

- vasoplegia if concentrations le 150 mgl

- cardiogenic if concentrations gt 150 mgl

Plasma chloroquine concentration le 12 M No death

12-25 microM death rate 2

gt 25 microM death rate 22

gt 50 microM death rate 60

Chloroquine poisoning In-hospital prognosis assessment using

blood concentrations

Clemessy JL Crit Care Med 1996

TKTD using blood concentrations TKTD using plasma concentrations

Chloroquine poisoning blood vs plasma concentrations

0 25 50 75 100 125 15000

05

10

15

20

25

30

35

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 096

0 10 20 30 40 5000

05

10

15

20

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 091

0 1 2 3 4 5 6 7 8 900

05

10

15

20

Plasma chloroquine concentration (micromolL)

Ep

inep

hri

ne

infu

sio

n r

ate

(mg

h)

0 5 10 15 20 250

1

2

3

4

Plasma chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh)

R2 = 005

R2 = 017

Patient 1

Patient 2

PKPD population modeling in chloroquine poisonings

Meacutegarbane B Clin Tox2010

Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings

Relationship Between PlasmaFlecainide Concentration and

Outcome

Survivors Fatalities

0

1

2

3

4

5

6

7

8

9

10

Outcome of Acute Poisonings

Pla

sm

a F

lecain

ide

Co

ncen

trati

on

s (

mg

L)

Meacutegarbane B Clin Tox 2007

Meacutegarbane B BCPT 2010

Verapamil poisonings

Flecainide poisonings

Meacutegarbane B Clin Tox 2002 (abstract)

0

5

10

15

20

25P

red

icte

d c

on

cen

trati

on

s (n

gm

l)

0

10

0

20

0

30

0

40

0

Time since ingestion (hours)

Predicted concentration profiles

Non suvivors C(t) = 242 exp (-0003t)

Survivors C(t) = 177 exp (-0019t)

Cut-off C(t) = 207 exp (-0011t)

0

20

40

60

80

Co

lch

icin

e p

lasm

a c

on

cen

tra

tion

on

ad

mis

sio

n(n

gm

l)

Alive patients (N = 18)

Dead patients(N = 5)

Colchicine poisonings prognostic value of the time-course of serum concentrations

Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments

Q = body load of glycoside to neutralize

Estimation using ingested amount of digitalis

Estimation using serum glycoside concentration

Q = Weight

(kg)

volume of distribution

digoxin 56 lkg

digitoxin 056 lkg

Serum glycoside concentration

(ngml) x x

Q = x Ingested amount (mg) digoxin bioavailability (60 )

digitoxin bioavailability (100 ) or

One vial of digibind (40 mg) neutralizes 06 mg of digoxin

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

Meprobamate poisonings Is serum concentration useful to indicate the

mechanism of shock

Charron C Intensive Care Med 2005

Dose-dependent hypotension with narrowed QRS

- hypovolemia

- vasoplegia if concentrations le 150 mgl

- cardiogenic if concentrations gt 150 mgl

Plasma chloroquine concentration le 12 M No death

12-25 microM death rate 2

gt 25 microM death rate 22

gt 50 microM death rate 60

Chloroquine poisoning In-hospital prognosis assessment using

blood concentrations

Clemessy JL Crit Care Med 1996

TKTD using blood concentrations TKTD using plasma concentrations

Chloroquine poisoning blood vs plasma concentrations

0 25 50 75 100 125 15000

05

10

15

20

25

30

35

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 096

0 10 20 30 40 5000

05

10

15

20

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 091

0 1 2 3 4 5 6 7 8 900

05

10

15

20

Plasma chloroquine concentration (micromolL)

Ep

inep

hri

ne

infu

sio

n r

ate

(mg

h)

0 5 10 15 20 250

1

2

3

4

Plasma chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh)

R2 = 005

R2 = 017

Patient 1

Patient 2

PKPD population modeling in chloroquine poisonings

Meacutegarbane B Clin Tox2010

Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings

Relationship Between PlasmaFlecainide Concentration and

Outcome

Survivors Fatalities

0

1

2

3

4

5

6

7

8

9

10

Outcome of Acute Poisonings

Pla

sm

a F

lecain

ide

Co

ncen

trati

on

s (

mg

L)

Meacutegarbane B Clin Tox 2007

Meacutegarbane B BCPT 2010

Verapamil poisonings

Flecainide poisonings

Meacutegarbane B Clin Tox 2002 (abstract)

0

5

10

15

20

25P

red

icte

d c

on

cen

trati

on

s (n

gm

l)

0

10

0

20

0

30

0

40

0

Time since ingestion (hours)

Predicted concentration profiles

Non suvivors C(t) = 242 exp (-0003t)

Survivors C(t) = 177 exp (-0019t)

Cut-off C(t) = 207 exp (-0011t)

0

20

40

60

80

Co

lch

icin

e p

lasm

a c

on

cen

tra

tion

on

ad

mis

sio

n(n

gm

l)

Alive patients (N = 18)

Dead patients(N = 5)

Colchicine poisonings prognostic value of the time-course of serum concentrations

Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments

Q = body load of glycoside to neutralize

Estimation using ingested amount of digitalis

Estimation using serum glycoside concentration

Q = Weight

(kg)

volume of distribution

digoxin 56 lkg

digitoxin 056 lkg

Serum glycoside concentration

(ngml) x x

Q = x Ingested amount (mg) digoxin bioavailability (60 )

digitoxin bioavailability (100 ) or

One vial of digibind (40 mg) neutralizes 06 mg of digoxin

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

Plasma chloroquine concentration le 12 M No death

12-25 microM death rate 2

gt 25 microM death rate 22

gt 50 microM death rate 60

Chloroquine poisoning In-hospital prognosis assessment using

blood concentrations

Clemessy JL Crit Care Med 1996

TKTD using blood concentrations TKTD using plasma concentrations

Chloroquine poisoning blood vs plasma concentrations

0 25 50 75 100 125 15000

05

10

15

20

25

30

35

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 096

0 10 20 30 40 5000

05

10

15

20

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 091

0 1 2 3 4 5 6 7 8 900

05

10

15

20

Plasma chloroquine concentration (micromolL)

Ep

inep

hri

ne

infu

sio

n r

ate

(mg

h)

0 5 10 15 20 250

1

2

3

4

Plasma chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh)

R2 = 005

R2 = 017

Patient 1

Patient 2

PKPD population modeling in chloroquine poisonings

Meacutegarbane B Clin Tox2010

Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings

Relationship Between PlasmaFlecainide Concentration and

Outcome

Survivors Fatalities

0

1

2

3

4

5

6

7

8

9

10

Outcome of Acute Poisonings

Pla

sm

a F

lecain

ide

Co

ncen

trati

on

s (

mg

L)

Meacutegarbane B Clin Tox 2007

Meacutegarbane B BCPT 2010

Verapamil poisonings

Flecainide poisonings

Meacutegarbane B Clin Tox 2002 (abstract)

0

5

10

15

20

25P

red

icte

d c

on

cen

trati

on

s (n

gm

l)

0

10

0

20

0

30

0

40

0

Time since ingestion (hours)

Predicted concentration profiles

Non suvivors C(t) = 242 exp (-0003t)

Survivors C(t) = 177 exp (-0019t)

Cut-off C(t) = 207 exp (-0011t)

0

20

40

60

80

Co

lch

icin

e p

lasm

a c

on

cen

tra

tion

on

ad

mis

sio

n(n

gm

l)

Alive patients (N = 18)

Dead patients(N = 5)

Colchicine poisonings prognostic value of the time-course of serum concentrations

Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments

Q = body load of glycoside to neutralize

Estimation using ingested amount of digitalis

Estimation using serum glycoside concentration

Q = Weight

(kg)

volume of distribution

digoxin 56 lkg

digitoxin 056 lkg

Serum glycoside concentration

(ngml) x x

Q = x Ingested amount (mg) digoxin bioavailability (60 )

digitoxin bioavailability (100 ) or

One vial of digibind (40 mg) neutralizes 06 mg of digoxin

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

TKTD using blood concentrations TKTD using plasma concentrations

Chloroquine poisoning blood vs plasma concentrations

0 25 50 75 100 125 15000

05

10

15

20

25

30

35

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 096

0 10 20 30 40 5000

05

10

15

20

Blood chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh) R2 = 091

0 1 2 3 4 5 6 7 8 900

05

10

15

20

Plasma chloroquine concentration (micromolL)

Ep

inep

hri

ne

infu

sio

n r

ate

(mg

h)

0 5 10 15 20 250

1

2

3

4

Plasma chloroquine concentration (micromolL)

Epi

neph

rine

infu

sion

rat

e (m

gh)

R2 = 005

R2 = 017

Patient 1

Patient 2

PKPD population modeling in chloroquine poisonings

Meacutegarbane B Clin Tox2010

Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings

Relationship Between PlasmaFlecainide Concentration and

Outcome

Survivors Fatalities

0

1

2

3

4

5

6

7

8

9

10

Outcome of Acute Poisonings

Pla

sm

a F

lecain

ide

Co

ncen

trati

on

s (

mg

L)

Meacutegarbane B Clin Tox 2007

Meacutegarbane B BCPT 2010

Verapamil poisonings

Flecainide poisonings

Meacutegarbane B Clin Tox 2002 (abstract)

0

5

10

15

20

25P

red

icte

d c

on

cen

trati

on

s (n

gm

l)

0

10

0

20

0

30

0

40

0

Time since ingestion (hours)

Predicted concentration profiles

Non suvivors C(t) = 242 exp (-0003t)

Survivors C(t) = 177 exp (-0019t)

Cut-off C(t) = 207 exp (-0011t)

0

20

40

60

80

Co

lch

icin

e p

lasm

a c

on

cen

tra

tion

on

ad

mis

sio

n(n

gm

l)

Alive patients (N = 18)

Dead patients(N = 5)

Colchicine poisonings prognostic value of the time-course of serum concentrations

Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments

Q = body load of glycoside to neutralize

Estimation using ingested amount of digitalis

Estimation using serum glycoside concentration

Q = Weight

(kg)

volume of distribution

digoxin 56 lkg

digitoxin 056 lkg

Serum glycoside concentration

(ngml) x x

Q = x Ingested amount (mg) digoxin bioavailability (60 )

digitoxin bioavailability (100 ) or

One vial of digibind (40 mg) neutralizes 06 mg of digoxin

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

PKPD population modeling in chloroquine poisonings

Meacutegarbane B Clin Tox2010

Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings

Relationship Between PlasmaFlecainide Concentration and

Outcome

Survivors Fatalities

0

1

2

3

4

5

6

7

8

9

10

Outcome of Acute Poisonings

Pla

sm

a F

lecain

ide

Co

ncen

trati

on

s (

mg

L)

Meacutegarbane B Clin Tox 2007

Meacutegarbane B BCPT 2010

Verapamil poisonings

Flecainide poisonings

Meacutegarbane B Clin Tox 2002 (abstract)

0

5

10

15

20

25P

red

icte

d c

on

cen

trati

on

s (n

gm

l)

0

10

0

20

0

30

0

40

0

Time since ingestion (hours)

Predicted concentration profiles

Non suvivors C(t) = 242 exp (-0003t)

Survivors C(t) = 177 exp (-0019t)

Cut-off C(t) = 207 exp (-0011t)

0

20

40

60

80

Co

lch

icin

e p

lasm

a c

on

cen

tra

tion

on

ad

mis

sio

n(n

gm

l)

Alive patients (N = 18)

Dead patients(N = 5)

Colchicine poisonings prognostic value of the time-course of serum concentrations

Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments

Q = body load of glycoside to neutralize

Estimation using ingested amount of digitalis

Estimation using serum glycoside concentration

Q = Weight

(kg)

volume of distribution

digoxin 56 lkg

digitoxin 056 lkg

Serum glycoside concentration

(ngml) x x

Q = x Ingested amount (mg) digoxin bioavailability (60 )

digitoxin bioavailability (100 ) or

One vial of digibind (40 mg) neutralizes 06 mg of digoxin

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

Prognostic value of plasma flecainide and verapamil concentrations in acute poisonings

Relationship Between PlasmaFlecainide Concentration and

Outcome

Survivors Fatalities

0

1

2

3

4

5

6

7

8

9

10

Outcome of Acute Poisonings

Pla

sm

a F

lecain

ide

Co

ncen

trati

on

s (

mg

L)

Meacutegarbane B Clin Tox 2007

Meacutegarbane B BCPT 2010

Verapamil poisonings

Flecainide poisonings

Meacutegarbane B Clin Tox 2002 (abstract)

0

5

10

15

20

25P

red

icte

d c

on

cen

trati

on

s (n

gm

l)

0

10

0

20

0

30

0

40

0

Time since ingestion (hours)

Predicted concentration profiles

Non suvivors C(t) = 242 exp (-0003t)

Survivors C(t) = 177 exp (-0019t)

Cut-off C(t) = 207 exp (-0011t)

0

20

40

60

80

Co

lch

icin

e p

lasm

a c

on

cen

tra

tion

on

ad

mis

sio

n(n

gm

l)

Alive patients (N = 18)

Dead patients(N = 5)

Colchicine poisonings prognostic value of the time-course of serum concentrations

Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments

Q = body load of glycoside to neutralize

Estimation using ingested amount of digitalis

Estimation using serum glycoside concentration

Q = Weight

(kg)

volume of distribution

digoxin 56 lkg

digitoxin 056 lkg

Serum glycoside concentration

(ngml) x x

Q = x Ingested amount (mg) digoxin bioavailability (60 )

digitoxin bioavailability (100 ) or

One vial of digibind (40 mg) neutralizes 06 mg of digoxin

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

Meacutegarbane B Clin Tox 2002 (abstract)

0

5

10

15

20

25P

red

icte

d c

on

cen

trati

on

s (n

gm

l)

0

10

0

20

0

30

0

40

0

Time since ingestion (hours)

Predicted concentration profiles

Non suvivors C(t) = 242 exp (-0003t)

Survivors C(t) = 177 exp (-0019t)

Cut-off C(t) = 207 exp (-0011t)

0

20

40

60

80

Co

lch

icin

e p

lasm

a c

on

cen

tra

tion

on

ad

mis

sio

n(n

gm

l)

Alive patients (N = 18)

Dead patients(N = 5)

Colchicine poisonings prognostic value of the time-course of serum concentrations

Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments

Q = body load of glycoside to neutralize

Estimation using ingested amount of digitalis

Estimation using serum glycoside concentration

Q = Weight

(kg)

volume of distribution

digoxin 56 lkg

digitoxin 056 lkg

Serum glycoside concentration

(ngml) x x

Q = x Ingested amount (mg) digoxin bioavailability (60 )

digitoxin bioavailability (100 ) or

One vial of digibind (40 mg) neutralizes 06 mg of digoxin

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

Estimation of body load of cardioglycoside to neutralize using anti-digoxin Fab fragments

Q = body load of glycoside to neutralize

Estimation using ingested amount of digitalis

Estimation using serum glycoside concentration

Q = Weight

(kg)

volume of distribution

digoxin 56 lkg

digitoxin 056 lkg

Serum glycoside concentration

(ngml) x x

Q = x Ingested amount (mg) digoxin bioavailability (60 )

digitoxin bioavailability (100 ) or

One vial of digibind (40 mg) neutralizes 06 mg of digoxin

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

Poor prognosticators

- Male

- Age over 55 years

- Underlying heart disease

- Atrioventricular block

- Bradycardia with HR lt 60 min despite atropine infusion (1 mg)

- Hyperkalemia gt 45 mmol L

Indication amp dosage regimen of Fab fragments

Half-molar neutralization for prophylactic treatment

bull Ventricular arrhythmia VF or VT

bull Bradycardia with HR le 40 min despite atropine infusion (1 mg)

bull Hyperkalemia gt 5 mmol L

bull Cardiogenic shock

bull Mesenteric infacrtion

Life-threatening conditions

Molar neutralization for curative treatment

Lapostolle F Crit Care Med 2009

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

050075100125150

00

25

50

75

100 Patient 2

Flecainide concentration (mgl)

Do

bu

tam

ine i

nfu

sio

n(micro

gk

gm

in)

Meacutegarbane B Clin Tox 2005 (abstract)

Assessment of catecholamine limitations in cardiotoxicant poisonings

Dobutamine infusion Epinephrine infusion

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

Baud FJ NEJM 1995

Assessment of efficacy and mechanism of action of immunotoxicotherapy in colchicine poisoning

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

French D Clin Tox 2011

French D Clin Tox 2011

Assessment of usefulness of lipid rescue in cardiotoxicant poisonings

Time-course of PD parameters

Time-course of PK

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

Pichon N Ann Emerg Med 2011 Time-course of PK

Time-course of PD parameters

Assessment of MARS usefulness in diltiazem and verapamil poisonings with

refractory vasoplegic shock

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

Toxicokinetics in severe poisonings requiring ECLS

- T12 30 h (pharmacology 4 h) - Vd 151 lkg - Clearance 262 lh

Meacutegarbane B Intensive Care Med 2006

Concentration on admission 224 μmoll Peak concentration 338 μmoll at 101 h Prolonged absorption despite MDAC T12 226 h (pharmacology 12-20 h)

Propafenone poisoning Carbamazepine poisoning

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

Level of interindividual variability and potential drug-drug interactions

Drug-drug PK interactions

AbsorptionExcretion (Membrane transporters)

Gene polymorphism

Metabolism (CYP450)

Pharmacodynamic effects (Recepteurs)

Elimination Renal function

Drug-drug PD interaction

Distribution (Plasma transporters)

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

E0 0

Emax 078 microgkgmin

EC50 239 micromoll

Hill coefficient 179

R2 099

Meacutegarbane B Intensive Care Med 2006

Cardiac toxicity in venlafaxine poisoning CYP 2D6-related individual vulnerability

Hypothesis Slow CYP 2D6 metabolizer

Normal range 025-085 micromoll

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

Elkalioubie A Eur J Clin Pharmacol 2011

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

- Ultrarapid metabolizer phenotype suggested by tramadolM1 metabolic ratio

- Heterozygous for duplicated wt allele predictive of CYP2D6 ultrarapid

metabolizer phenotype

+ Ketoconazole at inhibitory concentration of CYP3ACYPB6 (200 ngml)

Tramadol

O-desmethyltramadol (M1)

N-desmethyltramadol (M2)

CYP2D6 CYP2B6CYP3A4

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy

Conclusions

bull Poisonings with cardiotoxicants (especially with digitalis sodium-channel and calcium channel blockers) may lead to life-threatening symptoms and death

bull Adequate monitoring of clinical severity and assessment of prognostic criteria are mandatory to improve patient management

bull To date emergent decisions are exclusively based on clinical and biochemical parameters If rapidly available and adequately performed toxicological analysis may improve prognosis assessment and further management

bull Toxicological analysis remains mandatory for the definitive diagnosis (medico-legal issues) as well as for understanding mechanisms of toxicity patientrsquos vulnerability and treatment efficacy