The Combination of Vasopressin and Corticosteroids

in Septic Shock: Cutting the mustard or a lemon in disguise?

Emily Gordon, Pharm.D.

PGY2 Critical Care Pharmacy Resident

University Health System, San Antonio, Texas

Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy

Pharmacotherapy Education and Research Center,

University of Texas Health Science Center at San Antonio

September 12, 2014

Learning Objectives

1. Discuss the impact of septic shock on critically ill patients and current use of catecholamines for

hemodynamic support.

2. Based on the current Surviving Sepsis Campaign guidelines, explain when the addition of vasopressin

and/or corticosteroids is recommended in the management of septic shock.

3. Describe the potential interaction between vasopressin and corticosteroids in patients with septic

shock.

4. Evaluate the use of vasopressin and corticosteroids as combination therapy in patients with septic

shock.

I. What is sepsis?1,2

a. Suspected or documented infection with systemic manifestations

i. Patient must meet

1. Temperature

2. Heart rate >

3. Respiratory rate >

4. White blood cell (WBC) count >

b. Can progress to severe sepsis and septic shock

Figure 1. Progression of sepsis

II. Severe sepsis and septic shock

a. Affects millions of people each year

b. Major health concern

i. Multi-organ dysfunction

ii. Major cause of mortality in intensive care unit (ICU) patients

1. Third most common cause of death in the U

neoplasm5

2. Mortality rates have decrease

3. Incidence of i

a. Mortality rate

i. Comorbidities

iii. Estimated annual U.S. healthcare system cost

III. Pathophysiologic changes5

a. Diffuse endothelial injury

i. Increased endothelial permeability due to shedding of the endothelial glycocalyx and

development of microvascular

ii. Leads to tissue and organ edema, hypotension, and shock

b. Vasoplegic shock

i. Distributive shock due to failure of vascular smooth muscle

ii. Leads to arterial and venodilatation

1. Decreases venous return

c. Myocardial depression

Sepsis

Suspected or documented infection with systemic manifestations (Figure 1)

Patient must meet ≥ 2 of systemic inflammatory response syndrome (SIRS) criteria

Temperature > 38°C or < 36°C

90 beats per minute

Respiratory rate > 20 per minute

White blood cell (WBC) count > 12,000/mm3, < 4,000/mm3, or >

Can progress to severe sepsis and septic shock

Progression of sepsis2

s and septic shock1,3,4

Affects millions of people each year

dysfunction

cause of mortality in intensive care unit (ICU) patients

Third most common cause of death in the U.S. after heart disease and malignant

Mortality rates have decreased steadily over last quarter century

Incidence of in-hospital mortality up to 50%4,5

Mortality rates vary depending on patient-specific factors

Comorbidities, infecting pathogen, site of infection, o

Estimated annual U.S. healthcare system cost of $24.3 billion7

Diffuse endothelial injury and altered microvascular flow

endothelial permeability due to shedding of the endothelial glycocalyx and

microvascular leak

tissue and organ edema, hypotension, and shock

Distributive shock due to failure of vascular smooth muscle constriction

Leads to arterial and venodilatation

venous return and compounds intravascular volume deficit

E. Gordon | 2

)

c inflammatory response syndrome (SIRS) criteria

, or > 10% bands

after heart disease and malignant

steadily over last quarter century6

specific factors

, organ dysfunction

endothelial permeability due to shedding of the endothelial glycocalyx and

constriction

ompounds intravascular volume deficit

E. Gordon | 3

Initial Management of Severe Sepsis

I. Focus on early management3,5

a. Speed and appropriateness of therapy likely influence outcomes

b. Early, aggressive administration of intravenous (IV) fluids, antibiotics, and vasoactive agents

II. Initial resuscitation1,3

a. Sepsis-induced tissue hypoperfusion

i. Hypotension persisting after initial fluid challenge

ii. Blood lactate concentration ≥ 4 mmol/L

b. Early goal-directed therapy3,8

i. Goals during the first 6 hours of resuscitation

1. Central venous pressure (CVP) 8-12 mm Hg

2. Mean arterial pressure (MAP) ≥ 65 mm Hg

3. Urine output ≥ 0.5 mL/kg/hr

4. Superior vena cava oxygenation saturation (ScvO2) ≥ 70% or mixed venous oxygen

saturation (SvO2) ≥ 65%

c. Normalization of elevated serum lactate (≤ 4 mmol/L)

III. Fluid therapy1

a. Adequate fluid resuscitation is a fundamental aspect of hemodynamic support

b. Crystalloids

i. Initial fluid of choice for resuscitation

ii. Fluid challenge should be administered to patients with sepsis-induced tissue

hypoperfusion

1. Minimum of 30 mL/kg of crystalloids

c. Colloids

i. May be considered in patients refractory to crystalloids

ii. Theoretical benefits over crystalloids

1. Antioxidant and anti-inflammatory effects

2. Ability to stabilize the endothelial glycocalyx

iii. No proven mortality difference in septic shock when compared to crystalloids9,10

IV. Antimicrobial therapy1

a. Cultures should be obtained prior to initiation of antimicrobial therapy

b. Effective IV antimicrobials within the first hour of severe sepsis and septic shock recognition

i. Each hour delay in antibiotic administration associated with measurable increase in

mortality (Figure 2)11

Figure 2. Survival impact of effective antimicrobial initiation following onset of septic shock

11

E. Gordon | 4

c. Initial empiric antimicrobial therapy

i. Should include ≥ 1 medication with activity against all likely pathogens and provide

adequate tissue penetration

ii. De-escalation should be performed as soon as susceptibility profile is known

d. Imaging studies to confirm potential source of infection

e. Source control, if possible, should be performed as rapidly as possible within the first 12 hours

after diagnosis

Role of Vasopressors

I. Vasopressor agents1

a. Used to target an initial MAP of ≥ 65 mm Hg

i. Goal to maintain perfusion during life-threatening hypotension

1. When MAP falls below autoregulatory threshold of critical vascular beds, organ

blood flow decreases linearly5

a. MAP < 60 mm Hg will likely result in ischemia of brain, heart, and kidney

ii. Optimal MAP should be individualized12

1. Higher MAP goals may be required in patients with atherosclerosis or chronic

hypertension

b. MAP endpoints should be supplemented with other markers of perfusion

i. Serum lactate concentrations, mental status, urine output, skin perfusion

c. Ideally, fluid resuscitation should be achieved before vasopressors and inotropes utilized

II. Vasopressor activity (Table 1)

Table 1. Vasopressor Receptor Activity13,14

α1 β1 β2 DA V1

Epinephrine +++ +++ ++

Norepinephrine +++ ++

Dopamine > 10a 5-10a < 5a

Phenylephrine ++++

Vasopressin +++ aApproximate affects based on dopamine dose in mcg/kg/min

DA=dopamine; V1=vasopressin-1 receptor

III. Choosing a vasopressor1,14

a. Dopamine (DA) versus norepinephrine (NE)

i. 2012 meta-analysis15

1. DA use associated with increased risk of death and development of arrhythmias as

compared with NE in patients with septic shock

b. Norepinephrine

i. First choice vasopressor

ii. α1-vasoconstrictive effects increase MAP with little change in heart rate or stroke volume

c. Dopamine

i. Alternative agent to NE only in select patients

1. Indicated in absolute or relative bradycardia

ii. Increases MAP and cardiac output

d. Epinephrine

i. Added or substituted for NE when additional agent needed to maintain adequate organ

perfusion

ii. Increases aerobic lactate production: stimulation of β2 receptors on skeletal muscles

e. Phenylephrine

i. Pure α-adrenergic effects

ii. Not recommended for the t

1. Decreases stroke volume

iii. May be used in select circumstance

1. Patients with serious arrhythmias associated with

2. High cardiac output with persistently low blood pressure

3. Salvage therapy when combined inotrope,

have failed to maintain MAP

IV. Vasopressin1,16,17

a. Used as adjunctive therapy to NE

i. Increase MAP

ii. Decrease catecholamine requirement

b. Physiology of endogenous

i. Vasopressin is releas

1. Release stimulated by hypotension

ii. Vasopressin acts on a variety of receptors

1. At vasopressin concentrations

vasopressin predominate

2. Little effect on arterial pressure

Table 2. Vasopressin Receptors

Receptor

V1

V2

V3

c. Physiology of vasopressin in septic shock

i. Acts as a stress hormone during hypotension

1. Vasopressin levels increase to maintain blood pressure via vasoconstriction

predominate V

2. Minimal antidiuretic effects in shock

Figure 3. Physiology of vasopressin

adrenergic effects: least likely to produce arrhythmias

Not recommended for the treatment of septic shock

stroke volume, cardiac output, renal and splanchnic blood flow

May be used in select circumstances

atients with serious arrhythmias associated with NE

High cardiac output with persistently low blood pressure

therapy when combined inotrope, vasopressor, and vasopressin

have failed to maintain MAP

Used as adjunctive therapy to NE

Decrease catecholamine requirement

endogenous vasopressin

Vasopressin is released into systemic circulation from posterior pituitary gland

Release stimulated by hypotension, hypovolemia, and hypernatremia

Vasopressin acts on a variety of receptors16 (Table 2)

vasopressin concentrations < 10 pg/mL, antidiuretic actions (V

vasopressin predominate

Little effect on arterial pressure (V1 receptor) at physiologic concentrations

. Vasopressin Receptors16

Primary Location

Vascular smooth muscle

Renal collecting duct

Pituitary and hippocampus

Physiology of vasopressin in septic shock17 (Figure 3)

Acts as a stress hormone during hypotension

Vasopressin levels increase to maintain blood pressure via vasoconstriction

predominate V1 receptor activity

Minimal antidiuretic effects in shock

Physiology of vasopressin17

E. Gordon | 5

, cardiac output, renal and splanchnic blood flow

, and vasopressin therapy

ed into systemic circulation from posterior pituitary gland

and hypernatremia

(V2 receptor) of

physiologic concentrations

Vasopressin levels increase to maintain blood pressure via vasoconstriction due to

E. Gordon | 6

d. Relative vasopressin deficiency in septic shock16

i. Endogenous vasopressin concentrations (Table 3)

1. Elevated early in septic shock

2. Decrease to normal ranges within 24 to 48 hours

a. Initially due to depletion of vasopressin stores in posterior pituitary

b. Vasopressin levels remain inappropriately low suggesting a sustained

impairment of vasopressin synthesis and release

i. Down-regulation of vasopressin production by excessive nitric oxide

release in posterior pituitary

3. Exogenous vasopressin infusion used to restore vasopressin concentrations

Table 3. Serum Vasopressin Concentrations (pg/mL)17

Normotensive adult < 4

Cardiogenic shock > 20

Severe hypotensive hemorrhage 100-1000

Septic shock 1-3

Vasopressin infusion 0.01-0.04 units/min 25-100

e. Exogenous vasopressin administration1

i. Fixed-dose continuous infusion up to 0.04 units/min

f. Level of evidence supporting vasopressin use

i. Ungraded recommendation in Surviving Sepsis Campaign guidelines1

ii. The Vasopressin and Septic Shock Trial (VASST)18

1. Randomized controlled trial of vasopressin versus NE

2. Performed to address uncertainties regarding vasopressin in septic shock

3. Stratified patients by center and severity of septic shock as determined by NE

infusion rate the hour before study inclusion

a. Less severe septic shock: NE 5 to 14 mcg/min

b. More severe septic shock: NE ≥ 15 mcg/min

4. No significant difference between vasopressin-treated and NE-treated groups in

primary outcome of 28-day mortality

5. Secondary outcome evaluating effect of vasopressin in more severe septic shock

versus less severe septic shock

a. Less severe septic shock: vasopressin group had decreased 90-day mortality

i. Suggests that addition of vasopressin may be more beneficial when

initiated early in septic shock prior to escalation of catecholamines

6. Similar serious adverse event rates between groups

g. Benefit of vasopressin over catecholamines16,17,23

i. Function preserved in acidosis

ii. Corrects relative vasopressin deficiency

iii. Vasopressin-induced vasoconstriction spares cerebral, coronary, pulmonary, and afferent

glomerular capillary circulations

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Corticosteroid Controversy

I. Endogenous stress response primarily mediated by hypothalamic-pituitary-adrenal (HPA) axis and

sympathoadrenal system5

a. Activation of HPA axis causes increased secretion of corticotropin-releasing hormone (CRH) and

arginine vasopressin

b. Ultimately leads to increased production and release of cortisol

II. Critical illness-related corticosteroid insufficiency (CIRCI)19

a. Leads to exaggerated and protracted proinflammatory response

b. Caused by:

i. Inadequate cellular glucocorticoid activity

ii. Adrenal suppression and/or glucocorticoid tissue resistance

c. Clinical manifestation: hypotension refractory to fluid and vasopressor administration

d. Low-dose hydrocortisone (HC) supplementation (HC 25-200 mg/day) may be beneficial

i. Restore balance to altered HPA axis

ii. Increase adrenergic responsiveness

iii. Preserve endothelial glycocalyx

III. Replacement of corticosteroids (CCS) during septic shock

a. Effect of CCS on mortality in patients with septic shock20

i. Placebo-controlled, randomized, double-blind trial

ii. Designed to assess whether replacement therapy with HC and fludrocortisone (FC) could

improve 28-day survival in septic shock patients

iii. Regimens

1. CCS group: HC 50 mg IV every six hours, plus FC 50 mcg enteral daily

2. Placebo

iv. Primary outcome (Figure 4)

1. 28-day survival in non-responders to short corticotropin test

a. Cortisol samples drawn immediately before and at 30 and 60 minutes after

short corticotropin test

b. Non-responders defined as cortisol response < 9 mcg/dL between lowest and

highest concentration

*Non-responders to short corticotropin stimulation test

CI=confidence interval; FC=fludrocortisone; HC=hydrocortisone; OR=odds ratio

Figure 4. 28-day survival in non-responders to short corticotropin test20

*

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v. Secondary outcomes

1. 28-day survival in responders to corticotropin test: no significant difference

2. 28-day survival in all patients: no significant difference

3. 28-day, ICU, hospital, and 1-year mortality rates

a. Non-responders: 28-day, ICU, and hospital mortality significantly lower in

patients who received CCS

b. Responders: no significant difference

4. Time to vasopressor therapy withdrawal

a. Non-responders: significantly shorter in CCS group (7 vs. 10 days; p=0.001)

b. Responders: no significant difference

c. All patients: significantly shorter in CCS group (7 vs. 9 days; p=0.01)

vi. Take-home points

1. In non-responders, CCS therapy significantly reduced

a. 28-day, ICU, and hospital mortality (number needed to treat= 7)

b. Time to vasopressor withdrawal

2. Responders: no significant effect of CCS

3. All patients

a. No significant difference in mortality rates

b. CCS group had significantly shorter time to vasopressor withdrawal

4. No significant differences in adverse events

5. Overall mortality rate much lower (64%) than that expected (95%)

6. Frequency of non-responders higher than expected (actual 77%, expected 40%)

b. Corticosteroid Therapy of Septic Shock (CORTICUS) study21

i. Multicenter, randomized, double-blind, placebo-controlled study (Figure 5)

ii. Evaluated efficacy and safety of HC therapy in septic shock patients

*Corticotropin results unknown for 8 patients in HC group and 4 patients in placebo group

HC=hydrocortisone; non-responder=serum cortisol response of < 9 mg/dL after cosyntropin 250 mcg IV bolus

Figure 5. Enrollment of patients in CORTICUS study21

iii. Regimens

1. HC 50 mg IV every 6 hours for 5 days, then 50 mg IV every 12 hours on days 6-10,

then 50 mg IV daily on days 9-11

2. Placebo

iv. Primary endpoint: 28-day mortality in non-responders to corticotropin test

1. No significant difference between study groups

E. Gordon | 9

v. Secondary endpoints

1. Reversal of organ system failure

a. Time until shock reversal

i. Significantly shorter in patients who received HC (p<0.001)

1. 3.3 days HC group vs. 5.8 days placebo group

ii. Significantly shorter in responders to corticotropin test (p<0.001)

iii. No difference in time to shock reversal in non-responders (p=0.06)

2. No significant difference:

a. 28-day mortality in responders or in all patients

b. ICU, hospital, and 1-year mortality

c. ICU and hospital length of stay

vi. Safety was assessed by measuring adverse events

vii. Etomidate use

1. 60.4% (58/96) of patients who received etomidate prior to study enrollment did not

have a response to corticotropin compared to 43.4% (175/403) of patients who did

not receive etomidate (p=0.004)

viii. Take-home points

1. HC use had no significant effect on 28-day mortality, regardless of response to

corticotropin

2. Patients in HC group had decreased time to shock reversal, regardless of

corticotropin response

3. Increase incidence of new onset septic shock, hyperglycemia, and hypernatremia in

HC group

4. Sample size of 800 patients was not achieved to have statistical power

c. Comparison of Annane et al. and CORTICUS studies evaluating CCS use in septic shock (Table 4)

Table 4. Comparison of Annane et al. and CORTICUS Studies20,21

Annane et al.20

CORTICUS Study21

Mean SAPS II score 57-60 49-50

Overall mortality 63% 32%

CCS regimen HC + FC HC only

Administration of CCS Within 8 hours Within 72 hours

CCS discontinuation Abrupt Tapered

Adverse events No difference CCS > placebo

CCS=corticosteroid; FC=fludrocortisone; HC=hydrocortisone; SAPS II=Simplified Acute Physiology Score II (Appendix A)

IV. Time-dependent initiation of CCS has not been taken into consideration

a. Non-randomized prospective longitudinal study22

i. First study to investigate the importance of time frame between development of septic

shock and CCS initiation

ii. Enrollment (Table 5)

Table 5. 170 Total Enrolled Patients22

Initiation Group Quartiles Time frame between start of

vasopressor and start of HC Number of patients

Early

(46 patients) 1st 1-9 hours 46

Late

(124 patients)

2nd 10-24 hours 46

3rd 25-72 hours 39

4th >72 hours 39

E. Gordon | 10

iii. Primary endpoint: effect of HC time delay after start of vasopressors on final outcome

1. Proportion of survivors significantly greater in early initiation group (52.2% vs.

30.6%; p=0.012; OR, 0.40 [95% CI, 0.20-0.81]) (Figure 6a)

2. Univariate analysis determined that only APACHE II score (Appendix A), SOFA score

(Appendix A), and the delayed start of HC were linked with unfavorable outcomes

a. Early initiation of HC in patients with APACHE II score ≥ 19 increased survival

rate from 19.8% to 41.2% (p=0.021)

b. Early initiation of HC in patients with APACHE II score < 19 increased survival

rate from 55% to 83.3%

3. Mean time to withdrawal of vasopressor was 4 days in early initiation versus 15 days

for late initiation group (p<0.0001) (Figure 6b)

a) b)

Figure 6. a) Impact of early initiation of HC on final outcome; b) Impact of early initiation of HC on total time on

vasopressors 22

iv. Secondary endpoint: effect of HC time delay on cytokine stimulation in vitro (34 patients [9

from early initiation group, 25 from late initiation group])

1. Cytokine stimulation in vitro was lower in early initiation group

v. Take-home points

1. Early initiation group:

a. Survival significantly prolonged

b. Vasopressor withdrawal occurred sooner

c. Cytokine response decreased in vitro

2. Evaluated small sample of patients with severe septic shock

3. No comparison to a control group not receiving steroid therapy

4. Adverse event rates not reported

IV. Adverse events associated with CCS19

a. Dependent on dose, dosing strategy, and duration of therapy

b. Concerns with short-term CCS therapy

i. Increased risk infection

ii. Hyperglycemia

iii. Hypernatremia

iv. Others: myopathy, impaired wound healing, metabolic acidosis, psychosis, HPA axis and

glucocorticoid receptor suppression

E. Gordon | 11

Interaction of Vasopressin and Corticosteroids

I. Interaction of the HPA axis and the hypothalamic-posterior pituitary-vasopressin axis (Figure 7)16,19,23

a. Arginine vasopressin and CRH stimulate different signaling systems leading to synergistic effects

on release of adrenocorticotropic hormone (ACTH)

b. Vasopressin interacts with the HPA axis in response to hypotension or other stressors

i. Stimulation of anterior pituitary V3 receptors by vasopressin increases release of ACTH

1. ACTH levels are increased even in levels of stress when CCS levels are elevated

2. This effect is resistant to CCS negative feedback

ACTH=adrenocorticotropic hormone; CRH=corticotropin-releasing hormone

Figure 7. Interaction of vasopressin and HPA axis16

II. Interaction of exogenously administered vasopressin and CCS is not clearly understood, particularly in

the setting of septic shock16,20,21

III. A significant clinical interaction? (Table 6)

Table 6. Interaction Between Vasopressin and Corticosteroids16,23,24

Significant interaction No significant interaction

• Vasopressin may ↑ adrenal GC

production directly and through ↑ ACTH

• In presence of cortisol, NE inhibits

antidiuretic effect of vasopressin in

kidney

• CCS may restore hemodynamic

responsiveness to vasopressin

• CCS have been reported to ↑

vasopressin mRNA

• CCS do not change vasopressin levels

• CCS may delay vasopressin release

• CCS may ↓ vasopressin gene expression

ACTH=adrenocorticotripic hormone; CCS=corticosteroid; GC=glucocorticoid; NE=norepinephrine

E. Gordon | 12

42 patients included

21 patients in CCS arm

HC 50 mg IV q6h + FC 50 mcg PO daily

21 patients in control arm

Did not receive CCS

Patients matched based on:

• Primary ICU service

• APS component of APACHE II score

• # of vasopressors at initiation of vasopressin

• SBP ≤ 90 mm Hg or MAP ≤ 70 mm Hg within 1 hour before start of vasopressin

• Positive fluid balance

• Mechanical ventilation

• At least 2 SIRS criteria

• Positive culture or strong clinical suspicion of infection with the initiation of

antimicrobials

621 patients receiving vasopressin

579 patients excluded

-Vasopressin < 1 hr

-Vasopressin initiated in OR

-CCS for < 5 days

-CCS started after vasopressin stopped

-Study drug indication other than septic shock

-CI or preexisting disease indication for CCS

Inclusion Criteria

IV. Literature Review

a. Effect of CCS on vasopressin-containing regimens for septic shock25

i. Retrospective case-control study

ii. To clinically evaluate the effects of CCS on time to vasopressin withdrawal and mortality in

septic shock patients

iii. Patient population (Figure 8)

APS= Acute Physiology Score; APACHE II= Acute Physiology and Chronic Health Evaluation II (Appendix A);

CCS=corticosteroids; CI=contraindications; FC=fludrocortisone; HC=hydrocortisone; ICU=intensive care unit;

MAP=mean arterial pressure; PO=enteral; q6h=every six hours; SBP=systolic blood pressure; SIRS=systemic

inflammatory response syndrome

Figure 8. Patient population25

• Sex

• Age

E. Gordon | 13

1. Baseline characteristics

Table 7. Patient Baseline Characteristics25

CCS Control P value

CRRT during vasopressin 38% 4.8% 0.02

Non-responder to corticotropin stimulation test 95% 66% 0.02

Vasopressin for initial hemodynamic support 48% 57% 0.54

Vasopressin monotherapy 29% 48% 0.54 CCS=corticosteroids; CRRT=continuous renal replacement therapy; non-responder=change in serum cortisol ≤ 9

mcg/dL after 250 mcg cosyntropin test

iv. Outcomes (Figure 9)

1. Primary outcome: effect of CCS on time to withdrawal of vasopressin

2. Secondary outcomes

a. Proportion of patients alive without vasopressors at day 7

b. 28-day, ICU, hospital mortality

CCS=corticosteroid; ICU=intensive care unit

Figure 9. Study outcomes25

v. Take-home points

1. First study to clinically evaluate the effect of CCS on vasopressin

2. Significantly more patients in CCS group were alive without vasopressor support at 7

days

3. ICU, 28-day, and hospital mortality numerically lower in CCS group

4. Small sample size may have led to study being underpowered

5. Vasopressin used as the initial hemodynamic support agent in about 50% of all

patients and remained only hemodynamic agent for 38% of patients

6. Median time from vasopressor to CCS initiation was 22.2 hours

b. Post hoc analysis of VASST trial18,24

i. To investigate the interaction of vasopressin and CCS treatment in septic shock

1. Post hoc analysis of multicenter, blinded, randomized controlled trial

2. VASST patients (N=779) received NE or NE plus vasopressin

3. Vasopressor infusions were titrated to goal MAP of 65 to 75 mm Hg

a. If not achieved with study medications, open-label vasopressors were added

4. Assignment to CCS treatment not randomized nor blinded

E. Gordon | 14

ii. Patient population (Figure 10)

CCS=corticosteroids; NE=norepinephrine; VASST=The Vasopressin and Septic Shock Trial

Figure 10. Patient population in VASST trial who received corticosteroids18,24

iii. Outcomes

1. Primary outcome: 28-day mortality (Figure 11)

a. Vasopressin and CCS treatment were associated with lower 28-day mortality

compared to NE and CCS treatment (35.9% vs. 44.7%, p=0.03)

b. In patients not treated with CCS, vasopressin was associated with a trend

toward increased mortality (33.7% vs. 21.3%, p=0.06)

AVP=arginine vasopressin; CCS=corticosteroids; NE=norepinephrine

Figure 11. Probability of 28-day survival in corticosteroid versus no corticosteroid treated patients24

779 patients

included in

VASST trial

190 patients did

not receive CCS

589 patients

treated with CCS

296 patients

received

vasopressin + CCS

293 patients

received

NE + CCS

NE + AVP + CCS

NE + CCS

NE alone

NE + AVP

E. Gordon | 15

2. Secondary outcomes

a. 90-day mortality

i. Lower in vasopressin plus CCS group (45.2% vs. 55.5%, p=0.01)

b. Days alive and free from organ dysfunction over first 28 days

i. Trend towards more days free from any organ dysfunction in

vasopressin group (p=0.08)

3. Adverse events

a. Similar in two treatment groups

b. Significantly higher rate of cardiac arrests in NE patients treated with CCS

compared to vasopressin patients treated with CCS (2.4% vs. 0.3%, p=0.04)

4. Plasma vasopressin levels

a. Vasopressin and CCS patients had significantly higher plasma vasopressin

concentrations at 6 hours (p=0.006) and 24 hours (p=0.025)

b. NE and CCS patients’ plasma vasopressin levels were extremely low and were

not altered by CCS

iv. Take-home points

1. First trial to investigate the interaction of vasopressin and CCS on mortality and

organ dysfunction

2. Vasopressin plus CCS associated with lower 28-day mortality compared to

NE plus CCS

3. Patients treated with vasopressin who did not receive CCS had an increased

mortality compared with patients who received NE and no CCS

4. Due to CCS treatment being at the discretion of treating physician, this group had

increased severity of illness compared to those who did not receive CCS

a. In survival analysis, vasopressin was compared to NE within each CCS

subgroup rather than comparing to no CCS group

5. In patients who received vasopressin, CCS increased vasopressin levels by 67%

at 24 hours

6. Did not address the mechanism of potential benefit from vasopressin plus CCS

versus NE plus CCS

E. Gordon | 16

c. Pilot randomized controlled trial26

i. Open-label, randomized, placebo-controlled, parallel-group trial

ii. To investigate if there is an interaction between vasopressin and CCS and feasibility of

vasopressin as initial vasopressor therapy in septic shock

iii. Patient population and interventions (Figure 12)

ACS=acute coronary syndrome; ESRD=end-stage renal disease; HC=hydrocortisone; Vaso=vasopressin

Figure 12. Patient population and interventions26

1. CCS regimen

a. Once vasopressin rate of 0.06 units/min reached, patients started on HC 50 mg

or placebo IV every 6 hours for 5 days, every 12 hours for 3 days, then once

daily for 3 days

b. 5 patients given rescue CCS for treatment of life-threatening hypotension and

considered crossovers

2. Open-label vasopressors

a. Could be started if patient hypotensive after first dose of HC or placebo

3. Plasma vasopressin samples

a. Collected once max vasopressin infusion reached (T0), 6-12 hours (T1), and 24-

36 hours (T2) after the first dose of HC/placebo

Interaction analysis

Clinical outcome analysis

Eligible for HC

N=23

Eligible for

placebo

N=27

Vaso + HC

N=31

Vaso + placebo

N=30

269 patients excluded:

-Chronic steroid therapy

-ESRD, ACS, mesenteric ischemia, or

adrenal dysfunction

-Pregnancy

-Previous vasopressor infusion >6 hrs

-Physician decision

-Treatment limitations

330 patients screened

Patients randomized

N=61

MAP goal 65-75 mm Hg

Vasopressin initiated and titrated

(MAX: 0.06 units/min)

E. Gordon | 17

iv. Baseline characteristics

1. Vasopressin used as initial vasopressor in 18 (30%) patients

2. 43 (70%) patients received another agent as initial vasopressor in the emergency

setting to stabilize the patient

a. NE most commonly used

b. Median time to starting trial vasopressin was < 4 hours

v. Outcomes

1. Primary outcome (interaction analysis)

a. No difference in plasma vasopressin concentrations between groups

2. Secondary outcome (clinical outcome analysis)

a. Difference in vasopressin requirements

i. Patients in HC group received 3.1 day (95% CI, 1.1-5.1 days; p=0.001)

shorter duration of vasopressin infusion than placebo group (Figure 13a)

Figure 13a. Duration of vasopressin infusion

26 Figure 13b. Total dose of vasopressin

26

ii. HC patients used half the total dose (ratio, 0.47; 95% CI, 0.32-0.71;

p=0.001) of vasopressin compared to placebo group (Figure 13b)

iii. Duration of additional NE infusion was 2 days shorter in HC group (95%

CI, -7 to 0 days; p=0.015)

b. No difference in 28-day, ICU, or hospital mortality, organ failure-free days, or

onset of new organ failure

3. 6 HC patients versus 2 placebo patients never received any NE

vi. Adverse events: 14 reported

1. 4 defined as serious adverse events, one possibly related to study drugs

2. 5 minor adverse events possibly related to study medications

a. 3 cool/mottled peripheries, 1 elevated serum lactate, 1 elevated troponin

vii. Take-home points

1. First randomized controlled trial evaluating the impact of vasopressin and CCS

combination therapy in septic shock

2. Small sample size has limited power to detect differences in clinical outcomes

3. Vasopressin intended for initial vasopressor for hemodynamic support

a. Does not follow recommendations from 2012 Surviving Sepsis Campaign

guidelines

b. Only 30% of patients received vasopressin for initial hemodynamic support

4. Patients who received combination vasopressin and CCS had a significantly shorter

duration of vasopressin infusion and

5. Vasopressin 0.06

Surviving Sepsis Campaign guidelines

I. Future studies

a. Adjunctive CCS treatment in critically ill patients with septic shock (ADRENAL)

i. Randomized, double

ICU with septic shock given HC versus placebo will have improved 90

(http://clinicaltrials.gov/ct2/show/NCT01448109

b. Vasopressin versus NE as initial thera

i. Randomized, double

is more effective in reducing kidney dysfunction compared to NE

interaction between vasopressin and CCS in septic

trials.com/ISRCTN20769191

I. Summary

a. The clinical interaction between vasopressin and CCS in septic shock is poorly understood

b. Limited number of studies investigating clinical

vasopressin and CCS combination therapy

c. Outcomes in available trials

the treatment of septic shock

i. Decreased vasopressor requirements

ii. Decreased time to vasopressor withdrawal

iii. Decreased mortality

iv. Limited adverse events seen with combination of vasopressin and

II. Recommendations (Figure 14)

CCS=corticosteroids; MAP=mean arterial pressure; NE=norepinephrine

Figure 14. Recommendations

Patients who received combination vasopressin and CCS had a significantly shorter

duration of vasopressin infusion and decreased total dose requirement

asopressin 0.06 units/min maximum dose is higher than that recommended in the

Surviving Sepsis Campaign guidelines

Future Directions

treatment in critically ill patients with septic shock (ADRENAL)

double-blind, placebo-controlled trial to determine if patients admitted to

ICU with septic shock given HC versus placebo will have improved 90-

http://clinicaltrials.gov/ct2/show/NCT01448109)

Vasopressin versus NE as initial therapy in septic shock (VANISH)

double-blind, controlled trial to investigate if initial therapy with vasopressin

is more effective in reducing kidney dysfunction compared to NE and if

interaction between vasopressin and CCS in septic shock (http://www.controlled

trials.com/ISRCTN20769191)

Conclusion

interaction between vasopressin and CCS in septic shock is poorly understood

number of studies investigating clinical outcomes of septic shock patients treated with

vasopressin and CCS combination therapy

trials suggest a benefit with the combination of vasopressin and

the treatment of septic shock

Decreased vasopressor requirements

d time to vasopressor withdrawal

Decreased mortality

adverse events seen with combination of vasopressin and CCS

CCS=corticosteroids; MAP=mean arterial pressure; NE=norepinephrine

E. Gordon | 18

Patients who received combination vasopressin and CCS had a significantly shorter

requirement

is higher than that recommended in the

treatment in critically ill patients with septic shock (ADRENAL)

o determine if patients admitted to

-day survival

o investigate if initial therapy with vasopressin

and if there is any

http://www.controlled-

interaction between vasopressin and CCS in septic shock is poorly understood

outcomes of septic shock patients treated with

a benefit with the combination of vasopressin and CCS for

CCS

E. Gordon | 19

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Appendix

Appendix A. Severity of Illness Scores

Acute Physiology and

Chronic Health Evaluation

(APACHE) II Score27

• Severity of disease classification system determined from the worst

physiologic value during the initial 24 hours after ICU admission

• Consists of 3 components

o Acute physiology score (APS) points (0 to 48 points)

� Sum of 12 individual points: temperature, MAP, heart rate,

respiratory rate, oxygenation, arterial pH, serum sodium, serum

potassium, serum creatinine, hematocrit, WBC, GCS

o Age points (0 to 6 points)

o Chronic health points (2 or 5 points)

• Score interpretation (Score range 0 to 71 points)

Simplified Acute Physiology

Score (SAPS II)28

• Severity score and mortality estimation tool calculated from the worst

physiologic variables within the first 24 hours of ICU admission

• Consists of 12 physiologic variables and 3 disease-related variables

• Score Interpretation (Score range 0 to 163 points)

Sepsis-related Organ

Failure Assessment (SOFA)

Score29

• Morbidity severity score and mortality estimation tool calculated from

worst physiological variable collected serially every 24 hours of a

patient’s ICU admission

o Focused more on organ dysfunction and morbidity

• Consists of 6 variables, each representing an organ system

o Each organ system assigned a point value from 0 (normal) to 4 (high

degree of dysfunction)

• Score Interpretation (Score range 0 to 24 points)

SOFA Score Mortality

0 to 6 < 10%

7 to 9 15-20%

10 to 12 40-50%

13 to 14 50-60%

15 > 80%

15 to 24 > 90%