Pediatric and Neonatal Critical Care Neurology€¦ · Critical Care Neurology in Neonates and...

Pediatric and Neonatal Critical Care Neurology

Child Neurology MGH CME CourseOctober 2015

Patricia L Musolino MD, PhDCritical Care and Vascular Neurology

I have no financial disclosures

Critical Care Neurology in Neonates and Children

® Acute insults to the brain can be group into the same categories in Newborns, young children and teenagers

® Presentations and symptoms differs depending the stage of development of the brain and associated co morbidities ® myelination, established vs developing networks, synaptic plasticity,

susceptibility to metabolic disturbances)® A systems-symptoms based diagnostic approach can be used

at all ages® Therapeutic approach differs greatly depending on

® Nature of the Disorders® Age® Duration of symptoms® Degree of systemic diseases associated with neurological injury® Parents/family level of understanding ® Expected degree of neurological sequela

Disease Categories

® Brain Perfusion Disorders® Increase Intracranial Pressure ® Infections: encephalitis, meningitis, abscess ® Metabolic-Genetic Encephalopathies: MELAS, Inborn

Errors of Metabolism® Epilepsy-Status Epilepticus® Malignancies ® Traumatic Brain Injury

Pediatric Neurocritical Care® More children are surviving critical illness

® Overall PICU mortality decreased from 11% to 4.8% between 1982 and 2005

® Increased incidence of moderate to severe disability following ICU admission (8.4% in 1982 to 17.9% in 2005–2006 (p < .001)

® Brain injury is the most common proximate cause of death in the Pediatric ICU (mortality 65.4%)

TemporalCascadeofEventsà Post-anoxia

Lo. Nat Rev Neurosci. 2003;4:399

MolecularPathwaysofCellDeath• Excitotoxicity

and ionic imbalance

• Oxidative and nitrosative stress

• Apoptotic mechanisms

• Necrosis

Neuroprotection-SandwichModel

Glutamate

Mitochondria

Proteolysis

Oxidative Stress

ER Stress

Inflammation

Surv

ival

Dea

th

GlutamateMitochondriaProteolysis

Oxidative StressER Stress

Inflammation

Pediatric Code Blue

in the ED

Preventing Secondary Insults changes Outcome

McHugh G, Doortje CE, et al. J Neurotrauma 2007Kokoska et al. (1998), Journal of Pediatric Surgery, 33(2);

Number of Hypotensive Episodes

in the first 24 hours after TBI

Pediatric Neurology Handbook. Lippicontt. 2013

Normal Paremeter by Age: BP, MAP, ICP, CPP

Pediatric Neurology Handbook. Lippicontt. 2013

General Principles: Neuro Assessments

General Principles: Airway and Breathing

® Hypoxemia is a profound insult® Pediatric patients have both:

® Higher CMR O2 extraction (outside of newborn period)® Lower reserve oxygen supply (FRC)

® Indications for intubation® Impending or Acute Respiratory Failure® Inability to protect airway® Decrease work load of CV system

Adapted from Chugani, et al, Ann Neurol 1987

O2: too little is bad ... too much can be worse!

® Oxidative stress injury® Animal models suggest hyperoxia is harmful

® inflammation, neuronal death® Exacerbates neurologic dysfunction in several models® In newborns resuscitated with 21% vs 100% FiO2 meta-

analysis of RCT shows reduced risk of mortality, trend toward reduced risk of severe HIE

CBF

MAP(mmHg)

Normal 50 - 100 ml / min

Normal 60 - 150 mmHg

Cerebral Blood FlowRegulation of Cerebral Vascular Resistance

PaCo2 (mmHg)

Normal 30 - 50 mmHg

Adapted from: Rogers (1996) Textbook of Pediatric Intensive Care pp. 648 - 651

CBF-Ventilation

CBF pre- hyperventilation CBF post-hyperventilation

Adapted from research by Skippen et al. (1997)

Musts in the Care of Acute Neurological Insult in Children

® Serial neurologic assessments and physical examination

® Continuous cardio-respiratory, ICP, and CPP monitoring, +/- cerebral metabolism monitoring adjuncts

® Continuous EEG monitoring (seizures, ischemia, encephalopahty)

® Optimize Physiology:® Oxygenation and Ventilation® Perfusion® Cerebral metabolic rate® Address metabolic-electrolyte disturbances (see appendix for Hyponatremia)

® Normalize or Reduce Cerebral Metabolic Rate® Monitor for and prevent seizures (see appendix for Status Epilepticus algorithm)

® Reserve pentobarbital for refractory conditions® Avoid hyperthermia, +/- hypothermia® Avoid hyperglycemia (early) or hypoglycemia

Musts in the Care of Acute Neurological Insult in Children

® Avoid Increases in ICP® Prevent airway obstruction ® Treat pain and agitation - consider pre-medication for

nursing activities, +/- neuromuscular blockade (only when needed)

® Careful monitoring of ICP during nursing care, cluster nursing activities and limit handling when possible

® Suction only as needed, limit passes, pre-oxygenate / +/- pre-hyperventilate (PaCo2 not < 30) / use lidocaine IV or IT when possible

® After careful preparation of visitors, allow calm contact® Do not constrain venous return (tight neck collar)

Musts in the Care of Acute Neurological Insult in Children

® Normalize intracranial pressure ® Evacuate mass occupying lesions (tumor, hemorrhages) ® Consider draining CSF with ventriculostomy when

possible to prevent decrease CPP® Hyperosmolar therapy, +/- diuresis (cautious use to

avoid hypovolemia and decreased BP)® Mid-line neck, elevated head of bead (some research

supports elevation not > 30 degrees)

Musts in the Care of Acute Neurological Insult in Children

Management of Increase ICP in Children

Pathophysiology of increase ICP

Rosner, M. J Neurosurg 83:949–962, 1995

Signs and Symptoms of Increase ICP

Early® Headache® Emesis® Altered MS® Decrease GCS® Irritability® Sunsetting® Decrease eye contact® CN Dysfunction® Seizures

Late® Further Decrease in GCS® Bulging fontanel® Decrease Spontaneous

Movements® Posturing® Papilledema® Pupil dilatation® Increase BP, Irregular

Respirations ® Chushig’s triad

Exam and Respiratory Patterns Rostro-caudal Progression in Herniation Syndromes

Management of Increase ICP Algorithm

Pediatric Neurology Handbook. Lippicontt. 2013

Metabolic Emergencies

® Although individually rare, altogether they are 1:800-5000 incidence.

® Broadly Defined: An inherent deficiency in a key metabolic pathway resulting in® Cellular Intoxication® Energy deprivation® Combination of the two

Suspect IEM when

® Rapid deterioration in an otherwise well infant® Septic appearing infant ® History of Failure to thrive® Regression in milestones® Recurrent emesis or feeding difficulty, alterations

in respirations, abnl urine/body smell, changing MS/lethargy, jaundice, sz, intractable hiccups.

® Can masquerade like pyloric stenosis.® Dietary aversion-proteins, carbs.

Emergency Management:® ABC’s® Laboratory Investigation: ABG-acidosis, NH4, Lactate,

Pyruvate® NPO, reverse catabolism with D5-D10 1-1.5 x maint.® Correct hypoglycemia® Correct metabolic acidosis® Dialysis, lactulose if High/toxic NH4 (>100µmol/L)® Search for and treat precipitants; ie: Infection, dehydration ® Low threshold for Sepsis w/u + ABx if uncertain ® Pyridoxine for neonatal sz. if AED no-response® Ativan, Versed, Pentobarb coma, AEDs for status

epilepticus.® Carnitine for elimination of Organic Acid through creation

of carnitine esters® Sodium Benzoate, Phenylacetate for Hyper NH4

Without Focal Neurological Sx

With Neurological Sx

Cerebral Edema Extrapyramidal signsHemiplegiaHemianopia

MSUD, OTC MSUD, OTC, MMA, PA, PGK

MMA, GA I, Wilson dz,

Homocystinuria

Stroke-like episodes

UCD, MMA, RCD (MELAS), Fabry dz, PA, IVA, HMG-coA,

Homocystinuria, Thiamine-responsive megaloblastic anemia, Protein S or C Def, CDG, SCD,

PGK

Metabolic AcidosispH <7.2, CO3H <10,

PCO2 <25

HyperammonemiaNH3 >100, pH >7.45,

PCO2 <25

Hypoglycemia<20

Lactic AcidemiaLac >4

Ketosis +PCD, MDD, RCD, MMA, PA, IVA, GA I, MSUD, FDP, G6P

Ketosis –PDD, HMG-coA,

FAOD, FDP

Euglycemia UCD (OTC, CPS, ASS, AS)

HHH, LPI, AGS

HypoglycemiaFAOD, HMG-coA

Acidosis +Neoglucogenesis def

MSUD, HMG CoA

Acidosis -FAOD, HMG-CoA

EuglycemiaPC, MCD, RCD, Krebs & Mito DNA mut, PDH

HypoglycemiaFDP, G6P, PC,

FAOD

Metabolic Coma

Pediatric Neurology Handbook. Lippicontt. 2013

Neonatal Hyperammonemia

OTC DefCPS Def

No Acidosis

Sx < 24 hours of life Sx > 24 hours of life

Premature Full term

Transient Hyperammonemia of the neonate

IEM-Organic Acidemia-Pyruvate Carboxyl Deficiency

Acidosis

Organic Acidemias

Urea Cycle DefectsPlasma Amino Acids

Absent Citrulline Moderately elevated Citrulline, ASA present

Markedly elevated Citrulline, no ASA

CitrullinemiaArgininosuccinic aciduriaUrine Orotic Acid

Low High

HypoglycemiaHypoketosis

-Resp Chain Dz

Normoglycemia

Pediatric Neurology Handbook. Lippicontt. 2013

Normal Lactate Elevated Lactate

Abnormal Organic Acids

ORGANIC ACIDEMIA

MMA, PA, MDD

Dicarboxylic Aciduria

Hypoglycemia

Elevated Pyruvate, normal

L:P ratio

RCD, PCD

Abnormal Organic Acids

Normal Organic Acids

Anion Gap Metabolic Acidosis

Fatty Acid Oxidation Def

Normal-low Pyruvate,

elevated L:P ratio

No Hypoglycemia

PHD, PCD GSD I, Fructose 6-DP Def, PEP Carboxykinase

Def.

Pediatric Neurology Handbook. Lippicontt. 2013

ThankYou.AnyQuestions?

35

Appendix

Hyponatremia

Clinical Manifestations• Serum [Na] > 130 mmol/l

– Usually asymptomatic

• Serum [Na] 125-130 mmol/l– Predominantly GI symptoms (nausea,

vomiting)

• Serum [Na] < 125 mmol/l– Lethargy, headache, ataxia, psychosis,

weakness

– Severe cerebra edema-seizures, coma, brain-stem herniation, respiratory depression/arrest

Complications

• Complications of Hyponatremia– Rhabdomyolysis

– Seizures

– Permanent neurologic sequelae (from seizures or cerebral edema)

– Death

• Complications of Treatment– Fluid Overload

– Central Pontine Myelinolysis: ODS

Central Pontine Myelinolysis

• Focal demyelination of pontine and extrapontine areas

• Symptoms 1-3 days after rapid correction of Na– Dysarthria/dysphagia– Altered mental status, seizures

– Quadriparesis– Hypotension

• Often Irreversible

• Possible Therapy: relowering of Na with hypotonic fluids and desmopressin

Soupart A, Ngassa M: therapeutic lowering of the serum sodium in a patient after excessive correction of hyponatremia. Clin Nephrol. 1999 51 (6) 383-6

Whatkind?

Pediatric Neurology Handbook. Lippicontt. 2013

TreatmentofHyponatremiaSIADH:waterrestrictionandnormaltohypertonicsaline.CSW:saltloading,volumereplacementandfludrocortisone.

ACUTEHYPONATREMIA:IfNahasfallenrapidly(<48h),therearesymptoms,orNais

• <110mEq/L,thenitshouldbecorrectedrapidly.– Thegoaloftreatmentistoincreasetheserumsodiumlevelby1.5to2mEq/L/huntil

symptomssubsideoruntilthesodiumconcentrationis>118to120mEq/L,withtheprimaryfocustominimizetheriskofseizure.

– Eveninsymptomaticpatients,thesodiumlevelshouldnotbeincreasedby>12mEq/Linthefirst24h,orby>18mEq/Linthefirst48h,toavoidosmoticdemyelinationsyndrome.

• Whenpatientsbecomeasymptomaticandsodium levelsriseabove118mEq/L,correctionshouldbeslowedtono>8mEq/Lin24htoachievethetargetsodiumconcentration.

CHORNICHYPONATREMIAshouldbecorrectedataslowerrate,• Notexceeding0.5mmol/L/hor10to12mEq/Loverthefirst24h.• Useofhypertonic23%Nasolution iscontroversialinthePICUandreservedonlyfor

acutemanagementwhenimminentherniationorseizuresarepresent.

Status Epilepticus in Children

Management

Pediatric Neurology Handbook. Lippicontt. 2013

Neuroassessments

Reilly P.L., Simpson D.A, et al Child Nerv Sys 1998

Reilly P.L., Simpson D.A, et al Child Nerv Sys 1998

Kirkham, Newton et al 2008 Dev Med and Child Neurology

Infant Face Scale (IFS)

Durham et al, J Neurotrauma 2000

Pediatric Neurology Handbook. Lippicontt. 2013

TARGETED TEMPERATUREMANAGEMENT IN PEDIATRIC

NEUROCRITICAL CARE: CLINICAL UPDATE

Sarah Murphy, MDPediatric Critical Care/ Pediatric Neurocritical Care

MassGeneral Hospital for Children

I have no relevant financial relationships to disclose

Hypothermia

Therapeutic Hypothermia

Targeted Temperature Management

Induced Hypothermia

PUBMED KEYWORD SEARCH DP 2013-2015

• “Hypothermia” 2385

• “Hypothermia” and “TBI” 96

• “Hypothermia” and “Cardiac Arrest” 608

• “Targeted Temperature Management” 66

NEUROPROTECTION:

Thiopental

Corticosteroids

Mannitol Magnesium

Barbiturates Nimodipine

ICP MonitoringHypothermia

NEUROPROTECTION: TRIALS

Thiopental

Corticosteroids

Mannitol Magnesium

Barbiturates Nimodipine

ICP Monitoring

NEUROPROTECTION:

Thiopental

Corticosteroids

Mannitol Magnesium

Barbiturates Nimodipine

ICP Monitoring

HYPOTHERMIA

•There are both immediate and delayed processes of “secondary” injury

Pathophysiology of global ischemic event

• Cascade of brain injury begins within minutes

• Oxygen stores depleted within 20 seconds

• Glucose and ATP depleted within 5 min of ischemia

Ischemic Cascade

• Deplete ATP

• Na+ and K+ transmembrane gradients are lost

• Depolarization of cell membrane (Anoxic Depolarization)

• Increase in intracellular Ca

• Release of glutamate and other excitatory neurotransmitters

• Activation of Ca-dependent enzyme systems

Ischemic Cascde

• Even after ROSC insufficient perfusion of the brain persists

• “No re-flow” (microvascular dysfunction)

• Failure of cerebral autoregulation

Reperfusion Injury

• Oxygen free-radical species induce damage

• Lipid peroxidation

• Continued activation of glutamate

• Enhanced activity of inflammatory cells/immune-mediated damage

Lee, 2000 J Clin Investigations

Lee, 2000 J Clin Investigations

XENON

NO

EPO

• Increases tissue tolerance to ischemia

• Decreasing cerebral metabolic rate

• Mitigates damage

• Quiets the inflammatory cascade

• Decreases production of reactive oxygen species

Hypothermia

Dell’anna et al Curr Opin Critical Care 2014

??

Targeted Temperature Management

• Clinical indication: global hypoxic-ischemic injuries

• Post-cardiac arrest syndrome

• Neonatal Hypoxic-Ischemic Encephalopathy

Nielsen and TTM Trial Investigators2013, NEJM 369: 2197

THAPCA

What was the background?

Bernard HACA

n 77 275

temp 33 32-34

duration 12h 24h

rapidity 2 hrs, met goal 4 hrs, median 8

incl/excl vfib witnessed vfib/vtach

BERNARD:Adjusted for age and time to ROSC, odds ratio of

good outcome in HT group 5.25 (1.47-18.76, P=.011)

49% vs 26% (p=.046)

HACA:55% vs 39% “good” outcome

RR of good outcome 1.4 (1.08-1.81)Mortality 41% vs 55%

43 before-after studies in centers using new therapy

Improvement with TH compared with historical controls

Average good neurological outcome 53% Polderman, Circulation 2015

Sterz, Current Opinion in Critical Care 2003

How Ice Can Save Your Life'Therapeutic Hypothermia' Can Protect the Brain in the Aftermath of Cardiac Arrest

By RON WINSLOWUpdated Oct. 6, 2009 12:01 a.m. ET

The Wall Street Journal, 2009

‘‘A healthy brain and functional patient are the primary goal of cardiopulmonary-cerebral resuscita-tion. Brain-oriented intensive care is essential.’’—American Heart Association

Nielsen review• Included 5 RCTs (478) patients

• The hypothermia trials compare hypothermia with no temperature control

• Hypothermia should not be recommended without a trial comparing a “fever control” control group with “hypothermia” treatment group

• Prognostication and the problem of re-direction of care

• Most common cause of death in studies was withdrawal of life-support

• None of the studies specified how a decision about withdrawal of intensive care was made, whether assessor of prognostication was blinded

Int Journal Cardiology 2011

2001

OR of poor outcome: 2.26 (1.24–4.12) for every degree higher than 37 °C

2002

OR of survival 2.7 (1.2-6.2) for temp < 37.8

• RCT, randomized to TTM of 33 or 36

• Conducted at 36 centers in Europe and Australia

• Inclusion: Adults, OOHCA, GCS <8 on arrival to hospital, ROSC for 20min

• Exclusion: unwitnessed asystolic arrest, > 4hrs from ROSC to randomization, ICH or stroke, temp <30

• TTM for 28 hrs, both groups sedated, aggressive control of temp in control and intervention group

Nielsen and TTM Trial Investigators2013, NEJM 369: 2197

Intervention

• Intervention period was 36hrs from randomization

• All patients sedated, continuous temperature management, maintained at goal temperature (method not specified)

• At 28hrs began gradual rewarming to 37 by 0.5 deg/ hr

• Intention was to maintain < 37.5 for 72 hrs

• After 36hrs no mandatory sedation, at discretion of sites

• 950 patients enrolled

• Cooling initiated up to 4 hrs (avg time to cooling not given)

• Time to target temp 8 hrs

• Primary outcome: mortality

• Secondary outcome: poor neurologic function or death (CPC 3-4, MRS 4-6)

P<.001 for separation of temperature curves

• Mortality 50% in hypothermia group and 48% in the normothermia group [hazard ratio 1.06; 0.89-1.28, p=0.51]

• Risk ratio of a CPC of 3-5 for normothermia 1.02 [0.88-1.16, p=0.78]

• Risk ratio of MRS of 4-6 1.01 [0.89-1.14, p=0.87]

Withdrawal of care in 247 (26%) patients

??

2015 AHA POST-CARDIAC ARRESTGUIDELINES

• Window of 4 hrs too long? Another 4 hrs to cooling?

• Intra-arrest / Intra-cpr cooling?

• Hemodynamic optimization?

• Higher proportion of deaths before prognostication in 33 deg group?

• Effects of sedation?

• Too rapid re-warming?

• However, this finding was not borne out in a randomised controlled trial that included 1359 patients with out-of-hospital cardiac arrest due to both shock- able and non-shockable rhythms and found similar rates of sur- vival to discharge or neurological outcome.

22 Moreover, a higher incidence of hypoxia and pulmonary oedema after cold saline infusion was noted in the prehospital

cooling arm. It remains unclear whether the use of a surface cooling method, as used in the other hypothermia trials instead of cold saline infu- sion, would have altered the study’s outcome.

1. Kim F, Nichol G, Maynard C, et al. Effect of prehospital induction of mild hypothermia on survival and neurological status among adults with cardiac arrest: a randomized clinical trial. JAMA 2014;311:45–52.

Pediatric Cardiac Arrest

• Epidemiology of pediatric CA: ~9,500 children/yr in US

• High morbidity and mortality

• Usually due to asphyxia and shock as opposed to adults

• Most commonly PEA and asystole (rhythms excluded from RCTs)

Circulation, 2009

Adjusted for duration of CA, propensity scores, ECMORetrospective, included 79 patients from 5 Canadian centers

Hypothermia used more often after prolonged arrest or with ECMOMostly cardiac patients, neonatalDid treat/aimed to prevent fever

• Also compared targeted Normothermia (36.8) to Hypothermia (33)

THAPCA

• Conducted at 38 PICUs in US and Canada

• Children >48hrs and <18yo

• OOH cardiac arrest

• Exclusion: unable to be randomized by 6hrs, major trauma, elect not to pursue aggressive treatment, mGCS of 5 or 6

THAPCA - Out of Hospital Cardiac Arrest Trial

• Randomized 1:1 by permuted blocks

• TTM was actively maintained for 120 hrs in both groups

• Blanketrol III for core temp target for 48 hrs

• Rewarmed over 16hrs to 36.8

• Maintained at 36.8 x (remainder)120 hrs

THAPCA - Out of Hospital Cardiac Arrest Trial

• Primary outcome survival with good neurobehavioral outcome at 12 months

• “good outcome” standard score of 70 or higher on Vineland Adaptive Behavior Scalre

Targeted Temperature Management

• TBI (adult and pediatric)

• Stroke

• Spinal cord injury

• Primary brain injury from direct trauma

• Macroscopic:

• Shearing of white matter tracts

• Focal contusions

• Hematoma

• Edema

• Cellular:

• Microperforation of membranes

• Leaking ion channels

• Microhemorrhage

• Conformational changes in proteins

TBI

• Secondary injury (Acute/Subacute/Chronic)

• Neurotransmitter release

• Free radical formation/oxidative stress

• Ca-mediated damage

• Gene activation

• Mitochondrial dysfunction

• Inflammatory response

~Seizures

~ICH

TBI

TBI trials

NABIS:H I

TBI trials

NABIS:H I

NABIS: H II

TBI trials

NABIS:H I

NABIS: H II

TBI trials

NABIS:H I

NABIS: H II

TBI trials

EUROTHERM

Stroke trials

• Systematic review and meta-analysis: evidence of efficacy in animal models of AIS

•86 publications included, 15 abstracts

•Median temp of cooling 33 (24-35)

•Overall decrease in infarct size by 43.5% (95% CI: 40.1-47.0%)

•Overall improvement in neurobehavioral scores 45.7% (95%CI: 36.5-54.5%)

Stroke trials• Hypothermia improved outcome

• histological and functional outcome

• Efficacy was greatest:

• at lower temperatures

• when treatment was started before or at onset of ischemia

• in temporary ischemia models

Intravascular Cooling in the Treatment of Stroke (ICTuS) trial, awake stroke patients were successfully cooled using an endovascular cooling catheter

In the ICTuS-L study, the combination of endovascular hypothermia and thrombolysis was shown to be feasible and hypothermia had no increased risk of bleeding

ICTuS 2/3 designed to study safety of combined thrombolysis and endovascular hypothermia and to determine if the combination shows superiority compared with thrombolysis alone.

ICTuS Trials

FeverPOOR

Outcome

Clinical Associations• Fever in all brain injury types is associated with morbidity and

mortality (Greer Stroke 2008)

• Fever in the acute stage of SAH independently predicts morbidity and mortality (Fernandez Neurology 2007)

• Fever early after TBI is associated with increased ICP, worse neurologic outcome (Bohman Curr Opin Critical Care 2014)

• Degree and duration of fever correlated with outcome (Li J Neurotrauma 2012)

• Association between fever and poor neurologic outcome after severe TBI (Aiyagari J Neurol Sciences 2007)

Animal Evidence

• Elevations in temperature increase pro-inflammatory cytokines

• Increase accumulation of neutrophils in injured tissue

• Increase neuronal excitotoxicity

• Increase neurotransmitter release

• Accelerate free-radical production

• Increase intracellular acidosis

Fever

• Elevation of core body temp >37

• Common in patients with brain injury (Badjatia 2009, Thompson 2003)

• 7-13% increase in cerebral metabolism for each 1% increase in core body temp

• Though healthy human brains are able to tolerate increases in metabolism, injured brain may not

• Lower threshold for ischemia, at-risk of mismatch between impaired flow and increased demand

Conclusions:

Cardiac Arrest

TBIStroke

Other Neurologic Injury?