pediatric and neonatal critical care neurology

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

TargetedTemperatureManagementinPediatricNeurocriticalCare:Clinical

Update

SarahMurphy,MDPediatricCriticalCare/PediatricNeurocriticalCareMassGeneralHospitalforChildren

Ihavenorelevantfinancialrelationships todisclose

Hypothermia

TherapeuticHypothermia

TargetedTemperatureManagement

InducedHypothermia

Pubmed KeywordSEARCHdp 2013-2015

• “Hypothermia”2385• “Hypothermia”and“TBI”96• “Hypothermia”and“CardiacArrest”608• “TargetedTemperatureManagement”66

Neuroprotection:

Thiopental

Corticosteroids

Mannitol Magnesium

Barbiturates Nimodipine

ICPMonitoringHypothermia

Neuroprotection:trials

Thiopental

Corticosteroids

Mannitol Magnesium

Barbiturates Nimodipine

ICPMonitoring

Neuroprotection:

Thiopental

Corticosteroids

Mannitol Magnesium

Barbiturates Nimodipine

ICPMonitoring

HYPOTHERMIA

• Therearebothimmediateanddelayedprocessesof“secondary”injury

Pathophysiology ofglobalischemicevent

• Cascadeofbraininjurybeginswithinminutes• Oxygenstoresdepletedwithin20seconds• GlucoseandATPdepletedwithin5minofischemia

• AfterROSCinsufficientperfusionofthebrainpersists– “Nore-flow”(microvasculardysfunction)– Failureofcerebralautoregulation

IschemicCascade

• DepleteATP• Na+andK+transmembranegradientsarelost• Depolarizationofcellmembrane• IncreaseinintracellularCa• Releaseofglutamate• Activationofenzymesystems

ReperfusionInjury

• Oxygenfree-radicalspeciesinducedamage• Lipidperoxidation• Continuedactivationofglutamate• Enhancedactivityofinflammatorycells

• Increasestissuetolerancetoischemia– Decreasingcerebralmetabolicrate• Mitigatesdamage– Quietstheinflammatorycascadeandproductionofreactiveoxygenspecies

Hypothermia

Dell’anna et al Curr Opin Critical Care 2014

??

TargetedTemperatureManagement• Clinicalindication:globalhypoxic-ischemicinjuries

– Post-cardiacarrestsyndrome– NeonatalHypoxic-IschemicEncephalopathy

NielsenandTTMTrialInvestigators2013,NEJM369:2197

THAPCA

Whatwasthebackground?

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:AdjustedforageandtimetoROSC,oddsratioofgoodoutcomeinHTgroup5.25(1.47-18.76,P=.011)49%vs26%(p=.046)

HACA:55%vs39%“good”outcomeRRofgoodoutcome1.4(1.08-1.81)Mortality41%vs55%

Sterz,CurrentOpinioninCriticalCare2003

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

Though benefit was demonstrated in specific population: adults with out of hosp vfib/vtach witnessed arrest, the use of TH was extended to other, scenarios in advance of clinical trials that might prove benefit, including patients presenting with non-shockable rhythms, patients who had an in-hospital arrest, and pediatric patients.

Nielsenreview

• Included 5 RCTs (478) patients

• The majority of 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 is 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

IntJournalCardiology2011

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,randomizedtoTTMof33or36• Conductedat36centersinEuropeandAustralia• Inclusion:Adults,OOHCA,GCS<8onarrivaltohospital,ROSC

for20min,• Exclusion:unwitnessed asystolic arrest,>4hrsfromROSCto

randomization,ICHorstroke,temp<30• TTMfor28hrs,bothgroupssedated,aggressivecontrolof

tempincontrolandinterventiongroup• Intentionfornormothermia for72hrs

NielsenandTTMTrialInvestigators2013,NEJM369:2197

Intervention

• Interventionperiodwas36hrsfromrandomization

• Allpatientssedated,continuoustemperaturemanagement,maintainedatgoaltemperature(methodnotspecified)

• At28hrsbegangradualrewarmingto37by0.5deg/hr

• Intentionwastomaintain<37.5for72hrs• After36hrsnomandatorysedation,atdiscretionofsites

• 950patientsenrolled• Primaryoutcome:mortality– Followedfor180d• Secondaryoutcome:poorneurologicfunctionordeath(CPC3-4,MRS4-6)

P<.001forseparationoftemperaturecurves

• Mortality50%inhypothermiagroupand48%inthenormothermiagroup[hazardratio1.06;0.89-1.28,p=0.51]

• RiskratioofaCPCof3-5fornormothermia1.02[0.88-1.16,p=0.78]

• RiskratioofMRSof4-61.01[0.89-1.14,p=0.87]

Withdrawalofcarein247(26%)patients

??

2015Ahapost-cardiacarrestguidelines

• Windowof4hrstoolong?Another4hrstocooling?

• Intra-arrest/Intra-cprcooling?• Hemodynamicoptimization?• Higherproportionofdeathsbeforeprognosticationin33deggroup?

• Effectsofsedation?• Toorapidre-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.

PediatricCardiacArrest

• EpidemiologyofpediatricCA:10,000children/yr

• Highmorbidityandmortality• Usuallyduetoasphyxiaandshockasopposedtoadults

• MostcommonlyPEAandasystole(rhythmsexcludedfromRCTs)

• Betteroutcomesthanadults

Circulation,2009

AdjustedfordurationofCA,propensityscores,ECMORetrospective,included79patientsfrom5CanadiancentersHypothermiausedmoreoftenafterprolongedarrestorwithECMOMostlycardiacpatients,neonatalDidtreat/aimedtopreventfever

• AlsocomparedtargetedNormothermia(36.8)toHypothermia(33)

THAPCA

• Conductedat38PICUsinUSandCanada• Children>48hrsand<18yo• OOHcardiacarrest• Exclusion:unabletoberandomizedby6hrs,majortrauma,

electnottopursueaggressivetreatment,mGCSof5or6

THAPCA- OutofHospitalCardiacArrestTrial

• Randomized1:1bypermutedblocks• TTMwasactivelymaintainedfor120hrsinbothgroups

• BlanketrolIIIforcoretemptargetfor48hrs• Rewarmedover16hrsto36.8• Maintainedat36.8x120hrs

THAPCA- OutofHospitalCardiacArrestTrial

• Primaryoutcomesurvivalwithgoodneurobehavioraloutcomeat12months

• “goodoutcome”standardscoreof70orhigheronVinelandAdaptiveBehaviorScalre

TargetedTemperatureManagement

• TBI(adultandpediatric)• Stroke• Spinalcordinjury

• Primarybraininjuryfromdirecttrauma– Macroscopic:

• Shearingofwhitemattertracts• Focalcontusions• Hematoma• Edema

– Cellular:• Microperforationofmembranes• Leakingionchannels• Microhemorrhage• Conformationalchangesinproteins

TBI

• Secondaryinjury(Acute/Subacute/Chronic)– Neurotransmitterrelease– Freeradicalformation/oxidativestress– Ca-mediateddamage– Geneactivation– Mitochondrialdysfunction– Inflammatoryresponse

– Seizures– ICH

TBI

TBItrials

NABIS:HI

TBItrials

NABIS:HI

NABIS:HII

TBItrials

NABIS:HI

NABIS:HII

TBItrials

NABIS:HI

NABIS:HII

TBItrials

NABIS:HI

NABIS:HII

EUROTHERM

Stroketrials

• Systematicreviewandmeta-analysisforevidenceofefficacyinanimalmodelsofAIS

• 86publicationsincluded,15abstracts• Mediantempofcooling33(24-35)• Overalldecreaseininfarctsizeby43.5%(95%CI:40.1-47.0%)

• Overallimprovementinneurobehavioralscores45.7%(95%CI:36.5-54.5%)

Stroketrials• Hypothermiaimprovedoutcome– histologicalandfunctionaloutcome• Efficacywasgreatest:– atlowertemperatures– whentreatmentwasstartedbeforeoratonsetofischemia– intemporaryischemiamodels

IntravascularCoolingintheTreatmentofStroke(ICTuS)trial,awakestrokepatientsweresuccessfullycooledusinganendovascularcoolingcatheter

IntheICTuS-Lstudy,thecombinationofendovascularhypothermiaandthrombolysiswasshowntobefeasibleandhypothermiahadnoincreasedriskofbleeding

ICTuS2/3designedtostudysafetyofcombinedthrombolysisandendovascularhypothermiaandtodetermineifthecombinationshowssuperioritycomparedwiththrombolysisalone.

ICTuSTrials

FeverPOOR Outcome

ClinicalAssociations

• Feverinallbraininjurytypesisassociatedwithmorbidityandmortality(GreerStroke2008)

• FeverintheacutestageofSAHindependentlypredictsmorbidityandmortality(FernandezNeurology2007)

• FeverearlyafterTBIisassociatedwithincreasedICP,worseneurologicoutcome(BohmanCurrOpinCriticalCare2014)

• Degreeanddurationoffevercorrelatedwithoutcome(LiJNeurotrauma2012)

AnimalEvidence

• Elevationsintemperatureincreasepro-inflammatorycytokines

• Increaseaccumulationofneutrophilsininjuredtissue

• Increaseneuronalexcitotoxicity• Increaseneurotransmitterrelease• Acceleratefree-radicalproduction• Increaseintracellularacidosis

Fever

• Elevationofcorebodytemp>37• Commoninpatientswithbraininjury(Badjatia2009,

Thompson2003)

• 7-13%increaseincerebralmetabolismforeach1%increaseincorebodytemp

• Thoughhealthyhumanbrainsareabletotolerateincreasesinmetabolism,injuredbrainmaynot

• Lowerthresholdforischemia,at-riskofmismatchbetweenimpairedflowandincreaseddemand

Conclusions:

CardiacArrest

TBIStrokeOtherNeurologicInjury?