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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
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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
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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
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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%)
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TemporalCascadeofEventsà Post-anoxia
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Lo. Nat Rev Neurosci. 2003;4:399
MolecularPathwaysofCellDeath• Excitotoxicity
and ionic imbalance
• Oxidative and nitrosative stress
• Apoptotic mechanisms
• Necrosis
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Neuroprotection-SandwichModel
Glutamate
Mitochondria
Proteolysis
Oxidative Stress
ER Stress
Inflammation
Surv
ival
Dea
th
GlutamateMitochondriaProteolysis
Oxidative StressER Stress
Inflammation
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Pediatric Code Blue
in the ED
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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
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Pediatric Neurology Handbook. Lippicontt. 2013
Normal Paremeter by Age: BP, MAP, ICP, CPP
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Pediatric Neurology Handbook. Lippicontt. 2013
General Principles: Neuro Assessments
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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
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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
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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
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CBF-Ventilation
CBF pre- hyperventilation CBF post-hyperventilation
Adapted from research by Skippen et al. (1997)
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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)
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® 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
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® 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
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® 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
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Management of Increase ICP in Children
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Pathophysiology of increase ICP
Rosner, M. J Neurosurg 83:949–962, 1995
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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
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Exam and Respiratory Patterns Rostro-caudal Progression in Herniation Syndromes
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Management of Increase ICP Algorithm
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Pediatric Neurology Handbook. Lippicontt. 2013
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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
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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.
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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
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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
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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
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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
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ThankYou.AnyQuestions?
35
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Appendix
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Hyponatremia
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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
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Complications
• Complications of Hyponatremia– Rhabdomyolysis
– Seizures
– Permanent neurologic sequelae (from seizures or cerebral edema)
– Death
• Complications of Treatment– Fluid Overload
– Central Pontine Myelinolysis: ODS
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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
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Whatkind?
Pediatric Neurology Handbook. Lippicontt. 2013
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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.
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Status Epilepticus in Children
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Management
Pediatric Neurology Handbook. Lippicontt. 2013
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Neuroassessments
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Reilly P.L., Simpson D.A, et al Child Nerv Sys 1998
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Reilly P.L., Simpson D.A, et al Child Nerv Sys 1998
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Kirkham, Newton et al 2008 Dev Med and Child Neurology
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Infant Face Scale (IFS)
Durham et al, J Neurotrauma 2000
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Pediatric Neurology Handbook. Lippicontt. 2013
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TARGETED TEMPERATUREMANAGEMENT IN PEDIATRIC
NEUROCRITICAL CARE: CLINICAL UPDATE
Sarah Murphy, MDPediatric Critical Care/ Pediatric Neurocritical Care
MassGeneral Hospital for Children
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I have no relevant financial relationships to disclose
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Hypothermia
Therapeutic Hypothermia
Targeted Temperature Management
Induced Hypothermia
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PUBMED KEYWORD SEARCH DP 2013-2015
• “Hypothermia” 2385
• “Hypothermia” and “TBI” 96
• “Hypothermia” and “Cardiac Arrest” 608
• “Targeted Temperature Management” 66
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NEUROPROTECTION:
Thiopental
Corticosteroids
Mannitol Magnesium
Barbiturates Nimodipine
ICP MonitoringHypothermia
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NEUROPROTECTION: TRIALS
Thiopental
Corticosteroids
Mannitol Magnesium
Barbiturates Nimodipine
ICP Monitoring
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NEUROPROTECTION:
Thiopental
Corticosteroids
Mannitol Magnesium
Barbiturates Nimodipine
ICP Monitoring
HYPOTHERMIA
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•There are both immediate and delayed processes of “secondary” injury
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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
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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
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Ischemic Cascde
• Even after ROSC insufficient perfusion of the brain persists
• “No re-flow” (microvascular dysfunction)
• Failure of cerebral autoregulation
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Reperfusion Injury
• Oxygen free-radical species induce damage
• Lipid peroxidation
• Continued activation of glutamate
• Enhanced activity of inflammatory cells/immune-mediated damage
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Lee, 2000 J Clin Investigations
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Lee, 2000 J Clin Investigations
XENON
NO
EPO
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• Increases tissue tolerance to ischemia
• Decreasing cerebral metabolic rate
• Mitigates damage
• Quiets the inflammatory cascade
• Decreases production of reactive oxygen species
Hypothermia
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Dell’anna et al Curr Opin Critical Care 2014
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??
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Targeted Temperature Management
• Clinical indication: global hypoxic-ischemic injuries
• Post-cardiac arrest syndrome
• Neonatal Hypoxic-Ischemic Encephalopathy
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Nielsen and TTM Trial Investigators2013, NEJM 369: 2197
THAPCA
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What was the background?
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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
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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%
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43 before-after studies in centers using new therapy
Improvement with TH compared with historical controls
Average good neurological outcome 53% Polderman, Circulation 2015
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Sterz, Current Opinion in Critical Care 2003
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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
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‘‘A healthy brain and functional patient are the primary goal of cardiopulmonary-cerebral resuscita-tion. Brain-oriented intensive care is essential.’’—American Heart Association
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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
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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
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• 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
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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
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• 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)
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P<.001 for separation of temperature curves
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• 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]
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Withdrawal of care in 247 (26%) patients
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??
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2015 AHA POST-CARDIAC ARRESTGUIDELINES
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• 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?
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• 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.
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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)
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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
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• Also compared targeted Normothermia (36.8) to Hypothermia (33)
THAPCA
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• 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
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• 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
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• Primary outcome survival with good neurobehavioral outcome at 12 months
• “good outcome” standard score of 70 or higher on Vineland Adaptive Behavior Scalre
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Targeted Temperature Management
• TBI (adult and pediatric)
• Stroke
• Spinal cord injury
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• 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
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• Secondary injury (Acute/Subacute/Chronic)
• Neurotransmitter release
• Free radical formation/oxidative stress
• Ca-mediated damage
• Gene activation
• Mitochondrial dysfunction
• Inflammatory response
~Seizures
~ICH
TBI
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TBI trials
NABIS:H I
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TBI trials
NABIS:H I
NABIS: H II
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TBI trials
NABIS:H I
NABIS: H II
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TBI trials
NABIS:H I
NABIS: H II
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TBI trials
EUROTHERM
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Stroke trials
• Systematic review and meta-analysis: evidence of efficacy in animal models of AIS
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•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%)
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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
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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
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FeverPOOR
Outcome
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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)
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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
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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
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Conclusions:
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Cardiac Arrest
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TBIStroke
Other Neurologic Injury?