Neurocritical CarePearlsforthe
GeneralICUPractitioner
CoreyR.FehnelMD,MPH
AssistantProfessorofNeurology,HarvardMedicalSchool
Neuroscience IntensiveCareUnit, BethIsraelDeaconessMedicalCenter
AssistantScientist,HebrewSeniorLife MarcusInstituteforAgingResearch
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Disclosures
• NIH/NIAR03AG060186 (PI)
• NIH/NICHDR03HD096372 (Consultant)
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Outline
• WhytheNeuroICU?
• There’sastrokeinyourICU,whattodo.
• ICHpearls
• MysteryCase1
• Rationale forhyperosmolar therapy
• MysteryCase2
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Audienceresponse
• Doesyourhospitalhaveneurointensivists?
• Doesyourhospitalhaveadedicated
NeuroICU?
• DoesyourICUroutinely“board”NeuroICU
patients?COPYRIGHT
WhytheNeuroICU?
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ICHintheNeuroICU
• Improvedhospitalmortality
• Unchangedorreducedhospitallengthofstay
Diringer MN,EdwardsDF.Admission toaneurologic/neurosurgical intensive careunit is
associated withreducedmortality rateafterintracerebral hemorrhage. Crit CareMed.
2001;29:635–40.
Mirski MA,ChangCWJ,CowanR.Impactofaneuroscience intensive careuniton
neurosurgical patient outcomes andcostofcare:evidence-based supportforan
intensivist-directed specialty ICUmodel ofcare.JNeurosurg Anesthes. 2001;13:83–92.
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ICHpatientsinNeuroICU
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Neurocritical CareTeam
• Fulltimeneurointensivist
• Associatedwithreducedin-hospitalmortality
• Reduced length-of-stay (mixedresults)
Varelas PN,ContiMM,Spanaki MV,PottsE,BradfordD,Sunstrom C,Fedder W,Hacien-
Bey J,Jaradeh S,Gennarelli TA.The impact ofaneurointensivist-led teamona
semiclosed neurosciences intensive careunit.Crit CareMed.2004;32:2191–8.
SuarezJI,Zaidat OO,Suri MF,Feen ES,LynchG,HickmanJ,Georgiadis A,SelmanWR.
Lengthofstayandmortality inneurocritically illpatients: Impactofaspecialized
neurocritical careteam.CritCareMed.2004;32:2311–7.
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NeuroICU Magic?
• ICULOSlongerinneuroICU
• Morepatientswithtracheostomy
• Moreinvasivehemodynamicmonitoring
• Moreinvasiveintracranial pressuremonitoring
• Intravenous sedationwaslessprevalent
• Greaterandearliernutritionalsupport
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IschemicStrokeintheICU
• Timeisbrain,butLKWintheICU??
• Imagingbaseddecisions (DAWN,DEFUSE3)
• Lesscerebraledemawithreperfusion
• 6– 16hrs,LKW,LVOanteriorcirculation-
thrombectomy.
• 16- 24hrs,LKW,LVOanteriorcirculation-
reasonable.
DAWN Nogueira RGetal.NEngl JMed2017
DEFUSE 3 Albers GWetal.NEngl JMed2018
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Demaerschalk BM etal.Scientific Rationale forthe Inclusion andExclusion Criteria for
IntravenousAlteplase inAcute Ischemic Stroke:AStatement forHealthcare
Professionals FromtheAmericanHeartAssociation/American StrokeAssociation.
Stroke.2016.
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Audienceresponse
• Mostcommonamong“exclusioncriteria”
ignoredbyneurologists forgivingIVtPA?
– PriorICH
– Advancedage
– Anticoagulation
– RecentSTEMI
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AdvancedageandIVtPA
• ExcludedfromnumerousRCTs
• Meta-analyses achievedpowertodetect
benefitat3-hrwindow(OR1.68,CI1.20-2.34)
• Observational dataarelessclear
• Exclusionfor3-4.5hrsandage>80remains
Wardlaw JM.Recombinant tissue plasminogen activatorforacute ischaemic stroke: an
updated systematic reviewandmeta-analysis. Lancet. 2012.
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Whattime?Whatstudy?
TimefromLKW Imaging Evidence
3hrs NCHCT +CTA/P NINDSrt-PANEJM 1995
4.5hrs NCHCT +CTA/P ECASSIII
6hrs NCHCT/CTA +P HERMES
6-16hrs NCHCT/CTA/P (MRP) DAWN/DEFUSE 3
16-24hr NCHCT/CTA/P (MRP) DAWN/DEFUSE 3
**ItisestimatedLVOaccountsfor11%ofischemicstrokecases.
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Whoshouldhavethrombectomy?
At6-16hrs At16-24hrs
Consider thrombectomy:
- CTA showsLVO,NIHSS≥6
AND
- CTPshowscoreinfarctvolume <71cc
- mismatch ratio>1.8
- mismatch volume >15cc
Consider thrombectomy:
- CTAshowsLVO, NIHSS≥10
AND
- CTPshows coreinfarctvolume <21cc(age≥80)
- core infarct<31cc(age<80)
- core infarct31-51ccandNIHSS≥20(age<80)COPYRIGHT
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76MwithHTN,DM2,AFpresentswithsudden
onsetheadacheandRsidedweakness.
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On Arrival 6 Hours later…
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OralAnticoagulantRateofICH
• 0.3%to0.6%peryear
• Amongintracranial hemorrhages:
– Intracerebral (46%to86%)
– Subdural(13%to45%)
– Subarachnoid(1%to8%)
• 40%to65%(ICH)hastheworstprognosis.
HartRG,Diener HC,YangS,ConnollySJ,Wallentin L,Reilly PA,etal. Intracranial
hemorrhage inatrial fibrillation patients duringanticoagulation withwarfarinor
dabigatran: theRE-LYtrial.Stroke.2012;43:1511–1517.
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AnnualrateofICH
• 0.3%to0.6% VKAs
• 0.1%to0.2%onDOACs
• 50%reductioninrateofICHwithDOACs
RuffCT,Giugliano RP,Braunwald E,etal.Comparison oftheefficacyandsafetyof
neworalanticoagulants withwarfarininpatients withatrial fibrillation: a
metaanalysis ofrandomised trials. Lancet. 2014;383:955–962.
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AnticoagulationandICHmortality
• Mortalitydirectlyrelatedtohematoma
expansion.
• 30-40% rateofICHexpansion3-6hrs from
onsetoffOACs
• 54%rateamongVKAs
• PrelimrateforDOACs~36%
Purrucker JC,HaasK,Rizos T,etal.Earlyclinical andradiological course,management,
andoutcome ofintracerebral hemorrhage relatedtoneworalanticoagulants. JAMA
Neurol.2015;73:1–10.
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ICH Volume à GCS à Mortality
Broderick et al. Stroke 1993;24(7):987–993
ICHVolume(cc) GCS 30-dayMortality
<30 ≥8 19%
30-60 ≥8 46%
>60 ≥8 75%
<30 <8 44%
30-60 <8 74%
>60 <8 91%
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ReversalofAnticoagulation
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VitaminKAntagonists
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VitaminK
• GiveIV- Lowriskforanaphylaxis
• ~12hrs fornormalizationofINR
• AdministervitaminK(10mg IV)andPCC
concurrently.COPYRIGHT
ThevagariesofFFP
• 10-20mL/kg (Each unit FFP ~200 mL)
• Average patient requires 4-5 units.
• Slow administration time (30-45mins for
thaw/delivery)
• Risk for CHF
• “Rebound” INR
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PCC
• Prothrombin ComplexConcentrate (PCC)
• 3-factorà factorsII,IX,X,
• 4-factorà addsfactorVII.(Somew/proteinC,S)
• Asaresult,4-factorispreferred.
• Typicaldosing:25-50U/kgIV
*StrongevidenceforsuperiorityofPCCvs.FFP
Steiner T,Poli S,Griebe M,etal.LancetNeurol.2016;15:566–573.
Sarode R,Milling TJJr,Refaai MA,etal.Circulation. 2013;128:1234–1243.
Goldstein JN,Refaai MA,Milling TJJr,etal.Lancet. 2015;385:2077–2087.
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DOACrever$al
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Dabigatran reversal
• Drugname:Idarucizumab (Praxbind)
• Mechanismofaction:non-competitively
directlybindsdabigatran.
• Dose:2.5mgIVbolusx2(15minsapart)
• Cost:~$3,800COPYRIGHT
OtherOACreversal
Drugname:Andexanet alfa (Andexxa)
Mechanism: competes forbindingof
rivaroxaban, apixaban, edoxaban, fondaparinux–
antithrombin complex.
Dose:DependsonlastknowndoseofOAC
Cost:$20,000-$35,000
Alternatives:PCC,FEIBA(lessideal,poordata)
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How often to scan?
• High risk for hematoma expansion?
– Early repeat ~6hrs.
• If deterioration in exam.
• Every 12 +/- 2 hrs from initial CT.
• Stop once ICH volume stable ≥ 2
consecutive CT scans.
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Platelet dysfunction: transfusion
• Thrombocytopenia- (<100,000/uL)--
Transfuse with platelets until platelet count
exceeds 100,000/uL.
• No data to support platelet transfusion in
setting of ASA or clopidogrel use.
Baharoglu MI etal.PATCHInvestigators. Platelet transfusion versusstandard care
afteracutestrokeduetospontaneous cerebral haemorrhage associated with
antiplatelet therapy(PATCH):arandomised, open-label, phase3trial.Lancet.2016
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TargetBPafterICH?
• INTERACT2
• ATACHII
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INTERACT2
• SBP<140vs.SBP<180.
• Deathormajordisability (mRS ≥3;OR,0.87;95%
CI,0.75–1.01)
• Functional recoveryordinalanalysisofmRS (OR
forgreaterdisability,0.87;95%CI,0.77to1.00)
• MostICHvolumes~20cc
• AHAguidelinechangedSBP<140mm Hg
Anderson CS.etal.INTERACT2 Investigators.Rapid Blood-Pressure Lowering in
PatientswithAcute Intracerebral Hemorrhage. NEJM2013;368:2355-2365.
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ATACH II
Antihypertensive Treatment in Acute Cerebral Hemorrhage-II
• 1,000subjectswithin2.5hrsofICHonset.
• SBP<140vs.SBP<180mmHgfor24hfrom
randomization.
• Most(86%)subjectshadICHvolumeof<30cc
Qureshi etal.Intensive BloodPressureLowering inPatientswithAcuteCerebral
Hemorrhage. NEngl JMed.June8,2016atNEJM.org
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ATACH II take home
• Results do not support strict SBP < 140.
• More renal adverse events in SBP 140 arm.
• Target systolic blood pressure of 140 to179 mm Hg
appears to have equivalent outcomes with fewer AE’s.
• Clinical deterioration or ICH expansion should prompt
reconsideration of target BP.COPYRIGHT
Audienceresponse
• Thepatient’sFSBGsareinthe200’s.What
strategyshouldyoutakeforglucosecontrol?
– TargetBG120-180withRISS
– TargetBG80-130withRISS
– TargetBG120-180withinsulingtt
– TargetBG80-130withinsulingtt
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RobbinsNM,SwansonRA.Opposing Effects ofGlucose onStrokeandReperfusion Injury
Acidosis, OxidativeStress, andEnergyMetabolism. Stroke.2014;45:1881-1886.
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Glucosecontrol
• Hyperglycemia isbad.
• Hypoglycemiamaybeworse(GIST-UK,NICE
SUGAR)- ?Power.
• SHINE(ISC2019)
– Intervention=BG80-130withIVinsulingtt.
– Negativetrial,targetBG<180withSCinsulin.
BrunoA,Durkalski VL,HallCE,Juneja R,Barsan WG,JanisS,etal.TheStroke
Hyperglycemia InsulinNetworkEffort (SHINE)trialprotocol:arandomized,blinded,
efficacytrialofstandardvs.intensive hyperglycemia management inacutestroke. Int J
Stroke.2014;9(2):246–51.
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Temperaturemanagement
• Hypothermianeuroprotective inmodels
• Cerebralmetabolicrateofoxygen(CMRO2 )
tightlylinkedtotemperature
• Foreach1°Cchangeintemperature5–7%
changeinCMRO2COPYRIGHT
FeverGuidelines
Madden LK,HillM,MayTL,etal.TheImplementation ofTargeted Temperature
Management: AnEvidence-Based Guideline fromtheNeurocritical CareSociety.Neurocrit
Care2017Dec;27(3):468-487.
• Feverisassociatedwithpooroutcome.
• Evidenceforspecificmanagementpractice is
generallyoflowquality.
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Case2
• 32yo F with three days of headache, neck
pain, fever.
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Audienceresponse
• Whatdoyouwanttodonext?
– GetaheadCT
– Startantibacterials
– Calltheovernightintensivist andhopetheycan
figureitout
– NoneoftheaboveCOPYRIGHT
CSFprofile
• WBC80,1RBC
• 80%Lymphocytes
• Protein72
• Glucose78COPYRIGHT
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Audienceresponse
• Whatshouldyoudonext?
– Obtaincentralaccess
– Start3%NaCl
– Askneurosurgeryforhemicraniectomy and
temporallobectomy
– Givemannitol
– Alloftheabove
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Mainstudyfindings
• ½ofcasesnounderlyingcauseidentified
• PCRledtofalsepositivesEBV,HHV6
• >5%caseswereautoimmune.
– NMDAleadingcauseamongage<30
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Case3
• 26yoFwithheadache.
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• Worsewhenlayingflat.
• +nausea
• Non-smoker.
• NoFHstroke.
• TakesOCPsCOPYRIGHT
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AudienceResponse
Whatshouldyoudonext?
• Callneurosurgery
• GiveIVtPA
• StartheparinSC
• StartheparinIV
• Signherouttotheovernightintensivisthopingsheknowswhattodo.
• Alloftheabove
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Youarepagedthenurse…
• Patientisunresponsive
• Rpupildilated,non-reactive
• Decerebrate posturing
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Audienceresponse
Whatdoyoudonext?
- Pageneurosurgery
- GiveMannitol 0.5g/kg
- Give23%NaCl IV
- GetaSTATheadCT
- Intubateandhyperventilate
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IntracranialHypertension
• Clinical manifestations – Headache, nausea, vomiting, blurred vision, diplopia (CN VI
palsies), upgaze palsy (Parinaud s syndrome)
– Depressed level of consciousness
– Cushing s triad (hypertension, bradycardia, irregular respirations)
• Two major concerns with elevated ICP– Pressure gradient leading to tissue shifts (herniation syndromes)
– Reduction of CPP/CBF leading to secondary ischemic injury
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CranialContents
Average adult
Brain volume: 1500 ml
Blood volume: 150 ml
CSF volume: 150 ml
CSF production: 20 ml/hr
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Monro-KellieDoctrine
• Cranial vault is a fixed space
• As volume is added to skull, ICP will rise– Mass lesion (hematoma, tumor, abscess)
– Edema (cytotoxic or vasogenic)
– Hydrocephalus
• Initial increase in volume is compensated– CSF displaced into spinal thecal sac
– Distensible cerebral veins are compressed
• Further increase in volume will lead to dramatic increase in ICP
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IntracranialCompliance
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CerebralBloodFlow
0
25
50
75
100
125
150
0 25 50 75 100 125 150 175 200
CPP (mmHg)
CB
F (
cc/1
00g
m/m
in)
Range of Blood
Flow Regulation
Maximal
vasodilation
Maximal
vasoconstriction
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CPP/CBF
• CPP is directly dependent upon ICP
– CPP = MAP (– JVP) – ICP
• CBF is dependent upon CPP
– CBF = CPP/CVR (cerebral vascular resistance)
• CVR is proportional to viscosity and 1/r4
(Poiseuille)
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ICPWaveforms
Non-compliant brain leads to
Relative increase in tidal
wave (P2)
Increase in pulse pressure
(pulse amplitude)COPYRIGHT
SecondaryInjury
CBF is normally maintained at
~50 ml/100g/min.
As CBF drops from 50 to 20
ml/100g/min, oxygen extraction
fraction (OEF) increases, thereby
maintaining normal function
(misery perfusion)
Below 20 ml/100g/min, OEF is
maximized, and CMRO2 (cerebral
metabolic rate for oxygen) drops
(ischemia)
Over time, ischemia becomes
infarction
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IndicationsforMonitoring
• TBI:– Salvageable patients with GCS 3-8 (after resuscitation) and abnormal
CT1
– Salvageable patients with GCS 3-8, normal CT, and at least 2 of following: age > 40, unilateral or bilateral posturing, SBP < 901
– Patients with moderate TBI (GCS 9-12) for whom prolonged continuous sedation is necessary
• SAH, ICH, AIS (no clear guidelines):
– Poor grade SAH patients
– SAH patients requiring IA therapy for vasospasm
– Patients with difficult exam / mental status deterioration who are at risk for intracranial hypertension by exam and/or imaging
• Symptomatic hydrocephalus (treatment)
• Fulminant (acute) hepatic failure (debated):– Encephalopathy grade III or IV (marked confusion to coma) with NH3 >
150 umol/L2
1Brain Trauma Foundation. Journal of Neurotrauma 2007;24(S1):S37-S44.2Raghavan. Neurocritical Care 2006;4:179-189.
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MonitoringTechniques
• EVD
– Gold standard, accurate unless occluded, can be recalibrated
– Both diagnostic and therapeutic
– Complications: approximately 1% hemorrhage1, 8% ventriculitis2 by culture
• Intraparenchymal pressure monitors
– Initially accurate, but can develop zero drift, cannot be recalibrated
– Complications: few, but limited data.
– Indications: global cerebral edema with slit-like ventricles, limited duration need (ie intoxicated patient)
• Brain tissue oxygenation
– BOOST 3 pending.
• Jugular venous saturation and microdialysis monitors
– Not currently favored. Research only.
1Brain Trauma Foundation. Journal of Neurotrauma 2007;24(S1):S45-S54.2Brain Trauma Foundation. Journal of Neurotrauma 2007;24(S1):S26-S31.3Raghavan. Neurocritical Care 2006;4:179-189.
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ManagementStrategies
• ICP-guided therapy
– Keep ICP < 20-25 mainly to avoid herniation and low CPP
• CPP-guided therapy
– Increase MAP as needed to keep CPP > 70 in order to maximize CBF
– In a randomized trial, this strategy led to 5-fold increase in ARDS but no change in outcome versus an ICP guided strategy (with CPP > 50)
• PBTO2 Guided
– BOOST 3 pending…
1Rosner. J Neurosurg 1995;83:949-962.2Robertson. Crit Care Med 1999;27:2086-2095.3Eker. Crit Care Med 1998;26:1881-1886.4Nordstom. Anesthesiol 2003;98:809-814.
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Prevention/Maintenance
• Surgical evacuation of mass lesion
• Neutral head position– Avoid compression of jugular veins
• Head of bed at 30 degrees– Compromise of low ICP when upright and high MAP when flat
– Can optimize in monitored patients
• Euthermia (or mild hypothermia)– Fever raises CMRO2 and disproportionately raises CBF and CBV, and
therefore ICP
• Euglycemia– Hyperglycemia may worsen compliance
• Seizure prophylaxis in selected patients– Seizures increase CMRO2, and convulsive seizures increase ICP via
straining
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Prevention/Maintenance
• Euvolemic eunatremia (or mild hypernatremia)– Hypovolemia decreases ICP by decreasing hydrostatic pressure, but also
decreases CPP
– Hyponatremia (excess free water) leads to fluid accumulation in brain due to osmotic gradient
– Using 3% NaCl to drive Na to 145-160 may decrease number of high ICP episodes, but improvement in outcome is unclear
• Normocapnea (but low normal)– Hypocapnea reduces CBF, which lowers ICP but may lead to ischemia and
worse outcomes
– CBF is reduced in first few days after TBI, so hyperventilation should be avoided early
• Sedation and analgesia– Propofol alone or propofol plus fentanyl with the goal of a quiet, motionless
patient
– Bolus opiates can transiently drop MAP and CPP and increase ICP by reflex vasodilation
– Agitation and pain can increase CMRO2 and ICP via straining
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KeyPoints
• SpecializedneuroICU careisbeneficial.
• Preventionofsecondaryinjury isthemainstay.
• Despitemultimodalitymonitoring,clinicalexamremainsparamount
• Evacuationofmasslesionsisstep1inICPmanagement.
NextBestSteps
• Reviewyourpharmacyguidelinesforanticoagulantreversalandhowtokeeppacewithemergingtherapies.
• ReviewAHAguidelinesforIschemicstrokeandICH.
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Bibliography
• Diringer MN,EdwardsDF.Admissiontoaneurologic/neurosurgicalintensivecareunitisassociatedwithreducedmortalityrateafterintracerebralhemorrhage.Crit CareMed.2001;29:635–40.
• Mirski MA,ChangCWJ,CowanR.Impactofaneuroscienceintensivecareunitonneurosurgicalpatientoutcomesandcostofcare:evidence-basedsupportforanintensivist-directedspecialtyICUmodelofcare.JNeurosurg Anesthes.2001;13:83–92.
• Nogueira RGetal.DAWNinvestigatorsNEngl JMed2017
• AlbersGWetal.DEFUSE3NEngl JMed2018
• Demaerschalk BMetal.ScientificRationalefortheInclusionandExclusionCriteriaforIntravenousAlteplase inAcuteIschemicStroke:AStatementforHealthcareProfessionalsFromtheAmericanHeartAssociation/AmericanStrokeAssociation.Stroke.2016.
• Wardlaw JM.Recombinanttissueplasminogenactivatorforacuteischaemicstroke:anupdatedsystematicreviewandmeta-analysis.Lancet.2012.
• StrokePreventioninAtrialFibrillationIII(SPAFIII)randomised clinicaltrial.Lancet.1996;348(9028):633-8.
• HartRG,Diener HC,YangS,ConnollySJ,Wallentin L,ReillyPA,etal.Intracranialhemorrhageinatrialfibrillationpatientsduringanticoagulationwithwarfarinordabigatran:theRE-LYtrial.Stroke.2012;43:1511–1517.
• RuffCT,Giugliano RP,BraunwaldE,etal.Comparisonoftheefficacyandsafetyofneworalanticoagulantswithwarfarininpatientswithatrialfibrillation:ametaanalysis ofrandomised trials.Lancet.2014;383:955–962.
• Purrucker JC,HaasK,Rizos T,etal.Earlyclinicalandradiologicalcourse,management,andoutcomeofintracerebral hemorrhagerelatedtoneworalanticoagulants.JAMANeurol.2015;73:1–10.
• Brodericketal.Stroke1993;24(7):987–993
• SteinerT,Poli S,GriebeM,etal.LancetNeurol.2016;15:566–573.
• SarodeR,MillingTJJr,Refaai MA,etal.Circulation.2013;128:1234–1243.
• GoldsteinJN,Refaai MA,MillingTJJr,etal.Lancet.2015;385:2077–2087.
• Baharoglu MIetal.PATCHInvestigators.Platelettransfusionversusstandardcareafteracutestrokeduetospontaneouscerebralhaemorrhageassociatedwithantiplatelettherapy(PATCH):arandomised,open-label,phase3trial.Lancet.2016
• AndersonCS.etal.INTERACT2Investigators.RapidBlood-PressureLoweringinPatientswithAcuteIntracerebral Hemorrhage.NEJM2013;368:2355-2365.
• Qureshi etal.IntensiveBloodPressureLoweringinPatientswithAcuteCerebralHemorrhage.NEngl JMed.June8,2016.
• BrunoA,Durkalski VL,HallCE,Juneja R,BarsanWG,JanisS,etal.TheStrokeHyperglycemiaInsulinNetworkEffort(SHINE)trialprotocol:arandomized,blinded,efficacytrialofstandardvs.intensivehyperglycemiamanagementinacutestroke.Int JStroke.2014;9(2):246–51.
• BrainTraumaFoundation.JournalofNeurotrauma2007;24(S1):S37-S44.
• Raghavan.Neurocritical Care 2006;4:179-189.
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