The Neurological Catastrophe: From Stroke to Brain Death

A Comprehensive Review for Critical Care Practitioners

Dr Neeraj Manikath , Claude.ai

Abstract

Acute neurological catastrophes represent some of the most time-sensitive and challenging scenarios in critical care medicine. This review synthesizes current evidence and emerging paradigms in the management of devastating neurological events, from acute ischemic and hemorrhagic stroke to the diagnosis of brain death. We explore extended window therapeutic interventions, surgical decision-making in malignant cerebral edema, reversal strategies for anticoagulant-associated hemorrhage, and the rigorous protocols required for brain death determination. Emphasis is placed on practical clinical pearls, common pitfalls, and evidence-based approaches that optimize outcomes in these high-stakes scenarios.

Introduction

Neurological catastrophes in the intensive care unit demand rapid recognition, precise diagnosis, and aggressive management. The landscape of acute stroke care has transformed dramatically over the past decade, with therapeutic windows extending beyond traditional timeframes and endovascular techniques revolutionizing outcomes. Simultaneously, the intensivist must navigate complex decisions regarding surgical decompression, anticoagulation reversal, and ultimately, the solemn determination of brain death. This review provides a comprehensive, evidence-based approach to these critical scenarios, incorporating recent paradigm shifts and practical guidance for the bedside clinician.

1. Extended Window Thrombolysis and Thrombectomy: New Paradigms in Ischemic Stroke

The Evolution Beyond "Time is Brain"

The traditional 3-4.5 hour window for intravenous thrombolysis has been challenged by landmark trials demonstrating that tissue viability, rather than time alone, should guide treatment decisions.

Extended Window Intravenous Thrombolysis

WAKE-UP Trial (2018): Demonstrated safety and efficacy of alteplase in patients with unknown onset time (typically wake-up strokes) when MRI demonstrates DWI-FLAIR mismatch—a marker of tissue viability despite unclear timing.[1] This approach identifies patients with strokes likely within 4.5 hours based on imaging signatures rather than witnessed onset.

EXTEND Trial (2019): Utilized perfusion imaging (CT or MRI) to select patients 4.5-9 hours from onset with favorable mismatch profiles, demonstrating superior functional outcomes with thrombolysis versus placebo.[2]

Pearl: The paradigm has shifted from "when did it start?" to "is there salvageable tissue?" Advanced imaging (FLAIR negativity on MRI or perfusion mismatch on CT/MRI) can identify appropriate candidates beyond traditional windows.

Mechanical Thrombectomy: The 24-Hour Revolution

DAWN Trial (2018): Patients 6-24 hours from last known well with large vessel occlusion (LVO) and favorable clinical-core mismatch on perfusion imaging demonstrated dramatic benefit from thrombectomy (NNT=2.8 for improved functional outcome).[3]

DEFUSE-3 Trial (2018): Extended the window to 6-16 hours using perfusion imaging criteria, confirming substantial benefit in selected patients.[4]

Selection Criteria for Extended Window Thrombectomy

Clinical-Core Mismatch (DAWN criteria):

Age ≥80 years: NIHSS ≥10, core <21 mL
Age <80 years: NIHSS ≥10, core <31 mL, OR NIHSS ≥20, core 31-51 mL

Perfusion Mismatch (DEFUSE-3 criteria):

Ischemic core <70 mL
Mismatch ratio ≥1.8
Mismatch volume ≥15 mL

Oyster: Not all LVOs benefit equally. Patients with large established cores (>70-100 mL) or poor collateral circulation derive minimal benefit and may have increased hemorrhage risk. The "eyeball test" on non-contrast CT—if you see a massive established infarct, thrombectomy may be futile or harmful.

Practical Approach to Extended Window Cases

Rapid Imaging Protocol: Non-contrast CT, CTA, and perfusion imaging should be obtained immediately
Automated Software: RAPID or similar platforms provide objective core and penumbral estimates within minutes
Parallel Processing: Alert interventional team while imaging is being interpreted
Don't Delay for MRI: CT perfusion is sufficient; MRI adds time without clear benefit in most extended window scenarios

Hack: In patients last known well >24 hours ago but with witnessed symptom onset <6 hours prior (e.g., noticed stroke symptoms 2 hours ago but was last seen normal yesterday), treat based on witnessed symptom onset—many centers use pragmatic clinical judgment supported by favorable imaging.

The Collateral Circulation: The Great Equalizer

Good leptomeningeal collaterals can sustain penumbral tissue for extended periods. On CTA, robust collaterals appear as:

Prominent filling of MCA branches distal to occlusion
Symmetric appearance compared to contralateral hemisphere
Multiphase CTA shows delayed but eventual filling

Pearl: A simple collateral grading system on CTA:

Good: >50% filling of MCA territory
Intermediate: 50% filling
Poor: <50% filling

Poor collaterals predict larger final infarcts and worse outcomes regardless of recanalization success.[5]

Post-Thrombectomy Management Pearls

Blood Pressure Management: Post-recanalization, avoid hypotension (may worsen reperfusion injury) but also avoid severe hypertension (hemorrhage risk). Target SBP 140-180 mmHg in first 24 hours.[6]
Hemorrhage Watch: Obtain non-contrast CT at 24 hours before starting antiplatelet/anticoagulant therapy
Malignant Edema Surveillance: Younger patients with large infarcts (especially proximal MCA occlusions) require hourly neuro checks for 48-72 hours

2. Managing Malignant MCA Syndrome: From Medical Management to Hemicraniectomy

Defining the Malignant MCA Syndrome

Malignant MCA infarction refers to complete or near-complete MCA territory stroke with subsequent life-threatening cerebral edema, typically occurring 24-96 hours post-ictus. It occurs in approximately 10% of large MCA infarctions and carries 80% mortality without decompressive surgery.[7]

Predictors of Malignant Edema

Early Warning Signs (within 6 hours):

NIHSS >20
Involvement of >50% MCA territory on initial CT
Additional ACA or PCA territory involvement
Hyperdense MCA sign (thrombus burden)
Nausea/vomiting at onset (posterior circulation involvement)

Imaging Markers:

Infarct volume >145 cm³ on DWI
Complete MCA territory involvement
Insular ribbon involvement
Involvement of basal ganglia, particularly caudate

Pearl: The "DASH" prediction score uses Diffusion volume, Age, Stroke severity (NIHSS), and Hypodense lesion size to predict malignant edema with reasonable accuracy.[8]

Medical Management: Buying Time or Definitive Therapy?

Osmotic Therapy:

Hypertonic Saline (3%, 23.4%): Preferred agent in most centers due to sustained effect and ability to repeat dosing
- Bolus: 250 mL of 3% over 30 minutes, or 30 mL of 23.4% over 15 minutes
- Maintenance: 3% infusion targeting Na 145-155 mEq/L
- Monitor sodium q6h initially, avoid correction >10-12 mEq/L per 24h
Mannitol: 0.25-1 g/kg q4-6h
- Concerns: Rebound edema, hypovolemia, renal injury
- May be less effective in large territorial infarcts

Oyster: Osmotic therapy for malignant MCA syndrome is temporizing, not definitive. It may delay herniation by 12-24 hours but does not alter the fundamental trajectory. Use it to stabilize for surgical evaluation, not as a substitute for surgery in appropriate candidates.

Head-of-Bed Positioning: Elevate to 30 degrees to promote venous drainage

Temperature Management: Avoid hyperthermia; target normothermia (36.5-37°C). Prophylactic hypothermia is not recommended based on available evidence.

Sedation: In intubated patients, short-acting agents (propofol, dexmedetomidine) allow frequent neuro assessments. Propofol may reduce cerebral metabolic demand.

Hack: The "treat-to-target" approach: If you're using repeated boluses of osmotic agents every 4-6 hours to prevent clinical deterioration, the patient needs surgery, not more medical management.

Decompressive Hemicraniectomy: The Evidence

DECIMAL, DESTINY, HAMLET (pooled analysis): These three European trials demonstrated that decompressive hemicraniectomy performed within 48 hours of stroke onset in patients <60 years with malignant MCA infarction reduced mortality from 71% to 22% (NNT=2) and increased favorable outcomes (mRS 0-4) from 21% to 43%.[9]

DESTINY II (2014): Extended evaluation to patients >60 years, showing mortality reduction (70% to 33%) but with more survivors having severe disability. Importantly, 40% of surgical survivors achieved mRS ≤4, which includes moderate disability with ability to walk and perform self-care.[10]

The Decision Framework

Surgical Candidates:

Age <60 years (strong evidence)
NIHSS >15
Decreased level of consciousness
Infarct >50% MCA territory (or >145 cm³ on DWI)
Timing: Ideally within 48 hours, before signs of herniation

Age 60-80 years: Individualize based on:

Prestroke functional status
Patient/family values regarding disability
Dominant vs non-dominant hemisphere (dominant hemisphere strokes have higher severe disability rates)
Rate of clinical deterioration

Pearl: Early surgery (before clinical deterioration/herniation) yields better outcomes than delayed "salvage" surgery after herniation syndromes develop.[11]

Surgical Technique Considerations

Size matters: Craniectomy diameter should be ≥12 cm (ideally 14-16 cm)
Duraplasty: Generous dural expansion with patch material
Temporal squama: Must be adequately removed to decompress middle fossa
Bone flap: Typically stored in abdominal subcutaneous pocket or cryopreserved; cranioplasty at 3-6 months

The Difficult Conversation: Counseling Families

Oyster: When discussing hemicraniectomy, avoid binary "life vs death" framing. More accurate: "Surgery prevents death but survivors often have significant disability. Without surgery, most patients die within a week. With surgery, most survive but may be moderately to severely disabled, requiring assistance with daily activities."

Key Points for Family Discussion:

Natural history: ~80% mortality without surgery
Surgical outcomes: ~20-30% mortality, ~40% moderate-severe disability, ~30% survival with severe disability
Younger patients and non-dominant hemisphere strokes have better outcomes
Quality of life: Many surgical survivors report acceptable quality of life despite disability when surveyed retrospectively

3. Intracerebral Hemorrhage: Reversal of Anticoagulants and Controlling BP Lability

The Scope of the Problem

Intracerebral hemorrhage (ICH) accounts for 10-15% of strokes but carries 30-50% mortality at 30 days. Anticoagulant-associated ICH (particularly with warfarin, direct oral anticoagulants) represents a particularly challenging subset with higher mortality and hematoma expansion risk.[12]

Anticoagulant Reversal: Drug-Specific Strategies

Warfarin-Associated ICH

Four-Factor Prothrombin Complex Concentrate (4F-PCC):

Dose: 25-50 units/kg IV (typically use 1500-2000 units for most adults with severe bleeding)
Superiority over FFP: INCH trial demonstrated 4F-PCC achieved INR <1.3 in 62% vs 9% with FFP at 3 hours[13]
Speed: INR correction within 30 minutes vs 9+ hours for FFP
Volume: 50-100 mL vs 1-2 liters of FFP (crucial in ICH patients at risk for volume overload and increased ICP)

Vitamin K:

Dose: 10 mg IV slow push
Role: Sustains reversal beyond 4F-PCC's 12-24 hour effect
Onset: 6-12 hours; not for acute reversal alone

Pearl: Don't wait for INR results if history is clear and patient is clinically deteriorating. Empiric 4F-PCC administration can be life-saving. Repeat INR 15-30 minutes post-PCC to guide additional dosing.

Oyster: FFP is outdated for warfarin ICH. Volume load, delayed INR correction, and need for thawing/typing/crossmatching make it inferior. If 4F-PCC is unavailable, it's better to transfer the patient to a facility with PCC than to give FFP.

Direct Oral Anticoagulants (DOACs)

Dabigatran (Pradaxa):

Reversal agent: Idarucizumab 5 g IV (two 2.5 g vials) as rapid bolus
Mechanism: Monoclonal antibody fragment that binds dabigatran with 350-fold higher affinity than thrombin
Effect: Immediate reversal; dTT and aPTT normalize within minutes
RE-VERSE AD trial: 89% complete reversal, hemostasis in 68-75%[14]

Factor Xa Inhibitors (Rivaroxaban, Apixaban, Edoxaban):

Reversal agent: Andexanet alfa 400-800 mg IV bolus followed by 480-960 mg infusion over 2 hours
ANNEXA-4 trial: 82% reduction in anti-Xa activity, hemostasis in 80% of ICH patients[15]
Availability issue: Expensive, not universally available
Alternative: 4F-PCC 25-50 units/kg (off-label, evidence limited but practical reality in many centers)

Hack: If specific reversal agent unavailable and patient deteriorating:

Dabigatran: Consider 4F-PCC + hemodialysis (dabigatran is dialyzable; removes ~60% in 2-4 hours)
Xa inhibitors: 4F-PCC 50 units/kg empirically (despite lack of robust evidence, often used in practice)

Activated Charcoal: If DOAC ingestion within 2 hours, consider 50 g PO/NG (reduces absorption)

Heparin and LMWH

Unfractionated Heparin:

Protamine sulfate: 1 mg per 100 units of heparin given in last 2-3 hours (max 50 mg per dose)
Half-life consideration: Heparin t½ ~60-90 min; protamine dosing diminishes with time from last heparin dose

Low Molecular Weight Heparin:

Protamine sulfate: Less effective (~60% reversal)
Dose: 1 mg per 1 mg enoxaparin given in last 8 hours
If LMWH >8 hours ago: Consider smaller protamine dose (0.5 mg per mg enoxaparin)

Blood Pressure Management in Acute ICH

The pendulum has swung toward intensive early BP reduction to limit hematoma expansion.

INTERACT-2 and ATACH-II: Reconciling the Paradox

INTERACT-2 (2013): Intensive BP lowering (SBP <140 mmHg) vs standard (<180 mmHg) showed trend toward reduced death/disability (primary outcome not significant, but ordinal analysis favored intensive treatment).[16]

ATACH-II (2016): Intensive SBP 110-139 mmHg vs 140-179 mmHg showed no benefit and possible trend toward worse renal outcomes.[17]

Reconciliation: The rate of BP lowering may matter more than the absolute target. ATACH-II achieved targets very rapidly (often within 1 hour), potentially causing cerebral hypoperfusion.

Current Pragmatic Approach

AHA/ASA Guidelines (2022):[18]

SBP 150-220 mmHg: Acutely lower to SBP 140 mmHg safely (Class I recommendation)
SBP >220 mmHg: Aggressive reduction with continuous infusion and frequent monitoring
Avoid: Hypotension (SBP <120 mmHg) and precipitous drops

Pearl: The "15% rule"—reduce BP by ~15-20% over the first hour, then gradually to target of 140 mmHg. Avoid drops >25% in first hour.

Medication Strategies

First-line agents:

Nicardipine infusion: Start 5 mg/h, titrate by 2.5 mg/h q5-15min (max 15 mg/h)
- Smooth, titratable, no bolus needed
Labetalol: 10-20 mg IV bolus, repeat/double q10min (max 300 mg cumulative)
- Useful for acute control, then transition to infusion
Clevidipine: Ultra-short acting, precise titration (costly)

Avoid:

Hydralazine: Unpredictable, can cause reflex tachycardia
Nitroprusside: Theoretical concern for increased ICP (vasodilation)

Oyster: The patient with ICH and SBP 220 mmHg needs IV antihypertensive titration with arterial line monitoring, not intermittent labetalol boluses every "10-15 minutes as needed." Treat this as a medical emergency requiring continuous attention.

Monitoring for Hematoma Expansion

Timing: Peak expansion in first 3-6 hours; ~30% expand significantly
Imaging: Repeat CT at 6-24 hours (or sooner if clinical deterioration)
Spot sign: Contrast extravasation on CTA predicts expansion (sensitivity ~60%, specificity ~85%)[19]

Hack: Irregular hematoma shape, heterogeneous density, or fluid level on initial CT suggest active bleeding and higher expansion risk.

Hemostatic Therapy: Tranexamic Acid

TICH-2 Trial (2018): Tranexamic acid (1 g loading, 1 g over 8h) within 8 hours of ICH onset did not improve functional outcome despite reducing hematoma expansion.[20] Not routinely recommended but some centers use in specific scenarios (suspected coagulopathy, ongoing expansion).

4. The Clinical Diagnosis of Brain Death: The Protocol, the Pitfalls, and the Apnea Test

Prerequisites for Brain Death Determination

Brain death determination is a clinical diagnosis that requires rigorous adherence to protocol. Errors or incomplete examinations have profound ethical, legal, and medical implications.

Essential Prerequisites

Established Etiology: Clear cause of coma consistent with irreversible brain injury
- CT/MRI demonstrating catastrophic injury
- History consistent with known cause (trauma, massive stroke, anoxic injury, etc.)
Exclusion of Confounders:
- Hypothermia: Core temperature must be ≥36°C (some protocols require ≥36.5°C)
- Drug intoxication/poisoning: Sufficient time must elapse for clearance
  - Screen for sedatives, paralytics, alcohol, illicit drugs
  - Consider drug half-lives and metabolism in renal/hepatic dysfunction
- Severe metabolic derangements:
  - Sodium 115-160 mEq/L
  - Glucose >50 mg/dL
  - Phosphate, pH, liver enzymes not severely deranged
Systemic Stability:
- SBP ≥100 mmHg (vasopressors acceptable)
- Adequate oxygenation and ventilation

Oyster: The most common cause of invalid brain death examinations is inadequate time allowed for sedative/analgesic clearance. For patients receiving continuous propofol or benzodiazepines for days, waiting 5 half-lives may require 24-48 hours or more. When in doubt, check drug levels or perform ancillary testing.

The Clinical Examination

Brain death requires demonstration of absent function in all brain regions, including brainstem.

Coma (Absence of Cortical Function)

No response to noxious stimuli anywhere on the body
No spontaneous or purposeful movements
Distinguish from spinal reflexes (see below)

Absent Brainstem Reflexes

Pupillary reflex (midbrain):

Pupils mid-position (4-9 mm) or dilated
No response to bright light
Pitfall: Previous eye surgery, atropine exposure, or direct ocular trauma may confound

Corneal reflex (pons):

No blink response to cotton wisp touching cornea
Test both eyes

Oculocephalic reflex (pons/midbrain):

Doll's eyes: No eye movement when head rapidly turned side to side
Contraindication: Cervical spine instability (use oculovestibular instead)

Oculovestibular reflex (pons):

Cold caloric test: 50 mL ice water into ear canal (after ensuring intact tympanic membrane and patent external canal)
No eye deviation after 1 minute observation
Wait 5 minutes between ears

Pearl: The "COPS" mnemonic for brainstem reflexes: Corneal, Oculocephalic/Oculovestibular, Pupillary, Swallow/gag

Gag/cough reflex (medulla):

No gag with posterior pharynx stimulation
No cough with deep tracheal suctioning

Facial movement to noxious stimuli:

Deep pressure at supraorbital notch, temporomandibular joint, or nail beds should elicit no facial grimace

Spinal Reflexes: The Source of Confusion

Spinal reflexes may persist in brain death and do not invalidate the diagnosis:

Deep tendon reflexes
Triple flexion response (hip/knee/ankle flexion to plantar stimulation)
Abdominal reflexes
Lazarus sign (spontaneous arm flexion/shoulder elevation during apnea test or after death declaration)

Oyster: Inform families before examination that "reflex movements" may occur and do not indicate brain function. Witnessing unexpected movements during or after examination can be profoundly distressing if not forewarned.

The Apnea Test: The Final Arbiter

The apnea test demonstrates absence of medullary respiratory drive—the most primitive brainstem function.

Prerequisites

Core temperature ≥36.5°C
SBP ≥100 mmHg
Euvolemia
Pre-oxygenation: 100% FiO2 for 10 minutes to achieve PaO2 >200 mmHg
Baseline ABG: PaCO2 35-45 mmHg (normocapnia)
No evidence of hypercarbia or hypoxemia

Procedure

Adjust ventilator: 100% FiO2, PEEP maintained (usually 5 cm H2O)
Disconnect ventilator and provide apneic oxygenation:
- Method: Place oxygen catheter at level of carina via ETT, delivering 6-10 L/min O2
- Alternative: T-piece with continuous oxygen flow
Observe for 8-10 minutes:
- Look for respiratory effort (chest/abdominal movement)
- Continuous monitoring: SpO2, BP, cardiac rhythm
Obtain ABG at 8-10 minutes
Reconnect ventilator

Interpretation

Brain death confirmed if:

No respiratory effort during observation period, AND
PaCO2 ≥60 mmHg OR ≥20 mmHg increase from baseline

Pearl: Target PaCO2 ≥60 mmHg because this level provides maximal stimulus to respiratory centers. If baseline PaCO2 is 40 mmHg, a rise to 60 mmHg meets both criteria.

Abort Criteria

Terminate test and reconnect ventilator if:

Hypotension (SBP <90 mmHg)
Severe hypoxemia (SpO2 <85% for >30 seconds)
Cardiac arrhythmias

Oyster: If apnea test is aborted, the result is indeterminate, not negative. Proceed to ancillary testing rather than concluding brain death is absent.

Modifications for Specific Populations

COPD patients with chronic CO2 retention:

Baseline PaCO2 may be >45 mmHg
Target: PaCO2 ≥60 mmHg or ≥20 mmHg above baseline
May require longer observation (10-15 minutes)

ECMO patients:

Sweep gas flow must be minimized or stopped to allow CO2 accumulation
Modified protocols exist; consult institutional guidelines

Common Pitfalls in Brain Death Determination

Inadequate sedation washout: Most common error
Hypothermia: Even mild hypothermia (35°C) can suppress reflexes
Severe metabolic derangements not corrected
Incomplete examination: Missing one brainstem reflex invalidates clinical diagnosis
Misinterpreting spinal reflexes as purposeful movement
Inadequate CO2 rise during apnea test (ventilator not disconnected properly, O2 flush feature blowing off CO2)

Hack: Document your examination meticulously. Most institutions have a specific checklist/form that becomes part of the legal medical record. Incomplete documentation invites legal challenges.

5. The Role of Ancillary Testing (EEG, Blood Flow) in Brain Death Confirmation

When Ancillary Testing is Necessary

Ancillary tests are not required when full clinical examination including apnea test can be completed. However, they become essential when:

Clinical examination cannot be completed:
- Severe facial trauma preventing brainstem reflex assessment
- Pre-existing blindness or ocular abnormalities
- Ototoxic drugs or ear pathology preventing cold calorics
Apnea test cannot be completed or is contraindicated:
- Severe hypoxemia or hemodynamic instability preventing safe disconnection
- Chronic severe hypercapnia (uncertainty about target PaCO2)
- Previously aborted apnea test
Uncertainty about confounding factors:
- Residual sedation suspected but drug levels unavailable
- Metabolic derangements that cannot be fully corrected
Legal or institutional requirements: Some jurisdictions/hospitals mandate ancillary testing

Electroencephalography (EEG)

Technical Requirements for Brain Death EEG

AAN Guidelines:[21]

Minimum 8 scalp electrodes (full 10-20 montage preferred)
Interelectrode distance: ≥10 cm
Sensitivity: Increased to 2 μV/mm (to detect very low voltage activity)
Time constants: 0.3-0.4 seconds
Recording duration: Minimum 30 minutes
Integrity testing: Must verify electrode function and absence of artifacts
Stimulation: Auditory, visual, somatosensory stimuli applied during recording

Interpretation

Electrocerebral inactivity (ECI):

No electrical activity >2 μV amplitude
Artifacts (EKG, environmental, muscle) may be present but distinguished from cerebral activity

Pearl: Have a neurophysiologist or neurologist interpret the study. EEG showing "minimal activity" or "severe suppression" does not meet criteria for brain death—it must show complete absence of cerebral electrical activity.

Oyster: EEG can be falsely "flat" in drug intoxication (especially barbiturates) and severe hypothermia. These must be excluded before interpreting EEG as confirmatory of brain death.

Limitations of EEG

Technical challenges: Artifacts in ICU environment (ventilators, pumps, electrical interference)
Does not assess brainstem function directly: Records only cortical activity
Interpreter-dependent: Requires expertise in brain death EEG interpretation
Barbiturate confounding: Can produce isoelectric EEG in living patients

Cerebral Blood Flow Studies

These tests demonstrate absence of intracranial blood flow, confirming that brain perfusion has ceased.

Cerebral Angiography (Gold Standard)

Technique:

Four-vessel study (bilateral ICAs and vertebral arteries)
Injection must reach skull base/circle of Willis

Findings consistent with brain death:

No intracranial filling of ICA beyond carotid siphon
No filling of anterior or middle cerebral arteries
No filling of vertebrobasilar system
External carotid circulation remains intact

Advantages:

Most definitive test
Directly visualizes absence of flow

Disadvantages:

Invasive
Requires transport to angiography suite
Contrast exposure
Not widely available emergently

Transcranial Doppler (TCD)

Technique:

Ultrasound probe through temporal window
Insonates middle cerebral artery, basilar artery

Findings consistent with brain death:

Reverberating flow: Small systolic peaks with flow reversal in diastole
Systolic spikes: Brief, sharp systolic spikes without diastolic flow
Absence of flow signals (if flow previously detected, absence suggests herniation and cessation)

Pearl: Document bilateral MCAs and basilar artery. Finding reverberating or systolic spike pattern in all vessels strongly supports brain death.

Limitations:

Technical failure: 10-15% of patients lack adequate temporal windows (obesity, elderly, thickened bone)
Operator-dependent
Does not visualize flow directly: Infers absent flow from characteristic patterns

Radionuclide Imaging (Technetium-99m HMPAO or ECD)

Technique:

IV injection of lipophilic radiotracer
Immediate and delayed imaging (optional)

Findings consistent with brain death:

"Hollow skull" sign: No uptake in brain parenchyma
"Hot nose" sign: Intense uptake in nasal/facial structures (blood redistributes to external carotid territory)
Preserved scalp uptake

Advantages:

Can be performed at bedside (portable gamma camera)
Not operator-dependent
No contrast or arterial access needed
No temporal window requirement

Disadvantages:

Availability of nuclear medicine
Requires stable patient for transport to nuclear medicine (unless portable available)
Imaging delay (30-60 minutes post-injection)

CT Angiography (CTA)

Increasingly popular due to widespread CT availability

Findings consistent with brain death:

Absence of opacification of intracranial arteries (MCAs, ACAs, intracranial ICAs)
Opacification of external carotid branches and scalp vessels remains
Scoring systems (e.g., 7-point or 10-point scales) quantify absent filling[22]

Advantages:

Rapid (5-10 minute scan)
Widely available
Objective scoring systems

Disadvantages:

Radiation exposure
Contrast (renal concerns in potential organ donors)
Requires patient transport
Less validated than other methods: Not uniformly accepted in all jurisdictions

Practical Approach to Choosing Ancillary Tests

For incomplete clinical exam:

EEG if concern is cortical function only
Blood flow study preferred if brainstem reflexes cannot be assessed

For aborted apnea test:

Blood flow study preferred (demonstrates medullary ischemia indirectly)
TCD if immediately available and adequate windows

For drug intoxication concerns:

Avoid EEG (can be isoelectric with drugs)
Blood flow study (barbiturates/sedatives do not stop cerebral blood flow unless brain death occurs)

Hack: At many centers, TCD is the most practical first-line ancillary test—non-invasive, bedside, rapid. If inconclusive due to poor windows, proceed to nuclear scan or CTA. Interpreting Ancillary Test Results: Critical Nuances

Pearl: Ancillary tests demonstrate findings consistent with brain death but do not replace clinical examination. The diagnosis remains fundamentally clinical when examination can be completed.

Oyster: A "positive" ancillary test (supporting brain death) in the presence of confounders (hypothermia, drugs) does not confirm brain death. The prerequisites must still be met. Conversely, a technically inadequate or indeterminate ancillary test does not rule out brain death—it simply means the test was non-diagnostic.

Timing and Number of Examinations

United States (AAN Guidelines):[21]

Single examination by qualified physician is sufficient (including apnea test or ancillary testing)
Two physicians may be required by institutional policy or state law
Observation period: No mandatory waiting period between exams if prerequisites met, though many institutions require 6-24 hours between examinations in certain circumstances (e.g., anoxic injury)

International variation:

United Kingdom: Two examinations by two different physicians
Canada: One examination by one physician (two physicians for organ donation cases)
Pediatrics: Some guidelines recommend two examinations 12-24 hours apart in children

Hack: Know your institution's policy and state law. These supersede general guidelines. Document the legal standard you're following.

Clinical Pearls and Practical Hacks: Summary Section

Extended Window Stroke Treatment

PEARL #1: The "tissue window" has replaced the "time window." Perfusion imaging identifies salvageable brain regardless of time from onset.

PEARL #2: Good collaterals on CTA = extended penumbral survival. Poor collaterals = rapid infarct progression regardless of recanalization.

HACK #1: In patients with witnessed symptom onset <6 hours ago (even if last known well >24 hours), treat based on witnessed onset with supportive imaging.

HACK #2: Don't delay thrombectomy for IV tPA in extended window patients—direct to angiography suite while tPA infusing if already started.

OYSTER #1: Massive established core (>100 mL) + poor collaterals = high risk/low benefit scenario. Consider compassionate care rather than aggressive intervention.

Malignant MCA Syndrome

PEARL #3: If you're giving osmotic boluses every 4-6 hours to prevent herniation, you're temporizing—not treating. The patient needs surgery.

PEARL #4: Early hemicraniectomy (before herniation) beats late "salvage" surgery (after herniation). Don't wait for pupils to blow.

HACK #3: For age 60-80 patients, frame discussion around prestroke function and patient values, not binary age cutoffs. A 75-year-old marathon runner differs from a 65-year-old with severe dementia.

HACK #4: Non-dominant hemisphere strokes have better functional outcomes post-craniectomy—factor this into decision-making.

OYSTER #2: When counseling families, avoid "save their life" language. More accurate: "prevent death but survival likely includes significant disability."

Intracerebral Hemorrhage and Anticoagulation

PEARL #5: 4F-PCC reverses warfarin in 30 minutes; FFP takes 9+ hours and risks volume overload. FFP is obsolete for warfarin ICH.

PEARL #6: The "15% rule" for BP reduction—drop by 15-20% in first hour, then gradually to SBP 140 mmHg. Avoid precipitous drops.

HACK #5: If DOAC-specific reversal agent unavailable: Dabigatran → 4F-PCC + hemodialysis; Xa inhibitors → 4F-PCC 50 units/kg empirically.

HACK #6: Irregular hematoma shape, heterogeneous density, or fluid level on CT = active bleeding. Reimage in 1-2 hours, not 24 hours.

OYSTER #3: ICH with SBP >220 mmHg needs IV drip titration with A-line monitoring—not intermittent boluses "every 15 minutes PRN."

Brain Death Determination

PEARL #7: The "COPS" mnemonic for brainstem reflexes: Corneal, Oculocephalic/Oculovestibular, Pupillary, Swallow/gag.

PEARL #8: Spinal reflexes (triple flexion, Lazarus sign) can persist in brain death. Warn families before examination to prevent distress.

HACK #7: Target PaCO2 ≥60 mmHg in apnea test—provides maximal medullary stimulation and meets both absolute and delta criteria in most patients.

HACK #8: Document meticulously using institutional checklist. Incomplete documentation invites legal challenges years later.

OYSTER #4: Most common cause of invalid brain death exam: inadequate sedation washout. For continuous propofol/benzos for days, wait 24-48 hours minimum.

OYSTER #5: An aborted apnea test is indeterminate, not negative. Proceed to ancillary testing, don't conclude brain death is absent.

Ancillary Testing

PEARL #9: TCD showing reverberating flow or systolic spikes in bilateral MCAs + basilar = strong support for brain death.

HACK #9: TCD is the most practical first-line ancillary test—bedside, non-invasive, rapid. If poor windows, proceed to nuclear scan.

HACK #10: Avoid EEG as ancillary test if drug intoxication suspected (can be isoelectric with high-dose sedatives). Use blood flow study instead.

OYSTER #6: CTA for brain death is increasingly used but not uniformly accepted legally. Verify your state/institution accepts it before relying on it alone.

Special Populations and Challenging Scenarios

The Patient on ECMO

Both VV-ECMO (respiratory failure) and VA-ECMO (cardiogenic shock) present unique challenges for brain death determination.

Challenges:

Apnea testing: Sweep gas continuously removes CO2, preventing rise to target PaCO2
Blood flow studies: ECMO provides non-pulsatile flow, altering TCD patterns
Oxygenation: Difficult to achieve pre-oxygenation targets

Modified Approach:

Clinical examination: Can be completed normally
Apnea test modification:
- Option 1: Reduce sweep gas flow to minimum (0.5-1 L/min) for 10 minutes while maintaining oxygenation[23]
- Option 2: Disconnect from ventilator but maintain ECMO at reduced sweep; monitor ABGs q2-3 min until PaCO2 ≥60
- Option 3: Proceed directly to ancillary testing (nuclear scan or angiography preferred)

Hack: Involve ECMO specialists before attempting modified apnea test. Sudden sweep gas changes can cause rapid hemodynamic shifts.

Posterior Fossa Catastrophes

Massive cerebellar strokes or hemorrhages can cause brain death via:

Direct brainstem compression
Upward transtentorial herniation
Obstructive hydrocephalus with subsequent downward herniation

Key Considerations:

Pupils may be normal initially: Posterior fossa lesions can cause brain death via medullary compression without initially affecting midbrain (pupillary) function
Sudden decompensation: Can progress from alert to brain death within hours
EVD consideration: External ventricular drain for acute hydrocephalus may temporize but doesn't address primary problem
Suboccipital decompression: Window for surgical decompression is narrow (must be before brainstem infarction)

Pearl: In posterior fossa hemorrhage with hydrocephalus, EVD alone is often insufficient. Early neurosurgical consultation for possible suboccipital craniectomy is critical.

Anoxic Brain Injury After Cardiac Arrest

Timing Considerations:

Therapeutic hypothermia: Must rewarm to ≥36°C and allow sedation washout (typically 72+ hours post-arrest)
Prognostication: Brain death determination is part of prognostication continuum but represents only one end (immediate death vs prolonged coma vs recovery spectrum)

Multimodal Prognostication:

Even when brain death criteria not met, poor prognostic indicators include:

Absent pupillary and corneal reflexes at 72 hours
Bilateral absent N20 SSEP responses
Malignant EEG patterns (suppression-burst, status epilepticus)
Extensive DWI changes on MRI
High NSE (neuron-specific enolase) levels

Oyster: Don't rush to brain death determination in anoxic injury. Unlike stroke or trauma with anatomic destruction, anoxic injury severity may not be immediately apparent. Standard practice: Wait minimum 72 hours post-rewarming and after sedation clearance.

Pediatric Brain Death

Key Differences:

Observation periods: Recommendations vary by age
- 7 days to 2 months: Two exams 48 hours apart
- 2 months to 1 year: Two exams 24 hours apart
- >1 year: Two exams 12 hours apart (some guidelines allow single exam)
Apnea test: Target PaCO2 may be lower (≥60 mmHg or 20 mmHg above baseline still applies)
Ancillary testing: More commonly required due to difficulty completing full clinical exam

Pearl: Children have remarkable neurologic resilience but also vulnerability. Conservative approach with longer observation periods reflects both uncertainty and gravity of determination.

Religious and Cultural Considerations

Accommodation Without Compromising Medical Standards:

Religious objections to brain death concept: Some faiths equate death only with cardiac cessation
Approach: Acknowledge beliefs, explain medical/legal framework, involve chaplaincy, extend observation period if medically reasonable, but maintain that brain death is legal death
Organ donation: Some families decline based on religious beliefs; respect without judgment

Hack: Early involvement of palliative care and chaplaincy services helps navigate these complex conversations. They can often bridge medical and spiritual perspectives.

Medicolegal Considerations and Documentation

Essential Documentation Elements

For Stroke Thrombolysis/Thrombectomy:

Last known well time (or imaging-based eligibility)
NIHSS score
Inclusion/exclusion criteria checklist
Informed consent discussion (risks: hemorrhage, death; benefits: improved function)
Time metrics (door-to-imaging, door-to-needle, door-to-groin)

For Hemicraniectomy:

Informed consent with specific discussion of:
- Natural history without surgery (mortality ~80%)
- Expected outcomes with surgery (disability spectrum)
- Patient/family values and preferences
- Prestroke functional status
Neurosurgical consultation note

For ICH Anticoagulation Reversal:

Anticoagulant, dose, timing of last dose
Baseline coagulation parameters (INR, aPTT, anti-Xa level if available)
Reversal agent, dose, timing
Post-reversal labs with timing
Hematoma size and location on imaging

For Brain Death:

Complete checklist documenting:
- Prerequisites met (etiology, exclusion of confounders, temperature, hemodynamics)
- All brainstem reflexes tested and results
- Apnea test procedure and results (baseline/final ABGs, observation duration, respiratory effort)
- Physician qualification and credentials
- Date and time of death (time when all criteria met, including apnea test completion or ancillary test interpretation)
Ancillary testing: If performed, attach formal report
Family notification: Document discussion with family about findings

Oyster: The brain death determination becomes part of permanent medical and legal record. It may be scrutinized in litigation, organ donation cases, or insurance proceedings years later. Incomplete documentation cannot be "filled in" retrospectively.

Common Legal Pitfalls

Declaring death before completing full protocol: Death certificate date/time should reflect when all criteria met
Single physician exam when state law requires two
Inadequate documentation of confounding factor exclusion
Failing to wait appropriate time for sedation clearance
Ancillary test not meeting published standards (e.g., EEG duration <30 minutes)

Future Directions and Emerging Evidence

Stroke Treatment: Pushing Boundaries Further

Tenecteplase vs Alteplase:

NOR-TEST, EXTEND-IA TNK, TASTE: Tenecteplase (single bolus) showing non-inferiority or superiority to alteplase (infusion) for large vessel occlusions[24]
Advantage: Simpler dosing (0.25 mg/kg IV push), can be given pre-hospital or in community EDs before transfer
Status: Increasing adoption in many countries; FDA approval anticipated

Ultra-Early Thrombectomy:

Direct-to-angiography suite protocols bypassing ED for severe stroke patients identified in field
"Drip-and-ship" vs "mothership" models being refined with AI-assisted prehospital stroke severity scales

Neuroprotection:

Decades of failed trials, but renewed interest in:
- Nerinetide (post-thrombectomy neuroprotection in alteplase-naïve patients)[25]
- Hypothermia protocols for large strokes
- Combined reperfusion + neuroprotection strategies

ICH: Beyond Blood Pressure Control

Minimally Invasive Surgery:

MISTIE III: Stereotactic aspiration with thrombolysis (alteplase) for deep ICH showed reduction in mortality in subgroup with good hematoma clearance[26]
ENRICH trial (ongoing): Endoscopic evacuation for ICH
Future may include targeted evacuation for selected ICH (deep location, moderate size)

Ultra-Early Hemostatic Therapy:

Tranexamic acid timing (within 2 hours?) may show benefit in subset analyses
Factor VIIa revisited with better patient selection criteria

Spot Sign-Directed Therapy:

Using CTA spot sign to identify high-risk patients for intensive hemostatic intervention
Trials targeting this population specifically

Brain Death: Evolving Concepts

Neuro-Prognostication After Cardiac Arrest:

Moving toward multimodal approaches incorporating EEG, SSEP, imaging, biomarkers
Brain death represents one end of spectrum, but "prognostic withdrawal" discussions increasingly sophisticated

Circulatory Death in Context of Brain Death:

Some jurisdictions exploring donation after circulatory determination of death (DCDD) even when brain death criteria not fully met
Ethical debates ongoing

Cortical Death vs Whole Brain Death:

Philosophical debates continue about whether cortical death (permanent vegetative state) should be legally equivalent to whole brain death
Current legal standard remains whole brain death in most jurisdictions

Conclusion

Neurological catastrophes demand the intensivist's most vigilant attention, sophisticated clinical reasoning, and impeccable procedural execution. The field has witnessed remarkable advances: stroke patients once deemed untreatable now achieve functional independence through extended-window interventions; catastrophic cerebral edema can be managed through rational surgical decompression; anticoagulant-associated hemorrhages can be rapidly reversed with targeted agents; and brain death can be determined with rigorous protocols that respect both medical standards and human dignity.

Yet challenges remain. Every decision—whether to pursue aggressive intervention or allow natural death, whether to recommend surgery or medical management, whether to declare brain death or continue supportive care—carries profound consequences for patients, families, and society. The principles outlined in this review provide an evidence-based framework, but clinical wisdom requires integrating data with individual patient circumstances, values, and contexts.

The intensivist stands at the intersection of cutting-edge medical science and profound human experience. Mastery of the technical aspects—understanding mismatch ratios, calculating PCC doses, executing apnea tests—is necessary but insufficient. Equally essential is the ability to communicate uncertainty, guide families through unimaginable decisions, and recognize when aggressive intervention serves suffering rather than healing.

As we continue to push the boundaries of what is medically possible in neurological emergencies, we must remain grounded in what is ethically appropriate and humanly meaningful. The true measure of expertise in managing neurological catastrophes lies not only in what we can do, but in the wisdom to know when we should—and when we should not.

References

Thomalla G, Simonsen CZ, Boutitie F, et al. MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset. N Engl J Med. 2018;379(7):611-622.
Ma H, Campbell BCV, Parsons MW, et al. Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke. N Engl J Med. 2019;380(19):1795-1803.
Nogueira RG, Jadhav AP, Haussen DC, et al. Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct. N Engl J Med. 2018;378(11):11-21.
Albers GW, Marks MP, Kemp S, et al. Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging. N Engl J Med. 2018;378(8):708-718.
Menon BK, Smith EE, Modi J, et al. Regional Leptomeningeal Score on CT Angiography Predicts Clinical and Imaging Outcomes in Patients with Acute Anterior Circulation Occlusions. AJNR Am J Neuroradiol. 2011;32(9):1640-1645.
Mistry EA, Mistry AM, Mohamed W, et al. Systolic Blood Pressure Within 24 Hours After Thrombectomy for Acute Ischemic Stroke Correlates With Outcome. J Am Heart Assoc. 2017;6(5):e006167.
Hacke W, Schwab S, Horn M, Spranger M, De Georgia M, von Kummer R. 'Malignant' middle cerebral artery territory infarction: clinical course and prognostic signs. Arch Neurol. 1996;53(4):309-315.
Dittrich R, Kloska SP, Fischer T, et al. Accuracy of Perfusion-CT in Predicting Malignant Middle Cerebral Artery Brain Infarction. J Neurol. 2008;255(6):896-902.
Vahedi K, Hofmeijer J, Juettler E, et al. Early Decompressive Surgery in Malignant Infarction of the Middle Cerebral Artery: A Pooled Analysis of Three Randomised Controlled Trials. Lancet Neurol. 2007;6(3):215-222.
Jüttler E, Unterberg A, Woitzik J, et al. Hemicraniectomy in Older Patients with Extensive Middle-Cerebral-Artery Stroke. N Engl J Med. 2014;370(12):1091-1100.
Hofmeijer J, Kappelle LJ, Algra A, Amelink GJ, van Gijn J, van der Worp HB. Surgical Decompression for Space-Occupying Cerebral Infarction (the Hemicraniectomy After Middle Cerebral Artery infarction with Life-threatening Edema Trial [HAMLET]): A Multicentre, Open, Randomised Trial. Lancet Neurol. 2009;8(4):326-333.
Flaherty ML, Kissela B, Woo D, et al. The Increasing Incidence of Anticoagulant-Associated Intracerebral Hemorrhage. Neurology. 2007;68(2):116-121.
Sarode R, Milling TJ Jr, Refaai MA, et al. Efficacy and Safety of a 4-Factor Prothrombin Complex Concentrate in Patients on Vitamin K Antagonists Presenting with Major Bleeding: A Randomized, Plasma-Controlled, Phase IIIb Study. Circulation. 2013;128(11):1234-1243.
Pollack CV Jr, Reilly PA, van Ryn J, et al. Idarucizumab for Dabigatran Reversal - Full Cohort Analysis. N Engl J Med. 2017;377(5):431-441.
Connolly SJ, Crowther M, Eikelboom JW, et al. Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2019;380(14):1326-1335.
Anderson CS, Heeley E, Huang Y, et al. Rapid Blood-Pressure Lowering in Patients with Acute Intracerebral Hemorrhage. N Engl J Med. 2013;368(25):2355-2365.
Qureshi AI, Palesch YY, Barsan WG, et al. Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage. N Engl J Med. 2016;375(11):1033-1043.
Greenberg SM, Ziai WC, Cordonnier C, et al. 2022 Guideline for the Management of Patients With Spontaneous Intracerebral Hemorrhage: A Guideline From the American Heart Association/American Stroke Association. Stroke. 2022;53(7):e282-e361.
Demchuk AM, Dowlatshahi D, Rodriguez-Luna D, et al. Prediction of Haematoma Growth and Outcome in Patients with Intracerebral Haemorrhage Using the CT-Angiography Spot Sign (PREDICT): A Prospective Observational Study. Lancet Neurol. 2012;11(4):307-314.
Sprigg N, Flaherty K, Appleton JP, et al. Tranexamic Acid for Hyperacute Primary IntraCerebral Haemorrhage (TICH-2): An International Randomised, Placebo-Controlled, Phase 3 Superiority Trial. Lancet. 2018;391(10135):2107-2115.
Wijdicks EFM, Varelas PN, Gronseth GS, Greer DM. Evidence-Based Guideline Update: Determining Brain Death in Adults: Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2010;74(23):1911-1918.
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Campbell BCV, Mitchell PJ, Churilov L, et al. Tenecteplase versus Alteplase before Thrombectomy for Ischemic Stroke. N Engl J Med. 2018;378(17):1573-1582.
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Additional Recommended Reading

Stroke Management:

Powers WJ, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke. Stroke. 2019;50(12):e344-e418.

Neurocritical Care:

Wijdicks EFM. The Practice of Emergency and Critical Care Neurology. Oxford University Press; 2010.
Suarez JI. Critical Care Neurology and Neurosurgery. Humana Press; 2018.

Brain Death:

Greer DM, Shemie SD, Lewis A, et al. Determination of Brain Death/Death by Neurologic Criteria: The World Brain Death Project. JAMA. 2020;324(11):1078-1097.

Author's Note: This review represents current evidence and expert consensus as of early 2025. Neurological critical care is a rapidly evolving field. Clinicians should consult their institutional protocols, stay current with emerging evidence, and adapt practice to individual patient circumstances and local resources. When in doubt, early consultation with neurology, neurosurgery, and specialized neurocritical care services optimizes patient outcomes in these complex, time-sensitive scenarios.

Saturday, October 18, 2025