CONTENTS
- Introduction
- Early brain death is (still) death
- Prognostic value of historical information
- Confounding factors & hypothermia
- Timing & serial evaluation
- Prognostic tests
- Multimodal prognostication
- Related topics
- Podcast
- Questions & discussion
- Pitfalls
Patients often sustain severe neurologic injury during cardiac arrest. As the heart ceases to pump oxyhemoglobin, tissues with higher metabolic rates are more at risk of developing irreversible hypoxic injury. The brain, particularly the cortex, deep gray nuclei and cerebellum, have very high metabolic demand and are thus prone to sustain injury during periods of cardiac arrest. In these cases, the decision to provide ongoing support often hinges on whether the patient might regain meaningful consciousness. Prognostication is extraordinarily important. Excessively pessimistic prognostication could lead to a premature withdrawal of care in a patient with the potential to recover. However, overly optimistic prognostication may lead to ongoing support for days or weeks in a hopeless situation.
The TTM2 trial recently demonstrated that hypothermia at 33C following cardiac arrest was unhelpful. 🌊 The study also showed that maintaining patients at a target temperature of 37.5 degrees is safe. Maintaining patients in a normothermic temperature range (e.g., 36-37.5 C) while minimizing paralytics and sedatives facilitates more accurate neuroprognostication. Much of the literature obtained over the past 15 years has been obfuscated by the use of hypothermia, paralytics, and high doses of sedatives. As hypothermia falls out of favor, we may notice that diagnostic tests start working better than previously.
- Sometimes, patients develop rapidly progressive cerebral edema that progresses to herniation and brain death.
- There is no need to wait 72 hours to declare a patient brain dead. Brain death guidelines do recommend waiting 24 hours after arrest to declare brain death.(32761206) However, if an ancillary test demonstrates lack of blood flow to the brain (cerebral circulatory arrest), then any further waiting may be unnecessary.
- As a general rule, early brain death declaration should be pursued only if you have unequivocal head imaging (CT or MRI) that demonstrates catastrophic structural brain injury (i.e., global cerebral edema with tonsillar herniation) and once all other potential confounders have been ruled out. Further discussion of brain death: 📖
- Details regarding the cardiac arrest (e.g., down time) are often unreliable. Furthermore, it is often unclear what the rhythm and blood pressure truly were (e.g., the “pulseless” patient could be truly asystolic or they could have a non-palpable pulse).
- One possible exception is an arrest which was clearly asphyxial in mechanism (e.g., choking, airway loss during intubation, or asthma/COPD exacerbation which progressed to the point of cardiac arrest). Respiratory arrest will first cause hypoxemia and only later on progress to cardiac arrest. By the time the pulse is lost, the patient has been hypoxemic for a while. Thus, an asphyxial mechanism of cardiac arrest is a poor sign.
primary offender: sedatives & analgesics
- Perhaps the most important aspect of prognostication is avoidance of any sedating medications which can accumulate. Midazolam infusion is the worst offender, but even drugs like lorazepam and fentanyl may accumulate (especially when provided as a continuous infusion 🌊). In a patient with severe neurologic injury, it might not take much medication to delay awakening.
- Body habitus is also an important factor to consider – for example, active metabolites from midazolam are known to accumulate in fatty tissue, which may continue to cause lingering effects of this medication.
- Even propofol has a half-life which is longer than usually recognized (40 minutes initially, with some increase over time when provided as a continuous infusion). Thus, propofol should ideally be held for a considerable duration before neurological evaluation.
- 💡 For comatose or stuporous patients who are unresponsive to pain, the goal of sedation is to prevent dangerous ventilator dyssynchrony or shivering. The goal is not to prevent all movement nor to allow the patient to appear outwardly peaceful. The practice of providing high-dose opioid/sedative infusions to comatose patients is dubious, as this may make patients look better but is unlikely to truly help them (i.e., we're treating our discomfort, not the patient's).
- In summary, provide the least amount of sedation possible in order to confound the neurological picture as little as possible, and if possible/not needed, do not give ANY sedation whatsoever. This will give us the best opportunity to truly determine the patient’s neurological status.
normothermia facilitates early awakening & more accurate neuroprognostication
- TTM at 36-37.5C may generally be performed without the use of opioids or benzodiazepines. Shivering can be managed by a multimodal strategy as described here. Sedatives and analgesics should ideally be limited to agents with a shorter half-lives (e.g., propofol, dexmedetomidine, and pain-dose ketamine infusions). Liberalizing the target temperature to 37.5 may further limit shivering.
- If TTM can be performed at 36-37.5C with strict avoidance of opioids or benzodiazepines, then patients may awake earlier and neuroprognostication may be accurate at earlier time points (which would be similar to clinical practice before hypothermia became popular). The same general strategy for neuroprognostication should be used, but many tests will perform better in the absence of confounding medications.
additional confounding factors
- Prognostication can be confounded by any cause of altered mental status. For example, common confounders are:
- Toxic / metabolic:
- Untreated electrolyte abnormalities (e.g., hyponatremia, hypernatremia, hypoglycemia, hypophosphatemia, hypocalcemia).
- Untreated hepatic encephalopathy.
- Uremic encephalopathy.
- Severe pH disturbances, particularly severe metabolic acidosis.
- Multiorgan failure (especially due to septic shock).
- Iatrogenic:
- Receipt of sedative or analgesic medications.
- Deliriogenic medications (e.g., cefepime).
- Neurologic:
- Unrecognized seizures (including either intermittent seizures leading to a postictal state and inability to wake up, or non-convulsive status epilepticus).
- Coexisting traumatic brain injury.
- Toxic / metabolic:
- Confounding factors should be aggressively sought out and corrected.
- In the presence of confounders which cannot be immediately corrected, a greater amount of caution is required with neuroprognostication.
progression of neurological function over time
- In the absence of confounding factors, neurologic function tends to track out along various curves as shown above. As time progresses, it becomes increasingly clear where the patient will end up neurologically.
- Prognostication depends on integrating information about neurologic function over time.
- More rapid improvement carries a better prognosis (e.g., regaining corneal reflexes within a few hours is a favorable sign).
- Sluggish improvement carries a worse prognosis (e.g., regaining corneal reflexes after 80 hours is a poor sign).
- 💡 Any piece of information about neurologic function (e.g., EEG, clinical exam) is meaningful only when placed within the context of time and taking any lingering iatrogenic sedating medication effect into consideration.
critical time windows for different investigations
- Prognostic tests often have specific time windows in which they reveal the most information. For example:
- Neurologic examination at 72 hours is especially important.
- EEG between 24-48 hours may be most informative.
- CT scan is optimally obtained within 72 hours.
- It is important to make efforts to obtain accurate information within these time windows. If no organized effort is made to neuroprognosticate the patient over the first several days of their ICU stay, this may lead to a murky situation later on.
time course & goals of care
- Often, 72 hours post arrest (or post completion of therapeutic hypothermia) will be needed for definitive prognostication. However, malignant EEG patterns may alert the clinician after 24 hours that the patient is unlikely to recover (but only if these EEGs are obtained in the absence of sedating medications).
- It is useful to have sequential meetings with the family throughout the prognostication process (e.g., an initial meeting after 24 hours, then another meeting after 72 hours). This may help the family process information over time.
- Aside from neurodiagnostic testing, other critical pieces of information are the patient's baseline level of function and the level of disability the patient might be satisfied living with.
- The key question to be addressed in neuroprognostication is whether the patient will be able to improve to a level of function which they would find satisfactory. This involves an intersection of neuroprognostication with the patient/family's wishes. Other active medical problems may also factor into this assessment.
- Prognostic tests can be roughly grouped in terms of:
- Structural tests – radiologic tests looking at brain structure.
- Functional tests – measurements of brain function.
- Functional tests are generally superior, although they may be more susceptible to confounding (e.g., due to medications).
- Structural tests do have some advantages:
- They are not confounded by medications or metabolic abnormalities.
- They can be objectively assessed by independent observers (neuroradiologists).
- They have the capacity to reveal alternative diagnoses which may not have been previously suspected (e.g., intracranial hemorrhage, other primary neurologic disorders).
- A common mistake made during neuroprognostication is overemphasis on imaging tests, with inadequate attention to EEG and neurological examination (which are probably the two most powerful prognostic tests). MRI images are pretty, but they are less informative than serial evaluation of the neurologic examination and EEG over time.
motor response to pain
- After 72 hours:
- Inability to localize or withdraw from pain is worrisome for poor neurological outcome. However, recent data has cast some shade on the use of motor responses – specifically, a poor motor response at 72 hours may incorrectly suggest a poor outcome in patients who may in fact do well.(32915254)
- Ability to localize or withdraw from pain suggests a favorable outcome.
pupillary reflexes
- Pupillary reflexes may be particularly useful, as they seem to be fairly resistant to the effects of sedatives or paralytics (since the pupils contain smooth muscle, they are not affected by paralytics). The specificity of absent pupillary reflexes may be reduced among patients with baseline small pupils, where even an intact light reflex may cause only tiny changes in pupillary size.
- Between 0-24 hours:
- Lack of a pupillary response is nonspecific.
- Presence of pupillary responses may be an optimistic sign (especially if this occurs rapidly following cardiac arrest).
- After 72 hours, absence of any pupillary response is ~20% sensitive and ~99% specific for poor neurological outcome.
- After 96 hours, lack of any pupillary response bilaterally may approach 100% specificity for poor neurological outcome.(33765189)
corneal reflexes
- After 72 hours, absence of any corneal reflex is ~30% sensitive and ~95% specific for poor neurologic outcome.
- After 96 hours, absence of corneal reflexes may approach 100% specificity for a poor neurologic outcome.
- Some technical details regarding the corneal reflex:
- (1) It is essential to stimulate the cornea itself. One study showed that a quarter of physicians test this reflex by stimulating the temporal conjunctiva, rather than the actual cornea.(32915254)
- (2) It is also of importance to avoid touching the cornea over the pupil itself, as this may create a “blink to threat” response that could be misconstrued as a present corneal reflex.
- (3) For the purposes of prognostication, it's probably desirable to physically touch the cornea with gauze (rather than dropping saline flushes on the cornea).
- 💡 Pro-tip: if you touch the patient’s eye-lashes and elicit a corneal reflex, the patient has corneal reflexes and you do not need to advance further.
absence of gag or cough reflex
- Absence of a cough reflex (e.g., following endotracheal tube suctioning) after >48 hours was 100% specific for poor neurologic outcome in a few studies. However, further replication is required to determine the precise specificity of this finding.(32915254)
optimal timing of EEG & evolution over time
- EEG patterns evolve over time following anoxic brain injury, with patients usually transitioning from more malignant-appearing EEGs to more benign-appearing EEGs. Interpretation therefore depends on timing:
- Benign patterns: The sooner the patient is able to achieve a favorable EEG pattern, the more likely they are to recover. Patients with poor prognosis may eventually develop benign patterns several days after arrest, so a benign pattern is less meaningful at later time points.
- Malignant patterns: The longer the patient remains stuck in a malignant pattern, the worse their prognosis is. Malignant patterns in the first 12 hours may be nonspecific. However, remaining in a malignant pattern for >24 hours carries a very poor prognosis.
- Rarely, the EEG may deteriorate over time. In the absence of a reversible cause that is driving the deterioration, this usually indicates a poor outcome.(33591136)
- Therefore, the timing of various EEG patterns is critical. The best single time point to evaluate EEG seems to be ~24 hours after arrest. Beyond 24 hours, EEGs will often improve over time, thereby compromising their sensitivity to detect patients with poor neurological prognosis.(32915254)
obtaining high-quality EEG data
- Complete assessment of a comatose, post-arrest patient often involves the following steps applied daily:
- (1) Hold any sedative infusions if patients are on sedation (comatose patients may be on a propofol infusion to suppress myoclonus). These should be held for several half-lives to obtain and optimal recording.
- ⚠️ If the EEG is obtained on sedation, it should not be used for prognostication purposes.
- (2) Perform a complete neurological examination.
- (3) Motor artifacts (e.g., mylconus, shivering, respiration) can obscure the EEG. If the patient is clinically comatose and the EEG is equivocal, then paralytics should be administered to obtain a high-quality EEG (discussed further here: 📖).
- (1) Hold any sedative infusions if patients are on sedation (comatose patients may be on a propofol infusion to suppress myoclonus). These should be held for several half-lives to obtain and optimal recording.
- 🛑 Obtaining high-quality EEG data within appropriate time windows is essential. Failure to persue a high-quality EEG may substantially confound neuroprognostication.
The EEG may be thought of as a combination of the background pattern plus any additional superimposed activity. The background pattern is the single most important aspect of the EEG. The four most common background patterns are listed in order, from benign to malignant:
(#1/4) continuous background activity
- If a continuous background can be achieved within <12 hours, this is a particularly optimistic sign. (29525975)
- Among patients with good neurological outcome, 80% will achieve a continuous baseline by 30 hours.(32562686) Nearly all patients with a favorable outcome will achieve a continuous baseline within <60 hours.(32915254)
(#2/4) discontinuous background
- This refers to alternating periods of continuous activity with periods of suppression (flat EEG) that occur between 10-40% of the time.
- This pattern is nonspecific prognostically.
- A discontinuous pattern early on (e.g., after 6 hours) is often associated with a good prognosis. However, a discontinuous pattern occuring very late (e.g., after 120 hours) is associated with a poor prognosis.(34988537)
(#3/4) burst suppression
- Burst suppression is defined as periods of activity occurring in short bursts, interrupted by longer periods of complete electrographic suppression (with suppression occupying >50% of the time). Bursts are defined as having >3 phases and lasting >500 ms.(34988537)
- Significance:
- Causes of burst suppression:(33456874)
- High doses of sedatives or anesthetics.
- Status epilepticus.
- Severe encephalopathy (e.g., septic).
- Anoxic brain injury.
- Hypothermia.
- After anoxic brain injury, a burst suppression pattern occurring >24 hours after arrest indicated a poor prognosis in 99% of patients within most studies.(32915254) However, burst suppression only carries a poor prognosis if other causes are excluded (especially sedative medications).
- Causes of burst suppression:(33456874)
- Some subtypes of burst suppression are especially malignant:
- Burst suppression with identical bursts is highly malignant (defined as the first 0.5 second of each burst being identical). Numerous studies have found this pattern to be completely specific for poor outcome, regardless of timing.(34988537)
- Epileptiform burst suppression (burst suppression with high amplitude polyspikes) is strongly associated with poor outcomes, especially when occurring in the context of generalized status myoclonus.(35112033)
(#4/4) suppression
- Suppression is defined as an EEG where >99% of activity has a <10 uV amplitude (a very flat EEG).
- Causes of suppression:
- Profound brain injury (e.g., cerebral edema).
- Severe hypothermia.
- Extremely deep sedation.
- Acute hypoperfusion of the brain (e.g., profound shock with impending cardiac arrest).
- Following anoxic brain injury, a suppressed EEG occurring >24 hours after ROSC is one of the worst possible EEG findings. It is a reliable sign of poor prognosis, in the absence of another explanation (with nearly all studies showing 100% specificity for a poor neurological outcome).
- Related patterns:
- Low voltage pattern is similar to suppression, but a bit milder – with EEG activity having an amplitude <20 uV. This pattern also carries a poor prognosis, but ~5% of patients with this pattern may have a good outcome.(32915254)
- Electrocerebral inactivity is the most severe pattern, with the entire EEG having no electrical activity at all (<2 uV). This carries a similar significance compared to a suppressed EEG, with a similar differential diagnosis (as listed above). However, electrocerebral inactivity generally reflects more profound pathology. In the absence of alternative explanations, electrocerebral inactivity supports the diagnosis of brain death. More discussion of using the EEG to evaluate for brain death here: 📖
(Alpha coma pattern: discussed further here 📖)
periodic discharges & generalized periodic discharges (GPDs)
- A periodic discharge is a waveform that occurs repeatedly, with a quantifiable interval between waveforms. In and of itself, a periodic discharge carries no prognostic value and is purely a marker of brain injury.
- Periodic discharges can be a sign of poor prognosis in the right setting, but this is less important than the background:
- Generalized Periodic Discharges (GPDs) on a suppressed background are a highly malignant pattern, which invariably predicts poor prognosis (figure below).(32915254) If associated with myoclonus, this pattern is consistent with generalized status myoclonus, as discussed further below. 📖 (LaRoche 2018)
- Periodic discharges on a continuous background don't necessarily indicate a poor outcome. In a patient with optimistic clinical features, this might represent an “epileptic pattern” that could potentially respond to antiseizure medications.(35112033)
- Stimulus-induced periodic discharges (SIRPIDs 📖) may be seen in ~15% of post-cardiac arrest patients, with unclear significance.(33591136; 34988537)
sporadic epileptiform discharges
- Sporadic epileptiform discharges are sharp waves or spikes resembling those seen in patients with epilepsy, but lacking the regularity of a periodic pattern. 📖
- Sporadic epileptiform discharges may be rare (<1 per hour) or abundant (>1 every ten seconds).
- This is a concerning sign, with several studies finding sporadic epileptiform discharges to predict a poor outcome with 89-96% specificity.(33591136)
unequivocal seizures
- There standard EEG definition of a seizure may be found here: 📖
- Unequivocal seizures during the first 72 hours after ROSC have a low sensitivity, but high specificity for poor outcome (>>95%).
status epilepticus
- Status epilepticus is poor prognostic sign, even despite aggressive anti-seizure therapy (with poor outcomes in 98.2-100% of patients).(33591136)
- Some patients can do well, usually patients with the following characteristics:(LaRoche 2018; 32915254)
- (1) The background rhythm was continuous or nearly continuous prior to status epilepticus.
- (2) Status epilepticus occurs late in the clinical course after cardiac arrest (e.g., 45 hours vs. 29 hours after arrest).(34988537)
- (3) Patients with other favorable clinical features (e.g., preserved cranial nerves).
- Alternatively, status epilepticus that occurs without a preceding continuous background predicts a poor outcome.(34988537, 37028905)
The presence of myoclonus after cardiac arrest can represent status myoclonus or Lance-Adams myoclonus. Differentiation between these two entities is therefore critically important, because they have different prognostic implications.
generalized status myoclonus (aka myoclonic status epilepticus)
- This may be defined as follows:
- Onset within <48 hours of arrest.(34705079)
- Generalized myoclonus involves four limbs and the face. This should be synchronized, repetitive, symmetric, and unequivocal (not just a little jerking of the hands or face).
- Persists for >30 minutes.
- Associated with clinical coma.
- EEG shows either status epilepticus or a malignant pattern (e.g., burst suppression).(27351833) If EEG is obscured by muscle artifact, paralysis may be needed to obtain a reliable EEG reading.
- 🛑 If the EEG shows a continuous or reactive background, or the presence of spike-wave discharges synchronized with myoclonic jerks, that indicates Lance-Adams myoclonus, as described below.(33765189)
- When all of the above criteria are met, this has been associated with poor neurological outcome (specificity of perhaps ~99%).(33765189, 27017468) However, in some cases, treatment of status epilepticus with antiseizure medications may lead to a favorable outcome (e.g., levetiracetam, valproic acid, propofol).(29225535)
Lance-Adams syndrome
- This syndrome is defined by the following features:
- Myoclonus emerges later after the occurrence of cardiac arrest, often after several days.
- Patients are typically awake.
- Myoclonus occurs while the patient is attempting to move (intention myoclonus), or may be triggered by stimulation.
- This tends to be persistent.
- Lance-Adams syndrome does not carry the same negative prognostic implications as status myoclonus. About half of patients with Lance-Adams syndrome may have a slow neurological recovery.(32915254)
- SSEPs involve stimulating the hand with electricity and tracing the nerve impulse from the periphery to the sensory cortex of the brain. Failure of the nerve impulse to reach the cortex indicates cortical damage (absent N20 wave).
- Note that this is a highly technical study and the quality of the study can be severely affected by any electrical artifact, especially when performed away from the EEG lab and in an ICU. This can profoundly affect the reader’s ability to interpret the study. Caution is therefore advised when using this study in isolation for the purposes of prognostication, as this study should represent an additional piece of information when determining prognosis.
- Bilateral absence of a cortical signal more than 24 hours after arrest strongly predicts a poor outcome (e.g., with a sensitivity of ~45% and a specificity of >99%).(32562686)
- Intact SSEPs are nonspecific, as such patients often can still fare poorly. In this situation, the amplitude of the N20 waves may be used to provide additional information. If the amplitude of the N20 waves is >4 uV, this more strongly implies a favorable outcome.(Sandroni 2022) Alternatively, if the amplitude is <0.62 uV, this suggests an unfavorable outcome – even despite the presence of an N20 wave.(32562686)
- An absent N20 wave on one side combined with a low-voltage N20 wave on the contralateral side appears to predict a poor neurological outcome.(32915254)
- SSEPs can be depressed by a barbiturate coma, but are preserved with other sedatives.(33765189) SSEPs are not affected by hypothermia.(30739213)
- SSEPs CANNOT be performed if you suspect any cervical spinal cord injury, such as in patients who presented after choking, hanging, or after traumatic spinal cord injury. If the cord is injured, the signals from the SSEP may not be able to reach the cortex, and thus, their absence bares no weight when considering prognosis for awakening after cardiac arrest.
- The specificity of absent N20 waves approaches 100% with attention to technical details.(32562686)
- 🛑 Noise from muscle activity may be problematic, but this can be eliminated using paralytics. Thus, paralysis should be considered whenever possible.(33765189)
- SSEPs probably lack utility in patients with a benign EEG pattern. Such patients appear to reliably have normal SSEPs.(31394155)
signs of anoxic brain injury on CT scan may include:
- Reduction of the grey matter/white matter differentiation due to cytotoxic edema, which reduces the density of the grey matter. Similarly, this may cause hypoattenuation of the basal ganglia.(28865528) Quantitative evaluation of grey/white differentiation is discussed further below.
- Diffuse edema:
- (1) Effacement of cortical sulci, cisterns, and ventricles.
- (2) Herniation may occur in extreme cases.
- (3) White cerebellum sign – diffuse edema of the cerebral hemispheres with sparing of the posterior fossa structures results in apparent hyperdensity of the cerebellum and brainstem.(28865528)
- Pseudo-subarachnoid hemorrhage pattern may result from increased density in the basal cisterns due to dilation of superficial venous structures as a result of increased intracranial pressure (figure below). (28865528)
- Radiological findings:
- Symmetrical density in the basal cisterns (but not extending into the cerebral sulci).
- Often seen in combination with generalized cerebral edema and basal cistern effacement.
- Differential diagnosis: may occur due to meningitis, venous sinus thrombosis, or bilateral large subdural hemorrhages. 🌊
- Radiological findings:
- Increased optic nerve sheath diameter: similar to ultrasonography, this suggests elevated intracranial pressure. Some evidence suggests that an average optic nerve sheath diameter >6.5 mm would suggest a poor prognosis.(32915254)
qualitative CT scan for prognostication
- Initial CT scan is not very sensitive for anoxic brain injury. Cerebral edema may become more prominent over ~3-5 days following cardiac arrest, so delayed or repeat CT scanning could have improved sensitivity compared to an immediate post-arrest CT scan.
- When cerebral edema is unequivocally seen on CT scan, this is a grave sign.
- 🛑 Diagnosis of anoxic injury on CT scan can be difficult and subjective in some cases. Be very careful about overcalling this. Viewing the CT scan with stroke windows may help clarify whether there is diffuse edema that causes loss of grey-white differentiation.
The most precise approach to diagnosing cerebral edema is the grey/white ratio. Edema affects the grey matter preferentially (which is visually seen as a loss of grey-white differentiation). Thus, cerebral edema reduces the the grey/white density ratio towards a value of 1.
technique & interpretation
- Technique:
- Measure the density of the caudate and internal capsule on both sides, using small regions of interest (~0.1 square centimeters). This generates four density measurements.
- The sum of the Hounsfield units of the grey matter is then divided by the sum of the Hounsfield units of the white matter.(35931271)
- A ratio below <1.15-1.20 is highly specific for poor outcome.(37028905, 32590271, 35931271, 35372375, 35931271)
- Consider repeating this process, or having different people perform it. If values repeatedly are <1.15-1.20, this may increase confidence in the measurement. Alternatively, if the calculated ratio fluctuates above and below 1.20, then results are equivocal.
performance
- Within <24 hours of arrest, reduced quantitative grey/white ratio is ~25% sensitive for poor outcome, with high specificity.
- Beyond >24 hours after arrest, reduced quantitative grey/white ratio has increased sensitivity (perhaps ~70%), while retaining a high specificity.(35931271)
advantages of quantitative CT scanning over MRI scanning
- CT scanning is logistically easier to perform.
- CT scanning may be performed sooner as compared to MRI (>48 hours).
- CT scanning may be evaluated in a quantitative fashion that has been replicated across several studies and shown to have high specificity.
findings due to anoxic brain injury on MRI
- Cytotoxic edema due to anoxia has a similar MRI pattern compared to other forms of cytotoxic edema (e.g., due to ischemic stroke). Areas will demonstrate restricted diffusion, and appear hyperintense on diffusion weighted imaging (DWI), and hypointense on ADC mapping (a.k.a. restricted diffusion).
- Structures which are more susceptible to anoxic injury include:
- Basal ganglia and thalami.
- Cerebral cortex and cerebellum, including the hippocampi.
- Chronicity of MRI abnormalities: (Tang 2015)
- DWI abnormality peaks at ~3 days, after which it may eventually become pseudonormalized after the first week.
- T2/FLAIR hyperintensity becomes more prominent after 24 hours.
MRI use for prognostication
- MRI is useful only if the CT doesn't show severe anoxic injury.(32562686) If the CT scan shows unequivocal anoxic injury, the MRI will inevitably reveal this as well (since the MRI is more sensitive than the CT scan).
- The optimal time window for obtaining an MRI is 2-7 days after cardiac arrest.(33765189; Sandroni 2022; 34580886; 37028905)
- Occasionally, an MRI may be seen which doesn't show any substantive anoxic injury. This is a red flag that the diagnosis may be incorrect – the patient may not have severe anoxic brain injury. This should prompt an evaluation for the presence of other causes of altered consciousness. (e.g., see the delirium chapter here).
- Absence of diffusion restriction in the cortex or deep grey matter on MRI after 2-7 days is >80% specific for a good neurologic outcome.(Sandroni 2022)
- Several studies suggest that extensive diffusion restriction (ADC hypointensity) can predict poor prognosis with good sensitivity (>50%) and high specificity (>95%). Diffuse involvement of the cortex and deep grey matter bilaterally may be considered “severe.” (37028905)
- NSE is an enzyme released due to brain injury or hemolysis.
- Elevated and rising levels of NSE predict poor outcome.
- Limitations to the use of NSE include the following:
- Lack of availability at many centers.
- Disagreement regarding optimal cutoffs, due to an absence of calibration standards between laboratories.(32562686)
- False-positive elevation of NSE due to hemolysis or neuroendocrine tumors. If NSE is used, serial NSE levels at 24, 48, and 72 hours may help avoid confounding by a hemolyzed specimen. (33765189)
- Turnaround time is often long.
- It remains to be demonstrated whether NSE adds additional, independent prognostic information above and beyond what is available from other tests (especially if EEG is available).
- ⚠️ Canadian guidelines recommend that NSE shouldn't be routinely used.(37028905)
general approach to neuroprognostication
0-72 hours: supportive care
- ⚠️ Avoid confounders (e.g., hypothermia, benzodiazepines, opioids).
- Obtain prognostic information:
- Early prognostication may occasionally be possible:
- If patient is brain dead ➡️ they are deceased. 📖
- Diffuse cerebral edema causing herniation ➡️ grave prognosis.
- Localization/withdrawal to pain ➡️ favorable prognosis.
>72 hours: Prognosis is extremely poor if:
- NONE of the following are present:
- <<PLUS>>
- At least TWO of the following indicators are present:
- (1) No pupillary or corneal reflexes after >72 hours. 📖
- (2) Highly malignant EEG after >24 hours, in the absence of sedation (e.g., suppressed background, burst-suppression, or GPDs on a suppressed background). 📖
- (3) Early status myoclonus (within <72 hours). 📖
- (4) Imaging evidence of severe anoxic brain injury, including either:
- (5) Bilaterally absent N20 SSEP wave after >24 hours. 📖
- ⚠️ For patients treated with therapeutic hypothermia at 33C, prognostication should generally be delayed for 72 hours after rewarming (i.e., ~96 hours post arrest).(37028905)
if neurological prognosis is unclear:
- Provide ongoing supportive care.
- Evaluate for and treat any factors that may be suppressing mental status (i.e., causes of hypoactive delirium such as sedating medications, abnormal sodium level).
- Obtain additional data (e.g., MRI, SSEPs, serial neurological examination).
This is a general approach based on a combination of the ESICM and Canadian guidelines.(33765189, 37028905) However, the management of individual patients should be individualized based on clinical context and specific test results.
additional comments
general principle of multimodality neuroprognostication
- Neuroprognostication should be based on combining multiple sources of information. For example, most patients will have neuroimaging (at least a CT scan), serial neurological examinations, and video EEG.
- When all sources of information are in agreement, this may increase confidence. For example, a combination of cerebral edema on CT scan, poor serial neurologic examinations, and a malignant EEG pattern could indicate a poor prognosis with high confidence.
- When sources of information disagree with one another, then additional testing and/or additional time is required to allow for prognostication. For example, a poor neurological examination combined with a normal MRI scan would imply the presence of an alternative diagnosis (e.g., metabolic encephalopathy), and potentially a favorable outcome.
delayed awakening & patients with indeterminate prognosis
- Some patients may regain consciousness after three days (late awakening) – especially due to sedative medications, hypothermia, or any other causes of delirium (e.g., renal or hepatic dysfunction, sepsis).
- Risk factors for delayed awakening may include older age, renal insufficiency, and post-resuscitative shock.(34580886)
- These factors are largely the same as confounding factors listed above.📖
- One before-after study comparing midazolam/fentanyl sedation versus propofol/remifentanil sedation found that short-acting sedation lowered the odds of delayed awakening (with an odds ratio of 0.08).(22527063)
- Avoidance of any long-acting sedation (including fentanyl infusions) may help patients awaken earlier, thereby limiting their ICU course and avoiding iatrogenic complications. A recent review article wrote that “conclusions about prognosis should be delayed at least 72 hours after arrest to allow for the clearance of sedative drugs” – but a better approach may be to never use long-acting sedation in the first place.(32562686)
- Generally, the grey matter is more vulnerable to hypoxemia. However, isolated white-matter injury can occur. Many cases are associated with carbon monoxide exposure.
- Clinically, gradual onset of neuropsychiatric symptoms may occur days-weeks after apparent recovery from the hypoxic event. Symptoms may include hallucinations, psychosis, amnesia, and parkinsonism.
- MRI typically shows diffuse T2/FLAIR hyperintensity with diffusion restriction throughout the cerebral white matter (usually with sparing of the posterior fossa). The U-fibers are typically spared (figure below). 📖 There isn't contrast enhancement.
- Outcome is often poor, but recovery is reported.(Tang 2015)
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- The two most common and pervasive pitfalls:
- (#1) Use of long-acting sedatives (even fentanyl should be avoided). Long-acting medications may complicate the neurologic examination.
- (#2) Failure to use a guideline-directed, systematic approach that includes collection of key data at specific timepoints (e.g., EEG after 24 hours, neuro examination at 72 hours).
- If the patient spent a few days at an outside hospital before transfer, this must be accounted for. For example, if a patient is transferred to your hospital two days after arrest, the clock starts at the time of arrest (not the time of transfer).
- Failure to obtain a detailed and thorough neurologic examination at 72 hours is very problematic. The neurologic examination continues to evolve over time, rendering it less specific over time (e.g., if corneal reflexes appear after five days, this is less reassuring than corneal reflexes being present after three days).
- Overemphasis on fancy tests (e.g., MRI and SSEPs), while overlooking the neurologic exam and EEG.
Acknowledgement: Thanks to Dr. Richard Choi (@rkchoi) for thoughtful comments on this chapter.
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References
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