This is a summary of the factors which determine neurological outcome after cardiac arrest. It has been assembled from the college model answers to the many questions they always seem to ask about this topic (it is very popular with the SAQ writers), as well as using the most recent ERC/ESICM statement (Sandroni et al, 2014

 

A good  review of the evidence has been published in Neurology (2006)  by the American Academy of Neurology. It outlines the main factors which influence neurological outcome after cardiac arrest. However, all of the data therein must be taken with a grain of salt. Most of these studies were conducted in the pre-hypothermia era. One Seattle study which is often quoted aggregates data from 1977 to 2001! Who knows what those EMS hippies were doing in the 70s.

This 2006 statement has to some extent been superceded by the most recent ERC/ESICM statement (Sandroni et al, 2014). As the hot new thing, it was the source for much of what is presented below.

In order to simplify revision, a tabulated summary is offered:

Predictors of Poor Outcome in Comatose Survivors of Cardiac Arrest
Predictive sign or investigation Predictive utility Confounding factors
Absent pupillary reflex

 0% false positive rate at 72 hours, irrespective of cooling

  • Sedation
  • Hypothermia
  • Paralysis
  • Presence of shock
  • Metabolic derangements, eg. acidosis

 

Absent corneal reflex  0-15% false positive rate at 72 hours
Extensor motor response, or worse May be associated with poor outcomes
  • High false positive rate (~50%)
Myoclonic status epilepticus Persisting myoclonic status epilepticus has a 0% false positive rate within the first 24 hours
  • Interpreter-dependent
  • Findings may be subtle
  • Paralysis interferes with interpretation
Somatosensory evoked potentials:
absence of the N20 component
Absence of N20 predicts poor outcome with a0% false positive rate.

Presence of N20 does not rule out a poor outcome.

N20 responses may disappear on repeat testing.

N20 responses may reappear, but this does not suggest a good prognosis.

Burst suppression on EEG May be associated with poor outcome  Poor predicitive value; 
cannot be used for prognostication.
Absence of EEG reactivity Low false positive rate (0-5%) Confounded by sedation
Neuron-specific enolase NSE over 33μg/L at 1-3 days post CPR predicts poor outcome with a 0% false positive rate

NSE may be elevated for reasons other than brain injury; for instance, it may be secreted by neuroendocrine tumours

CT brain On CT, an inversed gray/white matter ratio in Hounsfield units was found in patients who failed to awaken after cardiac resuscitation. However, the predictive value of CT findings is not known

If performed too early, the CT may not demonstrate any findings.

A summary of false positive rates

Before launching into a detailed discussion of each predictive index, it is interesting to compair them together in a group. The numbers in the table below were derived from a relatively recent meta-analysis (Golan et al, 2014) which seems to be widely quoted (and which seems to form the basis of prognostic recommendations made by various society guidelines, for instance the new Canadian Guidelines).

Predictive Test False Positive Rate in % (and 95% CI)
Bilateral absence of pupillary reflexes more than 24 hours after ROSC 2% (1-6%)
Bilateral absence of somatosensory-evoked potentials between days 1 and 7 after ROSC 3% (1-7%)
Bilateral absence of corneal reflexes more than 24 hours after ROSC 4% (1-9%)
Myoclonic status epilepticus 5% (2-11%)
Unfavourable EEG patterns 7% (4-12%)
Motor score showing extensor posturing or worse 9% (6-13%)
Neuron-specific enolase >33mcg/L 12% (6-23%)

Timing of prognostication following cardiac arrest

The recommendations offered by the college in their answer to Question 20 from the first paper of 2015 are as follows:

  • 72 hours following cardiac arrest
  • 120 hours if therapeutic hypothermia was used (i.e 72 hours following the return of normothermia)

These recommendations seem to be based on the multimodal prognostication algorithm from the new 2014 statement.  The situation is confused by the fact that many testing modalities have their own ideal time window. Neuron-specific enloase can be tested at 24 hours following ROSC, EEGs and SSEPs can be performed during hypothermia (i.e. 24-48 hours post ROSC) and most of the studies of clinical examination findings waited until 72 hours after rosc. Given that the 2014 consensus statement repetitively recommends the simultaneous use of multiple markers, one is almost obliged to wait three days. The main reason for the delay is the assurance that all mind-altering and paralysing substances have been cleared.

The influence of historical features on outcome in cardiac arrest

Aetiology of cardiac arrest

The initial rhythm is the strongest predictor of mortality and morbidity.

VF arrest: This has the best prognosis. 69% survive the ambulance ride, and 40% survive until discharge from hospital. With cooling, roughly 49% of the survivors were either neurologically intact or suffered minor deficits.

Pulseless electrical activity: This has a poor prognosis. 23% survive the ambulance ride, and 11% survive until discharge from hospital. Of those 11%, roughly 80% were either neurologically intact or suffered minor deficits.

Asystole: This has the poorest prognosis. 10% survive the ambulance ride, and 2% survive until discharge from hospital. Of those 2%, roughly half (55%) were either neurologically intact or suffered minor deficits. None of the survivors were over 70 years old.

Location of cardiac arrest

According to the Seattle series, you have a much better chance of survival if your cardiac arrest is witnessed, and occurs in a public place. The commencement of bystander CPR is the key feature here. No matter how useless the bystanders, any CPR is probably better than no CPR.

Interestingly, being in a hospital is not especially protective. Of patients suffering in-hospital cardiac arrest (of all aetiologies) 49% had a restoration of spontaneous circulation and 15% survived until discharge; in another study 27% of suvivors had "good neurological function".

Duration of arrest

Duration of time before CPR is commenced could be important. In one study of in-hospital arrest a delay of over 5 minutes was strongly associated with mortality.  Duration of CPR itself could also be important. In the same study, CPR lasting longer than 20 minutes was strongly associated with increased mortality.

However, the AAN recommended that CPR duration be left out of the predictions regarding neurological outcome, as these variables do not discriminate accurately between those patients who will be neurologically damaged and those who will not. In their own words, "prognosis cannot be based on the duration of CPR".

Patient factors which influence outcome in cardiac arrest

Age of the patient

Age is a weaker predictor than the initial rhythm.

Still, the older you are, the less likely you are to survive until discharge. The large-scale Seattle series calculated that the odds of survival decrease for every year of age, with an odds ratio of 0.97 per year. Mortality in one series was ~ 94% for the over-80s, and ~68% for the under-45s. However, age did not seem to be predictive of neurological outcome - only mortality.

Presence of comorbidities

Comorbidities are a negative prognostic indicator. Conditions such as CCF, NIDDM, COPD, AF, hypertension et cetera- all of these adds a certain risk of poor outcome, with an odds ratio of 0.84 per condition.

Clinical findings associated with poor neurological outcome

Apart from the abovementioned 2014 society statement, the best reference for prognostically interesting clinical examination findings seems to be this 2013 paper by Greer et al.

Absence of pupillary response

Immediately after a cardiac arrest the pupils can be fixed and mid-size (or dilated) for a whole variety of reasosns, and this should not be used to prognosticate. However, at 72 hours following ROSC a bilateraly absent pupillary reflex has a 0% false positive rate in predicting poor neurological outcome, irrespective of whether the patient was cooled or not.

Absence of the corneal reflex

At 72 hours post arrest, absent corneal reflexes ohave a false positive rate of only 5% in identifying poor neurological outcome. However, having a normal corneal reflex does not predict a good outcome.

Myoclonus status epilepticus on day 1

Myoclonus status epilepticus (the repetitive, "unrelenting" jerking of the face and body) has been reported previously to have no association with prognosis; however the AAN reported that within their meta-analysis this feature (when present on day 1 post arrest) was strongly associated with poor neurological outcome even in the presence of brainstem reflexes or some motor response. The false positive rate was also 0%, which means you can use this early marker as a warning of poor outcome. This recommendation is upheld by the most recent 2014 psotion statement. Status myoclonus must begin within 48 hrs following ROSC in order to be avalid marker, and must be status myoclonus rather than intermittent jerks. The prognostic utility of this findign is tarnished somewhat by several case reports of patients who have recovered well after having early myoclonus.

Absent or extensor motor responses

Back in the days of "warm" arrest, the AAN strongly supported absent motor responses at 72 hours as predictors of poor outcome. The motor component of the Glasgow Coma Scale does not yield false positives after 72 hours, they said. Absent motor response or extensor responses were associated with poorer neurological outcomes: only 1% of such patients can hope to be independent. In short, you want to obey commands, localise to pain, or at least withdraw from it (63% of such patients went on to have a good neurological recovery, with some degree of independence).

However, in the hypothermia era the 2014 society statement has downgraded their support for this finding. More recent evidence has demonstrated that motor score has a very high false positive rate (almost 50% in some studies!). For example, in a post-hoc analysis of the TTM trial (33°C vs 36°C) performed by Dragancea et al (2015), a motor score of 2 or worse had a 19.6% false positive rate. Perhaps it was better in the pre-cooling era? The consensus is to only use this finding together with other, "more robust" predictive markers.

Electrophysiology findings associated with a poor neurological outcome

EEG findings

The 2006 AAN statement described a series of findings associated with poor outcome (eg. generalised epileptiform discharges, generalised periodic complexes on flat background) and suggested that they have poor predicitive value and cannot be used for prognostication. The model answer to Question 20 instead reports that generalised suppression burst suppression or generalised periodic complexes are strongly associated with a poor outcome. Indeed, since 2006 the evidence has shifted in favour of EEG. The 2014 statement has identified the following EEG findings which were associated with a poor outcome and had a false positive rate of around 0-7%:

  • Absence of EEG reactivity in cooled patients (during hypothermia)
  • Presence of status epilepticus during hypothermia or immediately after rewarming
  • A bispectral index (BIS) of less than 6 during therapeutic hypothermia

Burst suppression is actually compatible with a satisfactory neurological outcome. Low voltage EEG tracing in patients who are not being cooled also has a low false positive rate, but the voltage magnitude of the EEG can be influenced by hypotermia, and is therefore not very useful. In general, criticsm of EEG in this setting (and of its use in ICU in general) is that experienced interpreters have very high confidence in their EEG interpretations, but low inter- and intra-rater reliability.

Somatosensory evoked potentials (N20 wave)

The AAN recommended this as a more useful tool than the EEG. - many patients without meaningful recovery will have normal N20 responses. So interesting is this modality, that CICM made it the topic of an entire 10-mark SAQ (Question 11 from the second paper of 2014). Absence of the N20 component with median nerve stimulation accurately predicts poor outcome, but its presence does not rule out poor outcome - many patients without meaningful recovery will have normal N20 responses.

SSEPs are not confused by therapeutic hypothermia; in cooled patients bilateral absence of N20 SSEP is able to accurately predict a poor outcome with a false positive rate which approaches 0%. There are isolated case reports of false positive prediction, which are tarnished by allegations of poor tracing quality and interpretation error.

Overall, the new 2014 recommendations are as follows:

  • SSEPs are prognostic at > 72 hours in cooled patients
  • SSEPs are prognostic at >24 hours in non-cooled patients

Biomarkers associated with poor neurological outcome

Neuron-specific enolase

NSE over 33μg/L at 1-3 days post CPR predicts poor outcome with a 0% false positive rate and this does not seem to be affected by temperature control (Stammet et al, 2015). It may be more useful later rather than earlier. There is disagreement as to the precise threshold, but generally people agree that serial NSE levels over 60mcg/L are "very rarely associted with a good outcome".

S100 calcium-binding protein B

S100b is expressed primarily by astrocytes; its presence in the bloodstream indicates some sort of glial damage. Threshold values differ study to study, and every author seems to b using a different measurement technique. Though potentially promising, this biomarker needs experiments with better standards before anybody is able to recommend it.

Imaging findings associated with a poor neurological outcome

CT brain

You would be looking for diffuse cerebral oedema.On CT, an inversed gray/white matter ratio in Hounsfield units was found in patients who failed to awaken after cardiac resuscitation. However, the predictive value of CT findings is not known; and if performed too early, the CT may not demonstrate any findings. The false positive rate is around 8%. Attempts to make the interpretation of CT data into a more scientific quantitative method were made; people compared the density of grey and white matter to demonstrate that differentiation is lost. This strategy appeared to have a 0% false positive rate, but again with all the studies using different methods to calculate the density ratio.  In spite of these problems, the 2014 consensus statement suggests that a "marked reduction" in grey-white density ratio can be used as early as 24 hours following ROSC.

MRI brain

The earlist MRI changes (hyperintensity of signal in basal ganglia and cortex) have tended to accurately identify patients who are going to go on to have a persistent vegative state or death. However, all the studies have been cursed with a small sample size.

A suggested prognostication algorithm

The following recommendations were made by ESC/ESICM in 2014:

  • During the first 24 hours, do not prognosticate.
    • Status myoclonus or a particularly bad CT could be used to form an early opinion
  • At 72-120 hours (day 3 to 5), provided residual sedation and other metabolic confounders are excluded, one can be confident of a poor outcome if:
    • Bilaterally brainstem reflexes are absent
    • Bilateraly SSEP N20 waves are absent
  • Even if the abovementioned indicators are equivocal, around the 4th day one can be confident of a poor outcome in the presence of the following features:
    • Status myoclonus within 48 hours of ROSC
    • High serial neuron-specific enolase levels
    • Unreactive EEG or status epilepticus
    • Strongly suggestive CT or MRI findings

References

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