A young adult female with known diagnosis of poorly controlled type 1 diabetes mellitus was admitted with out-of-hospital cardiac arrest. She had only recently been discharged from hospital after an admission with diabetic ketoacidosis. On arrival she had a GCS 3 with minimal respiratory effort. She was in profound DKA. Her temperature was 34.7°C on admission to ICU and she had targeted temperature management aiming for 36°C which was achieved within 2 hours. Her pH had normalised to 7.35 within 8 hours. 48 hours later one pupil became fixed and dilated. CT brain was consistent with global hypoxic ischaemic injury. EEG and SSEP on day 3 revealed severe lack of normal cortical activity. After discussion with family, treatment was withdrawn on day 4.
How do we undertake neuroprognostication after cardiac arrest in the post-TTM era?
With the rise of prehospital care and widely recognised resuscitation algorithms, more and more patients are being admitted to ICU post arrest. Several interventions have been shown to potentially improve outcome in these patients, some of which can make assessment for prognostication of this patient group more challenging.
In 2006, a set of practice parameters for outcome prediction was published by the American Academy of Neurology (1). After review of studies carried out between 1966 and 2006, the authors advocated the use of clinical neurological examinations – namely pupillary light response, corneal reflexes, and motor response to pain – after 72 hours of observation to prognosticate outcome. Similarly, assessment of cortical response on EEG or SSEP 72 hours post return of spontaneous circulation was recommended to predict poor outcome.
At time of this publication, several trials had already been published supporting therapeutic hypothermia (TH) for improved outcome in cases of out of hospital cardiac arrest (2,3). These trials were summarised in a Cochrane review in 2009 (4) which supported targeting 35°C or below to achieve better survival (RR 1.55 with 95% CI 1.22 to 1.96). This recommendation which has since been adopted by post resuscitation care bundles created further debate regarding prognostication as it was unclear to what degree TH affected the previously practiced assessment at 72 hours post arrest. There is a generalised consensus that those who were rendered hypothermic should be assessed 72 hours post being re-warmed to normothermia but no evidence for the prognostic value of this approach. Reports of delayed (post 72 hours) improvement in consciousness post hypothermia in up to 32% of those who survive with favourable outcome (5) adds difficulty in prognosticating this group.
Other methods of prognostication available:
Although neurological assessment remains the gold standard, increasingly electrophysiology testing such as EEG and SSEP are being incorporated into assessments. This requires sufficient neurophysiology expertise and availability in the local centre. There has been a particular interest in the use of SSEP due to evidence that this is less affected by sedatives and hypothermia than clinical examination or EEG (6).
Neuron-specific enolase (NSE) has recently been shown to be a robust predictor of neurological outcome with little effect from core body temperature (7). 686 patients were randomised to target temperatures of 33°C or 36°C and NSE levels were measured every 24 hours. High serial NSEs predict neurological outcome with ROC values of 0.85 and 0.86 at 48 and 72 hours post randomisation respectively. In the author’s own experience, biomarkers are not used as part of the assessment in our own unit.
Finally, neuroimaging may add to the prognostication although their interpretation is less standardised and it relies on experienced neuroradiology support. Evidence of anoxic injury as was evident in the case study including diffuse oedema and loss of grey and white matter differentiation expressed as a ratio (GWR) has been shown to predict poor outcome with 100% specificity (8).
Targeted temperature management (TTM):
In 2013, an international trial including 939 patients was published on TTM (9). In contrast to previous reports leading to recommendation of TH, this study found that induced hypothermia at a targeted temperature of 33°C did not confer a benefit as compared with a targeted temperature of 36°C (Hazard ratio in 33°C group 1.06, p=0.51). Despite being a seemingly “negative” trial, this result is a positive outcome for the critical care community as no satisfactory evidence has been brought to light since uptake of TH as to optimal timing of prognostication. As this trial result is incorporated into the updated care bundles, the confusion surrounding timing of prognostication post TH is likely to resolve.
The key is not to take the neurological assessment at 72 hours as a sole indicator of prognosis. The underlying cause (if identified), the presence of underlying function, features of the arrest itself (rhythm at arrest), and whether the patient was hypothermic on admission also need to be taken into consideration. The recommended strategy is to use multiple modalities to add a degree of certainty to the outcome of clinical examination with electrophysiology, biomarkers, and neuroradiology assessments.
According to the TTM trial (2013), there were no significant benefits of targeting 33°C compared to 36°C in any of the primary or secondary end points. However, there is evidence of potential harm from temperature higher than 37°C and this should be avoided.
The use of electrophysiology, biomarkers, and imaging can add to the clinical findings to prognosticate. SSEP is relatively less affected by sedation and hypothermia and can be a useful prognostication tool.
1. Wijdicks EF, Hijdra A, Young GB, Bassetti CL, Wiebe S, Quality Standards Subcommittee of the American Academy of Neurology (2006) Practice parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. 2006. Neurology 67(2):203-10
2. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002. 346:557-63
3. The Hypothermia After Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002. 346:549-56
4. Arrich J, Holzer M, Herkner H, Mullner M. Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation. Cochrane Database Syst Rev. 2009. 7(4)
5. Mulder M, Gibbs HG, Smith SW, et al. Awakening and withdrawal of life sustaining treatment in cardiac arrest survivors treated with therapeutic hypothermia. Crit Care Med. 2014. 42:2493–2499.
6. Tiainen M, Kovala TT, Takkunen OS, Roine RO. Somatosensory and brainstem auditory evoked potentials in cardiac arrest patients treated with hypothermia. Crit Care Med. 2005. 33:1736–1740
7. Stammet P, Collingnon O, Hassager C, Wise MP et al. Neuron-Specific Enolase as a predictor of death or poor neurological outcome after out-of-hospital cardiac arrest and targeted temperature management at 33°C and 36°C. J Am Coll Cardiol. 2015. 65(19):2104-14
8. Kim SH, Choi SP, Park KN, et al. Early brain computed tomography findings are associated with outcome in patients treated with therapeutic hypothermia after out-of-hospital cardiac arrest. Scand J Trauma Resusc Emerg Med. 2013. 21:57
9. Nielsen N, et al; the TTM Trial Investigators. Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest. N Engl J Med. 2013. 369:23