Early predictors of poor outcome after out-of-hospital cardiac arrest

For patients who are unconscious after out-of-hospital cardiac arrest (OHCA) and treated with hypothermia, survival rates around 50% are reported [1, 2]. Pre-hospital factors such as time from collapse to start of cardiopulmonary resuscitation (CPR), time from collapse to return of spontaneous circulation (ROSC), initial rhythm, bystander CPR and lactate levels all are strongly correlated with outcome at a group level [2–7]. However, these correlations are based on large retrospective cohorts with no control for differences in patient treatment and may therefore be subject to bias. Furthermore, single predictors may not be reliable in individual cases, owing to difficulties in obtaining or recording precise information during pre-hospital management of cardiac arrest (CA) [8, 9]. Currently, neurological prognostication in patients remaining unconscious is not recommended earlier than 72 h after the CA [10]. Nevertheless, in the OHCA patient population, with its elevated mortality, an earlier prediction of poor outcome is desirable for the process of care and information provided to the patient’s relatives. An assessment of the risk for a poor outcome would also be of great value for comparing populations and to define patient risk when assessing effects in interventional studies. Efforts to construct a prediction score based on the set of data available at hospital admission have yielded the OHCA score [11] and the Cardiac Arrest Hospital Prognosis (CAHP) score [12]. When applied prospectively, the OHCA score showed moderate predictive accuracy [13]; however, none of these scores has been validated for clinical use.

The aim of this study was to establish a clinically useful association between parameters available from patient history and status at intensive care admission and outcome in comatose survivors of OHCA. The first step in the analysis was directed at determining the association between these factors and poor outcome at 6 months, defined as Cerebral Performance Category (CPC) 3–5 [14]. The second step was directed at constructing an easy-to-use risk score for prediction of a poor outcome.

We performed a post hoc analysis of data obtained in the Target Temperature Management (TTM) trial [15], in which researchers recruited patients from 36 intensive care units (ICUs) in Europe and Australia. The trial included adult patients (≥18 years) resuscitated from OHCA of a presumed cardiac cause who remained unconscious (Glasgow Coma Scale [GCS] score ≤8) more than 20 minutes after ROSC. The main exclusion criteria were unwitnessed asystole as the initial rhythm and refractory shock at hospital admission defined as sustained systolic blood pressure less than 80 mmHg despite administration of fluids, vasopressors, inotropes and/or treatment with an intra-aortic balloon pump or left ventricular assist device [16].

Pre-hospital data, including initial rhythm, witnessed arrest, administration of bystander CPR and time from collapse to ROSC, were systematically collected at admission according to the Utstein guidelines [17]. Time from CA to initiation of basic life support (BLS; administered by bystanders or first responders) and advanced life support (ALS) was recorded. No-flow and low-flow times were defined as the time from CA to the start of CPR (BLS or ALS) and the time from the start of CPR to ROSC, respectively. Time to ROSC was defined as the time from CA to the first recorded time point of sustained spontaneous circulation. Patients were included in the present analysis if their CPC was recorded at follow-up 6 months after CA. All sites participating in the TTM trial registered patient data in a common electronic case report form. The process was monitored at each site by external reviewers who visited the centres and verified the correctness of registered data. All the centres used the same study protocol that defined target temperature management over time and prompted multimodal investigations for neurological prognostication. The results of the main trial were subjected to sensitivity analyses for time, study centre and other possible biases, all of which turned out negative.

The TTM trial demonstrated no difference in mortality and neurological outcome between a target temperature of 33 °C and 36 °C. The result has been further elaborated in post hoc analyses and sub-studies, which have so far shown similar outcomes in the two target temperature groups [18–21]. Therefore, data were pooled for the present analysis.

A total of 939 patients were included in the original TTM trial. Neurological outcome data 6 months after CA were available for 933 (99%) patients, who consequently were included in the present analysis. Of these patients, 493 (52%) had a poor outcome of CPC 3–5. Their median age was 65 years (IQR 57–73 years), and 177 (19%) were female.

Risk for a poor outcome assessed by OHCA and CAPH scores

On the basis of the formula presented by Adrie et al. [11], we calculated the OHCA risk score in our cohort for each of the 50 imputations. This rendered a median (range) AUC of 0.746 (0.739–0.752), and 48 of the 50 imputations (96% of the imputed datasets) had a p value <0.05 for the Hosmer-Lemeshow goodness-of-fit test, indicating poor calibration. Median (range) concordance was 74.4 (73.8–75.1). For patients with a high risk according to the original paper (score >32.5), the sensitivity was 44% to 45% and the specificity was 89% to 89% for a poor outcome.

By visually estimating the parameters in the risk score model presented by Maupain et al. [12], we also calculated the CAHP risk score in our cohort for each of the 50 imputations, yielding a median (range) AUC of 0.746 (0.743–0.747), and 20 (40%) of the 50 imputations had p values <0.05 for the Hosmer-Lemeshow goodness-of-fit test, indicating poor calibration. The median (range) concordance percentage was 74.3 (74.0–74.6). In patients with a score above 200 points, which Maupain et al. defined as high risk, the sensitivity for poor outcome was 48% to 49% with a corresponding specificity of 82% to 83%.

The performance of the OHCA and CAHP scores is shown in Table 6. A comparison of the performance using ROC curves of the three risk scores is presented in Fig. 1.

The aim of this study was to identify independent parameters from patient history and status available at intensive care admission that could be used for early prediction and risk stratification of a poor outcome in comatose survivors following OHCA. Age, time to ROSC and initial temperature were previously reported from the TTM cohort [21, 23, 24]. Our findings using multiple variable analysis are also in line with earlier studies that older age, CA occurring at home, initial rhythm other than VF/VT, longer duration of no flow, longer duration of low flow, treatment with adrenaline, absence of corneal and pupillary reflexes, GCS-M1, a lower pH, and a PaCO₂ lower than 4.5 kPa on admission were independent predictors of a poor outcome [2, 6, 11, 18–20, 25–36]. Low-flow time from the initiation of CPR to ROSC has previously been associated with a poor outcome in various studies of OHCA [11, 29, 37], including the present cohort [21]. However, effective low flow may have been longer than registered because BLS was provided before arrival of ALS in 73% of the patients. Notwithstanding that BLS efficacy may vary considerably and is difficult to assess, registered low-flow time in the present study was somewhat longer than reported in the cohorts used to calculate OHCA and CAHP risk scores [11, 12]. The role of adrenaline in the resuscitation of OHCA victims is controversial, and in a recent meta-analysis, no benefit could be found [30]. In a Japanese study of 400,000 patients, researchers reported increased ROSC but decreased 1-month survival in patients who received adrenaline compared with those who did not [31]. Adrenaline is still part of European resuscitation guidelines [38], and it is possible that the association between adrenaline and a poor outcome that we found was related to more complicated resuscitations. Among variables potentially available at ICU admission, co-morbidity may be expected to be important. However, as in this analysis, it has previously been shown not to be associated with mortality in the present patient cohort [39].

To assess the risk for poor outcome after OHCA at an early stage, we constructed the TTM risk score on the basis of individual variables available at ICU admission. Several prediction methods have previously been investigated. The Acute Physiology and Chronic Health Evaluation II score [40], which is not disease-specific, has repeatedly been shown to be a poor predictor of outcome in OHCA [41]. The OHCA risk score presented in 2006 using variables available at hospital admission showed a similar performance. However, the OHCA risk score was based on a small cohort (n = 130). Also, the patients were relatively young compared with other OHCA cohorts, with a median age of 55 years and no patients older than 69 years [11]. The recently published CAHP risk score, based on a large number of patients, has performed best so far with an AUC of 0.93. However, some steps in its underlying calculations, such as the assumption of a linear association between outcome and time to ROSC, as well as outcome and pH, can be discussed [12]. When applied in our cohort, the OHCA and the CAPH scores lost performance as assessed by AUC, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). These discrepancies reflect the problem of low external validity for scores that are constructed in a single cohort. This may also apply to our score in spite of our use of a multicentre international cohort, and it needs to be validated in further trials. For the TTM risk score, a high value (>16 points, representing the fourth quartile of the patients) showed a promising PPV of 91% and a specificity of 95% to 96% and therefore indicated an acceptable margin not to predict a poor outcome in a patient with a good prognosis. However, the corresponding sensitivity was only 43%. Selecting a performance optimum cut-off of >13 points by use of Youden’s J statistics, yielding a sensitivity and specificity of 69% to 70% and 83% to 84%, respectively, does not render the score more useful, because the PPV is reduced to 82% to 83%. A low sensitivity when reaching a satisfactory specificity was also an issue for the CAHP risk score (sensitivity 46% to 56% in the development cohort). The high-risk cut-off OHCA score at 32.5 points (development cohort) described in the paper had an inadequate specificity of only 77% for poor outcome but a better sensitivity of 77% [11]. These results provoke the question whether better performance could be achieved with more, or contrarily, with fewer but highly discriminative, variables in a risk score model. Interestingly, Jabre et al. [42], using a development cohort of 1771 patients, found 0% (95% CI 0.0% to 0.5%) survival in 772 patients who fulfilled three criteria during pre-hospital resuscitation. These criteria were (1) OHCA not witnessed by emergency medical services personnel, (2) non-shockable initial cardiac rhythm and (3) no ROSC before receipt of a third 1-mg dose of epinephrine. However, comparison with our TTM trial cohort is difficult because the latter included only patients hospitalised alive after OHCA. Among 618 patients admitted alive in the Jabre et al. study, 22% were discharged alive. There is no information about the 180-day survival, which was close to 50% in the TTM cohort [15].

In a cohort of 933 patients with OHCA of a presumed cardiac cause extracted from the 939 patients included in the TTM trial, we found ten independent predictors of a poor outcome, defined as CPC 3–5 six months after CA. These included older age, CA occurring at home, initial rhythm other than VT/VF, longer duration of no flow, longer duration of low flow, administration of adrenaline, bilaterally absent pupillary and corneal reflexes, absent motor response to pain, a lower pH, and a PaCO₂ lower than 4.5 kPa at admission.

The predictors readily available at ICU admission were used to construct an easy and simple-to-use risk score that showed good association with outcome 6 months after the arrest. The score could further represent a helpful tool for treatment allocation and stratification in randomised studies as well as for comparison of cohorts in epidemiological studies. However, it is important to stress that the proposed risk score is not yet precise enough to be used for individual prognostication of outcome after OHCA, and it needs further validation in a large cohort of patients with OHCA.