Quantitative pupillometry in comatose out-of-hospital cardiac arrest patients: A post-hoc analysis of the TTH48 trial

Background: Quantitative pupillometry is an objective method to examine pupil reaction and subsequently grade the response on a neurological pupil index (NPi) scale from 0 to 5. The aim of the present sub-study was to explore the long-term prognostic value of NPi in comatose out-of-hospital cardiac arrest patients undergoing targeted temperature management (TTM). Methods: This planned sub-study of the “Targeted temperature management for 48 versus 24 h and neurological outcome after out-of-hospital cardiac arrest: A randomized clinical trial.” NPi was assessed from admission and throughout day 3 and linked to the Cerebral Performance Categories score at 6 months. We compared the prognostic performance of NPi in 65 patients randomized to a target temperature of 33 ± 1°C for 24 or 48 h. Results: The NPi values were not different between TTM groups (p > .05). When data were pooled, NPi was strongly associated with neurological outcome at day 1 with a mean NPi of 3.6 (95% CI 3.4–3.8) versus NPi 3.9 (3.6–4.1) in the poor versus good outcome group, respectively (p < .01). At day 2, NPi values were 3.6 (3.1–4.0) and 4.1 (3.9–4.2) (p = .01) and at day 3, the values were 3.3 (2.6–4.0) and 4.3 (4.1–4.6), respectively (p < .01). The prognostic ability of NPi, defined by area under the receiver operating characteristic curve was best at day three. Conclusion: Quantitative pupillometry measured by NPi was not different in the two TTM groups, but overall, significantly associated with good and poor neurological outcomes at 6 months. NPI has a promising diagnostic accuracy, but larger studies are warranted.publishedVersio

Factors Associated With Rebound Hyperthermia After Targeted Temperature Management in Out-of- Hospital Cardiac Arrest Patients: An Explorative Substudy of the Time- Differentiated Therapeutic Hypothermia in Out-of-Hospital Cardiac Arrest Survivors Trial

Peer reviewe

Comparison of four clinical risk scores in comatose patients after out-of-hospital cardiac arrest.

BACKGROUND AND AIMS Several different scoring systems for early risk stratification after out-of-hospital cardiac arrest have been developed, but few have been validated in large datasets. The aim of the present study was to compare the well-validated Out-of-hospital Cardiac Arrest (OHCA) and Cardiac Arrest Hospital Prognosis (CAHP)-scores to the less complex MIRACLE2- and Target Temperature Management (TTM)-scores. METHODS This was a post-hoc analysis of the Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial. Missing data were handled by multiple imputation. The primary outcome was discriminatory performance assessed as the area under the receiver operating characteristics-curve (AUROC), with the outcome of interest being poor functional outcome or death (modified Rankin Scale 4-6) at 6 months after OHCA. RESULTS Data on functional outcome at 6 months were available for 1829 cases, which constituted the study population. The pooled AUROC for the MIRACLE2-score was 0.810 (95% CI 0.790 - 0.828), 0.835 (95% CI 0.816 - 0.852) for the TTM-score, 0.820 (95% CI 0.800 - 0.839) for the CAHP-score and 0.770 (95% CI 0.748 - 0.791) for the OHCA-score. At the cut-offs needed to achieve specificities >95%, sensitivities were <40 % for all four scoring systems. CONCLUSIONS The TTM-, MIRACLE2- and CAHP-scores are all capable of providing objective risk estimates accurate enough to be used as part of a holistic patient assessment after OHCA of a suspected cardiac origin. Due to its simplicity, the MIRACLE2-score could be a practical solution for both clinical application and risk stratification within trials

A statistical analysis protocol for the time-differentiated target temperature management after out-of-hospital cardiac arrest (TTH48) clinical trial

Background: The TTH48 trial aims to determine whether prolonged duration (48 hours) of targeted temperature management (TTM) at 33 (+/- 1) degrees C results in better neurological outcomes compared to standard duration (24 hours) after six months in comatose out-of-hospital cardiac arrest (OHCA) patients. Methods: TTH48 is an investigator-initiated, multicentre, assessor-blinded, randomised, controlled superiority trial of 24 and 48 hours of TTM at 33 (+/- 1) degrees C performed in 355 comatose OHCA patients aged 18 to 80 years who were admitted to ten intensive care units (ICUs) in six Northern European countries. The primary outcome of the study is the Cerebral Performance Category (CPC) score observed at six months after cardiac arrest. CPC scores of 1 and 2 are defined as good neurological outcomes, and CPC scores of 3, 4 and 5 are defined as poor neurological outcomes. The secondary outcomes are as follows: mortality within six months after cardiac arrest, CPC at hospital discharge, Glasgow Coma Scale (GCS) score on day 4, length of stay in ICU and at hospital and the presence of any adverse events such as cerebral, circulatory, respiratory, gastrointestinal, renal, metabolic measures, infection or bleeding. With the planned sample size, we have 80% power to detect a 15% improvement in good neurological outcomes at a two-sided statistical significance level of 5%. Discussion: We present a detailed statistical analysis protocol (SAP) that specifies how primary and secondary outcomes should be evaluated. We also predetermine covariates for adjusted analyses and pre-specify sub-groups for sensitivity analyses. This pre-planned SAP will reduce analysis bias and add validity to the findings of this trial on the effect of length of TTM on important clinical outcomes after cardiac arrest.Peer reviewe

Biomarker prognostication of cognitive impairment may be feasible even in out-of hospital cardical arrest survivors with good neurological outcome

Background Patients surviving out-of hospital cardicac arrest, with good neurological outcome according to Cerebral Performance Category, frequently have neuropsychological impairment. We studied whether biomarker data (S-100b and neuron-specific enolase) obtained during the ICU stay predicted cognitive impairment 6 months after resuscitation. Methods Patients (N = 79) with a CPC-score ≤2 were recruited from two trial sites taking part in the TTH48 trial comparing targeted temperature management (TTM) for 48 h vs. 24 h at 33 ± 1 °C. We assessed patients 6 months after the OHCA. We measured biomarkers S-100b and NSE at arrival and at 24, 48 and 72 h after reaching the target temperature of 33 ± 1 °C. Four cognitive domain z-scores were calculated, and global cognitive impairment was defined as z < −1.67 on at least 3 out of 13 cognitive tests. Non-parametric correlations were used to assess the relationship between cognitive domain and biomarkers. ROC curves were used to assess prediction of cognitive impairment from the biomarkers. Logistic regression was used to investigate whether TTM duration moderated biomarker prediction of cognitive impairment. Results Cognitive impairment was present in 22% of the patients with memory impairment being the most common. The biomarkers correlated significantly with several cognitive domain scores and NSE at 48 h predicted cognitive impairment with 100% sensitivity and 56% specificity. The predictive properties of NSE at 48 h was unaffected by duration of TTM. Conclusions Early biomarker prognostication of cognitive impairment is feasible even in OHCA survivors with good neurological outcome as defined by CPC. NSE at 48 h predicted cognitive impairment.publishedVersio

Platelet aggregation during targeted temperature management after out-of-hospital cardiac arrest: A randomised clinical trial

Some studies conclude that mild hypothermia causes platelet dysfunction leading to an increased bleeding risk, whereas others state that platelet aggregation is enhanced during mild hypothermia. Therefore, the aim of this study was to clarify whether standard or prolonged duration of targeted temperature management affected platelet aggregation. We randomised 82 comatose patients resuscitated after out-of-hospital cardiac arrest to either 24 hours (standard group) or 48 hours (prolonged group) of targeted temperature management at 33±1°C. Blood samples were collected 22 hours, 46 hours and 70 hours after reaching target temperature. Platelet aggregation was assessed by impedance aggregometry employing a Multiplate®Analyser, using the COLtest®, TRAPtest®, ADPtest® and ASPItest® as agonists, and with the results reported as area under the curve (AUC, AU*min). The platelet aggregation was below the normal range in all blood samples. No differences were observed between the standard group and the prolonged group in either of the blood samples (all p ≥ 0.11), except for a 24% decreased aggregation (95% confidence interval (CI) (10%;37%), p = 0.002) when using the COLtest® in the 46-hour sample. Comparing the 22-hour sample with the 46-hour sample in the prolonged group separately, we found no differences when employing the COLtest®, the ASPItest® or the ADPtest® in patients without the use of adenosine diphosphate receptor inhibitors (all p values ≥0.21), but aggregation induced by the TRAPtest® decreased by 14% (95% CI −8%;−20%), p < 0.001). We concluded that the platelet aggregation post cardiac arrest was below the normal range independent of the core temperature. Moreover, no substantial difference was found in platelet aggregation between standard and prolonged targeted temperature management

Quantitative pupillometry in comatose out-of-hospital cardiac arrest patients: A post-hoc analysis of the TTH48 trial

Background: Quantitative pupillometry is an objective method to examine pupil reaction and subsequently grade the response on a neurological pupil index (NPi) scale from 0 to 5. The aim of the present sub-study was to explore the long-term prognostic value of NPi in comatose out-of-hospital cardiac arrest patients undergoing targeted temperature management (TTM). Methods: This planned sub-study of the “Targeted temperature management for 48 versus 24 h and neurological outcome after out-of-hospital cardiac arrest: A randomized clinical trial.” NPi was assessed from admission and throughout day 3 and linked to the Cerebral Performance Categories score at 6 months. We compared the prognostic performance of NPi in 65 patients randomized to a target temperature of 33 ± 1°C for 24 or 48 h. Results: The NPi values were not different between TTM groups (p > .05). When data were pooled, NPi was strongly associated with neurological outcome at day 1 with a mean NPi of 3.6 (95% CI 3.4–3.8) versus NPi 3.9 (3.6–4.1) in the poor versus good outcome group, respectively (p < .01). At day 2, NPi values were 3.6 (3.1–4.0) and 4.1 (3.9–4.2) (p = .01) and at day 3, the values were 3.3 (2.6–4.0) and 4.3 (4.1–4.6), respectively (p < .01). The prognostic ability of NPi, defined by area under the receiver operating characteristic curve was best at day three. Conclusion: Quantitative pupillometry measured by NPi was not different in the two TTM groups, but overall, significantly associated with good and poor neurological outcomes at 6 months. NPI has a promising diagnostic accuracy, but larger studies are warranted