Martin Frydland

TARGET TEMPERATURE MANAGEMENT OF 33°C AND 36°C IN PATIENTS WITH OUT-OF-HOSPITAL CARDIAC ARREST WITH INITIAL NON-SHOCKABLE RHYTHM - A TTM SUB-STUDY.

PURPOSE Despite a lack of randomized trials in comatose survivors of out-of-hospital cardiac arrest (OHCA) with an initial non-shockable rhythm (NSR), guidelines recommend induced hypothermia to be considered in these patients. We assessed the effect on outcome of two levels of induced hypothermia in comatose patient resuscitated from NSR. METHODS Hundred and seventy-eight patients out of 950 in the TTM trial with an initial NSR were randomly assigned to targeted temperature management at either 33°C (TTM33, n=96) or 36°C (TTM36, n=82). We assessed mortality, neurologic function (Cerebral Performance Score (CPC) and modified Rankin Scale (mRS)), and organ dysfunction (Sequential Organ Failure Assessment (SOFA) score). RESULTS Patients with NSR were older, had longer time to ROSC, less frequently had bystander CPR and had higher lactate levels at admission compared to patients with shockable rhythm, p<0.001 for all. Mortality in patients with NSR was 84% in both temperature groups (unadjusted HR 0.92, adjusted HR 0.75; 95% CI 0.53-1.08, p=0.12). In the TTM33 group 3% survived with poor neurological outcome (CPC 3-4, mRS 4-5), compared to 2% in the TTM36 group (adjusted OR 0.67; 95% CI 0.08-4.73, p=0.69 for both). Thirteen percent in the TTM33 group and 15% in the TTM36 group had good neurologic outcome (CPC 1-2, mRS 0-3, OR 1.5, CI 0.21-12.5, p=0.69). The SOFA-score did not differ between temperature groups. CONCLUSION Comatose patients after OHCA with initial NSR continue to have a poor prognosis. We found no effect of targeted temperature management at 33°C compared to 36°C in these patients.

Risk factors of late cardiogenic shock and mortality in ST-segment elevation myocardial infarction patients

Background: The incidence of cardiogenic shock (CS) in patients with ST-segment elevation myocardial infarction (STEMI) is as high as 10%. The majority of patients are thought to develop CS after admission (late CS), but the incidence in a contemporary STEMI cohort admitted for primary percutaneous intervention remains unknown. Aim: The aim of this study was to assess the incidence and time of CS onset in patients with suspected STEMI admitted in two high-volume tertiary heart centres and to assess the variables associated with the development of late CS. Methods: We included consecutive patients admitted for acute coronary angiography with suspected STEMI in a 1-year period. Cardiogenic shock was based on clinical criteria and subdivided into patients with shock on admission, patients developing shock during catheterisation and patients developing shock later during hospitalisation. Follow-up for all-cause mortality was done using registries. Results: A total of 2247 patients with suspected STEMI were included, whereof 225 (10%) developed CS. The majority (56%) had CS on admission, 16% developed CS in the catheterisation laboratory and 28% developed late CS. Thirty-day mortality was 3.1% versus 47% in non-CS versus CS patients (plogrank < 0.0001). Age, stroke, time from symptom onset to intervention, anterior STEMI, heart rate/systolic blood pressure ratio and being comatose after resuscitation from cardiac arrest were independently associated with the development of late CS. Conclusion: In this study, 10% of patients admitted with suspected STEMI for acute coronary angiography presented with or developed CS. Most were in shock on admission. Irrespective of the timing of shock, mortality was high.

Comorbidity burden is not associated with higher mortality after out-of-hospital cardiac arrest*

Abstract Objectives. We investigated whether comorbidity burden of comatose survivors of out-of-hospital cardiac arrest (OHCA) affects outcome and if comorbidity modifies the effect of target temperature management (TTM) on final outcome. Design. The TTM trial randomized 939 patients to 24 h of TTM at either 33 or 36 °C with no difference regarding mortality and neurological outcome. This post-hoc study of the TTM-trial formed a modified comorbidity index (mCI), based on available comorbidities from the Charlson comorbidity index (CCI). Results. Bystander cardiopulmonary resuscitation (CPR) decreased with higher comorbidity group, p = 0.01. Comorbidity groups were univariately associated with higher mortality compared to mCI0 (HRmCI1: 1.55, CI: 1.25–1.93, p < 0.001, HRmCI2: 2.01, CI: 1.55–2.62, p < 0.001, HRmCI ≥ 3: 2.16, CI: 1.57–2.97, p < 0.001). When adjusting for confounders there was a consistent, nonsignificant association between level of comorbidity and mortality (HRmC11: 1.17, CI: 0.92–1.48, p = 0.21, HRmCI2: 1.28, CI: 0.96–1.71, p = 0.10, HRmCI ≥ 3: 1.37, CI: 0.97–1.95, p = 0.08). There was no interaction between comorbidity burden and level of TTM on outcome, p = 0.61. Conclusion. Comorbidity burden was associated with higher mortality following OHCA, but when adjusting for confounders, the influence was no longer significant. The association between mCI and mortality was not modified by TTM. Comorbidity burden is associated with lower rates of bystander cardiopulmonary resuscitation after OHCA.

Neuroprotective Effects of the Glucagon-Like Peptide-1 Analog Exenatide After Out-of-Hospital Cardiac Arrest: A Randomized Controlled Trial

Background: In-hospital mortality in comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA) is ≈50%. In OHCA patients, the leading cause of death is neurological injury secondary to ischemia and reperfusion. Glucagon-like peptide-1 analogs are approved for type 2 diabetes mellitus; preclinical and clinical data have suggested their organ-protective effects in patients with ischemia and reperfusion injury. The aim of this trial was to investigate the neuroprotective effects of the glucagon-like peptide-1 analog exenatide in resuscitated OHCA patients. Methods: We randomly assigned 120 consecutive comatose patients resuscitated from OHCA in a double-blind, 2-center trial. They were administered 17.4 &mgr;g exenatide (Byetta) or placebo over a 6-hour and 15-minute infusion, in addition to standardized intensive care including targeted temperature management. The coprimary end points were feasibility, defined as initiation of the study drug in >90% patients within 240 minutes of return of spontaneous circulation, and efficacy, defined as the geometric area under the neuron-specific enolase curve from 24 to 72 hours after admission. The main secondary end points included a composite end point of death and poor neurological function, defined as a Cerebral Performance Category score of 3 to 5 assessed at 30 and 180 days. Results: The study drug was initiated within 240 minutes of return of spontaneous circulation in 96% patients. The median blood glucose 8 hours after admission in patients receiving exenatide was lower than that in patients receiving placebo (5.8 [5.2–6.7] mmol/L versus 7.3 [6.2–8.7] mmol/L, P<0.0001). However, there were no significant differences in the area under the neuron-specific enolase curve, or a composite end point of death and poor neurological function between groups. Adverse events were rare with no significant difference between groups. Conclusions: Acute administration of exenatide to comatose patients in the intensive care unit after OHCA is feasible and safe. Exenatide did not reduce neuron-specific enolase levels and did not significantly improve a composite end point of death and poor neurological function after 180 days. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02442791.

The effect of TIcagrelor administered through a nasogastric tube to COMAtose patients undergoing acute percutaneous coronary intervention: the TICOMA study

AIMS Patients in a coma after cardiac arrest may have adversely affected drug absorption and metabolism. This study, the first of its kind, aimed to investigate the early pharmacokinetic and pharmacodynamic effects of ticagrelor administered through a nasogastric tube (NGT) to patients resuscitated after an out of hospital cardiac arrest (OHCA) and undergoing primary percutaneous coronary intervention (pPCI). METHODS AND RESULTS Blood samples were drawn at baseline and at two, four, six, eight, 12, and 24 hours and then daily for up to five days after administration of a 180 mg ticagrelor loading dose (LD), followed by 90 mg twice daily in 44 patients. The primary endpoint was the occurrence of high platelet reactivity (HPR) 12 hours after the LD. Assessment by VerifyNow (VFN) showed 96 (15.25-140.5) platelet reactivity units (PRU), and five (12%) patients exhibited HPR. Multiplate analysis showed 19 (12-29) units (U) at twelve hours, and three patients (7%) had HPR. Ticagrelor and its main metabolite AR-C124910XX concentrations were 85.2 (37.2-178.5) and 18.3 (6.4-52.4) ng/mL. Median times to sufficient platelet inhibition below the HPR limit were 3 (2-6) hours (VFN) and 4 (2-8) hours (Multiplate). CONCLUSIONS Ticagrelor, administered as crushed tablets through a nasogastric tube, leads to sufficient platelet inhibition after 12 hours, and in many cases earlier, in the vast majority of patients undergoing pPCI and subsequent intensive care management after an OHCA.

Association between QRS duration on prehospital ECG and mortality in patients with suspected STEMI

BACKGROUND QRS duration has previously shown association with mortality in patients with acute myocardial infarction treated with thrombolytics, less is known in patients with suspected ST segment elevation myocardial infarction (STEMI) when assessing QRS duration on prehospital ECG. Thus, the objective was to investigate the prognostic effect of QRS duration on prehospital ECG and presence of classic left and right bundle branch block (LBBB/RBBB) for all-cause mortality in patients with suspected STEMI. METHOD In total 2105 consecutive patients (mean age 64±13years, 72% men) with suspected STEMI were prospectively included. QRS duration was registered from automated QRS measurement on prehospital ECG and patients were divided according to quartiles of QRS duration (<89ms, 89-98ms, 99-111ms and >111ms). Primary endpoint was all-cause 30-day mortality. Predictors of all-cause mortality were assessed using Cox proportional hazards analysis. RESULTS Among all patients median QRS duration was 98ms (IQR 88-112ms). RBBB-morphology was seen in 126 patients (6.0%) and LBBB in 88 patients (4.2%), 80% were treated with percutaneous coronary intervention and the final diagnosis was STEMI in 1777 patients (84%). Thirty-day mortality was 7.6% in patients with suspected STEMI. In multivariable analysis, QRS duration>111ms (hazard ratio (HR) 3.08; 95% confidence interval (CI): 1.71-5.57, p=0.0002), LBBB - morphology (HR 3.0; 95% CI: 1.38-6.53, p=0.006) and RBBB (HR 3.68; 95% CI: 1.95-6.95, p<0.0001) were associated with 30 day all-cause mortality. CONCLUSION In patients with suspected STEMI, QRS prolongation, LBBB, and RBBB on prehospital ECG are associated with increased risk of death.

Data on association between QRS duration on prehospital ECG and mortality in patients with confirmed STEMI

Data presented in this article relates to the research article entitled “Association between QRS duration on prehospital ECG and mortality in patients with suspected STEMI” (Hansen et al., in press) [1]. Data on the prognostic effect of automatically recoded QRS duration on prehospital ECG and presence of classic left and right bundle branch block in 1777 consecutive patients with confirmed ST segment elevation AMI is presented. Multivariable analysis, suggested that QRS duration >111 ms, left bundle branch block and right bundle branch block were independent predictors of 30 days all-cause mortality. For interpretation and discussion of these data, refer to the research article referenced above.

Importance of comorbidities in comatose survivors of shockable and non-shockable out-of-hospital cardiac arrest treated with target temperature management

Abstract Objective. Comorbidity prior to out-of-hospital cardiac arrest (OHCA) and primary rhythm in relation to survival is not well established. We aimed to assess the prognostic importance of comorbidity in relation to primary rhythm in OHCA-patients treated with Target Temperature Management (TTM). Design. Consecutive comatose survivors of OHCA treated with TTM in hospitals in the Copenhagen area between 2002–2011 were included. Utstein-based pre- and in-hospital data collection was performed. Data on comorbidity was obtained from The Danish National Patient Register and patient charts, assessed by the Charlson Comorbidity Index (CCI). Results. A total of 666 patients were included. A third (n = 233, 35%) presented with non-shockable rhythm, and they were less often male (64% vs. 82%, p < .001), and OHCA in public, witnessed OHCA, and bystander cardiopulmonary resuscitation (CPR) were less common compared to patients with a shockable primary rhythm (public: 27% vs. 48%, p < .001, witnessed: 79% vs. 90%, p < .001, bystander CPR: 47% vs. 63%, p < .001). 30-day mortality was 62% compared to 28% in patients with non-shockable and shockable rhythm, respectively. By Cox-regression analyses, any comorbidity (CCI ≥1) was the only factor independently associated with 30-day mortality in patients with non-shockable rhythm (HR =1.9 (95% CI: 1.2–2.9), p < .01), whereas in patients with shockable rhythm comorbidity was not associated with outcome after adjustment for prognostic factors (HR = 0.82 (0.55–1.2), p = .34). No significant interaction between primary rhythm and comorbidity in terms of mortality was present. Conclusion. A higher comorbidity burden was independently associated with a higher 30-day mortality rate in patients presenting with non-shockable primary rhythm but not in patients with shockable rhythm.

Osborn waves following out-of-hospital cardiac arrest—Effect of level of temperature management and risk of arrhythmia and death

BACKGROUND The Osborn or J-wave, an upright deflection of the J-point on the electrocardiogram (ECG), is often observed during severe hypothermia. A possible relation between Osborn waves (OW) and increased risk of ventricular arrhythmia has been reported. We sought to determine whether the level of targeted temperature management (TTM) following out-of-hospital cardiac arrest (OHCA) affects the prevalence of OW and to assess the associations between OW and risk of ventricular arrhythmia and death. METHODS AND RESULTS The present study is part of the TTM-trial ECG-substudy (including OHCA-patients randomized to TTM at 33 °C vs. 36 °C from 24 of 36 sites). Serial 12-lead ECGs from 680 (94%) patients were analysed and stratified by OW at predefined time-points (0, 4, 28, 36, 72-h after admission). On admission, the overall prevalence of OW was 16%, increasing to 32% at target temperature, with higher prevalence in the 33 °C-group (40% vs. 23%, p < 0.0001). No difference in prevalence was found between the 33 °C- and 36 °C-groups on admission (18% vs. 14%, p = .11) or after rewarming (13% vs. 10%, p = .44). OW were not associated with increased risk of ventricular arrhythmia (Odds ratio = 0.78 (0.51-1.20), p = .26), but associated with significantly lower 180-day mortality as compared to no OW (38% vs. 52%, plog-rank = 0.001) in univariable analyses only. CONCLUSION OW are frequent during TTM, particularly in patients treated with 33 °C. OW are not associated with increased risk of ventricular arrhythmia, and may be considered a benign physiological phenomenon, associated with lower mortality in univariable analyses.

Proteomic Discovery and Validation of the Confounding Effect of Heparin Administration on the Analysis of Candidate Cardiovascular Biomarkers

BACKGROUND Several plasma proteins have been suggested as markers for a variety of cardiovascular conditions but fail to qualify in independent patient cohorts. This may relate to interference of medication on plasma protein concentrations. We used proteomics to identify plasma proteins that changed in concentration with heparin administration and therefore potentially may confound their evaluation as biomarkers in situations in which heparin is used. METHODS We used a proteomic approach based on isobaric tagging and nano-LC-MS/MS analysis to quantify several hundred proteins in a discovery study in which individual plasma samples from 9 patients at intravascular ultrasound follow-up 12 months after an acute myocardial infarction before heparin administration and 2, 15, and 60 min after heparin administration; we validated our findings in 500 individual plasma samples obtained at admission from patients with suspected ST segment elevation myocardial infarction (STEMI), of whom 363 were treated with heparin before admission. RESULTS In the discovery study, 25 of 653 identified plasma proteins displayed a changed concentration after heparin administration (Bonferroni-corrected P value at P < 7.66 × 10-5). Fourteen of the proteins changed significantly among heparin-treated patients in the validation study (nominal significance level of P < 6.92 × 10-5). Among heparin-affected proteins in both the discovery study and the validation study were midkine, spondin 1, secreted frizzled-like protein 1, lipoprotein lipase, and follistatin, all previously associated with STEMI. CONCLUSIONS Medications such as heparin administration given before blood sampling may confound biomarker discovery and should be carefully considered in such studies.