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

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a multicentre, randomised, parallel-group, assessor-blinded clinical trial (the TTH48 trial): study protocol for a randomised controlled trial

Background The application of therapeutic hypothermia (TH) for 12 to 24 hours following out-of-hospital cardiac arrest (OHCA) has been associated with decreased mortality and improved neurological function. However, the optimal duration of cooling is not known. We aimed to investigate whether targeted temperature management (TTM) at 33 ± 1 °C for 48 hours compared to 24 hours results in a better long-term neurological outcome. Methods The TTH48 trial is an investigator-initiated pragmatic international trial in which patients resuscitated from OHCA are randomised to TTM at 33 ± 1 °C for either 24 or 48 hours. Inclusion criteria are: age older than 17 and below 80 years; presumed cardiac origin of arrest; and Glasgow Coma Score (GCS) <8, on admission. The primary outcome is neurological outcome at 6 months using the Cerebral Performance Category score (CPC) by an assessor blinded to treatment allocation and dichotomised to good (CPC 1–2) or poor (CPC 3–5) outcome. Secondary outcomes are: 6-month mortality, incidence of infection, bleeding and organ failure and CPC at hospital discharge, at day 28 and at day 90 following OHCA. Assuming that 50 % of the patients treated for 24 hours will have a poor outcome at 6 months, a study including 350 patients (175/arm) will have 80 % power (with a significance level of 5 %) to detect an absolute 15 % difference in primary outcome between treatment groups. A safety interim analysis was performed after the inclusion of 175 patients. Discussion This is the first randomised trial to investigate the effect of the duration of TTM at 33 ± 1 °C in adult OHCA patients. We anticipate that the results of this trial will add significant knowledge regarding the management of cooling procedures in OHCA patients

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

OBJECTIVES:To investigate rebound hyperthermia following targeted temperature management after cardiac arrest and its impact on functional outcome.DESIGN:Post hoc analysis.SETTING:Ten European ICUs.PATIENTS:Patients included in the time-differentiated therapeutic hypothermia in out-of-hospital cardiac arrest survivors trial treated with targeted temperature management at 33°C for 48 or 24 hours. Favorable functional outcome was defined as a Cerebral Performance Category of 1 or 2 at 6 months.INTERVENTIONS:None.MEASUREMENTS AND MAIN RESULTS:Of 338 included patients, 103 (30%) experienced rebound hyperthermia defined as a maximum temperature after targeted temperature management and rewarming exceeding 38.5°C. Using multivariate logistic regression analysis, increasing age (odds ratio, 0.97; 95% CI, 0.95–0.99; p = 0.02) and severe acute kidney injury within 72 hours of ICU admission (odds ratio, 0.35; 95% CI, 0.13–0.91; p = 0.03) were associated with less rebound hyperthermia, whereas male gender (odds ratio, 3.94; 95% CI, 1.34–11.57; p = 0.01), highest C-reactive protein value (odds ratio, 1.04; 95% CI, 1.01–1.07; p = 0.02), and use of mechanical chest compression during cardiopulmonary resuscitation (odds ratio, 2.00; 95% CI, 1.10–3.67; p = 0.02) were associated with more rebound hyperthermia. Patients with favorable functional outcome spent less time after rewarming over 38.5°C (2.5% vs 6.3%; p = 0.03), 39°C (0.14% vs 2.7%; p CONCLUSIONS:One-third of targeted temperature management patients experience rebound hyperthermia, and it is more common in younger male patients with an aggravated inflammatory response and those treated with a mechanical chest compression device. Later onset of rebound hyperthermia and temperatures exceeding 38.5°C associate with unfavorable outcome.</p

Time-differentiated target temperature management after out-of-hospital cardiac arrest : a multicentre, randomised, parallel-group, assessor-blinded clinical trial (the TTH48 trial): study protocol for a randomised controlled trial

Background: The application of therapeutic hypothermia (TH) for 12 to 24 hours following out-of-hospital cardiac arrest (OHCA) has been associated with decreased mortality and improved neurological function. However, the optimal duration of cooling is not known. We aimed to investigate whether targeted temperature management (TTM) at 33 +/- 1 degrees C for 48 hours compared to 24 hours results in a better long-term neurological outcome. Methods: The TTH48 trial is an investigator-initiated pragmatic international trial in which patients resuscitated from OHCA are randomised to TTM at 33 +/- 1 degrees C for either 24 or 48 hours. Inclusion criteria are: age older than 17 and below 80 years; presumed cardiac origin of arrest; and Glasgow Coma Score (GCS) <8, on admission. The primary outcome is neurological outcome at 6 months using the Cerebral Performance Category score (CPC) by an assessor blinded to treatment allocation and dichotomised to good (CPC 1-2) or poor (CPC 3-5) outcome. Secondary outcomes are: 6-month mortality, incidence of infection, bleeding and organ failure and CPC at hospital discharge, at day 28 and at day 90 following OHCA. Assuming that 50 % of the patients treated for 24 hours will have a poor outcome at 6 months, a study including 350 patients (175/arm) will have 80 % power (with a significance level of 5 %) to detect an absolute 15 % difference in primary outcome between treatment groups. A safety interim analysis was performed after the inclusion of 175 patients. Discussion: This is the first randomised trial to investigate the effect of the duration of TTM at 33 +/- 1 degrees C in adult OHCA patients. We anticipate that the results of this trial will add significant knowledge regarding the management of cooling procedures in OHCA patients.Peer reviewe

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

Operatsioonijärgse valuravi juhendi mõju hindamine

Eesmärk. Hinnata operatsioonijärgse valuravi juhendi mõju valuravi kvaliteedile, mõõdetuna valu tugevuse vähenemisena arvuskaalal ja muutustega valuvaigistite kasutuses. Metoodika. Uuring tehti PERHi kolmes ortopeedia osakonnas ajavahemikul septembrist 2005 kuni aprillini 2006. Uuringu esimeses etapis hinnati küsimustiku abil põlve või puusa totaalse endoproteesimise (TEP) läbi teinud patsientide valu tugevust ja valuvaigistite kasutust. Uuringu teise etapi algul võeti III ortopeedia osakonnas (sekkumisrühm) kasutusele valuravijuhend ning I ja II ortopeedia osakonnas (kontrollrühm) jätkati valuravi varasemal viisil. Juhendi kasutuselevõtu järel hinnati patsientide valu tugevust ja valuvaigistite kasutust. Tulemused. Uuringus osales 206 patsienti (104 esimeses ja 102 teises etapis). Sekkumisrühmas vähenes valu tugevus pärast valuravijuhendi rakendamist, kuid muutus polnud statistiliselt oluline. Oluliselt muutus valuvaigistite manustamisviis: vähenes lihasesiseselt manustatud ja suurenes suu kaudu manustatud valuvaigistite osakaal. Järeldused. Uuring näitas, et valuravijuhendi positiivne mõju valuravi kvaliteedile avaldub peamiselt muutustena valuvaigistite kasutuses ja mõõdukamalt muutustena patsientide valutugevuse hinnangutes. Eesti Arst 2011; 90(6):263–26

Hypothermic to ischemic ratio and mortality in post-cardiac arrest patients

Background We studied the associations between ischemia and hypothermia duration, that is, the hypothermic to ischemic ratio (H/I ratio), with mortality in patients included in a trial on two durations of targeted temperature management (TTM) at 33 degrees C. Methods The TTH48 (NCT01689077) trial compared 24 and 48 hours of TTM in patients after cardiac arrest. We calculated the hypothermia time from return of spontaneous circulation (ROSC) until the patient reached 37 degrees C after TTM and the ischemic time from CA to ROSC. We compared continuous variables with the Mann-Whitney U test. Using COX regression, we studied the independent association of the logarithmically transformed H/I ratio and time to death as well as interaction between time to ROSC, hypothermia duration, and intervention group. We visualized the predictive ability of variables with receiver operating characteristic curve analysis. Results Of the 338 patients, 237 (70%) survived for 6 months. The H/I ratio was 155 (IQR 111-238) in survivors and 114 (IQR 80-169) in non-survivors (P <.001). In a Cox regression model including factors associated with outcome in univariate analysis, the logarithmically transformed H/I ratio was a significant predictor of outcome (hazard ratio 0.52 (0.37-0.72, P = .001)). After removing an outlier, we found no interaction between time to ROSC and intervention group (P = .55) or hypothermia duration in quartiles (P = .07) with mortality. There was no significant difference in the area under the curve (AUC) between time to ROSC and H/I ratio (Delta AUC 0.03 95% CI -0.006-0.07, P = .10). Conclusions We did not find any consistent evidence of a modification of the effect of TTM based on ischemia duration.Peer reviewe

The influence of prolonged temperature management on acute kidney injury after out-of-hospital cardiac arrest: A post-hoc analysis of the TTH48 trial

Background Acute kidney injury (AKI) is common after cardiac arrest and targeted temperature management (TTM). The impact of different lengths of cooling on the development of AKI has not been well studied. In this study of patients included in a randomised controlled trial of TTM at 33°C for 24 versus 48hours after cardiac arrest (TTH48 trial), we examined the influence of prolonged TTM on AKI and the incidence and factors associated with the development of AKI. We also examined the impact of AKI on survival. Methods This study was a sub-study of the TTH48 trial, which included patients cooled to 33±1˚C after out-of-hospital cardiac arrest for 24 versus 48hours. AKI was classified according to the KDIGO AKI criteria based on serum creatinine and urine output collected until ICU discharge for a maximum of seven days. Survival was followed for up to six months. The association of admission factors on AKI was analysed with multivariate analysis and the association of AKI on mortality was analysed with Cox regression using the time to AKI as a time-dependent covariate. Results Of the 349 patients included in the study, 159 (45.5%) developed AKI. There was no significant difference in the incidence, severity or time to AKI between the 24- and 48-hour groups. Serum creatinine values had significantly different trajectories for the two groups with a sharp rise occurring during rewarming. Age, time to return of spontaneous circulation, serum creatinine at admission and body mass index were independent predictors of AKI. Patients with AKI had a higher mortality than patients without AKI (hospital mortality 36.5% vs 12.5%, pPeer reviewe