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

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

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

Etoricoxib - preemptive and postoperative analgesia (EPPA) in patients with laparotomy or thoracotomy - design and protocols

<p>Abstract</p> <p>Background and Objective</p> <p>Our objective was to report on the design and essentials of the <it>Etoricoxib </it>protocol<it>- Preemptive and Postoperative Analgesia (EPPA) </it>Trial, investigating whether preemptive analgesia with cox-2 inhibitors is more efficacious than placebo in patients who receive either laparotomy or thoracotomy.</p> <p>Design and Methods</p> <p>The study is a 2 × 2 factorial armed, double blinded, bicentric, randomised placebo-controlled trial comparing (a) etoricoxib and (b) placebo in a pre- and postoperative setting. The total observation period is 6 months. According to a power analysis, 120 patients scheduled for abdominal or thoracic surgery will randomly be allocated to either the preemptive or the postoperative treatment group. These two groups are each divided into two arms. Preemptive group patients receive etoricoxib prior to surgery and either etoricoxib again or placebo postoperatively. Postoperative group patients receive placebo prior to surgery and either placebo again or etoricoxib after surgery (2 × 2 factorial study design). The Main Outcome Measure is the cumulative use of morphine within the first 48 hours after surgery (measured by patient controlled analgesia PCA). Secondary outcome parameters include a broad range of tests including sensoric perception and genetic polymorphisms.</p> <p>Discussion</p> <p>The results of this study will provide information on the analgesic effectiveness of etoricoxib in preemptive analgesia and will give hints on possible preventive effects of persistent pain.</p> <p>Trial registration</p> <p>NCT00716833</p

Current trends in cannulation and neuroprotection during surgery of the aortic arch in Europe†‡

OBJECTIVES To conduct a survey across European cardiac centres to evaluate the methods used for cerebral protection during aortic surgery involving the aortic arch. METHODS All European centres were contacted and surgeons were requested to fill out a short, comprehensive questionnaire on an internet-based platform. One-third of more than 400 contacted centres completed the survey correctly. RESULTS The most preferred site for arterial cannulation is the subclavian-axillary, both in acute and chronic presentation. The femoral artery is still frequently used in the acute condition, while the ascending aorta is a frequent second choice in the case of chronic presentation. Bilateral antegrade brain perfusion is chosen by the majority of centres (2/3 of cases), while retrograde perfusion or circulatory arrest is very seldom used and almost exclusively in acute clinical presentation. The same pumping system of the cardio pulmonary bypass is most of the time used for selective cerebral perfusion, and the perfusate temperature is usually maintained between 22 and 26°C. One-third of the centres use lower temperatures. Perfusate flow and pressure are fairly consistent among centres in the range of 10-15 ml/kg and 60 mmHg, respectively. In 60% of cases, barbiturates are added for cerebral protection, while visceral perfusion still receives little attention. Regarding cerebral monitoring, there is a general tendency to use near-infrared spectroscopy associated with bilateral radial pressure measurement. CONCLUSIONS These data represent a snapshot of the strategies used for cerebral protection during major aortic surgery in current practice, and may serve as a reference for standardization and refinement of different approache