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Background: The aim of this study was to assess whether hypothermia increased survival and improved functional outcome when compared with normothermia in out-of-hospital cardiac arrest (OHCA) patients with similar characteristics than in previous randomized studies showing benefits for hypothermia., Methods: Post hoc analysis of a pragmatic, multicenter, randomized clinical trial (TTM-2, NCT02908308). In this analysis, the subset of patients included in the trial who had similar characteristics to patients included in one previous randomized trial and randomized to hypothermia at 33 °C or normothermia (i.e. target < 37.8 °C) were considered. The primary outcome was survival at 6 months; secondary outcomes included favorable functional outcome at 6 months, defined as a modified Rankin scale of 0-3. Time-to-death and the occurrence of adverse events were also reported., Results: From a total of 1891 included in the TTM-2 study, 600 (31.7%) were included in the analysis, 294 in the hypothermia and 306 in the normothermia group. At 6 months, 207 of the 294 patients (70.4%) in the hypothermia group and 220 of the 306 patients (71.8%) in the normothermia group had survived (relative risk with hypothermia, 0.96; 95% confidence interval [CI], 0.81 to 1.15; P = 0.71). Also, 198 of the 294 (67.3%) in the hypothermia group and 202 of the 306 (66.0%) in the normothermia group had a favorable functional outcome (relative risk with hypothermia, 1.03; 95% CI, 0.87 to 1.23; P = 0.79). There was a significant increase in the occurrence of arrythmias in the hypothermia group (62/294, 21.2%) when compared to the normothermia group (43/306, 14.1%-OR 1.49, 95% CI 1.05-2.14; p = 0.026)., Conclusions: In this study, hypothermia at 33˚C did not improve survival or functional outcome in a subset of patients with similar cardiac arrest characteristics to patients in whom benefit from hypothermia was shown in prior studies., (© 2024. The Author(s).)

Background: Targeted temperature management (TTM) is recommended following cardiac arrest; however, time to target temperature varies in clinical practice. We hypothesised the effects of a target temperature of 33 °C when compared to normothermia would differ based on average time to hypothermia and those patients achieving hypothermia fastest would have more favorable outcomes., Methods: In this post-hoc analysis of the TTM-2 trial, patients after out of hospital cardiac arrest were randomized to targeted hypothermia (33 °C), followed by controlled re-warming, or normothermia with early treatment of fever (body temperature, ≥ 37.8 °C). The average temperature at 4 h (240 min) after return of spontaneous circulation (ROSC) was calculated for participating sites. Primary outcome was death from any cause at 6 months. Secondary outcome was poor functional outcome at 6 months (score of 4-6 on modified Rankin scale)., Results: A total of 1592 participants were evaluated for the primary outcome. We found no evidence of heterogeneity of intervention effect based on the average time to target temperature on mortality (p = 0.17). Of patients allocated to hypothermia at the fastest sites, 71 of 145 (49%) had died compared to 68 of 148 (46%) of the normothermia group (relative risk with hypothermia, 1.07; 95% confidence interval 0.84-1.36). Poor functional outcome was reported in 74/144 (51%) patients in the hypothermia group, and 75/147 (51%) patients in the normothermia group (relative risk with hypothermia 1.01 (95% CI 0.80-1.26)., Conclusions: Using a hospital's average time to hypothermia did not significantly alter the effect of TTM of 33 °C compared to normothermia and early treatment of fever., (© 2022. The Author(s).)

Background: Optimal oxygen targets in patients resuscitated after cardiac arrest are uncertain. The primary aim of this study was to describe the values of partial pressure of oxygen values (PaO 2 ) and the episodes of hypoxemia and hyperoxemia occurring within the first 72 h of mechanical ventilation in out of hospital cardiac arrest (OHCA) patients. The secondary aim was to evaluate the association of PaO 2 with patients' outcome., Methods: Preplanned secondary analysis of the targeted hypothermia versus targeted normothermia after OHCA (TTM2) trial. Arterial blood gases values were collected from randomization every 4 h for the first 32 h, and then, every 8 h until day 3. Hypoxemia was defined as PaO 2  < 60 mmHg and severe hyperoxemia as PaO 2  > 300 mmHg. Mortality and poor neurological outcome (defined according to modified Rankin scale) were collected at 6 months., Results: 1418 patients were included in the analysis. The mean age was 64 ± 14 years, and 292 patients (20.6%) were female. 24.9% of patients had at least one episode of hypoxemia, and 7.6% of patients had at least one episode of severe hyperoxemia. Both hypoxemia and hyperoxemia were independently associated with 6-month mortality, but not with poor neurological outcome. The best cutoff point associated with 6-month mortality for hypoxemia was 69 mmHg (Risk Ratio, RR = 1.009, 95% CI 0.93-1.09), and for hyperoxemia was 195 mmHg (RR = 1.006, 95% CI 0.95-1.06). The time exposure, i.e., the area under the curve (PaO 2 -AUC), for hyperoxemia was significantly associated with mortality (p = 0.003)., Conclusions: In OHCA patients, both hypoxemia and hyperoxemia are associated with 6-months mortality, with an effect mediated by the timing exposure to high values of oxygen. Precise titration of oxygen levels should be considered in this group of patients., Trial Registration: clinicaltrials.gov NCT02908308 , Registered September 20, 2016., (© 2022. The Author(s).)

Oxygen (O 2 ) toxicity remains a concern, particularly to the lung. This is mainly related to excessive production of reactive oxygen species (ROS). Supplemental O 2 , i.e. inspiratory O 2 concentrations (F I O 2 ) > 0.21 may cause hyperoxaemia (i.e. arterial (a) PO 2  > 100 mmHg) and, subsequently, hyperoxia (increased tissue O 2 concentration), thereby enhancing ROS formation. Here, we review the pathophysiology of O 2 toxicity and the potential harms of supplemental O 2 in various ICU conditions. The current evidence base suggests that PaO 2  > 300 mmHg (40 kPa) should be avoided, but it remains uncertain whether there is an "optimal level" which may vary for given clinical conditions. Since even moderately supra-physiological PaO 2 may be associated with deleterious side effects, it seems advisable at present to titrate O 2 to maintain PaO 2 within the normal range, avoiding both hypoxaemia and excess hyperoxaemia., (© 2021. The Author(s).)

Background: In patients with vasodilatory shock, plasma concentrations of angiotensin I (ANG I) and II (ANG II) and their ratio may reflect differences in the response to severe vasodilation, provide novel insights into its biology, and predict clinical outcomes. The objective of these protocol prespecified and subsequent post hoc analyses was to assess the epidemiology and outcome associations of plasma ANG I and ANG II levels and their ratio in patients with catecholamine-resistant vasodilatory shock (CRVS) enrolled in the Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) study., Methods: We measured ANG I and ANG II levels at baseline, calculated their ratio, and compared these results to values from healthy volunteers (controls). We dichotomized patients according to the median ANG I/II ratio (1.63) and compared demographics, clinical characteristics, and clinical outcomes. We constructed a Cox proportional hazards model to test the independent association of ANG I, ANG II, and their ratio with clinical outcomes., Results: Median baseline ANG I level (253 pg/mL [interquartile range (IQR) 72.30-676.00 pg/mL] vs 42 pg/mL [IQR 30.46-87.34 pg/mL] in controls; P <  0.0001) and median ANG I/II ratio (1.63 [IQR 0.98-5.25] vs 0.4 [IQR 0.28-0.64] in controls; P <  0.0001) were elevated, whereas median ANG II levels were similar (84 pg/mL [IQR 23.85-299.50 pg/mL] vs 97 pg/mL [IQR 35.27-181.01 pg/mL] in controls; P = 0.9895). At baseline, patients with a ratio above the median (≥1.63) had higher ANG I levels (P <  0.0001), lower ANG II levels (P <  0.0001), higher albumin concentrations (P = 0.007), and greater incidence of recent (within 1 week) exposure to angiotensin-converting enzyme inhibitors (P <  0.00001), and they received a higher norepinephrine-equivalent dose (P = 0.003). In the placebo group, a baseline ANG I/II ratio <1.63 was associated with improved survival (hazard ratio 0.56; 95% confidence interval 0.36-0.88; P = 0.01) on unadjusted analyses., Conclusions: Patients with CRVS have elevated ANG I levels and ANG I/II ratios compared with healthy controls. In such patients, a high ANG I/II ratio is associated with greater norepinephrine requirements and is an independent predictor of mortality, thus providing a biological rationale for interventions aimed at its correction., Trial Registration: ClinicalTrials.gov identifier NCT02338843. Registered 14 January 2015.

Background: An important limitation of many critical care trial designs is that they hypothesize large, and potentially implausible, reductions in mortality. Interpretation of trial results could be improved by systematic assessment of the plausibility of trial hypotheses; however, such assessment has not been attempted in the field of critical care medicine. The purpose of this study was to determine clinicians' views about prior probabilities and plausible effect sizes for ongoing critical care trials where the primary endpoint is landmark mortality., Methods: We conducted a systematic review of clinical trial registries in September 2015 to identify ongoing critical care medicine trials where landmark mortality was the primary outcome, followed by a clinician survey to obtain opinions about ten large trials. Clinicians were asked to estimate the probability that each trial would demonstrate a mortality effect equal to or larger than that used in its sample size calculations., Results: Estimates provided by individual clinicians varied from 0% to 100% for most trials, with a median estimate of 15% (IQR 10-20%). The median largest absolute mortality reduction considered plausible was 4.5% (IQR 3.5-5%), compared with a median absolute mortality reduction used in sample size calculations of 5% (IQR 3.6-10%) (P = 0.27)., Conclusions: For some of the largest ongoing critical care trials, many clinicians regard prior probabilities as low and consider that plausible effects on absolute mortality are less than 5%. Further work is needed to determine whether pooled estimates obtained by surveying clinicians are replicable and accurate or whether other methods of estimating prior probability are preferred.

Introduction: The aim of this study was to develop consensus recommendations on safety parameters for mobilizing adult, mechanically ventilated, intensive care unit (ICU) patients., Methods: A systematic literature review was followed by a meeting of 23 multidisciplinary ICU experts to seek consensus regarding the safe mobilization of mechanically ventilated patients., Results: Safety considerations were summarized in four categories: respiratory, cardiovascular, neurological and other. Consensus was achieved on all criteria for safe mobilization, with the exception being levels of vasoactive agents. Intubation via an endotracheal tube was not a contraindication to early mobilization and a fraction of inspired oxygen less than 0.6 with a percutaneous oxygen saturation more than 90% and a respiratory rate less than 30 breaths/minute were considered safe criteria for in- and out-of-bed mobilization if there were no other contraindications. At an international meeting, 94 multidisciplinary ICU clinicians concurred with the proposed recommendations., Conclusion: Consensus recommendations regarding safety criteria for mobilization of adult, mechanically ventilated patients in the ICU have the potential to guide ICU rehabilitation whilst minimizing the risk of adverse events.

With great interest we read the article by Dr Schoeneberg and colleagues regarding gender-specific differences with respect to outcome in patients with severe traumatic injury. The authors show that, apart from the acute phase after trauma, women have a more favorable trauma severity-adjusted outcome, with shorter ICU and hospital stay and lower sepsis rates. However, a possible mechanism of action behind this difference was not suggested. We hypothesize that, in view of the fact that morbidity and mortality in the post-acute phase after trauma are often caused by infectious complications, gender differences in immunity might explain the observed differences.

Changes in body temperature are a characteristic feature of sepsis. The study by Kushimoto and colleagues in a recent issue of Critical Care demonstrates that hypothermia is a very important manifestation of infection associated with very high mortality. Combined with recent data suggesting that febrile patients with infections have the lowest mortality risk, the study raises the question of whether inducing therapeutic hyperthermia might be beneficial in this patient group. Body temperature is easily measured and manipulated in the ICU, and interventional trials defining the most appropriate temperature targets in ICU patients with infections are urgently needed. One such study is in progress.

Background: In the biological sciences the TCID50 (median tissue culture infective dose) assay is often used to determine the strength of a virus., Methods: When the so-called Spearman-Kaerber calculation is used, the ratio between the pfu (the number of plaque forming units, the effective number of virus particles) and the TCID50, theoretically approaches a simple function of Eulers constant. Further, the standard deviation of the logarithm of the TCID50 approaches a simple function of the dilution factor and the number of wells used for determining the ratios in the assay. However, these theoretical calculations assume that the dilutions of the assay are independent, and in practice this is not completely correct. The assay was simulated using Monte Carlo techniques., Results: Our simulation studies show that the theoretical results actually hold true for practical implementations of the assay. Furthermore, the simulation studies show that the distribution of the (the log of) TCID50, although discrete in nature, has a close relationship to the normal distribution., Conclusion: The pfu is proportional to the TCID50 titre with a factor of about 0.56 when using the Spearman-Kaerber calculation method. The normal distribution can be used for statistical inferences and ANOVA on the (the log of) TCID50 values is meaningful with group sizes of 5 and above.

Background: The Portex Soft Seal high-volume, low-pressure cuffed tracheal tube was compared with the Mallinckrodt HiLo, Sheridan Preformed and Portex Profile tracheal tubes for leakage of dye placed in the subglottic space of a pig's trachea which was used in a benchtop mechanical ventilation model and in six isolated pig tracheas., Results: There was no leakage, either in the ventilation model or in the isolated tracheas in the Portex Soft Seal group. There was rapid leakage in the ventilation model and in all the isolated tracheas for the Mallinckrodt HiLo, and five out of six isolated tracheas for the Sheridan Preformed and the Portex Profile group., Conclusions: This benchtop study suggests that the improved compliance characteristics of the Portex Soft Seal cuff are beneficial in preventing leakage of fluid in these models.