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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: The relationship between indices of mechanical ventilation and pulmonary artery pressures remains ill-defined in ARDS. As our understanding of mechanical ventilation has progressed, there is now a greater appreciation of the impact of high driving pressures and mechanical power in perpetuating lung injury. However, the relationship between the newer derived indices of mechanical ventilation and pulmonary artery pressure is unclear. We performed a post hoc analysis of the Fluid and Catheters Treatment Trial (FACTT) trial to investigate the associations between mechanical ventilation indices in ARDS patients and the prevalence of pulmonary hypertension. This may help elucidate future clinical targets for more, right ventricular protective, mechanical ventilation strategies., Methods: We performed a post hoc analysis of the FACTT database to identify ARDS patients who had a pulmonary artery catheter (PAC) inserted and pulmonary artery pressure readings recorded. We excluded any patient with a PAC inserted who was spontaneously breathing, as driving pressure and mechanical power are not validated in this cohort. Three independent analyses were performed: a univariate analysis, to assess for associations between mPAP and mechanical ventilation parameters using Pearson correlation coefficients, a multivariate analysis, to assess for independent associations with mPAP using a multiple regression model according to Akaike's information criteria and finally an analysis for nonlinearity, using the best-fitting model according to the Bayesian information criterion (BIC) from linear, quadratic, fractional polynomial and restricted cubic spline models., Results: All the ventilation parameters demonstrated a significant correlation with mPAP, except tidal volume (once adjusted for respiratory rate) in the univariate analysis. The multivariate analysis demonstrated that the blood pH level, P/F ratio, PaCO 2 level, mean airway pressure and the mechanical power indexed to compliance were independently associated with mPAP. In the final nonlinear analysis, associations did not differ from linearity except for 4 variables for which the fractional polynomial was the best-fitting model. These were mechanical power (p = 0.01 compared to the linear model), respiratory rate (p = 0.04), peak pressure (p = 0.03) and mean airway pressure (p = 0.01). Two nonlinear variables associated with mPAP were assessed in more detail, respiratory rate and mechanical power. Inflexion points at a respiratory rate of 16.8 cycles per minute and a mechanical power of 8.8 J/min were demonstrated., Conclusions: The associations identified between mPAP and mechanical ventilation variables in this analysis would suggest that classical ARDS lung protective strategies, including low tidal volume ventilation and permissive hypercapnia, may negatively impact the management of the subset of ARDS patients with associated right ventricular dysfunction or ACP. Additionally, respiratory rates above 17 cycles per minute show an incremental increase in mPAP. Therefore, increases in tidal volume (within the limitation of driving pressure < 18 cmH20) may represent a more right ventricular protective way to control CO2 and pH., (© 2022. 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: Targeted temperature management at 33 °C (TTM33) has been employed in effort to mitigate brain injury in unconscious survivors of out-of-hospital cardiac arrest (OHCA). Current guidelines recommend prevention of fever, not excluding TTM33. The main objective of this study was to investigate if TTM33 is associated with mortality in patients with vasopressor support on admission after OHCA., Methods: We performed a post hoc analysis of patients included in the TTM-2 trial, an international, multicenter trial, investigating outcomes in unconscious adult OHCA patients randomized to TTM33 versus normothermia. Patients were grouped according to level of circulatory support on admission: (1) no-vasopressor support, mean arterial blood pressure (MAP) ≥ 70 mmHg; (2) moderate-vasopressor support MAP < 70 mmHg or any dose of dopamine/dobutamine or noradrenaline/adrenaline dose ≤ 0.25 µg/kg/min; and (3) high-vasopressor support, noradrenaline/adrenaline dose > 0.25 µg/kg/min. Hazard ratios with TTM33 were calculated for all-cause 180-day mortality in these groups., Results: The TTM-2 trial enrolled 1900 patients. Data on primary outcome were available for 1850 patients, with 662, 896, and 292 patients in the, no-, moderate-, or high-vasopressor support groups, respectively. Hazard ratio for 180-day mortality was 1.04 [98.3% CI 0.78-1.39] in the no-, 1.22 [98.3% CI 0.97-1.53] in the moderate-, and 0.97 [98.3% CI 0.68-1.38] in the high-vasopressor support groups with regard to TTM33. Results were consistent in an imputed, adjusted sensitivity analysis., Conclusions: In this exploratory analysis, temperature control at 33 °C after OHCA, compared to normothermia, was not associated with higher incidence of death in patients stratified according to vasopressor support on admission. Trial registration Clinical trials identifier NCT02908308 , registered September 20, 2016., (© 2022. The Author(s).)

Background: Prognostication of neurological outcome in patients who remain comatose after cardiac arrest resuscitation is complex. Clinical variables, as well as biomarkers of brain injury, cardiac injury, and systemic inflammation, all yield some prognostic value. We hypothesised that cumulative information obtained during the first three days of intensive care could produce a reliable model for predicting neurological outcome following out-of-hospital cardiac arrest (OHCA) using artificial neural network (ANN) with and without biomarkers., Methods: We performed a post hoc analysis of 932 patients from the Target Temperature Management trial. We focused on comatose patients at 24, 48, and 72 h post-cardiac arrest and excluded patients who were awake or deceased at these time points. 80% of the patients were allocated for model development (training set) and 20% for internal validation (test set). To investigate the prognostic potential of different levels of biomarkers (clinically available and research-grade), patients' background information, and intensive care observation and treatment, we created three models for each time point: (1) clinical variables, (2) adding clinically accessible biomarkers, e.g., neuron-specific enolase (NSE) and (3) adding research-grade biomarkers, e.g., neurofilament light (NFL). Patient outcome was the dichotomised Cerebral Performance Category (CPC) at six months; a good outcome was defined as CPC 1-2 whilst a poor outcome was defined as CPC 3-5. The area under the receiver operating characteristic curve (AUROC) was calculated for all test sets., Results: AUROC remained below 90% when using only clinical variables throughout the first three days in the ICU. Adding clinically accessible biomarkers such as NSE, AUROC increased from 82 to 94% (p < 0.01). The prognostic accuracy remained excellent from day 1 to day 3 with an AUROC at approximately 95% when adding research-grade biomarkers. The models which included NSE after 72 h and NFL on any of the three days had a low risk of false-positive predictions while retaining a low number of false-negative predictions., Conclusions: In this exploratory study, ANNs provided good to excellent prognostic accuracy in predicting neurological outcome in comatose patients post OHCA. The models which included NSE after 72 h and NFL on all days showed promising prognostic performance.

Objective: Exposure to hyperoxemia and hypoxemia is common in out-of-hospital cardiac arrest (OHCA) patients following return of spontaneous circulation (ROSC), but its effects on neurological outcome are uncertain, and study results are inconsistent., Methods: Exploratory post hoc substudy of the Target Temperature Management (TTM) trial, including 939 patients after OHCA with return of spontaneous circulation (ROSC). The association between serial arterial partial pressures of oxygen (PaO 2 ) during 37 h following ROSC and neurological outcome at 6 months, evaluated by Cerebral Performance Category (CPC), dichotomized to good (CPC 1-2) and poor (CPC 3-5), was investigated. In our analyses, we tested the association of hyperoxemia and hypoxemia, time-weighted mean PaO 2 , maximum PaO 2 difference, and gradually increasing PaO 2 levels (13.3-53.3 kPa) with poor neurological outcome. A subsequent analysis investigated the association between PaO 2 and a biomarker of brain injury, peak serum Tau levels., Results: Eight hundred sixty-nine patients were eligible for analysis. Three hundred patients (35%) were exposed to hyperoxemia or hypoxemia at some time point after ROSC. Our analyses did not reveal a significant association between hyperoxemia, hypoxemia, time-weighted mean PaO 2 exposure or maximum PaO 2 difference and poor neurological outcome at 6-month follow-up after correction for co-variates (all analyses p = 0.146-0.847). We were not able to define a PaO 2 level significantly associated with the onset of poor neurological outcome. Peak serum Tau levels at either 48 or 72 h after ROSC were not associated with PaO 2 ., Conclusion: Hyperoxemia or hypoxemia exposure occurred in one third of the patients during the first 37 h of hospitalization and was not significantly associated with poor neurological outcome after 6 months or with the peak s-Tau levels at either 48 or 72 h after ROSC.

Background: Dyscarbia is common in out-of-hospital cardiac arrest (OHCA) patients and its association to neurological outcome is undetermined., Methods: This is an exploratory post-hoc substudy of the Target Temperature Management (TTM) trial, including resuscitated OHCA patients, investigating the association between serial measurements of arterial partial carbon dioxide pressure (PaCO 2 ) and neurological outcome at 6 months, defined by the Cerebral Performance Category (CPC) scale, dichotomized to good outcome (CPC 1 and 2) and poor outcome (CPC 3-5). The effects of hypercapnia and hypocapnia, and the time-weighted mean PaCO 2 and absolute PaCO 2 difference were analyzed. Additionally, the association between mild hypercapnia (6.0-7.30 kPa) and neurological outcome, its interaction with target temperature (33 °C and 36 °C), and the association between PaCO 2 and peak serum-Tau were evaluated., Results: Of the 939 patients in the TTM trial, 869 were eligible for analysis. Ninety-six percent of patients were exposed to hypocapnia or hypercapnia. None of the analyses indicated a statistical significant association between PaCO 2 and neurological outcome (P = 0.13-0.96). Mild hypercapnia was not associated with neurological outcome (P = 0.78) and there was no statistically significant interaction with target temperature (P interaction  = 0.95). There was no association between PaCO 2 and peak serum-Tau levels 48 or 72 h after return of spontaneous circulation (ROSC)., Conclusions: Dyscarbia is common after ROSC. No statistically significant association between PaCO 2 in the post-cardiac arrest phase and neurological outcome at 6 months after cardiac arrest was detected. There was no significant interaction between mild hypercapnia and temperature in relation to neurological outcome.

Background: We aimed to investigate the diagnostic performance of S100 as an outcome predictor after out-of-hospital cardiac arrest (OHCA) and the potential influence of two target temperatures (33 °C and 36 °C) on serum levels of S100., Methods: This is a substudy of the Target Temperature Management after Out-of-Hospital Cardiac Arrest (TTM) trial. Serum levels of S100 were measured a posteriori in a core laboratory in samples collected at 24, 48, and 72 h after OHCA. Outcome at 6 months was assessed using the Cerebral Performance Categories Scale (CPC 1-2 = good outcome, CPC 3-5 = poor outcome)., Results: We included 687 patients from 29 sites in Europe. Median S100 values were higher in patients with a poor outcome at 24, 48, and 72 h: 0.19 (IQR 0.10-0.49) versus 0.08 (IQR 0.06-0.11) μg/ml, 0.16 (IQR 0.10-0.44) versus 0.07 (IQR 0.06-0.11) μg/L, and 0.13 (IQR 0.08-0.26) versus 0.06 (IQR 0.05-0.09) μg/L (p < 0.001), respectively. The ability to predict outcome was best at 24 h with an AUC of 0.80 (95% CI 0.77-0.83). S100 values were higher at 24 and 72 h in the 33 °C group than in the 36 °C group (0.12 [0.07-0.22] versus 0.10 [0.07-0.21] μg/L and 0.09 [0.06-0.17] versus 0.08 [0.05-0.10], respectively) (p < 0.02). In multivariable analyses including baseline variables and the allocated target temperature, the addition of S100 improved the AUC from 0.80 to 0.84 (95% CI 0.81-0.87) (p < 0.001), but S100 was not an independent outcome predictor. Adding S100 to the same model including neuron-specific enolase (NSE) did not further improve the AUC., Conclusions: The allocated target temperature did not affect S100 to a clinically relevant degree. High S100 values are predictive of poor outcome but do not add value to present prognostication models with or without NSE. S100 measured at 24 h and afterward is of limited value in clinical outcome prediction after OHCA., Trial Registration: ClinicalTrials.gov identifier: NCT01020916 . Registered on 25 November 2009.

Background: Early identification of predictors for a poor long-term outcome in patients who survive the initial phase of out-of-hospital cardiac arrest (OHCA) may facilitate future clinical research, the process of care and information provided to relatives. The aim of this study was to determine the association between variables available from the patient's history and status at intensive care admission with outcome in unconscious survivors of OHCA., Methods: Using the cohort of the Target Temperature Management trial, we performed a post hoc analysis of 933 unconscious patients with OHCA of presumed cardiac cause who had a complete 6-month follow-up. Outcomes were survival and neurological function as defined by the Cerebral Performance Category (CPC) scale at 6 months after OHCA. After multiple imputations to compensate for missing data, backward stepwise multivariable logistic regression was applied to identify factors independently predictive of a poor outcome (CPC 3-5). On the basis of these factors, a risk score for poor outcome was constructed., Results: We identified ten independent predictors of a poor outcome: older age, cardiac arrest occurring at home, initial rhythm other than ventricular fibrillation/tachycardia, longer duration of no flow, longer duration of low flow, administration of adrenaline, bilateral absence of corneal and pupillary reflexes, Glasgow Coma Scale motor response 1, lower pH and a partial pressure of carbon dioxide in arterial blood value lower than 4.5 kPa at hospital admission. A risk score based on the impact of each of these variables in the model yielded a median (range) AUC of 0.842 (0.840-0.845) and good calibration. Internal validation of the score using bootstrapping yielded a median (range) AUC corrected for optimism of 0.818 (0.816-0.821)., Conclusions: Among variables available at admission to intensive care, we identified ten independent predictors of a poor outcome at 6 months for initial survivors of OHCA. They reflected pre-hospital circumstances (six variables) and patient status on hospital admission (four variables). By using a simple and easy-to-use risk scoring system based on these variables, patients at high risk for a poor outcome after OHCA may be identified early.

Despite advances in resuscitation medicine, including target temperature management as part of post-cardiac arrest care, many patients will have a poor neurological outcome, most often resulting in death. It is a commonly held belief that the ability to prognosticate outcome at an early stage after cardiac arrest would allow subsequent health care delivery to be tailored to individual patients. However, currently available predictive methods and biomarkers lack sufficient accuracy and therefore cannot be generally recommended in clinical practice. MicroRNAs have recently emerged as potential biomarkers of cardiovascular diseases. While the biomarker value of microRNAs for myocardial infarction or heart failure has been extensively studied, less attention has been devoted to their prognostic value after cardiac arrest. This review highlights the recent discoveries suggesting that microRNAs may be useful both to predict outcome and to treat patients after cardiac arrest.

Improving the quality of oral hygiene is recognised as an important counter measure for reducing the incidence of ventilator-associated pneumonia amongst critically ill patients. Toothbrushing physically disrupts the dental plaque that acts as a reservoir for pulmonary infection and therefore has the potential to reduce the incidence of ventilator-associated pneumonia. Gu and colleagues performed a systematic review and meta-analysis of oral hygiene with and without a toothbrush and found no difference in the incidence of pneumonia in mechanically ventilated patients. The diagnosis of ventilator-associated pneumonia is prone to bias and future studies of oral care interventions should focus on measures of oral cleanliness such as plaque and gingival scores. Once the optimal strategy for oral hygiene is defined in the critically ill, larger studies focussing on ventilator-associated pneumonia or mortality can be conducted.

Combination therapy with two antimicrobial agents is superior to monotherapy in severe community-acquired pneumonia, and recent data suggest that addition of a macrolide as the second antibiotic might be superior to other combinations. This observation requires confirmation in a randomised control trial, but this group of antibiotics have pleiotropic effects that extend beyond bacterial killing. Macrolides inhibit bacterial cell-to-cell communication or quorum sensing, which not only might be an important mechanism of action for these drugs in severe infections but may also provide a novel target for the development of new anti-infective drugs.