Critical Care Bulletin: April 2025

 

A randomized controlled trial of catheters with different tips and lengths for patients requiring continuous renal replacement therapy in intensive care unit

Critical Care volume 29, Article number: 148 (2025) Published: 11 April 2025

Background

The tip design and length of catheter impact catheter function. Two types of catheters with different tips, side-hole catheters and step-tip catheters, are commonly used during continuous renal replacement therapy (CRRT). However, there is insufficient evidence comparing their efficacy and safety in CRRT. In addition, whether the insertion of a longer catheter could enhance catheter function remains poorly studied and controversial.

Methods

In this open-label, three-arm, randomized trial, critically ill patients receiving CRRT were randomized to three groups. Group A received 20 cm side-hole catheters (GDHK‐1120), group B received 20 cm step-tip catheters (GDHK‐1320) and group C received 25 cm step-tip catheters (GDHK‐1325). The primary outcomes were the incidence of catheter dysfunction and catheter survival time.

Results

A total of 351 patients were enrolled, with 116 in group A, 117 in group B, and 118 in group C. The incidence of catheter dysfunction in group A (35.7%, 51/143) was significantly higher than that in group B (17.7%, 22/124) (P = 0.001). However, there was no difference between group B and group C (15.6%, 23/147) (P = 0.744). The catheter survival time was comparable between group A (5.5 days, IQR 2.5–9.3) and group B (5.0 days, IQR 3.0–10.0) (P = 0.626). In contrast, group C (6.4 days, IQR 3.9–12.0) demonstrated a significantly longer catheter survival time compared to group B (P = 0.019). Cox regression analysis identified BMI (HR 1.052, 95% CI 1.003–1.103, P = 0.036) as an independent risk factor for catheter dysfunction. Results were not consistent across BMI tertiles, with similar results observed only in patients with a lower BMI (BMI < 24.2) (chi-square 13.65, P = 0.001). There was also a trend that patients in group C have a longer filter lifespan (36.5 h, IQR 16.9–68.1, P = 0.001) and a lower incidence of catheter-related thrombosis (10.40 per 1000 catheter-days, 95% CI 5.93, 17.83, P = 0.019). Other secondary outcomes were not significantly different among groups.

Conclusions

Step-tip catheters may be preferable for CRRT, particularly for patients in the lower BMI tercile. Longer femoral vein catheterization demonstrated enhanced benefits in CRRT, especially among obese patients. Further high-quality, multicenter RCTs are essential to strengthen the evidence guiding catheter selection during CRRT.

 

 

Comparison of all-cause mortality with different blood glucose control strategies in patients with diabetes in the ICU: a network meta-analysis of randomized controlled trials

Annals of Intensive Care volume 15, Article number: 51 (2025) Published: 09 April 2025

Background

The optimal glucose control strategy for intensive care unit (ICU) patients with diabetes remains a topic of debate. This study aimed to compare the effects of strict glucose control, intermediate strict glucose control, liberal glucose control, and very liberal glucose control on reducing all-cause mortality in ICU patients with diabetes through a network meta-analysis.

Methods

We conducted a search in PubMed, Cochrane Library, Embase, and Web of Science for randomized controlled trials comparing different glucose control strategies in ICU patients with diabetes up to October 1, 2024. The primary outcome was all-cause 90-day mortality. The Risk of Bias 2 tool was used to assess bias in the included studies. Data analysis was performed using Stata (version 17).

Results

A total of 12 randomized controlled trials involving 5,297 participants were included in the final analysis. The results showed that there was no statistically significant difference between the four glucose control strategies in reducing all-cause 90-day mortality. The surface under the cumulative ranking (SUCRA), which was used to rank the strategies and display the probability of each strategy being ranked first, showed the following: intermediate strict control (SUCRA 88%), liberal control (SUCRA 55.3%), very liberal control (SUCRA 40.3%), and strict control (SUCRA 16.5%). The cumulative probability of each strategy’s rank in reducing all-cause mortality, from best to worst, showed that the most likely ranking was intermediate strict control, liberal control, very liberal control, and strict control.

Conclusions

In ICU patients with diabetes, no significant statistical difference was observed among the four glucose control strategies in reducing all-cause 90-day mortality. The SUCRA rankings are hypothesis-generating and require further validation. Therefore, the current evidence is insufficient to definitively conclude that any one strategy is superior to the others in reducing mortality.

 

Monitoring patients with acute respiratory failure during non-invasive respiratory support to minimize harm and identify treatment failure

Critical Care volume 29, Article number: 147 (2025) Published: 09 April 2025

Abstract

Non-invasive respiratory support (NRS), including high flow nasal oxygen therapy, continuous positive airway pressure and non-invasive ventilation, is a cornerstone in the management of critically ill patients who develop acute respiratory failure (ARF). Overall, NRS reduces the work of breathing and relieves dyspnea in many patients with ARF, sometimes avoiding the need for intubation and invasive mechanical ventilation with variable efficacy across diverse clinical scenarios. Nonetheless, prolonged exposure to NRS in the presence of sustained high respiratory drive and effort can result in respiratory muscle fatigue, cardiovascular collapse, and impaired oxygen delivery to vital organs, leading to poor outcomes in patients who ultimately fail NRS and require intubation. Assessment of patients’ baseline characteristics before starting NRS, close physiological monitoring to evaluate patients’ response to respiratory support, adjustment of device settings and interface, and, most importantly, early identification of failure or of paramount importance to avoid the negative consequences of delayed intubation. This review highlights the role of respiratory monitoring across various modalities of NRS in patients with ARF including dyspnea, general respiratory parameters, measures of drive and effort, and lung imaging. It includes technical specificities related to the target population and emphasizes the importance of clinicians’ physiological understanding and tailoring clinical decisions to individual patients’ needs.

 

Visual coronary artery calcification score to predict significant coronary artery stenosis in patients presenting with cardiac arrest without ST-segment elevation myocardial infarction

Annals of Intensive Care volume 15, Article number: 50 (2025) Published: 07 April 2025

Background

Emergency coronary angiogram after a cardiac arrest without ST-segment elevation myocardial infarction (STEMI) is still a matter of debate. To better select patients who may benefit from this procedure, we tested a visual coronary artery calcification (VCAC) score available in chest CT to predict significant coronary artery stenosis and/or culprit lesion or ad hoc or delayed percutaneous coronary intervention (PCI).

Results

A total of 113 patients with cardiac arrest and without STEMI who had a coronary angiogram and chest CT (January 2013 to March 2023, Croix-Rousse Hospital, Lyon, France) were retrospectively included. VCAC was scored from 0 (no calcification) to 3 (diffuse calcification) for each 4 four main arteries (left main, left anterior descending, circumflex, and right coronary artery). At baseline the median [interquartile range] age was 65.8 years [53.4–75.7], 61.9% were male, and 59.3% presented with ventricular fibrillation. Coronary angiogram identified at least one significant coronary artery stenosis in 32.7%, and ad hoc and delayed PCI were performed in 12.4% and 6.2% of the patients, respectively. VCAC score was an excellent predictor of significant coronary artery stenosis with an area under the ROC curve (AUC) of 0.95 (95%CI [0.90-1.00]) and the optimal threshold was ≥ 4 (specificity 94.7%, sensitivity 91.9%). For the detection of culprit coronary artery stenosis, the AUC was at 0.90 (95%CI [0.85–0.96]) and the optimal threshold was ≥ 5 (specificity 83.5%, sensitivity 87.5%). The AUC was 0.886 [0.823–0.948] (specificity 81.8%, sensitivity 85.7%) for ad hoc PCI and 0.921 [0.872–0.972] (specificity 85.3%, sensitivity 88.9%) for both delayed and ad hoc PCI with a same optimal threshold of VCAC ≥ 5. A VCAC score ≥ 4 had a sensitivity at 100% to predict a significant or culprit coronary artery stenosis and ad hoc or delayed PCI.

Conclusions

The present study found that a non-dedicated CT thorax may be useful to measure VCAC and if this is scored ≥ 4 it allows physicians to better select patients resuscitated from cardiac arrest with non-STEMI and without history of coronary artery disease who may benefit from an emergency coronary angiogram to detect a significant or culprit coronary artery stenosis and had PCI if appropriate.

 

Prognosis of liver abscess in the intensive care unit (POLAIR), a multicentre observational study

Critical Care volume 29, Article number: 146 (2025) Published: 07 April 2025

Background

Liver abscess (LA) is a rare but potentially serious condition with a high mortality rate. Current epidemiological data of LA patients requiring intensive care unit (ICU) admission are limited.

Methods

This multicentre retrospective study included adults admitted to 24 ICUs in France between January 2010 and December 2020. Risk factors for mortality were identified by multivariate analysis. A propensity score was used to adjust for confounders related to the presence of portal vein thrombosis.

Results

335 patients were enrolled. The median age was 66 years [53–73] and 68% were male. Commons comorbidities included diabetes (29.9%) and cancer or haematological disease. Septic shock was the main reason for admission (58%). The median SAPS2 score at ICU admission was 42 [31–53] and the SOFA score was 6 [3–9]. The putative origin of LA was biliary (31%), while 40% were cryptogenic. Most patients (60%) had a solitary LA, involving the right lobe (38.8%), with a median diameter of 67 mm [47–91]. Associated portal vein thrombosis (PVT) was present in 13.4% of cases. Microbiological documentation was obtained in 82% of patients, showing gram-negative bacilli (59.7%), mainly Escherichia coli (19.6%) and Klebsiella spp. (19.1%), and gram-positive cocci (29.6%), mainly Streptococcus spp. (17.1%). Drainage was performed in 62% of cases, 40% within 48 h. The median duration of antibiotic therapy was 35 days [21–42]. During hospitalisation, 62% of patients required vasopressors and 29% required mechanical ventilation. In-ICU mortality was 11.6%. Multivariate analysis showed that organ dysfunction illustrated by SOFA score (HR 3.45 [1.95–6.09], p < 0.001) and PVT (HR 3.14 [1.54–6.39], p = 0.001) were significant risk factors for mortality. Drainage was not associated with improved short-term survival (HR 1.22 [0.65–2.72], p = 0.52). In the population matched for PVT confounders, a higher sofa score was the only factor associated with mortality (HR 3.11 [1.76–5.49] IC95%, p = 0.001).

Conclusions

This multicentre study illustrates the severity of LA in French intensive care units and identifies organ dysfunction (SOFA score) and portal vein thrombosis as major risk factors for mortality. Prospective studies are needed to improve management strategies, as the survival benefit of drainage is unclear.

 

Does Levosimendan hasten veno-arterial ECMO weaning? A propensity score matching analysis

Annals of Intensive Care volume 15, Article number: 48 (2025) Published: 03 April 2025

 

Background

Preliminary evidence from small, single-center studies suggests levosimendan may improve the likelihood of successful venoarterial extracorporeal membrane oxygenation (VA-ECMO) weaning in patients with cardiogenic shock. However, the literature is limited and presents conflicting results. We aimed to assess the benefits of levosimendan on VA-ECMO for time to successful ECMO weaning, using a pragmatic and rigorous definition of successful VA-ECMO weaning in patients with potential for cardiac function recovery.

Methods

A retrospective bicentric study over 6 years was conducted, including patients who received levosimendan during their ECMO course. Patients with post-cardiotomy cardiogenic shock or end-stage chronic heart failure were excluded. Patients receiving levosimendan while on VA-ECMO were matched to those not receiving levosimendan during the same period, based on pre-specified variables and time from ECMO initiation. The primary endpoint was successful VA-ECMO weaning, defined as survival without death, heart transplantation, or LVAD within 30 days after VA-ECMO withdrawal.

Results

Over the study period, 320 patients treated with VA-ECMO for refractory cardiogenic shock were included, of whom 68 received levosimendan during their ECMO course. Propensity score matching yielded 47 unique pairs of patients with comparable characteristics. After matching, successful ECMO weaning was achieved in 16 out of 47 patients (34%) in the no-levosimendan group and 21 out of 47 patients (45%) in the levosimendan group (sHR, 1.45 [95% CI, 0.77–2.70]; P = 0.25). Similarly, there were no significant differences between the groups in terms of bridge-to-heart transplant, LVAD, or death. Left ventricular ejection fraction and aortic velocity time integral improved significantly after levosimendan in all patients, regardless of their VA-ECMO weaning status.

Conclusion

In patients with non-postoperative cardiogenic shock supported by peripheral VA-ECMO, levosimendan was not associated with increased rates of successful VA-ECMO weaning or improved 30-day and 6-month bridge-free survival. Results from double-blinded randomized controlled trials are urgently needed to clarify the effectiveness and optimal timing of levosimendan in this specific population.

 

Automatic continuous P0.1 measurements during weaning from mechanical ventilation: a clinical study

Annals of Intensive Care volume 15, Article number: 47 (2025) Published: 01 April 2025

Background

In critically ill patients, weaning from mechanical ventilation (MV) includes spontaneous breathing trial (SBT) usually followed by a reventilation period in order to recover from the alveolar derecruitement induced by the SBT. The measurement of occlusion pressure during the first 100 ms of an airway occlusion (P0.1) one of the non-invasive tools available for estimating the respiratory drive, is a determinant of patient respiratory effort. This clinical study explores the use of non-invasive continuous monitoring of occlusion pressure automatically calculated by ventilators in the first 100 ms of airway occlusion (P0.1 vent) during SBT and reventilation periods. The study aimed to investigate patient or respirator factors influencing P0.1 vent as well as the association of P0.1 vent values with extubation success or failure.

Patients and Methods

This prospective observational study, conducted from February 2022 to April 2023, included adult patients intubated for more than 24 h and screened for extubation weaning. SBTs were performed for one hour with zero pressure support and zero end-expiratory pressure (PS0 ZEEP). Reventilation followed for an hour with pressure support (8–12 cmH2O) and PEEP (5 cmH2O). Data included patient characteristics, ventilator parameters and extubation outcomes.

Results

The study involved 224 measurements from 212 patients, with 157 successful extubations, 46 extubation failures at day 7 and 21 SBT failures. P0.1 vent mean values were significantly higher for extubation failures and SBT failures compared to successful extubations (p < 0.001). Delta P0.1 vent ((P0.1 vent reventilation - P0.1 vent SBT)/ P0.1 vent SBT) was significantly different according to whether extubation was a success or a failure: 0.21 (0.02–0.62) cm H2O vs. P0.1 vent vs. 1.12 (0.54–2.38) cm H2O; p < 0.0001 respectively. Values significantly differed in both the SBT and the reventilation periods whether or not patients had previous ARDS: 1.08 (0.70; 2.02) cmH2O vs. 0.80 (0.54; 1.28) cmH2O respectively (p = 0.003). Noteworthy, P0.1 vent values were influenced by airway humidification systems (0.92 (0.57; 1.54) cmH2O with humidification vs. 1.27 (0.91; 2.24) cmH2O without, p = 0.003).

Conclusion

The delta of P0.1vent values between SBT and reventilation are higher for patients who fail extubation, especially for those who had ARDS. While elevated P0.1 vent values were associated with extubation failure, the overlap in values limits its usefulness as a reliable predictor.

 

Incidence and risk factors of weaning-induced pulmonary oedema: results from a multicentre, observational study

Critical Care volume 29, Article number: 140 (2025) Published: 31 March 2025

Background

During the weaning process, the transition from positive to negative pressure ventilation may induce cardiac dysfunction, which may lead to pulmonary oedema. The incidence of weaning-induced pulmonary oedema (WIPO) is poorly documented and shows huge variations. Our study aims to investigate the incidence and risk factors for WIPO during weaning from mechanical ventilation in general critically ill patients.

Methods

This multicentre study was conducted in France, Italy, and India. Adult critically ill patients receiving invasive ventilation were included once a spontaneous breathing trial (SBT) was performed. The SBT technique could be either T-piece or pressure support mode with (PSV-PEEP) or without positive end expiratory pressure (PEEP) (PSV-ZEEP). A consensual diagnosis of WIPO was made a posteriori by five experts who analysed changes observed during the SBT that were retrospectively recorded.

Results

From July 2019 to February 2021, 634 SBTs were performed in 500 patients from 13 ICUs. Weaning success occurred in 417 patients (66%) and weaning failure in 217 (34%). Weaning was short in 414 (83%) of SBTs, difficult in 47 (9%) SBTs, and prolonged in 39 (8%) SBTs. WIPO was diagnosed in 79 (12%) cases, which accounted for 36% of the 217 weaning failures. WIPO occurred in 54/358 (15%) of T-piece SBT, in 7/84 (8%) of PSV-PEEP SBT (p = 0.072 vs. T-piece), and in 18/192 (9%) of PSV-ZEEP SBT (p = 0.002 vs. T-piece). In multilevel logistic regression analysis including 202 weaning failures from 149 different patients, COPD, and previous cardiomyopathy were identified as independent risk factors associated with WIPO.

Conclusion

In general ICU patients, WIPO accounts for 36% of weaning failure cases. Previous heart disease and COPD are two independent risk factors for developing WIPO during the weaning process.

 

A consensus of European experts on the definition of ventilator-associated pneumonia recurrences obtained by the Delphi method: the RECUVAP study

Intensive Care Medicine: Published 31 March 2025

Background

There are recognized diagnostic criteria for a first ventilator-associated pneumonia (VAP) episode, but not for recurrences. Many randomized clinical trials (RCTs) have used the recurrence of VAP as a criterion for efficacy evaluation. Still, the different definitions used in RCTs make it difficult to compare studies. We aimed to develop a consensual definition of VAP recurrences and of the various types of VAP recurrences.

Methods

Thirty-six European experts constituting a multidisciplinary group of physicians (critical care, infectious diseases, microbiology) with special interest in the management of VAP were polled using the Delphi methodology.

Results

After the completion of four iterations of the DELPHI method, 94% of experts agreed that the diagnostic criteria for a first VAP episode could also be used for recurrences, except for the radiological criterion, which not all the experts considered to be mandatory. Consensus was also reached regarding the definition of four distinct entities: relapse, persistent VAP, superinfection, and new-pathogen VAP. For relapse and persistent VAP, bacteriological findings were identical for different VAP episodes, whereas they differed for superinfection and new-pathogen VAP. The distinction between relapse and persistent VAP, and between superinfection and new-pathogen VAP depended on the timing of antibiotic treatment (before or after 48–72 h after the end of antibiotic therapy) and the clinical course. Microbiological criteria were proposed to facilitate the diagnosis of persistent VAP.

Conclusion

This consensus by European experts proposes four different VAP recurrence entities which should facilitate the harmonization of recurrence criteria for clinical practice and future studies.

 

Haloperidol in treating delirium, reducing mortality, and preventing delirium occurrence: Bayesian and frequentist meta-analyses

Critical Care volume 29, Article number: 126 (2025) Published: 20 March 2025

Background

Although haloperidol is commonly used to treat or prevent delirium in intensive care unit (ICU) patients, the evidence remains inconclusive. This study aimed to comprehensively evaluate the efficacy and safety of haloperidol for delirium treatment and prevention in ICU patients.

Methods

We searched MEDLINE, the cochrane central register of controlled trials, EMBASE, ClinicalTrial.gov, and PubMed without language restrictions from database inception to June 27, 2024. We included double-blind randomized controlled trials (RCTs) on haloperidol versus placebo for treating and preventing delirium in adult ICU patients. In addition to frequentist analyses, Bayesian analysis was used to calculate the posterior probabilities of any benefit/harm and clinically important benefit/harm (CIB/CIH). The primary outcomes for delirium treatment were all-cause mortality and serious adverse events (SAEs). For delirium prevention, the primary outcomes included incident delirium, all-cause mortality, and SAEs. The secondary outcomes for efficacy were delirium-or coma-free days, ventilator-free days, length of stay in ICU, length of stay in hospital, and rescue benzodiazepine use. The secondary outcomes for safety were QTc prolongation and extrapyramidal syndrome.

Results

We included seven RCTs on delirium treatment (n = 1767) and five on delirium prevention (n = 2509). The Bayesian analysis showed that, compared to placebo for delirium treatment, haloperidol had a 68% probability of achieving CIB (defined as risk difference [RD] < −0.02) in reducing all-cause mortality, a 2% probability of achieving CIH (RD > 0.02) in causing SAEs, and a 78% probability of achieving CIB (RD < −0.02) in reducing the need for rescue benzodiazepine use. The probabilities of haloperidol causing CIH (RD > 0.02) across all other safety outcomes were low (all < 50%). In frequentist analysis on delirium treatment, the pooled estimated RD for haloperidol compared to placebo was -0.05 (−0.09, −0.00; I2 = 0%) for rescue benzodiazepine use. In Bayesian analysis on delirium prevention, haloperidol had a 12% probability of achieving CIB in all-cause mortality, a 34% probability of achieving CIB in delirium incidence, and a 0% probability of achieving CIB in SAEs. Importantly, haloperidol had a 65% probability of causing CIH (risk ratio > 1.1) for QTc prolongation, while the posterior probabilities of achieving CIB across all efficacy outcomes were low (all < 50%). In frequentist analysis on delirium prevention, all primary and secondary outcomes were not statistically significant in frequentist analysis.

Conclusion

Our study supported the use of haloperidol for delirium treatment in adult ICU patients, but not for delirium prevention.

 

Intraosseous versus intravenous vascular access in out-of-hospital cardiac arrest: a systematic review and meta-analysis of randomized controlled trials

 

Critical Care volume 29, Article number: 124 (2025) Published: 19 March 2025

 

Background

Rapid and reliable vascular access is crucial during cardiopulmonary resuscitation for out-of-hospital cardiac arrest (OHCA). While intraosseous (IO) and intravenous (IV) access are used, their comparative effectiveness for patient outcomes remains uncertain.

Methods

We searched PubMed, Embase, and ClinicalTrials.gov for RCTs comparing IO vs. IV access in adults with OHCA. The primary outcome was survival (30 days or until discharge), while secondary outcomes included sustained ROSC, favorable neurological outcome, successful first-attempt vascular access, and time from emergency medical service arrival to access. Pooled odds ratios (OR), mean differences (MD), and 95% confidence intervals (CI) were calculated.

Results

Four RCTs with 9475 patients were included. No significant differences were found between IO and IV groups in survival (6.6% vs. 6.9%, OR 0.99, 95% CI 0.84–1.18) or favorable neurological outcome (4.7% vs. 4.6%, OR 1.07, 95% CI 0.88–1.30). The sustained ROSC rate was numerically, but not significantly, lower in IO vs. IV access (24.6% vs. 27.0%, OR 0.92, 95% CI 0.80–1.06). IO access had a higher first-attempt success rate (92.3% vs. 62.3%; OR 6.18, 95% CI 3.50–10.91) and was 15 s faster than IV for vascular access (IO: 11.03 ± 5.57, IV: 11.35 ± 6.16 min, MD − 0.25, 95% CI − 0.48 to − 0.01).

Conclusions

IO access had a higher first-attempt success rate and faster establishment than IV access, but no significant differences were found in survival or favorable neurological outcomes in adults with OHCA. Sustained ROSC was numerically lower with IO access than IV access, although the difference was not statistically significant.

Critical Care Bulletin: February 2025

 

Relationship between skin microvascular blood flow and capillary refill time in critically ill patients

Critical Care volume 29, Article number: 57 (2025)

Published: 04 February 2025

Background

Capillary refill time (CRT) and skin blood flow (SBF) have been reported to be strong predictors of mortality in critically ill patients. However, the relationship between both parameters remains unclear.

Methods

We conducted a prospective observational study in a tertiary teaching hospital. All patients older than 18 years admitted in the intensive care unit (ICU) with circulatory failure and a measurable CRT were included. We assessed index SBF by laser doppler flowmetry and CRT on the fingertip, at T0 (Within the first 48 h from admission) and T1 (4 to 6 h later). Correlation was computed using Spearman or Pearson’s formula.

Results

During a 2-month period, 50 patients were included, 54% were admitted for sepsis. At baseline median CRT was 2.0 [1.1–3.9] seconds and median SBF was 46 [20–184] PU. At baseline SBF strongly correlated with CRT (R2 = 0.89; p < 0.0001, curvilinear relationship), this correlation was maintained whether patients were septic or not (R2 = 0.94; p = 0.0013; R2 = 0.87; p < 0.0001, respectively), and whether they received norepinephrine or not (R2 = 0.97; p = 0.0035; R2 = 0.92; p < 0.0001, respectively). Between T0 and T1, changes in SBF also significantly correlated with changes in CRT (R2 = 0.34; p < 0.0001). SBF was related to tissue perfusion parameters such as arterial lactate level (p = 0.02), whilst no correlation was found with cardiac output. In addition, only survivors significantly improved their SBF between T0 and T1. SBF was a powerful predictor of day-28 mortality as the AUROC at T0 was 85% [95% IC [76–91]] and at T1 90% [95% IC [78–100]].

Conclusion

We have shown that index CRT and SBF were correlated, providing evidence that CRT is a reliable marker of microvascular blood flow.

Trial registration Comité de protection des personnes Ouest II N° 2023-A02046-39.

 

Heterogeneity of treatment effect: the case for individualising oxygen therapy in critically ill patients

Critical Care volume 29, Article number: 50 (2025) 

Published: 28 January 2025

Abstract

Oxygen therapy is ubiquitous in critical illness but oxygenation targets to guide therapy remain controversial despite several large randomised controlled trials (RCTs). Findings from RCTs evaluating different approaches to oxygen therapy in critical illness present a confused picture for several reasons. Differences in both oxygen target measures (e.g. oxygen saturation or partial pressure) and the numerical thresholds used to define lower and higher targets complicate comparisons between trials. The duration of and adherence to oxygenation targets is also variable with consequent substantial variation in both the dose and the dose separation. Finally, heterogeneity of treatment effects (HTE) may also be a significant factor. HTE is defined as non-random variation in the benefit or harm of a treatment, in which the variation is associated with or attributable to patient characteristics. This narrative review aims to make the case that such heterogeneity is likely in relation to oxygen therapy for critically ill patients and that this has significant implications for the design and interpretation of trials of oxygen therapy in this context. HTE for oxygen therapy amongst critically ill patients may explain the contrasting results from different clinical trials of oxygen therapy. Individualised oxygen therapy may overcome this challenge, and future studies should incorporate ways to evaluate this approach.

 

Extremely early initiation of vasopressors might not decrease short-term mortality for adults with septic shock: a systematic review and meta-analysis

Annals of Intensive Care volume 15, Article number: 18 (2025)

Published: 27 January 2025

Background

The optimal timing for initiating vasopressor therapy in patients with septic shock remains unclear. This study aimed to assess the impact of early versus late vasopressor initiation on clinical outcomes.

Methods

A systematic review and meta-analysis were conducted by searching PubMed, Embase, and Cochrane databases. Studies comparing early and late vasopressor administration in septic shock patients were included. The primary outcome was short-term mortality, and subgroup analyses were performed based on different initiation timings.

Results

Eleven studies with 6,661 patients were included. Different studies define the ‘early administration’ timeframe variously, ranging from one to seven hours. No significant difference in short-term mortality was observed between early and late administration in the combined analysis of 3,757 patients from two RCTs and three quasi-experimental studies (OR: 0.66, 95% CI: [0.36, 1.19], I²: 82%). However, lower mortality was found in subgroups with early but not extremely early initiation (one to three hours, OR: 0.70, 95% CI: [0.60, 0.82], I²: 0%), and those using septic shock diagnosis as time zero (OR: 0.64, 95% CI: [0.48, 0.85], I²: 39%).

Conclusion

Our findings found that earlier initiation of vasopressor therapy, particularly within one to three hours after the diagnosis of septic shock, may be associated with reduced short-term mortality in certain subgroups. However, due to the heterogeneity in study definitions and potential confounding factors, these results should be interpreted cautiously. Further standardized investigations are warranted to precisely determine the optimal timing for vasopressor initiation to maximize survival outcomes in patients with septic shock.

 

Sex disparities in ICU care and outcomes after cardiac arrest: a Swiss nationwide analysis

Critical Care volume 29, Article number: 42 (2025) 

Published: 23 January 2025

Background

Conflicting data exist regarding sex-specific outcomes after cardiac arrest. This study investigates sex disparities in the provision of critical care and outcomes of in-hospital (IHCA) and out-of-hospital cardiac arrest (OHCA) patients.

Methods

Analysis of adult cardiac arrest patients admitted to certified Swiss intensive care units (ICUs) (01/2008–12/2022) using the nationwide prospective ICU registry. The primary outcome was ICU mortality, with secondary outcomes including ICU admission probability and advanced treatment provision.

Results

Among 41,733 individuals (34.9% women), 21,692 patients (30.6% women) were admitted to ICUs (16,571 OHCA patients/5121 IHCA patients). Women were less likely to be admitted to the ICU than men (incidence rate ratio 0.82 [95% CI 0.80–0.85] and had a higher ICU mortality (41.8% vs 36.2%; p < 0.001). Mortality differences were more pronounced in OHCA patients (unadjusted HR: 1.35 [95% CI 1.28–1.43]; adjusted HR: 1.19 [95% CI 1.12–1.25]). In IHCA patients, mortality differences were less pronounced (unadjusted HR: 1.14 [95% CI 1.04–1.25]) and vanished after adjustment for confounders: adjusted HR: 1.03 [95% CI 0.94–1.13]). Women after cardiac arrest were older, more severely ill, and received fewer interventions before (44.7% vs 54.0%; p < 0.001) and during ICU stay. A subgroup analysis of 11,202 patients revealed that treatment limitations were more frequent in women (46.7% vs 38.7%; p < 0.001). However, these limitations were associated with an increased risk of death in both sexes.

Conclusions

This study highlights sex disparities in short-term mortality and ICU resource allocation among cardiac arrest patients, with women potentially facing disadvantages, in particular after OHCA. The limitations of ICU registry data, particularly the lack of detailed cardiac arrest-specific and comorbidity information, restrict definitive conclusions. Future research should prioritize prospective studies with more granular data to better understand and address these disparities.

 

The association between pain, analgesia, and delirium among critically ill adults: a systematic review and meta-analysis

Intensive Care Medicine

Published: 22 January 2025

Purpose

We performed a systematic review with meta-analysis examining the relationship between pain or pain medications and delirium occurence, duration, and severity.

Methods

We searched MEDLINE, EMBASE, CINAHL and the Cochrane Central Register of Controlled Trials from inception to May 15, 2023. We included randomised or observational studies among critically ill adults, that reported data on pain or exposure to analgesics, and reported delirium presence, duration, or severity with no language or region restrictions. PROSPERO ID: CRD42022367715. Two authors independently screened records and extracted data. Risk of bias was evaluated using Risk of Bias 2 or the Risk of Bias In Non-randomized Studies of Interventions. We pooled data using the Hartung-Knapp Sidik-Jonkmann random effects model. PRISMA was followed.

Results

From 8,054 citations, 90 studies (119,230 patients) published between 2001 and 2023 were included in the systematic review. 41 studies were included in the primary meta-analysis examining prevalent delirium: seven studies evaluated pain; 12 studies evaluated fentanyl; and five studies evaluated morphine. There was a trend to association between pain and delirium occurrence (OR 2.49, 95% CI 0.98–6.30), and a significant association between pain and incident delirium (OR 3.70, 95% CI 1.73–7.93). Fentanyl (OR 2.49, 95% CI 1.45–4.27) and morphine (OR 2.13, 95% CI 1.21–3.75) were associated with delirium occurrence. Risk of bias was critical for many studies.

Conclusions

We observed an association between pain and incident delirium among critically ill adults. Exposure to morphine or fentanyl (but no other pain medications) was associated with increased risk of delirium occurrence.

 

The role of phospholipid transfer protein in sepsis-associated acute kidney injury

Critical Care volume 29, Article number: 33 (2025) 

Published: 20 January 2025

Background

Phospholipid transfer protein (PLTP), a glycoprotein widely expressed in the body, is primarily involved in plasma lipoprotein metabolism. Previous research has demonstrated that PLTP can exert anti-inflammatory effects and improve individual survival in patients with sepsis and endotoxemia by neutralizing LPS and facilitating LPS clearance. However, the role of PLTP in sepsis-associated acute kidney injury (SA-AKI) and the specific mechanism of its protective effects are unclear. This study aimed to assess the potential role of PLTP in SA-AKI.

Methods

This is a population-based prospective observational study of patients with sepsis admitted to the intensive care unit. Blood samples were collected on days 1, 3, 5, and 7 after admission to the ICU. Plasma PLTP lipotransfer activity was measured to assess outcomes, including the incidence of SA-AKI and 30-day major adverse kidney events (MAKE 30). The correlation between PLTP lipotransfer activity and SA-AKI and MAKE 30 was evaluated through logistic regression modeling. Receiver operating characteristic curves were used to assess the diagnostic value of PLTP lipotransfer activity for SA-AKI and MAKE 30. The PLTP lipotransfer activity was categorized into high and low groups based on the optimal cut-off values. The differences between the high and low PLTP lipotransfer activity groups in terms of MAKE 30 were evaluated using Kaplan–Meier analysis. The SA-AKI mouse model was established via cecum ligation and puncture (CLP) in the animal experimental phase. The impact of PLTP on renal function was then investigated in wild-type and PLTP ± mice. The wild-type mice were given recombinant human PLTP (25 μg, 200 μL each/dose) via the tail vein at 1-, 7-, and 23-h intervals on the day preceding CLP. The control group received an equal volume of solvent. The 10-day survival and kidney function among the treatment groups were then evaluated.

Results

A total of 93 patients were enrolled in this clinical trial, of which 52 developed acute kidney injury (AKI). A total of 32 patients died over the course of the 30-day follow-up period, 34 underwent kidney replacement therapy, 37 developed persistent acute kidney injury, and 55 patients met the composite endpoint. The plasma PLTP lipotransfer activity was identified as an independent predictor of SA-AKI (crude OR = 0.96, 95% CI 0.95–0.98, p < 0.001; adjusted OR = 0.92, 95% CI 0.86–0.96, p = 0.001) and MAKE 30 (crude OR = 0.97, 95% CI 0.96–0.98, p < 0.001; adjusted OR = 0.96, 95% CI 0.93–0.98, p = 0.001). The area under the curve (AUC) of plasma PLTP lipotransfer activity within 24 h of ICU admission could predict the occurrence of SA-AKI and MAKE 30 in septic patients (AUC values; 0.87 (95% CI 0.79–0.94) and 0.87 (95% CI 0.80–0.94), respectively). The cumulative incidence of main kidney adverse events was significantly lower in the high group than in the low group (p < 0.001). Compared with the controls, creatinine levels were significantly elevated in the CLP mice, while PLTP lipotransfer activity was significantly decreased at 24 h postoperatively. Moreover, the PTLP ± mice exhibited significantly impaired renal function and markedly elevated plasma levels of inflammatory mediators compared with the wild-type CLP mice. Notably, human recombinant PTLP significantly prolonged 10-day survival, improved renal function, and attenuated mitochondrial structural damage in wild-type CLP mice.

Conclusions

These findings indicate that PLTP is a potential therapeutic target in sepsis-associated acute kidney injury.

 

Impact of frailty and older age on weaning from invasive ventilation: a secondary analysis of the WEAN SAFE study

Annals of Intensive Care volume 15, Article number: 13 (2025)

Published: 20 January 2025

Objective

To understand the impact of both frailty and chronologic age on outcomes of weaning from invasive mechanical ventilation (MV).

Methods

The study population consisted of patients enrolled in the ‘WorldwidE. AssessmeNt of Separation of pAtients From ventilatory assistancE (WEAN SAFE) study. We defined 4 non-overlapping groups, namely: ‘frail’ (clinical frailty scale [CFS] score > 4; age < 80 years); ‘elderly’ (CFS ≤ 4; age ≥ 80y), ‘frail \elderly’ (CFS > 4; age ≥ 80 years), and a ‘not frail or elderly’ population. The primary outcome was the impact of frailty and older age on delayed weaning and failed weaning from invasive MV. Secondary outcomes included the impact of frailty and age on ICU and hospital survival.

Results

In the study population, 760 (17%) were frail, while 360 (8%) were elderly, 197 (4%) were frail and elderly, while 3,176 (70%) were not frail or elderly. The frail and elderly cohorts were more likely to be female, had hypoxemic/hypercapnic respiratory failure or sepsis, and had more comorbidities. The proportion of delayed weaning and of failed weaning from invasive MV was significantly higher in the frail (28 and 23%), the elderly (25 and 19%), and the frail and elderly groups (22% and 25%), compared to the not frail or elderly population (12% and 13%, P < 0.01). ICU and hospital mortality was higher in the frail (21 and 33%), the elderly (19 and 31%), and the frail and elderly groups (26 and 46%), compared to the not frail or elderly population (12% and 18%, P < 0.001). In multivariate analyses, there was an independent association between frailty and delayed weaning initiation and weaning failure. Old age was independently associated with risk of weaning failure.

Conclusions

Frailty status had a more consistent impact than older age on weaning outcomes. However, overall outcomes in these cohorts are encouraging once separation attempts have been initiated.

 

 

Cardiovascular effects of lactate in healthy adults

Critical Care volume 29, Article number: 30 (2025) 

Published: 17 January 2025

Background

Low-volume hypertonic solutions, such as half-molar lactate (LAC), may be a potential treatment used for fluid resuscitation. This study aimed to evaluate the underlying cardiovascular effects and mechanisms of LAC infusion compared to sodium-matched hypertonic sodium chloride (SAL).

Methods

Eight healthy male participants were randomized in a controlled, single-blinded, crossover study. Each participant received a four-hour infusion of LAC and SAL in a randomized order. Assessor-blinded echocardiography and blood samples were performed. The primary endpoint was cardiac output (CO) measured by echocardiography.

Results

During LAC infusion, circulating lactate levels increased by 1.9 mmol/L (95% CI 1.8–2.0 mmol/L, P < 0.001) compared with SAL. CO increased by 1.0 L/min (95% CI 0.5–1.4 L/min, P < 0.001), driven primarily by a significant increase in stroke volume of 11 mL (95% CI 4–17 mL, P = 0.002), with no significant change in heart rate. Additionally, left ventricular ejection fraction improved by 5 percentage points (P < 0.001) and global longitudinal strain by 1.5 percentage points (P < 0.001). Preload indicators were elevated during SAL infusion compared with LAC infusion. Concomitantly, afterload parameters, including systemic vascular resistance and effective arterial elastance, were significantly decreased with LAC infusion compared with SAL, while mean arterial pressure remained similar. Indicators of contractility improved during LAC infusion.

Conclusions

In healthy participants, LAC infusion enhanced cardiac function, evidenced by increases in CO, stroke volume, and left ventricular ejection fraction compared with SAL. Indicators of contractility improved, afterload decreased, and preload remained stable. Therefore, LAC infusion may be an advantageous resuscitation fluid, particularly in patients with cardiac dysfunction.

 

Procedural sedative effect of remimazolam in ICU patients on invasive mechanical ventilation: a randomised, prospective study

Annals of Intensive Care volume 15, Article number: 8 (2025)

Published: 14 January 2025

Background

Invasive procedures and environmental factors in the intensive care unit (ICU) may cause anxiety and discomfort in patients, who often require sedation therapy. The aim of this study was to assess the safety of remimazolam tosilate for procedural sedation in ICU patients receiving mechanical ventilation following endotracheal intubation. Eighty patients from a single centre were randomly assigned to either the propofol group or the remimazolam group. Blood tests were conducted to evaluate changes in lactate, blood lipids, liver and kidney function, and inflammatory markers, and patients’ vital signs were observed over several periods. This study compared the incidence of delirium, the impact on liver and kidney function, circulatory effects, and changes in blood lipids between the two groups. These findings have optimised the selection of medications, providing ICU patients with more options for sedation therapy.

Methods

In this single-centre randomised controlled trial, intubated patients were randomly assigned to the remimazolam group or the propofol group. Under the same analgesic regimen, the two groups received remimazolam and propofol for procedural sedation.

Results

Our primary outcome was the mean arterial pressure (MAP), which significantly differed on Days 4 and 7 (P = 0.021, control group vs. experimental group = 85.23 ± 11.24 vs. 94.36 ± 13.18, P = 0.023, 83.55 ± 8.94 vs. 92.66 ± 7.02). With respect to liver and kidney function, the ∆AST value in the remimazolam group was significantly lower than that in the control group on Day 7 (P = 0.023). There were significant differences in triglyceride (TG) levels on Days 4 and 7 (P = 0.020) and in the ∆LDL on Day 7 (P = 0.027). Furthermore, the rates of dyslipidaemia and delirium in the remimazolam group were lower than those in the propofol group (85.0%, n = 40 vs. 90.0%, n = 40; 27.5%, n = 40 vs. 55%, n = 40).

Conclusion

Remimazolam is a novel benzodiazepine that has demonstrated promising applications in general anaesthesia and procedural sedation; however, its use in ICU sedation is still in the early stages of research. Current evidence suggests that remimazolam is a safe sedative that is particularly well suited for patients with haemodynamic instability. Large sample-size randomised clinical trials are warranted.

 

Creatinine production rate is an integrative indicator to monitor muscle status in critically ill patients

Critical Care volume 29, Article number: 23 (2025)

Published: 14 January 2025

Background

Both quantitative and qualitative aspects of muscle status significantly impact clinical outcomes in critically ill patients. Comprehensive monitoring of baseline muscle status and its changes is crucial for risk stratification and management optimization. However, repeatable and accessible indicators are lacking. We hypothesized that creatinine production rate (CPR) could serve as an integrative indicator of skeletal muscle status.

Methods

We conducted a series of animal and clinical studies. First, animal experiments were performed to determine whether CPR reflects not only muscle volume, but also qualitative muscle properties. We also evaluated the effects of acute systemic inflammation, a common feature of critical illness, on CPR, as well as its impact on muscle volume and metabolism. In clinical studies, we analyzed CPR, calculated based on urinary creatinine excretion and changes in serum creatinine, of critically ill patients. We assessed the factors affecting CPR on ICU admission and its temporal changes. Finally, we evaluated the clinical utility of CPR by examining the associations of the CPR index (CPR divided by height squared) on ICU admission and its changes with one-year survival.

Results

Animal studies revealed that CPR is determined by muscle volume, creatine content, and metabolic status. Systemic inflammation accompanied by muscle loss led to reduced CPR. Moreover, even without muscle loss, systemic inflammation decreased CPR, likely due to metabolic derangements. In ICU patients, CPR on admission strongly correlated with muscle cross-sectional area (CSA), with age and sex as additional significant factors. In contrast, the percent change in CPR showed a weak correlation with muscle CSA changes. Additionally, the acute-phase CPR trajectories did not show a consistent decline, suggesting multifactorial influences. In a cohort of 629 ICU patients, lower baseline CPR index (hazard ratio [HR] 1.125 per 0.1 g/day/m2 less, P < .001) and a decrease in CPR over the first three days (HR 1.028 per 5%, P = 0.032) were independently associated with higher one-year mortality.

Conclusions

CPR represents an integrative indicator of skeletal muscle status in critically ill patients, reflecting both quantitative and qualitative aspects. Monitoring CPR in the ICU may facilitate risk stratification and optimization of patient care.