Pharmacotherapy for Reducing RBC Transfusion for Patients in the ICU: A Systematic Review and Network Meta-Analysis.

OBJECTIVES: To determine optional therapeutic strategies by comparing monotherapies and combination therapies to reduce RBC transfusion requirement for patients in the ICU. DATA SOURCES: MEDLINE, CENTRAL, and Embase were searched for studies published from database inception until July 2023. DATA EXTRACTION: We included randomized controlled trials comparing erythropoiesis-stimulating agents (Epo), iron, combination therapy with iron and Epo, hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), vitamin D 3 (VD3), and placebo/no treatment. A frequentist network meta-analysis (NMA) was performed using a random effects model, and the confidence in NMA was rated. DATA SYNTHESIS: Of 117 eligible studies, 75 studies (15,091 patients) were included in the quantitative analysis. Compared with placebo/no treatment, the combination therapy reduces the requirement for RBC transfusion (risk ratio [RR]: 0.60; 95% CI, 0.49-0.74; confidence rating: moderate). The Epo or iron monotherapy may reduce the requirement for RBC transfusion (RR: 0.81; 95% CI, 0.63-1.04; confidence rating: low; RR: 0.83; 95% CI, 0.70-0.98; confidence rating: low, respectively). Combination therapy may not increase the prevalence of both venous thromboembolism (VTE) (RR: 0.73; 95% CI, 0.25-2.08; confidence rating: low) and infection. Epo monotherapy may not increase the prevalence of VTE but may increase that of infections (RR: 1.27; 95% CI, 0.94-1.73; confidence rating: low). Iron monotherapy may not increase the prevalence of both VTE and infection. Evidence for VD3 and HIF-PHI remains uncertain. CONCLUSIONS: Combination therapy with iron and Epo likely reduces the requirement for RBC transfusion and may be less harmful than other therapies.

Japanese Clinical Practice Guidelines for Rehabilitation in Critically Ill Patients 2023 (J-ReCIP 2023).

Providing standardized, high-quality rehabilitation for critically ill patients is a crucial issue. In 2017, the Japanese Society of Intensive Care Medicine (JSICM) promulgated the "Evidence-Based Expert Consensus for Early Rehabilitation in the Intensive Care Unit" to advocate for the early initiation of rehabilitations in Japanese intensive care settings. Building upon this seminal work, JSICM has recently conducted a rigorous systematic review utilizing the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. This endeavor resulted in the formulation of Clinical Practice Guidelines (CPGs), designed to elucidate best practices in early ICU rehabilitation. The primary objective of this guideline is to augment clinical understanding and thereby facilitate evidence-based decision-making, ultimately contributing to the enhancement of patient outcomes in critical care settings. No previous CPGs in the world has focused specifically on rehabilitation of critically ill patients, using the GRADE approach. Multidisciplinary collaboration is extremely important in rehabilitation. Thus, the CPGs were developed by 73 members of a Guideline Development Group consisting of a working group, a systematic review group, and an academic guideline promotion group, with the Committee for the Clinical Practice Guidelines of Early Mobilization and Rehabilitation in Intensive Care of the JSICM at its core. Many members contributed to the development of the guideline, including physicians and healthcare professionals with multiple and diverse specialties, as well as a person who had been patients in ICU. Based on discussions among the group members, eight important clinical areas of focus for this CPG were identified. Fourteen important clinical questions (CQs) were then developed for each area. The public was invited to comment twice, and the answers to the CQs were presented in the form of 10 GRADE recommendations and commentary on the four background questions. In addition, information for each CQ has been created as a visual clinical flow to ensure that the positioning of each CQ can be easily understood. We hope that the CPGs will be a useful tool in the rehabilitation of critically ill patients for multiple professions.

Instruments to assess post-intensive care syndrome assessment: a scoping review and modified Delphi method study.

BACKGROUND: The assessment of post-intensive care syndrome (PICS) is challenging due to the numerous types of instruments. We herein attempted to identify and propose recommendations for instruments to assess PICS in intensive care unit (ICU) survivors. METHODS: We conducted a scoping review to identify PICS follow-up studies at and after hospital discharge between 2014 and 2022. Assessment instruments used more than two times were included in the modified Delphi consensus process. A modified Delphi meeting was conducted three times by the PICS committee of the Japanese Society of Intensive Care Medicine, and each score was rated as not important (score: 1-3), important, but not critical (4-6), and critical (7-9). We included instruments with ≥ 70% of respondents rating critical and ≤ 15% of respondents rating not important. RESULTS: In total, 6972 records were identified in this scoping review, and 754 studies were included in the analysis. After data extraction, 107 PICS assessment instruments were identified. The modified Delphi meeting reached 20 PICS assessment instrument recommendations: (1) in the physical domain: the 6-min walk test, MRC score, and grip strength, (2) in cognition: MoCA, MMSE, and SMQ, (3) in mental health: HADS, IES-R, and PHQ-9, (4) in the activities of daily living: the Barthel Index, IADL, and FIM, (5) in quality of life: SF-36, SF-12, EQ-5D-5L, 3L, and VAS (6), in sleep and pain: PSQI and Brief Pain Inventory, respectively, and (7) in the PICS-family domain: SF-36, HADS, and IES-R. CONCLUSION: Based on a scoping review and the modified Delphi method, 20 PICS assessment instruments are recommended to assess physical, cognitive, mental health, activities of daily living, quality of life, sleep, and pain in ICU survivors and their families.

Effects of Mobilization within 72 h of ICU Admission in Critically Ill Patients: An Updated Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Previous systematic review and meta-analysis indicates that rehabilitation within a week of intensive care unit (ICU) admission benefits physical function in critically ill patients. This updated systematic review and meta-analysis aim to clarify effects of initiating rehabilitation within 72 h of ICU admission on long-term physical, cognitive, and mental health. We systematically searched the MEDLINE, Cochrane Central Register of Controlled Trials, and Igaku Chuo Zasshi for randomized controlled trials (RCTs) between April 2019 and November 2022 to add to the previous review. Two investigators independently selected and extracted data. Pooled effect estimates for muscle strength, cognitive function, mental health after discharge, and adverse events were calculated. Evidence certainty was assessed via Grading of Recommendations, Assessment, Development, and Evaluations. Eleven RCTs were included in the meta-analysis. Early rehabilitation may improve muscle strength (three trials; standard mean difference [SMD], 0.16; 95% confidence interval [CI], -0.04-0.36) and cognitive function (two trials; SMD, 0.54; 95% CI, -0.13-1.20). Contrastingly, early mobilization showed limited impact on mental health or adverse events. In summary, initiating rehabilitation for critically ill patients within 72 h may improve physical and cognitive function to prevent post-intensive care syndrome without increasing adverse events. The effect on mental function remains uncertain.

Follow-up focused on psychological intervention initiated after intensive care unit in adult patients and informal caregivers: a systematic review and meta-analysis.

Psychological dysfunction is one of the considerable health-related outcomes among critically-ill patients and their informal caregivers. Follow-up of intensive care unit (ICU) survivors has been conducted in a variety of different ways, with different timing after discharge, targets of interest (physical, psychological, social) and measures used. Of diverse ICU follow-up, the effects of follow-ups which focused on psychological interventions are unknown. Our research question was whether follow-up with patients and their informal caregivers after ICU discharge improved mental health compared to usual care. We published a protocol for this systematic review and meta-analysis in https://www.protocols.io/ (https://dx.doi.org/10.17504/protocols.io.bvjwn4pe). We searched PubMed, Cochrane Library, EMBASE, CINAHL and PsycInfo from their inception to May 2022. We included randomized controlled trials for follow-ups after ICU discharge and focused on psychological intervention for critically ill adult patients and their informal caregivers. We synthesized primary outcomes, including depression, post-traumatic stress disorder (PTSD), and adverse events using the random-effects method. We used the Grading of Recommendations Assessment, Development and Evaluation approach to rate the certainty of evidence. From the 10,471 records, we identified 13 studies (n = 3, 366) focusing on patients and four (n = 538) focusing on informal caregivers. ICU follow-up for patients resulted in little to no difference in the prevalence of depression (RR 0.89, 95% CI [0.59-1.34]; low-certainty evidence) and PTSD (RR 0.84, 95% CI [0.55-1.30]; low-certainty evidence) among patients; however, it increased the prevalence of depression (RR 1.58 95% CI [1.01-2.46]; very low-certainty evidence), PTSD (RR 1.36, 95% CI [0.91-2.03]; very low-certainty evidence) among informal caregivers. The evidence for the effect of ICU follow-up on adverse events among patients was insufficient. Eligible studies for informal caregivers did not define any adverse event. The effect of follow-ups after ICU discharge that focused on psychological intervention should be uncertain.

Effect of Neuromuscular Electrical Stimulation in Patients With Critical Illness: An Updated Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVES: Neuromuscular electrical stimulation (NMES) is used in the rehabilitation of patients with critical illness. However, it is unclear whether NMES prevents ICU-acquired weakness (ICU-AW). For this purpose, we conducted an updated systematic review and meta-analysis. DATA SOURCES: We searched the MEDLINE, Cochrane Central Register of Controlled Trials, and Igaku Chuo Zasshi databases from April 2019 to November 2022 to identify new randomized controlled trials to the previous meta-analysis. STUDY SELECTION: We systematically searched the literature for all randomized controlled trials on the effect of NMES in patients with critical illness. DATA EXTRACTION: Two authors independently selected the studies and extracted data. They calculated the pooled effect estimates associated with the occurrence of ICU-AW and adverse events as primary outcomes and muscle mass change, muscle strength, length of ICU stay, mortality, and quality of life as secondary outcomes. The certainty of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation approach. DATA SYNTHESIS: Overall, eight studies were added to the previous 10 studies. Evidence suggests that the use of NMES reduces the occurrence of ICU-AW (six trials; risk ratio [RR], 0.48; 95% CI, 0.32-0.72); however, NMES may have little to no effect on pricking sensation in patients (eight trials; RR, 6.87; 95% CI, 0.84-56.50). NMES is likely to reduce the change in muscle mass (four trials; mean difference, -10.01; 95% CI, -15.54 to -4.48) and may increase muscle strength (six trials; standardized mean difference, 0.43; 95% CI, 0.19-0.68). Further, NMES may result in little to no difference in the length of ICU stay, and the evidence is uncertain about the effect on mortality and quality of life. CONCLUSIONS: This updated meta-analysis revealed that the use of NMES may result in a lower occurrence of ICU-AW in patients with critical illness, but its use may have little to no effect on pricking sensation in patients.

A burden of fluid, sodium, and chloride due to intravenous fluid therapy in patients with respiratory support: a post-hoc analysis of a multicenter cohort study.

BACKGROUND: Fluid creep, including fluids administered as drug diluents and for the maintenance of catheter patency, is the major source of fluid intake in critically ill patients. Although hypoxemia may lead to fluid restriction, the epidemiology of fluid creep in patients with hypoxemia is unclear. This study aimed to address the burden due to fluid creep among patients with respiratory support according to oxygenation status. METHODS: We conducted a post-hoc analysis of a prospective multicenter cohort study conducted in 23 intensive care units (ICUs) in Japan from January to March 2018. Consecutive adult patients who underwent invasive or noninvasive ventilation upon ICU admission and stayed in the ICU for more than 24 h were included. We excluded the following patients when no fluids were administered within 24 h of ICU admission and no records of the ratio of arterial oxygen partial pressure to fractional inspired oxygen. We investigated fluid therapy until 7 days after ICU admission according to oxygenation status. Fluid creep was defined as the fluids administered as drug diluents and for the maintenance of catheter patency when administered at ≤ 20 mL/h. RESULTS: Among the 588 included patients, the median fluid creep within 24 h of ICU admission was 661 mL (25.2% of the total intravenous-fluid volume), and the proportion of fluid creep gradually increased throughout the ICU stay. Fluid creep tended to decrease throughout ICU days in patients without hypoxemia and in those with mild hypoxemia (p < 0.001 in both patients), but no significant trend was observed in those with severe hypoxemia (p = 0.159). Similar trends have been observed in the proportions of sodium and chloride caused by fluid creep. CONCLUSIONS: Fluid creep was the major source of fluid intake among patients with respiratory support, and the burden due to fluid creep was prolonged in those with severe hypoxemia. However, these findings may not be conclusive as this was an observational study. Interventional studies are, therefore, warranted to assess the feasibility of fluid creep restriction. Trial registration UMIN-CTR, the Japanese clinical trial registry (registration number: UMIN 000028019, July 1, 2017).

Insertion site of central venous catheter among hospitalized adult patients: A systematic review and network meta-analysis.

Introduction: Central venous catheterization is a commonly performed procedure, accounting for approximately 8% of hospitalized patients. Based on the current literatures, the most acceptable site for central venous catheterization is inconclusive, considering various complications in hospitalized patients. Herein, we conducted a network meta-analysis to assess the clinically important complications among internal jugular, subclavian, femoral, and peripheral insertion. Materials and methods: The Cochrane Central Register of Controlled Trials, MEDLINE, Web of Science, Ichushi databases, Clinicaltrials.gov, and International Clinical Trials Registry Platform were searched. Studies including adults aged ≥ 18 years and randomized control trials that compared two different insertion sites (internal jugular, subclavian, femoral, and peripheral vein) were selected. The primary outcomes were clinically important infectious, thrombotic, and mechanical complications. Results: Among the 5,819 records initially identified, 13 trials (6,201 patients) were included for a network meta-analysis. For clinically important infectious complication, subclavian insertion decreased the complication risk, compared with internal jugular [risk ratio (RR), 0.30; 95% confidence interval (CI), 0.11-0.81; moderate certainty], and femoral insertion increased than subclavian insertion (RR 2.56; 95% CI, 1.02-6.44; moderate certainty). Peripheral insertion was also significantly associated with a lower risk compared with internal jugular (RR 0.06; 95% CI, 0.01-0.32; low certainty); subclavian (RR 0.21; 95% CI, 0.05-0.77; moderate certainty); and femoral insertion (RR 0.08; 95% CI, 0.02-0.40; low certainty). For clinically important thrombotic complication, we did not find significant differences between insertion sites. For clinically important mechanical complication, femoral insertion decreased the complication risk, compared with internal jugular (RR 0.42; 95% CI, 0.21-0.82; moderate certainty) and subclavian insertion (RR 0.33; 95% CI, 0.16-0.66; moderate certainty). Peripheral insertion was also associated with the lower complication risk compared with internal jugular (RR 0.39; 95% CI, 0.18-0.85; low certainty) and subclavian insertion (RR 0.31; 95% CI, 0.13-0.75; moderate certainty). Conclusion: The insertion site of the central venous catheter, which is most likely to cause the fewest complications, should be selected. Our findings can provide the rationale for deciding the insertion site for a central venous catheter. Systematic review registration: [www.protocols.io], identifier [61375].

Steroid treatment in patients with acute respiratory distress syndrome: a systematic review and network meta-analysis.

PURPOSE: Although the most recent systematic review and meta-analyses on acute respiratory distress syndrome (ARDS) have shown that the use of steroids decreases mortality in adult patients, its benefits and risks may differ depending on the type and dosage of the steroid. Therefore, we conducted a network meta-analysis (NMA) to compare the differences in the efficacy among different doses and types of steroids. METHODS: We searched MEDLINE, CENTRAL, ICHUSHI, ClinicalTrials.gov, and WHO ICTRP databases from the earliest records to March 2021 for randomized control trials, which compared steroids with placebo or conventional therapy for ARDS. Using the random-effects model, we compared various categories of steroids (high-dose methylprednisolone, low-dose methylprednisolone, hydrocortisone, dexamethasone, and no steroid) concerning hospital mortality, incidence of infection, and ventilator-free days (VFD). RESULTS: We analyzed nine studies involving adult patients (n = 1212). Although there were no significant differences between the groups in terms of the mortality and incidence of infection, the number of VFD were greater when using low-dose methylprednisolone than when not using any steroids (Mean difference: 6.06; 95% confidence intervals: [2.5, 10.5]). Moreover, the rank probability showed that low-dose methylprednisolone might be the optimal treatment, whereas using no steroid or high-dose methylprednisolone may be inferior to other treatments in terms of mortality, infection, and VFD. CONCLUSION: This NMA suggested that the effect of steroids on the outcome in patients with ARDS might depend on the type of the steroid drug administered. Moreover, further studies are needed to identify the optimal type and dosage.

Clinical prediction scores and early anticoagulation therapy for new-onset atrial fibrillation in critical illness: a post-hoc analysis.

PURPOSE: This study sought to describe the epidemiology of anticoagulation therapy for critically ill patients with new-onset atrial fibrillation (NOAF) according to CHA2DS2-VASc and HAS-BLED scores and to assess the efficacy of early anticoagulation therapy. METHOD: Adult patients who developed NOAF during intensive care unit stay were included. We compared the patients who were treated with and without anticoagulation therapy within 48 h from AF onset. The primary outcome was a composite outcome that included mortality and ischemic stroke during the period until hospital discharge. RESULTS: In total, 308 patients were included in this analysis. Anticoagulants were administered to 95 and 33 patients within 48 h and after 48 h from NOAF onset, respectively. After grouping the patients into four according to their CHA2DS2-VASc and HAS-BLED bleeding scores, we found that the proportion of anticoagulation therapy administered was similar among all groups. After adjustment using a multivariable Cox regression model, we noted that early anticoagulation therapy did not decrease the composite outcome (adjusted hazard ratio [HR] 0.77; 95% confidence interval [CI] 0.47‒1.23). However, in patients without rhythm control drugs, early anticoagulation was significantly associated with better outcomes (adjusted HR 0.46; 95% CI; 0.22‒0.87, P = 0.041). CONCLUSIONS: We found that clinical prediction scores were supposedly not used in the decision to implement anticoagulation therapy and that early anticoagulation therapy did not improve clinical outcomes in critically ill patients with NOAF. Trial registration UMIN-CTR UMIN000026401. Registered 5 March 2017.

A reassessment about included studies and certainty of evidence on a systematic review and meta-analysis of steroid for patients with acute respiratory distress syndrome.

We comment on the study by Hirano et al. about the effect of steroids in patients with acute respiratory distress syndrome. It might be necessary to include only the existing randomized control trials and to reassess the certainty of evidence about the primary outcomes.

Recombinant Human-Soluble Thrombomodulin Contributes to Reduced Mortality in Sepsis Patients With Severe Respiratory Failure: A Retrospective Observational Study Using a Multicenter Dataset.

BACKGROUND: Recombinant human-soluble thrombomodulin (rhTM) is a novel class therapeutic agent for managing disseminated intravascular coagulation. The progression of severe respiratory failure may be related to intra-alveolar coagulation/fibrinolytic disorders. We aimed to determine the efficacy of rhTM in treating sepsis patients with severe respiratory failure. METHODS: We performed a retrospective observational study using an existing dataset collected from 42 intensive care units (ICUs) in Japan. Of 3,195 patients with severe sepsis or septic shock from the dataset, we selected sepsis patients with severe respiratory failure, and compared patient outcomes based on the administration of rhTM (rhTM group and no rhTM group). Propensity score analysis was performed between the two groups. Outcomes of interest were ICU mortality, hospital mortality, and ventilator-free days (VFDs). RESULTS: In this study, 1,180 patients (rhTM, n = 356; no rhTM, n = 824) were analyzed. After adjusting for baseline imbalances with propensity score matching, the survival-time analysis revealed a significant difference between the two groups (hazard ratio, 0.654; 95% confidence interval, 0.439-0.974, P = 0.03). ICU mortality was lower in the rhTM group (rhTM: 22.1% [33/149] vs. no rhTM: 36.2% [54/149], P = 0.01). Hospital mortality was also lower in the rhTM group (35.6% [53/149] vs. 49.7% [74/149], P = 0.02). VFDs trended to be higher in the rhTM group than the no rhTM group (12.8 ±â€Š10.1 days vs. 10.6 ±â€Š10.6 days, P = 0.09). CONCLUSIONS: Administration of rhTM was positively correlated with a reduction in mortality in sepsis patients with severe respiratory failure.

Low-dose immunoglobulin G is not associated with mortality in patients with sepsis and septic shock.

BACKGROUND: The administration of low-dose intravenous immunoglobulin G (IVIgG) (5 g/day for 3 days; approximate total 0.3 g/kg) is widely used as an adjunctive treatment for patients with sepsis in Japan, but its efficacy in the reduction of mortality has not been evaluated. We investigated whether the administration of low-dose IVIgG is associated with clinically important outcomes including intensive care unit (ICU) and in-hospital mortality. METHODS: This is a post-hoc subgroup analysis of data from a retrospective cohort study, the Japan Septic Disseminated Intravascular Coagulation (JSEPTIC DIC) study. The JSEPTIC DIC study was conducted in 42 ICUs in 40 institutions throughout Japan, and it investigated associations between sepsis-related coagulopathy, anticoagulation therapies, and clinical outcomes of 3195 adult patients with sepsis and septic shock admitted to ICUs from January 2011 through December 2013. To investigate associations between low-dose IVIgG administration and mortalities, propensity score-based matching analysis was used. RESULTS: IVIgG was administered to 960 patients (30.8%). Patients who received IVIgG were more severely ill than those who did not (Acute Physiology and Chronic Health Evaluation (APACHE) II score 24.2 ± 8.8 vs 22.6 ± 8.7, p < 0.001). They had higher ICU mortality (22.8% vs 17.4%, p < 0.001), but similar in-hospital mortality (34.4% vs 31.0%, p = 0.066). In propensity score-matched analysis, 653 pairs were created. Both ICU mortality and in-hospital mortality were similar between the two groups (21.0% vs 18.1%, p = 0.185, and 32.9% vs 28.6%, p = 0.093, respectively) using generalized estimating equations fitted with logistic regression models adjusted for other therapeutic interventions. The administration of IVIgG was not associated with ICU or in-hospital mortality (odds ratio (OR) 0.883; 95% confidence interval (CI) 0.655-1.192, p = 0.417, and OR 0.957, 95% CI, 0.724-1.265, p = 0.758, respectively). CONCLUSIONS: In this analysis of a large cohort of patients with sepsis and septic shock, the administration of low-dose IVIgG as an adjunctive therapy was not associated with a decrease in ICU or in-hospital mortality. TRIAL REGISTRATION: University Hospital Medical Information Network Individual Clinical Trials Registry, UMIN-CTR000012543 . Registered on 10 December 2013.

Antithrombin Supplementation and Mortality in Sepsis-Induced Disseminated Intravascular Coagulation: A Multicenter Retrospective Observational Study.

Supplemental doses of antithrombin (AT) are widely used to treat sepsis-induced disseminated intravascular coagulation (DIC) in Japan. However, evidence on the benefits of AT supplementation for DIC is insufficient. This multicenter retrospective observational study aimed to clarify the effect of AT supplementation on sepsis-induced DIC using propensity score analyses. Data from 3,195 consecutive adult patients admitted to 42 intensive care units for severe sepsis treatment were retrospectively analyzed; 1,784 patients were diagnosed with DIC (n = 715, AT group; n = 1,069, control group). Inverse probability of treatment-weighted propensity score analysis indicated a statistically significant association between AT supplementation and lower in-hospital all-cause mortality (n = 1,784, odds ratio [95% confidence intervals]: 0.748 [0.572-0.978], P = 0.034). However, quintile-stratified propensity score analysis (n = 1,784, odds ratio: 0.823 [0.646-1.050], P = 0.117) and propensity score matching analysis (461 matching pairs, odds ratio: 0.855 [0.649-1.125], P = 0.263) did not show this association. In the early days after intensive care unit admission, the survival rate was statistically higher in the propensity score-matched AT group than in the propensity score-matched control group (P = 0.007). In DIC patients without concomitant heparin administration, similar results were observed. In conclusion, AT supplementation may be associated with reduced in-hospital all-cause mortality in patients with sepsis-induced DIC. However, the statistical robustness of this connection was not strong. In addition, although the number of transfusions needed in patients with AT supplementation increased, severe bleeding complications did not.

Characteristics, treatments, and outcomes of severe sepsis of 3195 ICU-treated adult patients throughout Japan during 2011-2013.

Severe sepsis is a major concern in the intensive care unit (ICU), although there is very little epidemiological information regarding severe sepsis in Japan. This study evaluated 3195 patients with severe sepsis in 42 ICUs throughout Japan. The patients with severe sepsis had a mean age of 70 ± 15 years and a mean Acute Physiology and Chronic Health Evaluation II score of 23 ± 9. The estimated survival rates at 28 and 90 days after ICU admission were 73.6 and 56.3 %, respectively.