A Randomized Trial of Intravenous Amino Acids for Kidney Protection.

BACKGROUND: Acute kidney injury (AKI) is a serious and common complication of cardiac surgery, for which reduced kidney perfusion is a key contributing factor. Intravenous amino acids increase kidney perfusion and recruit renal functional reserve. However, the efficacy of amino acids in reducing the occurrence of AKI after cardiac surgery is uncertain. METHODS: In a multinational, double-blind trial, we randomly assigned adult patients who were scheduled to undergo cardiac surgery with cardiopulmonary bypass to receive an intravenous infusion of either a balanced mixture of amino acids, at a dose of 2 g per kilogram of ideal body weight per day, or placebo (Ringer's solution) for up to 3 days. The primary outcome was the occurrence of AKI, defined according to the Kidney Disease: Improving Global Outcomes creatinine criteria. Secondary outcomes included the severity of AKI, the use and duration of kidney-replacement therapy, and all-cause 30-day mortality. RESULTS: We recruited 3511 patients at 22 centers in three countries and assigned 1759 patients to the amino acid group and 1752 to the placebo group. AKI occurred in 474 patients (26.9%) in the amino acid group and in 555 (31.7%) in the placebo group (relative risk, 0.85; 95% confidence interval [CI], 0.77 to 0.94; P = 0.002). Stage 3 AKI occurred in 29 patients (1.6%) and 52 patients (3.0%), respectively (relative risk, 0.56; 95% CI, 0.35 to 0.87). Kidney-replacement therapy was used in 24 patients (1.4%) in the amino acid group and in 33 patients (1.9%) in the placebo group. There were no substantial differences between the two groups in other secondary outcomes or in adverse events. CONCLUSIONS: Among adult patients undergoing cardiac surgery, infusion of amino acids reduced the occurrence of AKI. (Funded by the Italian Ministry of Health; PROTECTION ClinicalTrials.gov number, NCT03709264.).

The N-acetylglucosaminyltransferase Radical fringe contributes to defects in JAG1-dependent turnover and signaling of NOTCH3 CADASIL mutants.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic vascular dementia characterized by age-related degeneration of vascular mural cells and accumulation of a NOTCH3 mutant protein. NOTCH3 functions as a signaling receptor, activating downstream gene expression in response to ligands like JAG1 and DLL4, which regulate the development and survival of mural cells. This signal transduction process is thought to be connected with NOTCH3 endocytic degradation. However, the specific cellular circumstances that modulate turnover and signaling efficacy of NOTCH3 mutant protein remain largely unknown. Here, we found elevated NOTCH3 and Radical fringe (RFNG) expression in senescent human pericyte cells. We then investigated impacts of RFNG on glycosylation, degradation, and signal activity of three NOTCH3 CADASIL mutants (R90C, R141C, and C185R) in EGF-like repeat-2, 3, and 4, respectively. Liquid chromatography with tandem mass spectrometry analysis showed that RFNG modified NOTCH3 WT and C185R to different degrees. Additionally, coculture experiments demonstrated that RFNG significantly promoted JAG1-dependent degradation of NOTCH3 WT but not that of R141C and C185R mutants. Furthermore, RFNG exhibited a greater inhibitory effect on JAG1-mediated activity of NOTCH3 R141C and C185R compared to that of NOTCH3 WT and R90C. In summary, our findings suggest that NOTCH3 R141C and C185R mutant proteins are relatively susceptible to accumulation and signaling impairment under cellular conditions of RFNG and JAG1 coexistence.

Ketamine versus etomidate as an induction agent for tracheal intubation in critically ill adults: a Bayesian meta-analysis.

BACKGROUND: Tracheal intubation is a high-risk intervention commonly performed in critically ill patients. Due to its favorable cardiovascular profile, ketamine is considered less likely to compromise clinical outcomes. This meta-analysis aimed to assess whether ketamine, compared with other agents, reduces mortality in critically ill patients undergoing intubation. METHODS: We searched MEDLINE, Embase, and the Cochrane Library from inception until April 27, 2023, for randomized controlled trials and matched observational studies comparing ketamine with any control in critically ill patients as an induction agent. The primary outcome was mortality at the longest follow-up available, and the secondary outcomes included Sequential Organ Failure Assessment score, ventilator-free days at day 28, vasopressor-free days at day 28, post-induction mean arterial pressure, and successful intubation on the first attempt. For the primary outcome, we used a Bayesian random-effects meta-analysis on the risk ratio (RR) scale with a weakly informative neutral prior corresponding to a mean estimate of no difference with 95% probability; the estimated effect size will fall between a relative risk of 0.25 and 4. The RR and 95% credible interval (CrI) were used to estimate the probability of mortality reduction (RR < 1). The secondary outcomes were assessed with a frequentist random-effects model. We registered this study in Open Science Framework ( https://osf.io/2vf79/ ). RESULTS: We included seven randomized trials and one propensity-matched study totaling 2978 patients. Etomidate was the comparator in all the identified studies. The probability that ketamine reduced mortality was 83.2% (376/1475 [25%] vs. 411/1503 [27%]; RR, 0.93; 95% CrI, 0.79-1.08), which was confirmed by a subgroup analysis excluding studies with a high risk of bias. No significant difference was observed in any secondary outcomes. CONCLUSIONS: All of the included studies evaluated ketamine versus etomidate among critically ill adults requiring tracheal intubation. This meta-analysis showed a moderate probability that induction with ketamine is associated with a reduced risk of mortality.

Renin as a Prognostic Marker in Intensive Care and Perioperative Settings: A Scoping Review.

Serum renin increases in response to sympathetic nerve activation and hypotension. Recent studies have reported the association of serum renin levels with adverse clinical outcomes in acute care settings. This scoping review aimed to systematically review the available literature on renin as a prognostic marker in intensive care and perioperative patients. We searched for studies published since inception until March 31, 2023, which assessed the association between serum renin levels and clinical outcomes or the effect of synthetic angiotensin II administration on serum renin levels in critically ill and perioperative patients in PubMed, Embase, and the Cochrane Library. The primary outcome was mortality at the longest follow-up; the secondary outcomes were adverse renal outcomes (ie, acute kidney injury, the need for renal replacement therapy, and major adverse kidney events), hemodynamic instability, outcomes to angiotensin II administration, and prognostic performance for mortality when compared with lactate. Among the 2081 studies identified, we included 16 studies with 1573 patients (7 studies on shock, 5 on nonspecific critical illness, 2 on cardiac surgery, 1 on noncardiac surgery, and 1 on coronavirus disease 2019). A significant association between serum renin levels and poor outcomes was identified in 14 studies, with 10 studies demonstrating an association with mortality. One post hoc analysis found that angiotensin II administration reduced mortality in patients with markedly elevated renin values. Two studies showed that renin was superior to lactate as a prognostic marker of mortality. Our scoping review showed that elevated serum renin levels may be associated with clinically relevant outcomes among various perioperative and intensive care populations. Increased serum renin levels may identify patients in which synthetic angiotensin II administration improves clinical outcomes and may outperform serum lactate in predicting mortality.

Association between the intraoperative fluid balance during cardiac surgery and postoperative sequential organ failure assessment score: a post hoc analysis of the BROTHER study, a retrospective multicenter cohort study.

Although intraoperative intravenous fluids are commonly administered to reverse intraoperative hypotension during cardiac surgery, the appropriate volume remains unclear. This study aimed to evaluate the relationship between the intraoperative fluid balance and sequential organ failure assessment (SOFA) score in patients undergoing cardiac surgery to determine the impact of intraoperative intravenous fluids on their organs. This was a post hoc analysis using data from a multicenter, retrospective, observational study across 14 intensive care units (ICUs) in Japan. Adult patients admitted to ICUs after elective coronary artery bypass grafting or valve surgery from January 1 to December 31, 2018 were enrolled. We compared patients with intraoperative fluid balance < 20 ml/kg to those with fluid balance ≥ 20 ml/kg and conducted a multiple regression analysis for the SOFA score within 24 h of ICU admission. Of the 1567 included patients, 870 met the eligibility criteria. A total of 725 patients (83%) had an intraoperative fluid balance of ≥ 20 ml/kg. In the univariate analysis, the SOFA score (interquartile range) was 7 (6-8) and 7 (6-9) in the intraoperative fluid balance < 20 ml/kg and ≥ 20 ml/kg groups, respectively (p = 0.017). Multiple regression analysis showed a positive association between intraoperative fluid balance and SOFA score within 24 h of ICU admission [standardized coefficient 0.0065 (95% confidence interval 0.0036-0.0095), p < 0.001]. Intraoperative fluid balance in patients undergoing cardiac surgery was significantly associated with higher SOFA scores within 24 h of ICU admission.

The epidemiology of postoperative dobutamine and phosphodiesterase inhibitors after adult elective cardiac surgery and its impact on the length of hospital stay: a post hoc analysis from the multicenter retrospective observational study.

The optimal administration of inotrope after cardiac surgery is unknown. This study aimed to investigate the impact of postoperative inotrope on clinical outcomes in adult elective cardiac surgery patients. Data from the Blood Pressure and Relative Optimal Target after Heart Surgery in Epidemiologic Registry study were analyzed, employing propensity score considering the hospital of admission. The primary outcome was the length of hospital stay evaluated using quantile regression. Secondary outcomes were kidney injury progression, renal replacement therapy, atrial fibrillation, mortality, mechanical ventilation duration, and length of intensive care unit (ICU) stay. Among 870 patients from 14 ICUs in Japan, 535 received inotropes within 24 h of ICU admission, with usage rates ranging from 40 to 100% among facilities. After propensity score matching, 218 patients were included in each group. The inotrope group had a significantly longer hospital stay compared to the control group (16 days vs. 14 days; median difference 1.78 [95% confidence interval [CI] 0.31-3.24]; p = 0.018). However, no significant differences were observed in the secondary outcomes, except for mechanical ventilation duration. The results of the sensitivity analysis using a mixed-effects quantile regression analysis considering the hospital of admission for length of hospital stay in the original cohort were consistent with the results of the propensity analyses (median difference in days, 2.35 [95% CI, 0.35-4.36]; p = 0.022). The use of inotropes within 24 h of ICU admission in adult elective cardiac surgery patients was associated with an extended hospitalization period of approximately 2 days, without offering any prognostic benefit. Clinical trial registration: UMIN-CTR, https://www.umin.ac.jp/ctr/index-j.htm , UMIN000037074.

Haptoglobin Administration for Intravascular Hemolysis: A Systematic Review.

INTRODUCTION: Exogenous haptoglobin administration may enhance plasma-free hemoglobin (pfHb) clearance during hemolysis and reduce its end-organ damage: we systematically reviewed and summarized available evidence on the use of haptoglobin as a treatment for hemolysis of any cause. METHODS: We included studies describing haptoglobin administration as treatment or prevention of hemolysis-related complications. Only studies with a control group reporting at least one of the outcomes of interest were included in the quantitative synthesis. Primary outcome was the change in pfHb concentration 1 h after haptoglobin infusion. RESULTS: Among 573 articles, 13 studies were included in the review (677 patients, 52.8% received haptoglobin). Median initial haptoglobin intravenous bolus was 4,000 (2,000, 4,000) IU. Haptoglobin was associated with lower pfHb 1 h (SMD -11.28; 95% CI: -15.80 to -6.75; p < 0.001) and 24 h (SMD -2.65; 95% CI: -4.73 to -0.57; p = 0.001) after infusion. There was no difference in all-cause mortality between haptoglobin-treated patients and control group (OR 1.41; 95% CI: 0.49-4.95; p = 0.520). Haptoglobin was associated with a lower incidence of acute kidney injury (OR 0.64; 95% CI: 0.44-0.93; p = 0.020). No adverse events or side effects associated with haptoglobin use were reported. CONCLUSIONS: Haptoglobin administration has been used in patients with hemolysis from any cause to treat or prevent hemolysis-associated adverse events. Haptoglobin may reduce levels of pfHb and preserve kidney function without increase in adverse events.

Blood Pressure Management for Hypotensive Patients in Intensive Care and Perioperative Cardiovascular Settings.

Blood pressure is a critical physiological parameter, particularly in the context of cardiac intensive care and perioperative settings. As a primary indicator of organ perfusion, the maintenance of adequate blood pressure is imperative for the assurance of sufficient tissue oxygen delivery. Among critically ill and major surgery patients, the continuous monitoring of blood pressure is performed as a standard practice for patients. Nonetheless, uncertainties remain regarding blood pressure goals, and there is no consensus regarding blood pressure targets. This review describes the determinants of blood pressure, examine the influence of blood pressure on organ perfusion, and synthesize the current clinical evidence from various intensive care and perioperative settings to provide a concise guidance for daily clinical practice.

Methylene Blue Reduces Mortality in Critically Ill and Perioperative Patients: A Meta-Analysis of Randomized Trials.

Vasodilatory hypotension is common in critically ill and perioperative patients, and is associated with adverse outcomes. As a nitric oxide production inhibitor, methylene blue (MB) exerts its vasoconstrictor property and is an adjuvant for catecholamine-refractory vasodilatory shock. However, the effects of MB on clinically relevant outcomes remain unclear. Therefore, the authors performed a meta-analysis of randomized trials on MB in critically ill and perioperative patients. The authors searched through databases for randomized trials on MB in critically ill and perioperative patients, which yielded 11 studies consisting of 556 patients. The primary outcome was mortality at the longest follow-up. Secondary outcomes included hemodynamic parameters and organ dysfunction (PROSPERO: CRD42023409243). Nine out of the 11 included randomized trials reported mortality, which was significantly lower in the MB group (risk ratio, 0.60 [95% CI 0.43-0.84] p = 0.003), with findings confirmed in septic shock and cardiac surgery subgroups. The authors found reduced lengths of stay in the intensive care unit (mean difference [MD], -0.9 days [95% CI -1.06 to -0.77] p < 0.001) and in the hospital (MD, -2.2 days [95% CI, -2.68 to -1.70] p < 0.001) in the MB group. MB was associated with increased mean arterial pressure (MD, 8.4 mmHg [95% CI 5.01-11.75] p < 0.001) and systemic vascular resistance (MD, 94.5 dyn/s/cm5 [95% CI 17.73-171.15] p = 0.02), with no difference in cardiac output (standardized MD, 0.16 [95% CI, -0.25 to 0.57] p = 0.45). This meta-analysis showed that MB reverses vasodilation in critically ill and perioperative patients and might improve survival. Further adequately powered randomized trials are needed to confirm these findings.

Amino Acid Infusion for Perioperative Functional Renal Protection: A Meta-analysis.

OBJECTIVES: Acute kidney injury (AKI) is a common perioperative complication. To date, no single intervention has been proven effective for AKI prevention in this setting. However, intravenous amino acids (AA) administration may recruit renal functional reserve and, thereby, attenuate the perioperative loss of the glomerular filtration rate. DESIGN: We performed a meta-analysis to assess the efficacy of AA infusion for perioperative renal functional protection. SETTING AND PARTICIPANTS: We performed a meta-analysis of controlled studies in perioperative patients evaluating intravenous AA infusion versus any comparator. MEASUREMENTS: The primary outcome was AKI at longest follow-up. We performed a random effects meta-analysis on the relative risk (RR) scale to assess the effect of AA infusion. We used a Bayesian approach to estimate the probability of benefit (RR < 1) for the primary outcome. Secondary outcomes included renal replacement therapy, serum creatinine, and estimated glomerular filtration rate. Tertiary outcomes included mechanical ventilation duration, intensive care unit and hospital length of stay and mortality (PROSPERO: CRD42024547225). RESULTS: We identified 15 studies (14 randomized controlled trials and 1 prospective before-after study) reporting at least one outcome of interest (4,544 patients), with 6 studies (4,084 patients) reporting the primary outcome. AKI occurred 504 of 2,041 (24.7%) in AA patients versus 614 of 2,041 (30.1%) in controls (RR, 0.66; 95% confidence interval, 0.47-0.94; I2 = 50%; p = 0.02), which corresponded with a 99.1% probability of AKI reduction with AA. Moreover, consistent with these findings, AA decreased serum creatinine and hospital length of stay and increased the estimated glomerular filtration rate. CONCLUSIONS: This meta-analysis suggests that AA administration likely decreased the perioperative incidence of AKI.

The Effects of Corticosteroids on Survival in Pediatric and Nonelderly Adult Patients Undergoing Cardiac Surgery: A Meta-analysis of Randomized Studies.

OBJECTIVE: Cardiac surgery can be complicated by the development of a systemic inflammatory response syndrome related to cardiopulmonary bypass. This potentially contributes to the occurrence of postoperative morbidity and mortality. Corticosteroids can be used to reduce such inflammation, but the overall balance between potential harm and benefit is unknown and may be age-dependent. The present meta-analysis aims to evaluate the effects of prophylactic corticosteroids in pediatric and non-elderly adult cardiac surgery patients. DESIGN: Systematic review and meta-analysis of randomized trials. SETTING: Cardiac surgery with cardiopulmonary bypass. PARTICIPANTS: Patients younger than 65 years old (pediatric and non-elderly adults). INTERVENTIONS: Perioperative use of corticosteroids versus placebo or standard care. MEASUREMENTS AND MAIN RESULTS: Two independent investigators searched PubMed, EMBASE and the Cochrane Library from inception to January 20, 2024. The primary outcome was mortality at the longest follow-up available. Secondary outcomes included acute kidney injury, atrial fibrillation, myocardial injury, cerebrovascular events, and infections. Our search strategy identified a total of 17 randomized trials involving 6,598 patients. Mortality was significantly reduced in the corticosteroid group (78/3321 [2.3%] vs. 116/3277 [3.5%]; risk ratio = 0.69; 95% confidence interval, 0.52 to 0.92; P = 0.01; I2 = 0%; NNT = 91). Moreover, the highest postoperative vasoactive inotropic score (VIS) was significantly lower in corticosteroid group (MD: -2.07, 95% CI -3.69 to -0.45, P = 0.01, I2 = 0%). No significant differences in secondary outcomes between the two treatment groups were recorded. CONCLUSIONS: This meta-analysis of randomized trials highlights the potential benefits of corticosteroids on survival in cardiac surgery for patients younger than 65 years old.

Improvement of coracoid process union rates: a comparative study of conventional open and arthroscopic-assisted Bristow procedures for treating anterior shoulder instability in rugby players.

BACKGROUND: The Bristow coracoid transfer procedure is a reliable technique for treating anterior shoulder instability in patients with large glenoid bone loss or those involved in collision sports. However, its success is marred by its inferior bone union rate of the coracoid process as compared to the Latarjet procedure. This study aimed to evaluate whether arthroscopic confirmation of the secured coracoid fixation during the Bristow procedure improves the bone union rate and clinical outcomes as compared to the open procedure. METHODS: We retrospectively reviewed 104 rugby players (n = 111 shoulders) who underwent an open (n = 66 shoulders) or arthroscopy (AS)-assisted (n = 45 shoulders) Bristow procedure at our center from 2007 to April 2019. In the AS-assisted group, the screw fixation and coracoid stability and contact were confirmed under arthroscopic visualization. Graft union was evaluated through computed tomography at 3 months, 6 months, and 1 year postoperatively. Patient-reported outcome measures were assessed based on the American Shoulder and Elbow Surgeons score, Rowe score, and satisfaction rate. Recurrence, the rate of return to play (RTP), and the frequency of pain after RTP were also assessed. RESULTS: The mean follow-up period was 73.5 (range: 45-160) months for the open group and 32.3 (range: 24-56) months for the AS-assisted group. In the former, the rates of bone union were 50%, 72.7%, and 88.9% at 3 months, 6 months, and 1 year, respectively. In contrast, the AS-assisted group had significantly greater bone union rates-88.9%, 93.3%, and 95.6% at 3 months, 6 months, and 1 year, respectively. Both groups showed significant improvement in the American Shoulder and Elbow Surgeons and Rowe scores compared to preoperative values as well as high satisfaction rates (open: 92%; AS-assisted: 95.7%). There were no statistically significant differences in the recurrence and RTP rates as well as the frequency of pain after RTP between the 2 groups. CONCLUSION: The AS-assisted procedure allows early and high bone healing without compromising the clinical outcomes.

Exfoliatable Layered 2D Honeycomb Crystals of Host-guest Complexes Networked by CH-π Hydrogen Bonds.

Studies of graphene show that robust chemical bonds such as covalent bonds with trigonal-planar atoms afford layered atomic 2D crystals possessing unique properties. Although layered molecular crystals are of interest to diversify elements and structures of 2D materials, the structural diversity of molecules as well as weak intermolecular interactions inevitably makes the design to be one-off and individual. We herein report a versatile method to assemble layered molecular crystals. By developing a D3-symmetry host at vertices to form a honeycomb layer, a diverse range of layered 2D host-guest crystals were obtained. Substituents on the host, elements/structures of the guest, the stereochemistry of the host and types of intercalants were diversified, which should allow for 6×32×3×2 combinations for structural diversification.

An updated "norepinephrine equivalent" score in intensive care as a marker of shock severity.

Vasopressors and fluids are the cornerstones for the treatment of shock. The current international guidelines on shock recommend norepinephrine as the first-line vasopressor and vasopressin as the second-line vasopressor. In clinical practice, due to drug availability, local practice variations, special settings, and ongoing research, several alternative vasoconstrictors and adjuncts are used in the absence of precise equivalent doses. Norepinephrine equivalence (NEE) is frequently used in clinical trials to overcome this heterogeneity and describe vasopressor support in a standardized manner. NEE quantifies the total amount of vasopressors, considering the potency of each such agent, which typically includes catecholamines, derivatives, and vasopressin. Intensive care studies use NEE as an eligibility criterion and also an outcome measure. On the other hand, NEE has several pitfalls which clinicians should know, important the lack of conversion of novel vasopressors such as angiotensin II and also adjuncts such as methylene blue, including a lack of high-quality data to support the equation and validate its predictive performance in all types of critical care practice. This review describes the history of NEE and suggests an updated formula incorporating novel vasopressors and adjuncts.

Propofol and survival: an updated meta-analysis of randomized clinical trials.

BACKGROUND: Propofol is one of the most widely used hypnotic agents in the world. Nonetheless, propofol might have detrimental effects on clinically relevant outcomes, possibly due to inhibition of other interventions' organ protective properties. We performed a systematic review and meta-analysis of randomized controlled trials to evaluate if propofol reduced survival compared to any other hypnotic agent in any clinical setting. METHODS: We searched eligible studies in PubMed, Google Scholar, and the Cochrane Register of Clinical Trials. The following inclusion criteria were used: random treatment allocation and comparison between propofol and any comparator in any clinical setting. The primary outcome was mortality at the longest follow-up available. We conducted a fixed-effects meta-analysis for the risk ratio (RR). Using this RR and 95% confidence interval, we estimated the probability of any harm (RR > 1) through Bayesian statistics. We registered this systematic review and meta-analysis in PROSPERO International Prospective Register of Systematic Reviews (CRD42022323143). RESULTS: We identified 252 randomized trials comprising 30,757 patients. Mortality was higher in the propofol group than in the comparator group (760/14,754 [5.2%] vs. 682/16,003 [4.3%]; RR = 1.10; 95% confidence interval, 1.01-1.20; p = 0.03; I2 = 0%; number needed to harm = 235), corresponding to a 98.4% probability of any increase in mortality. A statistically significant mortality increase in the propofol group was confirmed in subgroups of cardiac surgery, adult patients, volatile agent as comparator, large studies, and studies with low mortality in the comparator arm. CONCLUSIONS: Propofol may reduce survival in perioperative and critically ill patients. This needs careful assessment of the risk versus benefit of propofol compared to other agents while planning for large, pragmatic multicentric randomized controlled trials to provide a definitive answer.

Positive single-center randomized trials and subsequent multicenter randomized trials in critically ill patients: a systematic review.

BACKGROUND: It is unclear how often survival benefits observed in single-center randomized controlled trials (sRCTs) involving critically ill patients are confirmed by subsequent multicenter randomized controlled trials (mRCTs). We aimed to perform a systemic literature review of sRCTs with a statistically significant mortality reduction and to evaluate whether subsequent mRCTs confirmed such reduction. METHODS: We searched PubMed for sRCTs published in the New England Journal of Medicine, JAMA, or Lancet, from inception until December 31, 2016. We selected studies reporting a statistically significant mortality decrease using any intervention (drug, technique, or strategy) in adult critically ill patients. We then searched for subsequent mRCTs addressing the same research question tested by the sRCT. We compared the concordance of results between sRCTs and mRCTs when any mRCT was available. We registered this systematic review in the PROSPERO International Prospective Register of Systematic Reviews (CRD42023455362). RESULTS: We identified 19 sRCTs reporting a significant mortality reduction in adult critically ill patients. For 16 sRCTs, we identified at least one subsequent mRCT (24 trials in total), while the interventions from three sRCTs have not yet been addressed in a subsequent mRCT. Only one out of 16 sRCTs (6%) was followed by a mRCT replicating a significant mortality reduction; 14 (88%) were followed by mRCTs with no mortality difference. The positive finding of one sRCT (6%) on intensive glycemic control was contradicted by a subsequent mRCT showing a significant mortality increase. Of the 14 sRCTs referenced at least once in international guidelines, six (43%) have since been either removed or suggested against in the most recent versions of relevant guidelines. CONCLUSION: Mortality reduction shown by sRCTs is typically not replicated by mRCTs. The findings of sRCTs should be considered hypothesis-generating and should not contribute to guidelines.

Mechanisms of Action of the Detrimental Effects of Propofol on Survival.

Due to its favorable pharmacologic features, propofol is the most commonly used hypnotic agent in perioperative and intensive care settings. However, it also has adverse effects like propofol infusion syndrome and an increased risk of infection. Growing evidence suggests that propofol may worsen clinical outcomes by inhibiting the organ-protective properties of other interventions, such as volatile anesthetics or remote ischemic preconditioning. This editorial describes possible mechanisms underlying the detrimental effects of propofol, and provides an overview of the results of clinical trials evaluating the effects of propofol in various settings.

Del Nido Cardioplegia in Adult Cardiac Surgery: Meta-Analysis of Randomized Clinical Trials.

OBJECTIVE: To compare the outcomes of patients receiving del Nido solution versus any other type of cardioplegia. DESIGN: A systematic review and meta-analysis of randomized trials. SETTING: Cardiac operating rooms. PARTICIPANTS: Adult patients (≥18 years old) undergoing cardiac surgery. INTERVENTIONS: The EMBASE, MEDLINE, and CENTRAL databases were searched systematically from their inception until August 2022 for randomized controlled trials comparing del Nido versus other cardioplegias. MEASUREMENTS AND MAIN RESULTS: Ten studies were included, including 1,812 patients (871 in the del Nido group and 941 in the control group), and published after 2017. There were significant reductions in postoperative stroke and/or transient ischemic attack rate in the del Nido group: 9/467 (1.9%) v 25/540 (4.6%); odds ratio (OR), 0.43; 95% CI, 0.20-0.92 (p = 0.007). Del Nido cardioplegia was also associated with significantly shorter aortic cross-clamp time (mean difference, -8.99 minutes; 95% CI, -17.24 to -0.73 [p < 0.001]), significantly reduced need for defibrillation (89/582 [15%] v 252/655 [38%]; OR, 0.33; 95% CI, 0.15-0.72 [p < 0.001]), significantly lower risk of postoperative acute kidney injury (21/235 [8.9%] v 34/301 [11%]; OR, 0.50; 95% CI, 0.26-0.97 [p = 0.04]), with no effect on mortality (14/607 [2.3%] v 12/681 [1.8%]; p = 0.5). CONCLUSION: According to the authors' meta-analysis of recent randomized clinical trials, del Nido is a safe cardioplegic solution, which might provide better organ protection in adult cardiac surgery without differences in mortality when compared to other cardioplegic solutions.

Continuous vs Intermittent Meropenem Administration in Critically Ill Patients With Sepsis: The MERCY Randomized Clinical Trial.

Importance: Meropenem is a widely prescribed ß-lactam antibiotic. Meropenem exhibits maximum pharmacodynamic efficacy when given by continuous infusion to deliver constant drug levels above the minimal inhibitory concentration. Compared with intermittent administration, continuous administration of meropenem may improve clinical outcomes. Objective: To determine whether continuous administration of meropenem reduces a composite of mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria compared with intermittent administration in critically ill patients with sepsis. Design, Setting, and Participants: A double-blind, randomized clinical trial enrolling critically ill patients with sepsis or septic shock who had been prescribed meropenem by their treating clinicians at 31 intensive care units of 26 hospitals in 4 countries (Croatia, Italy, Kazakhstan, and Russia). Patients were enrolled between June 5, 2018, and August 9, 2022, and the final 90-day follow-up was completed in November 2022. Interventions: Patients were randomized to receive an equal dose of the antibiotic meropenem by either continuous administration (n = 303) or intermittent administration (n = 304). Main Outcomes and Measures: The primary outcome was a composite of all-cause mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28. There were 4 secondary outcomes, including days alive and free from antibiotics at day 28, days alive and free from the intensive care unit at day 28, and all-cause mortality at day 90. Seizures, allergic reactions, and mortality were recorded as adverse events. Results: All 607 patients (mean age, 64 [SD, 15] years; 203 were women [33%]) were included in the measurement of the 28-day primary outcome and completed the 90-day mortality follow-up. The majority (369 patients, 61%) had septic shock. The median time from hospital admission to randomization was 9 days (IQR, 3-17 days) and the median duration of meropenem therapy was 11 days (IQR, 6-17 days). Only 1 crossover event was recorded. The primary outcome occurred in 142 patients (47%) in the continuous administration group and in 149 patients (49%) in the intermittent administration group (relative risk, 0.96 [95% CI, 0.81-1.13], P = .60). Of the 4 secondary outcomes, none was statistically significant. No adverse events of seizures or allergic reactions related to the study drug were reported. At 90 days, mortality was 42% both in the continuous administration group (127 of 303 patients) and in the intermittent administration group (127 of 304 patients). Conclusions and Relevance: In critically ill patients with sepsis, compared with intermittent administration, the continuous administration of meropenem did not improve the composite outcome of mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28. Trial Registration: ClinicalTrials.gov Identifier: NCT03452839.

High versus low blood pressure targets for cardiac surgery while on cardiopulmonary bypass.

BACKGROUND: Cardiac surgery is performed worldwide. Most types of cardiac surgery are performed using cardiopulmonary bypass (CPB). Cardiac surgery performed with CPB is associated with morbidities. CPB needs an extracorporeal circulation that replaces the heart and lungs, and performs circulation, ventilation, and oxygenation of the blood. The lower limit of mean blood pressure to maintain blood flow to vital organs increases in people with chronic hypertension. Because people undergoing cardiac surgery commonly have chronic hypertension, we hypothesised that maintaining a relatively high blood pressure improves desirable outcomes among the people undergoing cardiac surgery with CPB. OBJECTIVES: To evaluate the benefits and harms of higher versus lower blood pressure targets during cardiac surgery with CPB. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search of databases was November 2021 and trials registries in January 2020. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing a higher blood pressure target (mean arterial pressure 65 mmHg or greater) with a lower blood pressure target (mean arterial pressure less than 65 mmHg) in adults undergoing cardiac surgery with CPB. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Primary outcomes were 1. acute kidney injury, 2. cognitive deterioration, and 3. all-cause mortality. Secondary outcomes were 4. quality of life, 5. acute ischaemic stroke, 6. haemorrhagic stroke, 7. length of hospital stay, 8. renal replacement therapy, 9. delirium, 10. perioperative transfusion of blood products, and 11. perioperative myocardial infarction. We used GRADE to assess certainty of evidence. MAIN RESULTS: We included three RCTs with 737 people compared a higher blood pressure target with a lower blood pressure target during cardiac surgery with CPB. A high blood pressure target may result in little to no difference in acute kidney injury (risk ratio (RR) 1.30, 95% confidence interval (CI) 0.81 to 2.08; I² = 72%; 2 studies, 487 participants; low-certainty evidence), cognitive deterioration (RR 0.82, 95% CI 0.45 to 1.50; I² = 0%; 2 studies, 389 participants; low-certainty evidence), and all-cause mortality (RR 1.33, 95% CI 0.30 to 5.90; I² = 49%; 3 studies, 737 participants; low-certainty evidence). No study reported haemorrhagic stroke. Although a high blood pressure target may increase the length of hospital stay slightly, we found no differences between a higher and a lower blood pressure target for the other secondary outcomes. We also identified one ongoing RCT which is comparing a higher versus a lower blood pressure target among the people who undergo cardiac surgery with CPB. AUTHORS' CONCLUSIONS: A high blood pressure target may result in little to no difference in patient outcomes including acute kidney injury and mortality. Given the wide CIs, further studies are needed to confirm the efficacy of a higher blood pressure target among those who undergo cardiac surgery with CPB.