Low Versus High Blood Pressure Targets in Critically Ill and Surgical Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVES: Hypotension is associated with adverse outcomes in critically ill and perioperative patients. However, these assumptions are supported by observational studies. This meta-analysis of randomized controlled trials aims to compare the impact of lower versus higher blood pressure targets on mortality. DATA SOURCES: We searched PubMed, Cochrane, and Scholar from inception to February 10, 2024. STUDY SELECTION: Randomized trials comparing lower versus higher blood pressure targets in the management of critically ill and perioperative settings. DATA EXTRACTION: The primary outcome was all-cause mortality at the longest follow-up available. This review was registered in the Prospective International Register of Systematic Reviews, CRD42023452928. DATA SYNTHESIS: Of 2940 studies identified by the search string, 28 (12 in critically ill and 16 in perioperative settings) were included totaling 15,672 patients. Patients in the low blood pressure target group had lower mortality (23 studies included: 1019/7679 [13.3%] vs. 1103/7649 [14.4%]; relative risk 0.93; 95% CI, 0.87-0.99; p = 0.03; I2 = 0%). This corresponded to a 97.4% probability of any increase in mortality with a Bayesian approach. These findings were mainly driven by studies performed in the ICU setting and with treatment lasting more than 24 hours; however, the magnitude and direction of the results were similar in the majority of sensitivity analyses including the analysis restricted to low risk of bias studies. We also observed a lower rate of atrial fibrillation and fewer patients requiring transfusion in low-pressure target groups. No differences were found in the other secondary outcomes. CONCLUSIONS: Based on pooled randomized trial evidence, a lower compared with a higher blood pressure target results in a reduction of mortality, atrial fibrillation, and transfusion requirements. Lower blood pressure targets may be beneficial but there is ongoing uncertainty. However, the present meta-analysis does not confirm previous findings and recommendations. These results might inform future guidelines and promote the study of the concept of protective hemodynamics.

Interventions reducing mortality in COVID-19 patients: a systematic review of randomized evidence.

INTRODUCTION: COVID-19 pandemic changed the way medical research is published, possibly forever. As the need for rapidity led to the rise of preprint servers, the undeniable drop in the overall quality of scientific publications requires an in-depth review of all available evidence. The present manuscript aims to identify and summarize all treatments which have been reported to reduce mortality in randomized trials in hospitalized COVID-19 patients. EVIDENCE ACQUISITION: Independent investigators searched MEDLINE/PubMed, Scopus, and Embase databases to identify all randomized trials of any intervention influencing mortality in hospitalized COVID-19 patients up to August 18th, 2022. Articles were selected only when they fulfilled all the following: randomized trial design; dealing with any kind of interventions in adult hospitalized COVID-19 patients; and statistically significant reduction in mortality. EVIDENCE SYNTHESIS: We identified 28 interventions (42 manuscripts) reducing mortality in hospitalized COVID-19 patients. About 60% of the studies (26/42) were multicentric, for a total of 1140 centers involved worldwide. Several of these studies were published in high-ranked, peer-reviewed journals. Interventions with randomized evidence of mortality reduction in hospitalized COVID-19 patients belonged to 5 domains: corticosteroids, immunomodulators, antimicrobials, supportive therapies, and other drugs. CONCLUSIONS: Many interventions have the potential to reduce mortality in COVID-19 hospitalized patients. The correct treatment of future pandemics relies on large, multicentric randomized clinical trials for further evaluation of these promising strategies.

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.

Intraoperative hypotension and postoperative outcomes: a meta-analysis of randomised trials.

INTRODUCTION: Intraoperative hypotension is associated with adverse postoperative outcomes; however these findings are supported only by observational studies. The aim of this meta-analysis of randomised trials was to compare the postoperative effects permissive management with targeted management of intraoperative blood pressure. METHODS: We searched PubMed, Cochrane, and Embase up to June 2023 for studies comparing permissive (mean arterial pressure ≤60 mm Hg) with targeted (mean arterial pressure >60 mm Hg) intraoperative blood pressure management. Primary outcome was all-cause mortality at the longest follow-up available. Secondary outcomes were atrial fibrillation, myocardial infarction, acute kidney injury, delirium, stroke, number of patients requiring transfusion, time on mechanical ventilation, and length of hospital stay. RESULTS: We included 10 randomised trials including a total of 9359 patients. Mortality was similar between permissive and targeted blood pressure management groups (89/4644 [1.9%] vs 99/4643 [2.1%], odds ratio 0.88, 95% confidence interval [CI], 0.65-1.18, P=0.38, I2=0% with nine studies included). Atrial fibrillation (102/3896 [2.6%] vs 130/3887 [3.3%] odds ratio 0.71, 95% CI 0.53-0.96, P=0.03, I2=0%), and length of hospital stay (mean difference -0.20 days, 95% CI -0.26 to -0.13, P<0.001, I2=0%) were reduced in the permissive management group. No significant differences were found in subgroup analysis for cardiac and noncardiac surgery. CONCLUSION: Pooled randomised evidence shows that a target intraoperative mean arterial pressure ≤60 mm Hg is not associated with increased mortality; nevertheless it is surprisingly associated with a reduced rate of atrial fibrillation and of length of hospital stay. SYSTEMATIC REVIEW PROTOCOL: PROSPERO CRD42023393725.

High dose esomeprazole as an anti-inflammatory agent in sepsis: Protocol for a randomized controlled trial.

BACKGROUND: Sepsis is caused by dysregulated immune responses due to infection and still presents high mortality rate and limited efficacious therapies, apart from antibiotics. Recent evidence suggests that very high dose proton pump inhibitors might regulate major sepsis mediators' secretion by monocytes, which might attenuate excessive host reactions and improve clinical outcomes. This effect is obtained with doses which are approximately 50 times higher than prophylactic esomeprazole single daily administration and 17 times higher than the cumulative dose of a three day prophylaxis. We aim to perform a randomized trial to investigate if high dose esomeprazole reduces organ dysfunction in patients with sepsis or septic shock. METHODS: This study, called PPI-SEPSIS, is a multicenter, randomized, double blind, placebo-controlled clinical trial on critically ill septic patients admitted to the emergency department or intensive care unit. A total of 300 patients will be randomized to receive high dose esomeprazole (80 mg bolus followed by 12 mg/h for 72 h and a second 80 mg bolus 12 h after the first one) or equivolume placebo (sodium chloride 0.9%), with 1:1 allocation. The primary endpoint of the study will be mean daily Sequential Organ Failure Assessment (SOFA) score over 10 days. Secondary outcomes will include antibiotic-free days, single organ failure severity, intensive care unit-free days at day 28, and mortality. DISCUSSION: This trial aims to test the efficacy of high dose esomeprazole to reduce acute organ dysfunction in patients with septic shock. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov with the trial identification NCT03452865 in March 2018.

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.

Two-year multidisciplinary follow-up of COVID-19 patients requiring invasive and noninvasive respiratory support.

BACKGROUND: COVID-19 patients frequently develop respiratory failure requiring mechanical ventilation. Data on long-term survival of patients who had severe COVID-19 are insufficient. We assessed and compared two-year survival, CT imaging, quality of life, and functional recovery of COVID-19 ARDS patients requiring respiratory support with invasive (IMV) versus noninvasive ventilation (NIV). METHODS: Patients with COVID-19 pneumonia admitted up to May 28th, 2020, who required IMV or NIV, and survived to hospital discharge were enrolled. Patients were contacted two years after discharge to assess vital status, functional, psychological, and cognitive outcomes using validated scales. Patients with persistent respiratory symptoms or high burden of residual lung damage at previous CT scan received a two-year chest CT scan. RESULTS: Out of 61 IMV survivors, 98% were alive at two-year follow-up, and 52 completed the questionnaire. Out of 82 survivors receiving NIV only, 94% were alive at two years, and 47 completed the questionnaire. We found no major differences between invasively and noninvasively ventilated patients, with overall acceptable functional recovery. Among the 99 patients completing the questionnaire, 23 have more than moderate exertional dyspnea. Chest CT scans showed that 4 patients (all received IMV) had fibrotic-like changes. CONCLUSIONS: Patients who received mechanical ventilation due to COVID-19 and were discharged from hospital had a 96% survival rate at the two-year follow-up. There was no difference in overall recovery and quality of life between patients who did and did not require IMV, although respiratory morbidity remains high.

Heart Rate Variability in Subjects with Severe Allergic Background Undergoing COVID-19 Vaccination.

Anti-Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) vaccination is the world's most important strategy for stopping the pandemic. Vaccination challenges the body's immune response and can be complicated by hypersensitivity reactions. The autonomic nervous system can modulate the inflammatory immune response, therefore constituting a potential marker to characterize individuals at high risk of hypersensitivity reactions. Autonomic nervous system functionality was assessed through measurement of the heart rate variability (HRV) in subjects with a history of severe allergic reactions and 12 control subjects. HRV parameters included the mean electrocardiograph RR interval and the standard deviation of all normal R-R intervals (SDNN). All measurements were performed immediately before the anti-SARS-CoV-2 vaccination. The median RR variability was lower in the study than in the control group: 687 ms (645-759) vs. 821 ms (759-902); p = 0.02. The SDNN was lower in the study group than in the control group: 32 ms (23-36) vs. 50 ms (43-55); p < 0.01. No correlation was found between age and the SDNN. Autonomic nervous system activity is unbalanced in people with a severe allergy background.

Efficacy of Cetylpyridinium Chloride mouthwash against SARS-CoV-2: A systematic review of randomized controlled trials.

INTRODUCTION: COVID-19 is a transmissible respiratory and multisystem disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Viral transmission occurs mainly through the spread of salivary droplets or aerosol from an infected subject. Studies suggest that salivary viral load is correlated with disease severity and probability of transmission. Cetylpyridinium chloride mouthwash has been found to be effective in reducing salivary viral load. The aim of this systematic review of randomized controlled trials is to evaluate the efficacy of the mouthwash ingredient cetylpyridinium chloride on salivary viral load in SARS-CoV-2 infection. METHODS: Randomized controlled trials comparing cetylpyridinium chloride mouthwash with placebo and other mouthwash ingredients in SARS-CoV-2 positive individuals were identified and evaluated. RESULTS: Six studies with a total of 301 patients that met the inclusion criteria were included. The studies reported the efficacy of cetylpyridinium chloride mouthwashes in reduction on SARS-CoV-2 salivary viral load compared to placebo and other mouthwash ingredients. CONCLUSION: Mouthwashes containing cetylpyridinium chloride are effective against salivary viral load of SARS-CoV-2 in vivo. There is also the possibility that the use of mouthwash containing cetylpyridinium chloride in SARS-CoV-2 positive subjects could reduce transmissibility and severity of COVID-19.

Opioid Free Anesthesia in Thoracic Surgery: A Systematic Review and Meta Analysis.

Introduction: Recent studies showed that balanced opioid-free anesthesia is feasible and desirable in several surgical settings. However, in thoracic surgery, scientific evidence is still lacking. Thus, we conducted the first systematic review and meta-analysis of opioid-free anesthesia in this field. Methods: The primary outcome was the occurrence of any complication. Secondary outcomes were the length of hospital stay, recovery room length of stay, postoperative pain at 24 and 48 h, and morphine equivalent consumption at 48 h. Results: Out of 375 potentially relevant articles, 6 studies (1 randomized controlled trial and 5 observational cohort studies) counting a total of 904 patients were included. Opioid-free anesthesia compared to opioid-based anesthesia, was associated with a lower rate of any complication (74 of 175 [42%] vs. 200 of 294 [68%]; RR = 0.76; 95% CI, 0.65−0.89; p < 0.001; I2 = 0%), lower 48 h morphine equivalent consumption (MD −14.5 [−29.17/−0.22]; p = 0.05; I2 = 95%) and lower pain at 48 h (MD −1.95 [−3.6/0.3]; p = 0.02, I = 98%). Conclusions: Opioid-free anesthesia in thoracic surgery is associated with lower postoperative complications, and less opioid demand with better postoperative analgesia at 48 h compared to opioid-based anesthesia.

Mitral Valve Systolic Anterior Motion in Robotic Thoracic Surgery as the Cause of Unexplained Hemodynamic Shock: From a Case Report to Recommendations.

Robotic major lung resection for lung cancer carries a risk for intraoperative hemodynamic instability. Systolic anterior motion (SAM) of the mitral valve is a rare and often misrecognized cause of intraoperative hemodynamic instability. If not promptly recognized, SAM leads to a complicated perioperative course. Here, we report for the first time a case of a patient with SAM with a severe degree of left ventricular outflow obstruction (LVOTO) undergoing robotic lung lobectomy and its challenging intraoperative management. A 70-year-old man undergoing robotic left upper lobectomy developed immediately after the induction of general anesthesia hemodynamic instability due to SAM-related LVOTO. The diagnosis was possible, thanks to the use of transesophageal echocardiography (TEE). The treatment strategies applied were preload optimization without fluid overload, ultra-short-acting beta-blockers, and vasopressors. Peripheral nerve blockades were preferred over epidural analgesia to avoid vasodilatation. The patient reported a good quality of recovery and no pain the day after surgery. The management of patients with higher risk of SAM and LVOTO development during robotic thoracic surgery requires a dedicated and skilled team together with high-impact treatment strategies driven by TEE. Since current guidelines do not recommend the use of TEE, even for patients with higher cardiac risk undergoing noncardiac surgery, the present case report may stimulate interest in future recommendations.

How many of the COVID-19 deaths occurred in the Intensive Care Unit?

BACKGROUND: The percentage of overall COVID-19 deaths which occurred in intensive care units (ICU) is unknown. We estimated 18% in Italy from February 21, 2020, to February 21, 2021, using cumulative numbers from publicly available databases. This study aims to confirm this percentage using raw data from Italian and European registries. METHODS: We searched PubMed, government health reports, and medical websites to obtain the ratio between number of COVID-19 deaths in ICUs and total number of COVID-19 deaths in the most hit European regions during the first year of the pandemic. When available, we distinguished between different waves and interwaves periods. We performed a forest plot with random effect of proportions to calculate the overall European percentage. RESULTS: We found data for six European countries (United Kingdom, Netherlands, Norway, Italy, Denmark, and Germany). The percentage of COVID-19 deaths which occurred in United Kingdom ICUs was 10% and 11% during the first and the second pandemic waves, respectively. Netherlands and Norway counted 13% and 16%. Italy had 18% of the overall COVID-19 deaths occurring in the ICU during both pandemic waves, and 17% during the intra-pandemic period. Denmark and Germany counted 20% and 22%. Overall, 16% of the COVID-19 deaths occurred in European ICUs. CONCLUSIONS: The percentage of COVID-19 deaths which occurred in European ICUs was 16% and consistent across different countries, ranging from 10% to 22%. Interestingly, we observed no difference between pandemic waves and intra-pandemic periods.

One-Year Multidisciplinary Follow-Up of Patients With COVID-19 Requiring Invasive Mechanical Ventilation.

OBJECTIVES: Patients with COVID-19 frequently develop acute respiratory distress syndrome (ARDS) requiring intensive care unit (ICU) admission. Data on long-term survival of these patients are lacking. The authors investigated 1-year survival, quality of life, and functional recovery of patients with COVID-19 ARDS requiring invasive mechanical ventilation. DESIGN: Prospective observational study. SETTING: Tertiary-care university hospital. PARTICIPANTS: All patients with COVID-19 ARDS receiving invasive mechanical ventilation and discharged alive from hospital. INTERVENTIONS: Patients were contacted by phone after 1 year. Functional, cognitive, and psychological outcomes were explored through a questionnaire and assessed using validated scales. Patients were offered the possibility to undergo a follow-up chest computed tomography (CT) scan. MEASUREMENTS AND MAIN RESULTS: The study included all adult (age ≥18 years) patients with COVID-19-related ARDS admitted to an ICU of the authors' institution between February 25, 2020, and April 27, 2020, who received at least 1 day of invasive mechanical ventilation (IMV). Of 116 patients who received IMV, 61 (52.6%) survived to hospital discharge. These survivors were assessed 1 year after discharge and 56 completed a battery of tests of cognition, activities of daily living, and interaction with family members. They had overall good functional recovery, with >80% reporting good recovery and no difficulties in usual activities. A total of 52 (93%) of patients had no dyspnea at rest. Severe anxiety/depression was reported by 5 (8.9%) patients. Comparing 2-month and 1-year data, the authors observed the most significant improvements in the areas of working status and exertional dyspnea. One-year chest CT scans were available for 36 patients; fibrotic-like changes were present in 4 patients. CONCLUSIONS: All patients who survived the acute phase of COVID-19 and were discharged from the hospital were alive at the 1-year follow up, and the vast majority of them had good overall recovery and quality of life.

COVID-19 seasonality in temperate countries.

INTRODUCTION: While the beneficial effect of vaccination, restrictive measures, and social distancing in reducing mortality due to SARS-CoV-2 is intuitive and taken for granted, seasonality (predictable fluctuation or pattern that recurs or repeats over a one-year period) is still poorly understood and insufficiently taken into consideration. We aimed to examine SARS-CoV-2 seasonality in countries with temperate climate. METHODS: We identified countries with temperate climate and extracted average country temperature data from the National Center for Environmental information and from the Climate Change Knowledge Portal. We obtained mortality and vaccination rates from an open access database. We used the stringency index derived from the Oxford COVID-19 Government Response Tracker to quantify restriction policies. We used Spearman's and rank-correlation non-parametric test coefficients to investigate the association between COVID-19 mortality and temperature values. We employed multivariate regression models to analyze how containment measures, vaccinations, and monthly temperatures affected COVID-19 mortality rates. RESULTS: The time series for daily deaths per million inhabitants and average monthly temperatures of European countries and US states with a temperate climate had a negative correlation (p < 0.0001 for all countries, 0.40 < R < 0.86). When running multivariate regression models with country fixed effects, we noted that mortality rates were significantly lower when temperature were higher. Interestingly, when adding an interaction term between monthly temperatures and vaccination rates, we found that as monthly temperatures dropped, the effect of the vaccination campaign on mortality was larger than at higher temperatures. DISCUSSION: Deaths attributed to SARS-CoV-2 decreased during the summer period in temperate countries. We found that the effect of vaccination rates on mortality was stronger when temperatures were lower. Stakeholders should consider seasonality in managing SARS-CoV-2 and future pandemics to minimize mortality, limit the pressure on hospitals and intensive care units while maintaining economic and social activities.