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.

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.

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.

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.

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.

Efficacy and safety of IL-6 inhibitors in patients with COVID-19 pneumonia: a systematic review and meta-analysis of multicentre, randomized trials.

PURPOSE: COVID-19 is characterized by dysregulated immune response, respiratory failure and a relevant mortality rate among hospitalized patients. Interleukin-6 (IL-6) is involved in COVID-19-associated cytokine storm, and several trials investigated whether its inhibition could improve patients' outcome. We performed a meta-analysis of randomized trials (RCT) to test this hypothesis. MATERIALS AND METHODS: Two independent investigators searched PubMed, Scopus, ClnicalTrials.gov and medRxiv up to September 1st, 2021. Inclusion criteria were: administration of tocilizumab or sarilumab; COVID-19 adult patients with pneumonia; and being a RCT. Primary outcome was mortality at the longest follow-up. Secondary outcomes included intubation rate and incidence of adverse events. Two independent investigators extracted data from eligible trials. RESULTS: Of the 763 studies assessed, 15 RCTs were included (9,320 patients), all were multicentre, and the majority open-label vs standard treatment. IL-6 inhibitors were associated with reduced all-cause mortality at the longest follow-up (1315/5,380 [24.4%] in the IL-6 inhibitors group versus 1080/3,814 [28.3%] in the control group, RR = 0.90; 95% CI 0.84 to 0.96; p for effect = 0.003, I2 = 0%, with 13 studies included), with reduction in 28/30-day mortality and intubation rates, and with no increase in adverse events and secondary infections. CONCLUSION: IL-6 inhibitors reduced longest follow-up mortality and intubation in COVID-19 patients. Findings need to be confirmed in high-quality RCTs.

A radiological predictor for pneumomediastinum/pneumothorax in COVID-19 ARDS patients.

PURPOSE: To determine whether Macklin effect (a linear collection of air contiguous to the bronchovascular sheath) on baseline CT imaging is an accurate predictor for subsequent pneumomediastinum (PMD)/pneumothorax (PNX) development in invasively ventilated patients with COVID-19-related acute respiratory distress syndrome (ARDS). MATERIALS AND METHODS: This is an observational, case-control study. From a prospectively acquired database, all consecutive invasively ventilated COVID-19 ARDS patients who underwent at least one baseline chest CT scan during the study time period (February 25th, 2020-December 31st, 2020) were identified; those who had tracheal lesion or already had PMD/PNX at the time of the first available chest imaging were excluded. RESULTS: 37/173 (21.4%) patients enrolled had PMD/PNX; specifically, 20 (11.5%) had PMD, 10 (5.8%) PNX, 7 (4%) both. 33/37 patients with subsequent PMD/PNX had Macklin effect on baseline CT (89.2%, true positives) 8.5 days [range, 1-18] before the first actual radiological evidence of PMD/PNX. Conversely, 6/136 patients without PMD/PNX (4.4%, false positives) demonstrated Macklin effect (p < 0.001). Macklin effect yielded a sensitivity of 89.2% (95% confidence interval [CI]: 74.6-96.9), a specificity of 95.6% (95% CI: 90.6-98.4), a positive predictive value (PV) of 84.5% (95% CI: 71.3-92.3), a negative PV of 97.1% (95% CI: 74.6-96.9) and an accuracy of 94.2% (95% CI: 89.6-97.2) in predicting PMD/PNX (AUC:0.924). CONCLUSIONS: Macklin effect accurately predicts, 8.5 days in advance, PMD/PNX development in COVID-19 ARDS patients.

Sufentanil Sublingual Tablet System (SSTS) for the management of postoperative pain after major abdominal and gynecological surgery within an ERAS protocol: an observational study.

BACKGROUND: The Sufentanil Sublingual Tablet System (SSTS) is a new, pre-programmed, noninvasive, handheld system for patient-controlled analgesia (PCA) which may allow a faster postoperative recovery compared with standard PCA. The efficacy of SSTS in controlling pain after open abdominal surgery has already been documented. However, to our knowledge SSTS has never been investigated in patients undergoing major surgery within an Enhanced Recovery After Surgery (ERAS) protocol. METHODS: This observational, retrospective analysis included consecutive patients undergoing elective major abdominal and gynecological surgery. All patients received the SSTS device once they were fully awake and had a good control of pain at the end of the surgery. We analyzed changes in pain intensity according to the numerical rating scale (NRS) throughout the treatment as well as its duration, the number of administrations, and possible related adverse events. Patients were also interviewed to assess their quality of sleep and overall satisfaction with the SSTS device. RESULTS: The study included 308 patients. Compared to the first SSTS administration, pain intensity decreased from a median NRS of 6 to 0 at day 3, for an overall reduction of 79%. Results were already statistically significant at postoperative day 1 (p<0.01). Adverse reactions were observed in 62 patients, with nausea being the most frequent (12%), and in 93% of patients SSTS was discontinued because it was considered no longer necessary. Patient satisfaction was high, with 89% of them judging the device as "easy" or "very easy" to use. CONCLUSIONS: Although the retrospective and observational nature of the study as well as the absence of a comparative group limits the strength of evidence, our results consider SSTS an effective and safe tool for the management of postoperative pain after major abdominal and gynecological surgery within an ERAS protocol.