A High Respiratory Drive Is Associated with Weaning Failure in Patients with COVID-19-Associated Acute Respiratory Distress Syndrome: The Role of the Electrical Activity of the Diaphragm.

BACKGROUND: Mechanical ventilation is the main supportive treatment of severe cases of COVID-19-associated ARDS (C-ARDS). Weaning failure is common and associated with worse outcomes. We investigated the role of respiratory drive, assessed by monitoring the electrical activity of the diaphragm (EAdi), as a predictor of weaning failure. METHODS: Consecutive, mechanically ventilated patients admitted to the ICU for C-ARDS with difficult weaning were enrolled. Blood gas, ventilator, and respiratory mechanic parameters, as well as EAdi, were recorded at the time of placement of EAdi catheter, and then after 1, 2, 3, 7, and 10 days, and compared between patients with weaning success and weaning failure. RESULTS: Twenty patients were enrolled: age 66 (60-69); 85% males; PaO2/FiO2 at admission 148 (126-177) mmHg. Thirteen subjects (65%) were classified as having a successful weaning. A younger age (OR(95%CI): 0.02 (0.01-0.11) per year), a higher PaO2/FiO2 ratio (OR(95%CI): 1.10 (1.01-1.21) per mmHg), and a lower EAdi (OR(95%CI): 0.16 (0.08-0.34) per µV) were associated with weaning success. CONCLUSION: In critically ill patients with moderate-severe C-ARDS and difficult weaning from mechanical ventilation, a successful weaning was associated with a lower age, a higher oxygenation, and a lower respiratory drive, as assessed at the bedside via EAdi monitoring.

Respiratory Variations of Central Venous Pressure as Indices of Pleural Pressure Swings: A Narrative Review.

The measurement of pleural (or intrathoracic) pressure is a key element for a proper setting of mechanical ventilator assistance as both under- and over-assistance may cause detrimental effects on both the lungs and the diaphragm. Esophageal pressure (Pes) is the gold standard tool for such measurements; however, it is invasive and seldom used in daily practice, and easier, bedside-available tools that allow for rapid and continuous monitoring are greatly needed. The tidal swing of central venous pressure (CVP) has long been proposed as a surrogate for pleural pressure (Ppl); however, despite the wide availability of central venous catheters, this variable is very often overlooked in critically ill patients. In the present narrative review, the physiological basis for the use of CVP waveforms to estimate Ppl is presented; the findings of previous and recent papers that addressed this topic are systematically reviewed, and the studies are divided into those reporting positive findings (i.e., CVP was found to be a reliable estimate of Pes or Ppl) and those reporting negative findings. Both the strength and pitfalls of this approach are highlighted, and the current knowledge gaps and direction for future research are delineated.

Peripherally-active mu-opioid receptor antagonists for constipation in critically ill patients receiving opioids: A case-series and a systematic review and meta-analysis of the literature.

BACKGROUND: Constipation is frequent in critically ill patients, and potentially related to adverse outcomes. Peripherally-active mu-opioid receptor antagonists (PAMORAs) are approved for opioid-induced constipation, but information on their efficacy and safety in critically ill patients is limited. We present a single-center, retrospective, case-series of the use of naldemedine for opioid-associated constipation, and we systematically reviewed the use of PAMORAs in critically ill patients. METHODS: Case-series included consecutive mechanically-ventilated patients; constipation was defined as absence of bowel movements for >3 days. Naldemedine was administered after failure of the local laxation protocol. Systematic review: PubMed was searched for studies of PAMORAs to treat opioid-induced constipation in adult critically ill patients. PRIMARY OUTCOMES: time to laxation, and number of patients laxating at the shortest follow-up. SECONDARY OUTCOMES: gastric residual volumes and adverse events. KEY RESULTS: A total of 13 patients were included in the case-series; the most common diagnosis was COVID-19 ARDS. Patients had their first bowel movement 1 [0;2] day after naldemedine. Daily gastric residual volume was 725 [405;1805] before vs. 250 [45;1090] mL after naldemedine, p = 0.0078. Systematic review identified nine studies (two RCTs, one prospective case-series, three retrospective case-series and three case-reports). Outcomes were similar between groups, with a trend toward a lower gastric residual volume in PAMORAs group. CONCLUSIONS & INFERENCES: In a highly-selected case-series of patients with refractory, opioid-associated constipation, naldemedine was safe and associated to reduced gastric residuals and promoting laxation. In the systematic review and meta-analysis, the use of PAMORAs (mainly methylnaltrexone) was safe and associated with a reduced intolerance to enteral feeding but no difference in the time to laxation.

Neurally Adjusted Ventilatory Assist in Acute Respiratory Failure-A Narrative Review.

Maintaining spontaneous breathing has both potentially beneficial and deleterious consequences in patients with acute respiratory failure, depending on the balance that can be obtained between the protecting and damaging effects on the lungs and the diaphragm. Neurally adjusted ventilatory assist (NAVA) is an assist mode, which supplies the respiratory system with a pressure proportional to the integral of the electrical activity of the diaphragm. This proportional mode of ventilation has the theoretical potential to deliver lung- and respiratory-muscle-protective ventilation by preserving the physiologic defense mechanisms against both lung overdistention and ventilator overassistance, as well as reducing the incidence of diaphragm disuse atrophy while maintaining patient-ventilator synchrony. This narrative review presents an overview of NAVA technology, its basic principles, the different methods to set the assist level and the findings of experimental and clinical studies which focused on lung and diaphragm protection, machine-patient interaction and preservation of breathing pattern variability. A summary of the findings of the available clinical trials which investigate the use of NAVA in acute respiratory failure will also be presented and discussed.

Incidence, clinical characteristics and outcome of barotrauma in critically ill patients with COVID-19: a systematic review and meta-analysis.

INTRODUCTION: Barotrauma is rare in patients with acute respiratory distress syndrome undergoing mechanical ventilation. Its incidence seems increased among critically ill COVID-19 patients. We performed a systematic review and meta-analysis to investigate the incidence, risk factors and clinical outcomes of barotrauma among critically ill COVID-19 patients. EVIDENCE ACQUISITION: PubMed was searched from March 1st, 2020 to August 31st, 2021; case series and retrospective cohort studies concerning barotrauma in adult critically ill COVID-19 patients, either hospitalized in the Intensive Care Unit (ICU) or invasively ventilated were included. Primary outcome was the incidence of barotrauma in COVID-19 versus non-COVID-19 patients. Secondary outcomes were clinical characteristics, ventilator parameters, mortality and length of stay between patients with and without barotrauma. EVIDENCE SYNTHESIS: We identified 21 studies (six case series, 15 retrospective cohorts). The overall incidence of barotrauma was 11 [95% CI: 8-14]% in critically ill COVID-19 patients, vs. 2 [1-3]% in non-COVID-19, P<0.001; the incidence in mechanically ventilated patients was 14 [11-17]% vs. 4 [2-5]% non-COVID-19 patients, P<0.001. There were no differences in demographic, clinical, ventilatory parameters between patients who did and did not develop barotrauma, while, on average, protective ventilation criteria were always respected. Among COVID-19 patients, those with barotrauma had a higher mortality (60 [55-66] vs. 48 [42-54]%, P<0.001) and a longer ICU length of stay (20 [14-26] vs. 13 [10,5-16] days, P=0.03). CONCLUSIONS: Barotrauma is a frequent complication in critically ill COVID-19 patients and is associated with a poor prognosis. Since lung protective ventilation was delivered, the ventilatory management might not be the sole factor in the development of barotrauma.

Evidence of SARS-CoV-2 in nasal brushings and olfactory mucosa biopsies of COVID-19 patients.

The aim of the present study is to detect the presence of SARS-CoV-2 of patients affected by COVID-19 in olfactory mucosa (OM), sampled with nasal brushing (NB) and biopsy, and to assess whether a non-invasive procedure, such as NB, might be used as a large-scale procedure for demonstrating SARS-CoV-2 presence in olfactory neuroepithelium. Nasal brushings obtained from all the COVID-19 patients resulted positive to SARS-CoV-2 immunocytochemistry while controls were negative. Double immunofluorescence showed that SARS-CoV-2 positive cells included supporting cells as well as olfactory neurons and basal cells. OM biopsies showed an uneven distribution of SARS-CoV-2 positivity along the olfactory neuroepithelium, while OM from controls were negative. SARS-CoV-2 was distinctively found in sustentacular cells, olfactory neurons, and basal cells, supporting what was observed in NB. Ultrastructural analysis of OM biopsies showed SARS-CoV-2 viral particles in the cytoplasm of sustentacular cells. This study shows the presence of SARS-CoV-2 at the level of the olfactory neuroepithelium in patients affected by COVID-19. For the first time, we used NB as a rapid non-invasive tool for assessing a potential neuroinvasion by SARS-CoV-2 infection.

Association of COVID-19 Vaccinations With Intensive Care Unit Admissions and Outcome of Critically Ill Patients With COVID-19 Pneumonia in Lombardy, Italy.

Importance: Data on the association of COVID-19 vaccination with intensive care unit (ICU) admission and outcomes of patients with SARS-CoV-2-related pneumonia are scarce. Objective: To evaluate whether COVID-19 vaccination is associated with preventing ICU admission for COVID-19 pneumonia and to compare baseline characteristics and outcomes of vaccinated and unvaccinated patients admitted to an ICU. Design, Setting, and Participants: This retrospective cohort study on regional data sets reports: (1) daily number of administered vaccines and (2) data of all consecutive patients admitted to an ICU in Lombardy, Italy, from August 1 to December 15, 2021 (Delta variant predominant). Vaccinated patients received either mRNA vaccines (BNT162b2 or mRNA-1273) or adenoviral vector vaccines (ChAdOx1-S or Ad26.COV2). Incident rate ratios (IRRs) were computed from August 1, 2021, to January 31, 2022; ICU and baseline characteristics and outcomes of vaccinated and unvaccinated patients admitted to an ICU were analyzed from August 1 to December 15, 2021. Exposures: COVID-19 vaccination status (no vaccination, mRNA vaccine, adenoviral vector vaccine). Main Outcomes and Measures: The incidence IRR of ICU admission was evaluated, comparing vaccinated people with unvaccinated, adjusted for age and sex. The baseline characteristics at ICU admission of vaccinated and unvaccinated patients were investigated. The association between vaccination status at ICU admission and mortality at ICU and hospital discharge were also studied, adjusting for possible confounders. Results: Among the 10 107 674 inhabitants of Lombardy, Italy, at the time of this study, the median [IQR] age was 48 [28-64] years and 5 154 914 (51.0%) were female. Of the 7 863 417 individuals who were vaccinated (median [IQR] age: 53 [33-68] years; 4 010 343 [51.4%] female), 6 251 417 (79.5%) received an mRNA vaccine, 550 439 (7.0%) received an adenoviral vector vaccine, and 1 061 561 (13.5%) received a mix of vaccines and 4 497 875 (57.2%) were boosted. Compared with unvaccinated people, IRR of individuals who received an mRNA vaccine within 120 days from the last dose was 0.03 (95% CI, 0.03-0.04; P < .001), whereas IRR of individuals who received an adenoviral vector vaccine after 120 days was 0.21 (95% CI, 0.19-0.24; P < .001). There were 553 patients admitted to an ICU for COVID-19 pneumonia during the study period: 139 patients (25.1%) were vaccinated and 414 (74.9%) were unvaccinated. Compared with unvaccinated patients, vaccinated patients were older (median [IQR]: 72 [66-76] vs 60 [51-69] years; P < .001), primarily male individuals (110 patients [79.1%] vs 252 patients [60.9%]; P < .001), with more comorbidities (median [IQR]: 2 [1-3] vs 0 [0-1] comorbidities; P < .001) and had higher ratio of arterial partial pressure of oxygen (Pao2) and fraction of inspiratory oxygen (FiO2) at ICU admission (median [IQR]: 138 [100-180] vs 120 [90-158] mm Hg; P = .007). Factors associated with ICU and hospital mortality were higher age, premorbid heart disease, lower Pao2/FiO2 at ICU admission, and female sex (this factor only for ICU mortality). ICU and hospital mortality were similar between vaccinated and unvaccinated patients. Conclusions and Relevance: In this cohort study, mRNA and adenoviral vector vaccines were associated with significantly lower risk of ICU admission for COVID-19 pneumonia. ICU and hospital mortality were not associated with vaccinated status. These findings suggest a substantial reduction of the risk of developing COVID-19-related severe acute respiratory failure requiring ICU admission among vaccinated people.

Comparison between Nutric Score and modified nutric score to assess ICU mortality in critically ill patients with COVID-19.

BACKGROUND AND AIMS: NUTrition Risk in the Critically ill (NUTRIC score) and modified Nutric score (mNUTRIC score) have been validated as screening tool for quantifying risk of adverse outcome in patients admitted in intensive care department. They differ for the measurement of IL-6 levels. In patients with COVID-19 disease the inflammatory response plays a crucial role leading to cytochine storm responsible of multiple organ damage. In this population, levels of IL-6 have been measured as indicator of inflammatory status. Aim of the study is to compare prognostic performance of both scores in predicting ICU mortality between patients with COVID-19 disease. METHODS: A single centre, retrospective, cohort study on patients admitted in ICU with confirmed diagnosis of COVID-19 was performed. Prognostic performance of NUTRIC score and mNUTRIC score were assessed and compared for discriminative abilities for ICU-mortality. RESULTS: 43 patients were enrolled, age 64 (55; 70), BMI 28 ± 4. Mean NUTRIC score was 2.5 ± 1, mNUTRIC was 2.6 ± 1.1. Mortality was 39.5%, all patients had low nutritional risk according to both scores (≤5 and ≤ 4 for NUTRIC and mNUTRIC score respectively). The discriminative ability of Nutric Score for ICU mortality was 0.675 (95% CI: 0.524-0.825), while that of mNutric score was 0.655 (0.513-0.861), p = 0.667. CONCLUSIONS: Prognostic performance of Nutric score and mNutric score is comparable, but the discriminative ability is low even in patients with high inflammatory status as in COVID-19 affected population. These scores may not be appropriate in patients with COVID-19 for the determination of nutritional risk.

Effect of Different Corticosteroid Regimens on the Outcome of Severe COVID-19-Related Acute Respiratory Failure. A Retrospective Analysis.

BACKGROUND: Systemic corticosteroids are associated with reduced mortality in COVID-19-related acute respiratory failure; however, the type and dose has not yet been established. OBJECTIVES: To compare the outcomes of dexamethasone vs. methylprednisolone, along with the effects of rescue, short-term, high-dose boluses of corticosteroids. METHODS: Before/after and case/control retrospective analysis of consecutive critically ill COVID-19 subjects. Subjects were initially given dexamethasone; however, after review of the local protocol, methylprednisolone was suggested. A three-day course of 1000 mg/day of methylprednisolone was administered in the case of refractory hypoxemia within the first 10 days of treatment. Propensity score-adjusted comparisons were performed. RESULTS: A total of 81 consecutive subjects were included (85% males, 60 ± 10 years, SAPS II 27 ± 7, SOFA 4 [IQR 3, 6] points) and 51 of these subjects (62.9%) received dexamethasone and 29 (35.8%) had methylprednisolone. The groups were well matched for age, comorbidities, and severity at admission. No differences were found in the duration of ICU stay, hospital mortality, or infectious complications between the groups. A total of 22 subjects (27.2%) received a rescue bolus; these subjects had a significantly lower oxygenation, a higher driving pressure, and an increased ventilatory ratio during the first ten days. Short-term/high-dose boluses were associated with higher hospital mortality, longer mechanical ventilation and ICU and hospital stay, and more infectious complications. A subgroup of subjects who received the boluses had significantly improved oxygenation and lower hospital mortality. CONCLUSIONS: We were unable to find any difference between dexamethasone or methylprednisolone on the explored outcomes; high-dose boluses of corticosteroids were associated with a worse outcome. However, a subgroup of subjects was identified in whom the high-dose boluses seemed beneficial.

Successful treatment of acute spleno-porto-mesenteric vein thrombosis after ChAdOx1 nCoV-19 vaccine. A case report.

Several cases of deep venous thrombosis in people who had recently received Vaxzevria (previously known as COVID-19 Vaccine AstraZeneca) have recently been reported, mainly presenting as cerebral vein/cerebral venous sinus thrombosis. This syndrome has been termed "vaccine-induced immune thrombotic thrombocytopenia (VITT)". Acute spleno-porto-mesenteric vein thrombosis is an uncommon but serious condition with potential sequelae, such as small-bowel gangrene and end-stage liver failure. We describe a case of concomitant thrombosis of portal, superior mesenteric and splenic veins in a young female patient with no other risk factors who received Vaxzevria (previously ChAdOx1 nCoV-19 vaccine, AstraZeneca) 17 days before. The diagnostic workup and the successful endovascular treatment and systemic anticoagulation management is reported.

Qualitative and quantitative muscle ultrasound changes in patients with COVID-19-related ARDS.

OBJECTIVES: Severe forms of the novel coronavirus-19 (COVID-19) are associated with systemic inflammation and hypercatabolism. The aims of this study were to compare the time course of the size and quality of both rectus femoris and diaphragm muscles between critically ill, COVID-19 survivors and non-survivors and to explore the correlation between the change in muscles size and quality with the amount of nutritional support delivered and the cumulative fluid balance. METHODS: This was a prospective observational study in the general intensive care unit (ICU) of a tertiary care hospital for COVID-19. The right rectus femoris cross-sectional area and the right diaphragm thickness, as well as their echo densities were assessed within 24 h from ICU admission and on day 7. We recorded anthropometric and biochemical data, respiratory mechanics and gas exchange, daily fluid balance, and the number of calories and proteins administered. RESULTS: Twenty-eight patients were analyzed (65 ± 10 y of age; 80% men, body mass index 30 ± 7.8 kg/m2). Rectus femoris and diaphragm sizes were significantly reduced at day 7 (median = -26.1 [interquartile ratio [IQR], = -37.8 to -15.2] and -29.2% [-37.8% to -19.6%], respectively) and this reduction was significantly higher in non-survivors. Both rectus femoris and diaphragm echo density were significantly increased at day 7, with a significantly higher increase in non-survivors. The change in both rectus femoris and diaphragm size at day 7 was related to the cumulative protein deficit (R = 0.664, P < 0.001 and R = 0.640, P < 0.001, respectively), whereas the change in rectus femoris and diaphragm echo density was related to the cumulative fluid balance (R = 0.734, P < 0.001 and R = 0.646, P < 0.001, respectively). CONCLUSIONS: Early changes in muscle size and quality seem related to the outcome of critically ill COVID-19 patients, and to be influenced by nutritional and fluid management strategies.

Management of critically ill patients with COVID-19: suggestions and instructions from the coordination of intensive care units of Lombardy.

With 63,098 confirmed cases on 17 April 2020 and 11,384 deaths, Lombardy has been the most affected region in Italy by coronavirus disease 2019 (COVID-19). To cope with this emergency, the COVID-19 Lombardy intensive care units (ICU) network was created. The network identified the need of defining a list of clinical recommendations to standardize treatment of patients with COVID-19 admitted to Intensive Care Unit (ICU). Three core topics were identified: 1) rational use of intensive care resources; 2) ventilation strategies; 3) non-ventilatory interventions. Identification of patients who may benefit from ICU treatment is challenging. Clinicians should consider baseline performance and frailty status and they should adopt disease-specific staging tools. Continuous positive airway pressure, mainly delivered through a helmet as elective method, should be considered as initial treatment for all patients with respiratory failure associated with COVID-19. In case of persisting dyspnea and/or desaturation despite 4-6 hours of noninvasive ventilation, endotracheal intubation and invasive mechanical ventilation should be considered. In the early phase, muscle relaxant use and volume-controlled ventilation is recommended. Prone position should be performed in patients with PaO2/FiO2≤100 mmHg. For patients admitted to ICU with COVID-19 interstitial pneumonia, we do not recommend empiric antibiotic therapy for community-acquired pneumonia. Consultation of an infectious disease specialist is suggested before start of any antiviral therapy. In conclusion, the COVID-19 Lombardy ICU Network identified a list of best practice statements supported by the available evidence and clinical experience or identified as panel members expert opinions for the management of critically ill patients with COVID-19.

SARS-CoV-2 RNA detection in the air and on surfaces in the COVID-19 ward of a hospital in Milan, Italy.

The COVID-19 outbreak has rapidly progressed worldwide finding the health system, scientists and society unprepared to face a little-known, fast spreading, and extremely deadly virus. Italy is one of the countries hardest hit by the pandemic, resulting in healthcare facilities bearing heavy burdens and severe restrictive measures. Despite efforts to clarify the virus transmission, especially in indoor scenarios, several aspects of SARS-CoV-2 spread are still rudimentary. This study evaluated the contamination of the air and surfaces by SARS-CoV-2 RNA in the COVID-19 isolation ward of a hospital in Milan, Italy. A total of 42 air and surface samples were collected inside five different zones of the ward including contaminated (COVID-19 patients' area), semi-contaminated (undressing room), and clean areas. SARS-CoV-2 RNA detection was performed using real time reverse transcription polymerase chain reaction. Overall, 24.3% of swab samples were positive, but none of these were collected in the clean area. Thus, the positivity rate was higher in contaminated (35.0%) and semi-contaminated (50.0%) areas than in clean areas (0.0%; P<0.05). The most contaminated surfaces were hand sanitizer dispensers (100.0%), medical equipment (50.0%), medical equipment touch screens (50.0%), shelves for medical equipment (40.0%), bedrails (33.3%), and door handles (25.0%). All the air samples collected from the contaminated area, namely the intensive care unit and corridor, were positive while viral RNA was not detected in either semi-contaminated or clean areas. These results showed that environmental contamination did not involve clean areas, but the results also support the need for strict disinfection, hand hygiene and protective measures for healthcare workers as well as the need for airborne isolation precautions.

ABO blood types and major outcomes in patients with acute hypoxaemic respiratory failure: A multicenter retrospective cohort study.

INTRODUCTION: ABO blood type A was reported to correlate with an increased risk of acute respiratory distress syndrome (ARDS) in white patients with severe sepsis and major trauma compared with patients with other blood types. Information regarding ABO phenotypes and major outcomes in patients with ARDS is unavailable. The primary aim was to determine the relationship between ABO blood type A and intensive care unit (ICU) mortality in patients with acute hypoxemic respiratory failure (AHRF). The secondary aim was to describe the association between ABO blood type A and ICU length of stay (LOS) in this study population. METHODS: In a multicenter, retrospective cohort study, we collected the clinical records of patients admitted from January 2012 to December 2014 in five ICUs of Northern Italy. We included adult white patients admitted to the ICU who were diagnosed with AHRF requiring mechanical ventilation. RESULTS: The electronic records of 1732 patients with AHRF were reviewed. The proportion of patients with ABO blood type A versus other blood types was 39.9% versus 60.1%. ICU mortality (25%) and ICU LOS (median [interquartile range], 5 [2-12] days) were not different when stratified by ABO blood type (ICU mortality, overall p value = 0.905; ICU LOS, overall p value = 0.609). SAPSII was a positive predictor of ICU mortality (odds ration [OR], 32.80; 95% confidence interval [CI], 18.80-57.24; p < 0.001) and ICU LOS (ß coefficient, 0.55; 95% CI, 0.35-0.75; p < 0.001) at multivariate analyses, whereas ABO blood type did not predict ICU outcome when forced into the model. CONCLUSION: ABO blood type did not correlate with ICU mortality and ICU LOS in adult patients with AHRF who were mechanically ventilated.

Relation between peak and integral of the diaphragm electromyographic activity at different levels of support during weaning from mechanical ventilation: a physiologic study.

PURPOSE: To investigate the relationship between peak (EAdipeak) and area under the curve (EAdiAUC) of diaphragm electrical activity, and to evaluate the validity of their ratio (P/I index) as a measure of the imbalance between drive and sustainability of effort demand at different support levels. MATERIALS: Prospective physiological study on 18 ready-to-wean patients ventilated with neurally adjusted ventilatory assist (NAVA) undergoing 2 levels of NAVA (NAVA100% and NAVA50%) followed by a weaning trial with continuous positive airway pressure, according to which patients were classified as success or failure. Tidal volume (VT), respiratory rate, EAdipeak, EAdiAUC, rapid shallow breathing index (respiratory rate/VT), neuroventilatory index (VT/EAdipeak), and P/I index were obtained at the end of each step. RESULTS: The slopes of regression line between EAdipeak and EAdiAUC (a mathematical equivalent of P/I index) and P/I index were significantly higher in failures. At variance with other variables, P/I index did not vary with level of support. P/I index was inversely correlated with inspiratory time at all support levels. CONCLUSIONS: The relationship between EAdipeak and EAdiAUC and the P/I index may give important information on the balance between respiratory drive and inspiratory demand sustainability.