Biomarkers of Cholestasis and Liver Injury in the Early Phase of Acute Respiratory Distress Syndrome and Their Pathophysiological Value

Background: Impaired liver function and cholestasis are frequent findings in critically ill patients and are associated with poor outcomes. We tested the hypothesis that hypoxic liver injury and hypoxic cholangiocyte injury are detectable very early in patients with ARDS, may depend on the severity of hypoxemia, and may be aggravated by the use of rescue therapies (high PEEP level and prone positioning) but could be attenuated by extracorporeal membrane oxygenation (ECMO). Methods: In 70 patients with ARDS, aspartate-aminotransferase (AST), alanin-aminotransferase (ALT) and gamma glutamyltransferase (GGT) were measured on the day of the diagnosis of ARDS and three more consecutive days (day 3, day 5, day 10), total bile acids were measured on day 0, 3, and 5. Results: AST levels increased on day 0 and remained constant until day 5, then dropped to normal on day 10 (day 0: 66.5 U/l; day 3: 60.5 U/l; day 5: 63.5 U/l, day 10: 32.1 U/l), ALT levels showed the exact opposite kinetic. GGT was already elevated on day 0 (91.5 U/l) and increased further throughout (day 3: 163.5 U/l, day 5: 213 U/l, day 10: 307 U/l), total bile acids levels increased significantly from day 0 to day 3 (p = 0.019) and day 0 to day 5 (p < 0.001), but not between day 3 and day 5 (p = 0.217). Total bile acids levels were significantly correlated to GGT on day 0 (p < 0.001), day 3 (p = 0.02), and in a trend on day 5 (p = 0.055). PEEP levels were significantly correlated with plasma levels of AST (day 3), ALT (day 5) and GGT (day 10). Biomarker levels were not associated with the use of ECMO, prone position, the cause of ARDS, and paO2. Conclusions: We found no evidence of hypoxic liver injury or hypoxic damage to cholangiocytes being caused by the severity of hypoxemia in ARDS patients during the very early phase of the disease. Additionally, mean PEEP level, prone positioning, and ECMO treatment did not have an impact in this regard. Nevertheless, GGT levels were elevated from day zero and rising, this increase was not related to paO2, prone position, ECMO treatment, or mean PEEP, but correlated to total bile acid levels.

Air leak syndromes (Pneumomediastinum, pneumothorax, and subcutaneous emphysema) in Critically ill COVID – 19 patients – Prevalence, risk factors, and outcome.

BACKGROUND: A high incidence of air leak syndromes (ALS) has been reported in critically ill COVID-19 patients. This not only prolongs the hospital stay of patients but also affects the disease outcome.OBJECTIVE: Our objective is to evaluate the incidence, clinical outcome, and risk factors associated with ALS in critically ill COVID-19 patients receiving invasive or non-invasive positive pressure ventilationRESULT: Out of 79 patients, 16(20.2%) patients had ALS. The mean age of the ALS group was 48.6±13.1 years as compared to 52.8±13.1 (p = 0.260) years in the non-ALS group. The ALS group had a lower median BMI (25.9 kg/m2 vs 27.6 kg/m2 , p = 0.096), a higher D-dimer value at presentation (1179.5 vs 762.0, p = 0.024) , lower saturation (74% vs 88%, p = 0.006) and lower PF (134 vs 189, p = 0.028) ratio at presentation as compared to the ALS group. Patients who developed ALS were found to have received a higher median PEEP (10 cm vs 8 cm of water, p = 0.005). Pressure support, highest driving pressure, and peak airway pressure were not significantly different in the two groups. ALS group was seen to have a significantly longer duration of hospital stay (17.5 days vs 9 days, p = 0.003). Multiple Logistic Regressions analysis indicated patients who received Inj. Dexamethasone was less likely to develop ALS (OR: 12.6 (95% CI 1.6-95.4), p=0.015). CONCLUSION: A high incidence of ALS is present in critically ill COVID 19 patients. High inflammatory parameters, severe hypoxia at presentation, and use of high PEEP are significant risk factors associated with the development of ALS. The risk of developing ALS was observed to be lower in patients who received Inj. Dexamethasone. ALS is associated with a longer duration of hospital stay.

Outcomes in Ventilated Burn Patients With Acute Respiratory Distress Syndrome: An Evaluation of Early High-PEEP Strategy Using Berlin Criteria

Acute respiratory distress syndrome (ARDS) remains a formidable sequela, complication, and mortality risk in patients with large burns with or without inhalation injury. Alveolar recruitment using higher Positive end expiratory pressures (PEEP) after the onset of ARDS has been tried with varying success. Studies have identified benefits for several rescue maneuvers in ARDS patients with refractory hypoxemia. A prophylactic strategy utilizing an early recruitment maneuver, however, has not, to our knowledge, been explored in ventilated burn patients. This study was designed to evaluate the natural progression and clinical outcomes of ARDS severity (mild, moderate, and severe) using Berlin criteria in ventilated burn patients treated with an early high-PEEP ventilator strategy. A single-center retrospective review of burn patients who were mechanically ventilated for greater than 48 hours utilizing an early high-PEEP &gt;10 mmHg (10.36) ventilator strategy was performed at the Level 1 trauma and regional burn center in Wright State University. ARDS severity was defined according to the Berlin criteria and then compared to published results of ARDS severity, clinical outcomes, and mortality. Demographic data, as well as respiratory and clinical outcomes, were evaluated. Eighty-three patients met inclusion criteria and were evaluated. Utilizing the Berlin definition as a benchmark, 42.1% of patients met ARDS criteria on admission, and most patients (85.5%) developed ARDS within the first seven days: 28 (34%) mild, 32 (38.6%) moderate, and 11 (13.3%) severe ARDS. The mean percent total body surface area was 24.6 + 22.1, with 68.7% of patients diagnosed with inhalation injury. The highest incidence of ARDS was 57.8% on day 2 of admission. Most cases remained in the mild to moderate ARDS category with severe ARDS (2.4%) being less common by hospital day 7. Overall, 30-day in-hospital and inhalation injury mortality rates were 9.6% and 15.8%, respectively. No correlation was observed between plateau pressures (22.8), mean arterial pressures (84.4), or vasopressor requirements; and oxygen requirements down trended quickly over the first 24 to 48 hours. In our study, implementing prophylactic, immediate high-PEEP in mechanically ventilated burn patients was associated with trends toward decreased severity and rapid resolution of ARDS in the first week following burn injury. This correlated with low 30-day in-hospital mortality in this population. This short and less severe course suggests that early high-PEEP support may be a viable protective strategy in the treatment of ventilated burn patients with ARDS.

Transoesophageal Ultrasound Assessment of Lung Aeration in Patients With Acute Respiratory Distress Syndrome

Introduction: The effect of positive end-expiratory pressure (PEEP) depends closely on the potential for lung recruitment. Bedside assessment of lung recruitability is crucial for personalized lung-protective mechanical ventilation in acute respiratory distress syndrome (ARDS) patients.Methods: We developed a transoesophageal lung ultrasound (TE-LUS) method in which a quantitative (computer-assisted) grayscale determination served as a guide to PEEP-induced lung recruitment. The method is based on the following hypothesis: when the PEEP increases, inflation of the recruited alveoli leads to significant changes in the air/water ratio. Normally ventilated areas are hypoechoic because the ultrasound waves are weakly reflected while poorly aerated areas or non-aerated areas are hyperechoic. We calculated the TE-LUS re-aeration score (RAS) as the ratio of the mean gray scale level at low PEEP to that value at high PEEP for the lower and upper lobes. A RAS &gt; 1 indicated an increase in ventilated area. We used this new method to detect changes in ventilation in patients with a low (&lt;0.5) vs. high (≥0.5) recruitment-to-inflation (R/I) ratio (i.e., the ratio between the recruited lung compliance and the respiratory system compliance at low PEEP).Results: We included 30 patients with moderate-to-severe ARDS. In patients with a high R/I ratio, the TE-LUS RAS was significantly higher in the lower lobes than in the upper lobes (1.20 [1.12–1.63] vs. 1.05 [0.89–1.38]; p = 0.05). Likewise, the TE-LUS RAS in the lower lobes was significantly higher in the high R/I group than in the low R/I group (1.20 [1.12–1.63] vs. 1.07 [1.00–1.20]; p = 0.04).Conclusion: The increase in PEEP induces a substantial gain in the ventilation detected by TE-LUS of poorly or non-aerated lower lobes (dependent lung regions), especially in patients with a high R/I ratio.

Identification of distinct clinical phenotypes of acute respiratory distress syndrome with differential responses to treatment

Background Acute respiratory distress syndrome (ARDS) is a heterogeneous syndrome, and the identification of homogeneous subgroups and phenotypes is the first step toward precision critical care. We aimed to explore whether ARDS phenotypes can be identified using clinical data, are reproducible and are associated with clinical outcomes and treatment response. Methods This study is based on a retrospective analysis of data from the telehealth intensive care unit (eICU) collaborative research database and three ARDS randomized controlled trials (RCTs) (ALVEOLI, FACTT and SAILS trials). We derived phenotypes in the eICU by cluster analysis based on clinical data and compared the clinical characteristics and outcomes of each phenotype. The reproducibility of the derived phenotypes was tested using the data from three RCTs, and treatment effects were evaluated. Results Three clinical phenotypes were identified in the training cohort of 3875 ARDS patients. Of the three phenotypes identified, phenotype I (n = 1565; 40%) was associated with fewer laboratory abnormalities, less organ dysfunction and the lowest in-hospital mortality rate (8%). Phenotype II (n = 1232; 32%) was correlated with more inflammation and shock and had a higher mortality rate (18%). Phenotype III (n = 1078; 28%) was strongly correlated with renal dysfunction and acidosis and had the highest mortality rate (22%). These results were validated using the data from the validation cohort (n = 3670) and three RCTs (n = 2289) and had reproducibility. Patients with these ARDS phenotypes had different treatment responses to randomized interventions. Specifically, in the ALVEOLI cohort, the effects of ventilation strategy (high PEEP vs low PEEP) on ventilator-free days differed by phenotype (p = 0.001); in the FACTT cohort, there was a significant interaction between phenotype and fluid-management strategy for 60-day mortality (p = 0.01). The fluid-conservative strategy was associated with improved mortality in phenotype II but had the opposite effect in phenotype III. Conclusion Three clinical phenotypes of ARDS were identified and had different clinical characteristics and outcomes. The analysis shows evidence of a phenotype-specific treatment benefit in the ALVEOLI and FACTT trials. These findings may improve the identification of distinct subsets of ARDS patients for exploration in future RCTs.

A Nationwide Cross-Sectional Online Survey on the Treatment of COVID-19-ARDS: High Variance in Standard of Care in German ICUs

Introduction: Coronavirus disease (COVID-19) has recently dominated scientific literature. Incomplete understanding and a lack of data concerning the pathophysiology, epidemiology, and optimal treatment of the disease has resulted in conflicting recommendations. Adherence to existing guidelines and actual treatment strategies have thus far not been studied systematically. We hypothesized that capturing the variance in care would lead to the discovery of aspects that need further research and—in case of proven benefits of interventions not being performed—better communication to care providers. Methods: This article is based on a quantitative and qualitative cross-sectional mixed-methods online survey among intensive-care physicians in Germany during the COVID-19 pandemic by the CEOsys (COVID-19 Evidence Ecosystem) network, endorsed by the German Interdisciplinary Association for Intensive Care and Emergency Medicine (DIVI) conducted from December 3 to 31 December 2020. Results: We identified several areas of care with an especially high variance in treatment among hospitals in Germany. Crucially, 51.5% of the participating ICUs (n = 205) reported using intubation as a last resort for respiratory failure in COVID-19 patients, while 21.8% used intubation early after admission. Furthermore, 11.5% considered extracorporeal membrane oxygenation (ECMO) in awake patients. Finally, 72.3% of respondents used the ARDS-network-table to titrate positive end-expiratory-pressure (PEEP) levels, with 36.9% choosing the low-PEEP table and 41.8% the high-PEEP table. Conclusions: We found that significant differences exist between reported treatment strategies and that adherence to published guidelines is variable. We describe necessary steps for future research based on our results highlighting significant clinical variability in care.

Effects of individualized high positive end-expiratory pressure and crystalloid administration on postoperative pulmonary function in patients undergoing robotic-assisted radical prostatectomy: a prospective randomized single-blinded pilot study

Background Robotic-assisted laparoscopic prostatectomy (RALP) using a combination of capnoperitoneum and steep Trendelenburg positioning (STP) results in important pathophysiological pulmonary changes. The aim of the study was to evaluate if restrictive crystalloid administration and individual management of positive end-expiratory pressure (PEEP) improve peri- and postoperative pulmonary function in patients undergoing RALP in permanent 45 degree STP.Methods 98 patients undergoing RALP under standardized anesthesia were either allocated to a standard PEEP (5 mmHg) group or an individualized high PEEP group. Furthermore, each group was divided into a liberal vs restrictive crystalloid group (30 ml vs 15 ml per kg predicted body weight). Individualized PEEP levels were determined by means of preoperative PEEP titration in STP. In each of the four study groups following intraoperative parameters were analyzed: ventilation setting (PIP, driving pressure [Pdriv], lung compliance [LC], mechanical power [MP]), and postoperative pulmonary function (bed-side spirometry). The following spirometric parameters were measured pre- and postoperatively: the Tiffeneau index (FEV1/FVC ratio) and mean forced expiratory flow (FEF25 − 75). Data are shown as mean ± standard deviation (SD), and groups were compared with ANOVA. A P-value of < 0.05 was considered significant.Results The two individualized high PEEP groups (mean PEEP 15.5 [± 1.71 cmH2O]) showed significantly higher PIP and MP levels but significantly decreased Pdriv and increased LC. On the first and second postoperative day, patients with individualized higher PEEP levels had a significantly higher mean Tiffeneau index (day 1: 77.6% (± 6.6) vs 73.6% (± 8.8), P = 0.014; day 2: 76.5% (± 6.1) vs 72.7% (± 9.3), P = 0.021) and FEF25 − 75 (day 1: 2.41 liter/sec (± 0.9) vs 1.95 liter/sec (± 0.8), P = 0.009; day 2: 2.45 liter/sec (± 0.9) vs 2.07 liter/sec (± 0.8), P = 0.033). Perioperative oxygenation and postoperative spirometric parameters were not influenced by restrictive or liberal crystalloid infusion in either of the two PEEP groups.Conclusions Higher individualized PEEP levels during RALP improved blood oxygenation, lung-protective ventilation, and postoperative pulmonary function up to 48 hours after surgery. Restrictive crystalloid infusion during RALP seemed to have no effect on peri- and postoperative oxygenation and pulmonary function.

Acute kidney injury (AKI) in patients with Covid-19 infection is associated with ventilatory management with elevated positive end-expiratory pressure (PEEP)

Background Acute kidney injury (AKI) in Covid-19 patients admitted to the intensive care unit (ICU) is common, and its severity may be associated with unfavorable outcomes. Severe Covid-19 fulfills the diagnostic criteria for acute respiratory distress syndrome (ARDS); however, it is unclear whether there is any relationship between ventilatory management and AKI development in Covid-19 ICU patients. Purpose To describe the clinical course and outcomes of Covid-19 ICU patients, focusing on ventilatory management and factors associated with AKI development. Methods Single-center, retrospective observational study, which assessed AKI incidence in Covid-19 ICU patients divided by positive end expiratory pressure (PEEP) tertiles, with median levels of 9.6 (low), 12.0 (medium), and 14.7 cmH2O (high-PEEP). Results Overall mortality was 51.5%. AKI (KDIGO stage 2 or 3) occurred in 38% of 101 patients. Among the AKI patients, 19 (53%) required continuous renal replacement therapy (CRRT). In AKI patients, mortality was significantly higher versus non-AKI (81% vs. 33%, p < 0.0001). The incidence of AKI in low-, medium-, or high-PEEP patients were 16%, 38%, and 59%, respectively (p = 0.002). In a multivariate analysis, high-PEEP patients showed a higher risk of developing AKI than low-PEEP patients (OR = 4.96 [1.1–21.9] 95% CI p < 0.05). ICU mortality rate was higher in high-PEEP patients, compared to medium-PEEP or low-PEEP patients (69% vs. 44% and 42%, respectively; p = 0.057). Conclusion The use of high PEEP in Covid-19 ICU patients is associated with a fivefold higher risk of AKI, leading to higher mortality. The cause and effect relationship needs further analysis. Graphic abstract

Mechanical Ventilation. Total Eclipse of the Heart (Editorial)

Results from recent large randomized trials investigating the use of high PEEP in patients without ARDS all evidence that high levels may increase mortality due to hypotension and bradycardia. A careful assessment of cardiac function – with particular focus on the right ventricle – should be performed before planning our ventilation strategy in any setting, including COVID-19 and ARDS in general. Mechanical ventilation should be respectful in regards of heart function, and tolerant with moderate hypoxia and hypercapnia, noninvasive (as soon as possible) and synchronized.

Extubation Failure in Critically Ill COVID-19 Patients: Risk Factors and Impact on In-Hospital Mortality

Purpose: We sought to identify clinical factors that predict extubation failure (reintubation) and its prognostic implications in critically ill COVID-19 patients. Materials and Methods: Retrospective, multi-center cohort study of hospitalized COVID-19 patients. Multivariate competing risk models were employed to explore the rate of reintubation and its determining factors. Results: Two hundred eighty-one extubated patients were included (mean age, 61.0 years [±13.9]; 54.8% male). Reintubation occurred in 93 (33.1%). In multivariate analysis accounting for death, reintubation risk increased with age (hazard ratio [HR] 1.04 per 1-year increase, 95% confidence interval [CI] 1.02 -1.06), vasopressors (HR 1.84, 95% CI 1.04-3.60), renal replacement (HR 2.01, 95% CI 1.22-3.29), maximum PEEP (HR 1.07 per 1-unit increase, 95% CI 1.02 -1.12), paralytics (HR 1.48, 95% CI 1.08-2.25) and requiring more than nasal cannula immediately post-extubation (HR 2.19, 95% CI 1.37-3.50). Reintubation was associated with higher mortality (36.6% vs 2.1%; P < 0.0001) and risk of inpatient death after adjusting for multiple factors (HR 23.2, 95% CI 6.45-83.33). Prone ventilation, corticosteroids, anticoagulation, remdesivir and tocilizumab did not impact the risk of reintubation or death. Conclusions: Up to 1 in 3 critically ill COVID-19 patients required reintubation. Older age, paralytics, high PEEP, need for greater respiratory support following extubation and non-pulmonary organ failure predicted reintubation. Extubation failure strongly predicted adverse outcomes.