Pursuing the real midazolam clearance during continuous renal replacement therapy in ICU patients with COVID-19: are midazolam and metabolites dialyzable?

Introduction: Midazolam based continuous iv sedation became again prominent during the COVID-19 pandemic. However, this sedation therapy is associated with a high incidence of benzodiazepine-related delirium and an increased number of days spent in coma. Given the high midazolam dose requirements in some patients and due to the renal clearance (CL) of the active metabolite 1-OH-midazolam-glucuronide (OHmidazolamGluc), ICU patients with COVID-19 and continuous renal replacement therapy (CRRT) may are at risk of prolonged sedation. Therefore, the aim of the study was to investigate the CL of midazolam and metabolites in 5 critically ill COVID-19 patients with CRRT. Method(s): Pre-filter blood samples and ultrafiltrate samples were collected simultaneously. Midazolam, 1-OH-midazolam (OHmidazolam) and OHmidazolamGluc plasma samples were analysed by an UPLCMS/ MS method. CL of midazolam and metabolites were calculated by the delivered renal dose and sieving (SC) coefficient. Subsequently, the CL and delivered renal dose were corrected for downtime therapy and filter integrity by a filter urea ratio. Result(s): We included 4 cases of CVVHD and 2 cases of CVVHDF. Midazolam, OHmidazolam and OHmidazolamGluc concentrations in mug/l ranged from 0 to 6070, 0 to 295 and 1727 to 39,000, respectively. SCs ranged from 0.02 to 0.03 for midazolam, 0.05 to 0.06 for OHmidazolam and 0.23-0.43 for OHmidazolamGluc. The CL in ml/min by the delivered renal dose was 0.82-1.67 for midazolam, 2.20-3.46 for OHmidazolam and 4.0-27.65 for OHmidazolamGluc. The CL in ml/min by the corrected renal dose was 0.68-1.50, 1.83-2.33 and 3.40-25.4, respectively. The urea ratios were 0.53 to 1.0. Conclusion(s): Midazolam and OHmidazolam are not removed efficiently by CRRT and OHmidazolamGluc approximately up to 43%. Type of CRRT, filter integrity and downtime of CRRT affect the CL of midazolam and metabolites. Our results have implications for more personalized titration of midazolam in COVID-19 patients with CRRT, mainly to avoid oversedation.

Dynamic prediction of mortality in COVID-19 patients in the intensive care unit: A retrospective multi-center cohort study.

Background: The COVID-19 pandemic continues to overwhelm intensive care units (ICUs) worldwide, and improved prediction of mortality among COVID-19 patients could assist decision making in the ICU setting. In this work, we report on the development and validation of a dynamic mortality model specifically for critically ill COVID-19 patients and discuss its potential utility in the ICU. Methods: We collected electronic medical record (EMR) data from 3222 ICU admissions with a COVID-19 infection from 25 different ICUs in the Netherlands. We extracted daily observations of each patient and fitted both a linear (logistic regression) and non-linear (random forest) model to predict mortality within 24 h from the moment of prediction. Isotonic regression was used to re-calibrate the predictions of the fitted models. We evaluated the models in a leave-one-ICU-out (LOIO) cross-validation procedure. Results: The logistic regression and random forest model yielded an area under the receiver operating characteristic curve of 0.87 [0.85; 0.88] and 0.86 [0.84; 0.88], respectively. The recalibrated model predictions showed a calibration intercept of -0.04 [-0.12; 0.04] and slope of 0.90 [0.85; 0.95] for logistic regression model and a calibration intercept of -0.19 [-0.27; -0.10] and slope of 0.89 [0.84; 0.94] for the random forest model. Discussion: We presented a model for dynamic mortality prediction, specifically for critically ill COVID-19 patients, which predicts near-term mortality rather than in-ICU mortality. The potential clinical utility of dynamic mortality models such as benchmarking, improving resource allocation and informing family members, as well as the development of models with more causal structure, should be topics for future research.

Incidence of thrombotic complications and overall survival in hospitalized patients with COVID-19 in the second and first wave.

INTRODUCTION: In the first wave, thrombotic complications were common in COVID-19 patients. It is unknown whether state-of-the-art treatment has resulted in less thrombotic complications in the second wave. METHODS: We assessed the incidence of thrombotic complications and overall mortality in COVID-19 patients admitted to eight Dutch hospitals between September 1st and November 30th 2020. Follow-up ended at discharge, transfer to another hospital, when they died, or on November 30th 2020, whichever came first. Cumulative incidences were estimated, adjusted for competing risk of death. These were compared to those observed in 579 patients admitted in the first wave, between February 24th and April 26th 2020, by means of Cox regression techniques adjusted for age, sex and weight. RESULTS: In total 947 patients with COVID-19 were included in this analysis, of whom 358 patients were admitted to the ICU; 144 patients died (15%). The adjusted cumulative incidence of all thrombotic complications after 10, 20 and 30 days was 12% (95% confidence interval (CI) 9.8-15%), 16% (13-19%) and 21% (17-25%), respectively. Patient characteristics between the first and second wave were comparable. The adjusted hazard ratio (HR) for overall mortality in the second wave versus the first wave was 0.53 (95%CI 0.41-0.70). The adjusted HR for any thrombotic complication in the second versus the first wave was 0.89 (95%CI 0.65-1.2). CONCLUSIONS: Mortality was reduced by 47% in the second wave, but the thrombotic complication rate remained high, and comparable to the first wave. Careful attention to provision of adequate thromboprophylaxis is invariably warranted.

Feeding practises and REE in critically ill COVID-19 patients

Rationale: The optimal feeding strategy in critically ill COVID-19 patients is challenging. They seem particularly difficult to feed enterally, presenting with high gastric residual volumes (GRV) and diarrhoea. Our aim was to describe feeding practises and measured resting energy expenditure (mREE) during the acute and late phases of critical illness. Methods: Observational study including critically ill mechanically ventilated adult COVID-19 patients. Indirect calorimetry (IC;Q-NRG+) was used to determine mREE during the acute (day 1-7) and late phase (> day 7) of critical illness. Data on enteral nutrition (EN) and parenteral nutrition (PN) were collected on the same day. Comparison of mREE and predicted REE (pREE) (mREE/pREE *100%) was performed to explore hypometabolism (<90%) and hypermetabolism (>110%). In both phases parameters for intolerance to EN were collected on consequent days such as GRV (mL/d), vomiting, abdominal distention and diarrhoea. Results: We enrolled 35 patients in whom 42 IC measurements were performed (20 acute phase;22 late phase). Median age 63 year [IQR 47-69], 80% male. BMI upon admission was 27.8 kg/m2 [IQR 24.2-34.0], 43% obese (BMI>30 kg/m2). During the acute phase mREE was 1956 kcal [IQR 1846-2441] and respiratory quotient (RQ) 0,72 [IQR 0,67-0,81];10% was hypometabolic, 60% hypermetabolic. The median delivery of energy was 64% of mREE. All patients received EN;70% via nasogastric tube (NGT) and 30% via nasoduodenal tube (NDT). Median GRV was 195 mL/d [IQR 41-450], 5% vomited, 5% abdominal distention and 20% diarrhoea. In the late phase mREE was 2374 kcal [IQR 1828-2711] and RQ 0,81 [IQR 0,74-0,86];9% was hypometabolic and 68% hypermetabolic. The median delivery of energy was 92% of mREE. All patients except one received EN;50% NGT and 50% NDT, with a median GRV of 48 mL/d [IQR 15-180]. A total of 5% vomited, 9% abdominal distention and 15% diarrhoea. Conclusion: In both the acute and late phase the majority of the patients were hypermetabolic. Almost all patients were fed enterally, with a slightly higher presence of EN intolerance parameters during the acute phase. In the acute phase patients were fed hypocaloric whereas in the late phase this was almost normocaloric (64% vs 92% of mREE) conform our ESPEN based nutrition protocol. Elaborate data analysis are planned and will be presented at the conference. Disclosure of Interest: None declared

Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis.

INTRODUCTION: We recently reported a high cumulative incidence of thrombotic complications in critically ill patients with COVID-19 admitted to the intensive care units (ICUs) of three Dutch hospitals. In answering questions raised regarding our study, we updated our database and repeated all analyses. METHODS: We re-evaluated the incidence of the composite outcome of symptomatic acute pulmonary embolism (PE), deep-vein thrombosis, ischemic stroke, myocardial infarction and/or systemic arterial embolism in all COVID-19 patients admitted to the ICUs of 2 Dutch university hospitals and 1 Dutch teaching hospital from ICU admission to death, ICU discharge or April 22nd 2020, whichever came first. RESULTS: We studied the same 184 ICU patients as reported on previously, of whom a total of 41 died (22%) and 78 were discharged alive (43%). The median follow-up duration increased from 7 to 14 days. All patients received pharmacological thromboprophylaxis. The cumulative incidence of the composite outcome, adjusted for competing risk of death, was 49% (95% confidence interval [CI] 41-57%). The majority of thrombotic events were PE (65/75; 87%). In the competing risk model, chronic anticoagulation therapy at admission was associated with a lower risk of the composite outcome (Hazard Ratio [HR] 0.29, 95%CI 0.091-0.92). Patients diagnosed with thrombotic complications were at higher risk of all-cause death (HR 5.4; 95%CI 2.4-12). Use of therapeutic anticoagulation was not associated with all-cause death (HR 0.79, 95%CI 0.35-1.8). CONCLUSION: In this updated analysis, we confirm the very high cumulative incidence of thrombotic complications in critically ill patients with COVID-19 pneumonia.

Incidence of thrombotic complications in critically ill ICU patients with COVID-19.

INTRODUCTION: COVID-19 may predispose to both venous and arterial thromboembolism due to excessive inflammation, hypoxia, immobilisation and diffuse intravascular coagulation. Reports on the incidence of thrombotic complications are however not available. METHODS: We evaluated the incidence of the composite outcome of symptomatic acute pulmonary embolism (PE), deep-vein thrombosis, ischemic stroke, myocardial infarction or systemic arterial embolism in all COVID-19 patients admitted to the ICU of 2 Dutch university hospitals and 1 Dutch teaching hospital. RESULTS: We studied 184 ICU patients with proven COVID-19 pneumonia of whom 23 died (13%), 22 were discharged alive (12%) and 139 (76%) were still on the ICU on April 5th 2020. All patients received at least standard doses thromboprophylaxis. The cumulative incidence of the composite outcome was 31% (95%CI 20-41), of which CTPA and/or ultrasonography confirmed VTE in 27% (95%CI 17-37%) and arterial thrombotic events in 3.7% (95%CI 0-8.2%). PE was the most frequent thrombotic complication (n = 25, 81%). Age (adjusted hazard ratio (aHR) 1.05/per year, 95%CI 1.004-1.01) and coagulopathy, defined as spontaneous prolongation of the prothrombin time > 3 s or activated partial thromboplastin time > 5 s (aHR 4.1, 95%CI 1.9-9.1), were independent predictors of thrombotic complications. CONCLUSION: The 31% incidence of thrombotic complications in ICU patients with COVID-19 infections is remarkably high. Our findings reinforce the recommendation to strictly apply pharmacological thrombosis prophylaxis in all COVID-19 patients admitted to the ICU, and are strongly suggestive of increasing the prophylaxis towards high-prophylactic doses, even in the absence of randomized evidence.