Gastrointestinal ultrasound in the critically ill: A narrative review and a proposal for a protocol.

Critically ill patients are at risk of presenting with gastrointestinal dysfunction at intensive care unit admission or during their stay. However, identifying gastrointestinal dysfunction is difficult because clinical evaluation is frequently nonspecific and validated biomarkers are lacking. In this context, ultrasound of the digestive tract may help to identify gastrointestinal dysfunction. In this narrative review, we summarize available evidence and propose a protocol for assessment of the gastrointestinal tract with ultrasound. First, we report available evidence from use of four available protocols: the gastrointestinal and urinary tract sonography protocol, the acute gastrointestinal injury ultrasound score, the transabdominal gastrointestinal ultrasound protocol, and the Lai protocol, each addressing somewhat different aspects. Outputs from these protocols have been associated with clinical scores of gastrointestinal failure, feeding intolerance, and 28-day mortality. Second, we describe the potential pitfalls of using ultrasound in the critically ill, such as obesity, abdominal dressings, or the presence of intraluminal gas. Third, we suggest perspectives of ultrasound in monitoring the response to enteral nutrition and for early identification of nonocclusive mesenteric ischemia. Fourth, we propose a structured protocol for gastrointestinal ultrasound describing all the different structures that should be evaluated and provide detailed guidance for a clockwise abdominal examination. In conclusion, the use of a specific and structured protocol might help to identify patients presenting with gastrointestinal dysfunction, guide nutrition, and allow the proposal of pathophysiological hypotheses (complications of enteral nutrition, intra-abdominal infection, bowel ischemia, etc.). The benefit of using a structured protocol requires further investigation.

CT evaluation of bowel wall enhancement in pneumatosis intestinalis: preventing non-therapeutic laparotomies.

PURPOSE: To evaluate the diagnostic performance of bowel wall enhancement for diagnosing concomitant bowel ischemia in patients with parietal pneumatosis (PI) diagnosed at abdominal CT. MATERIALS AND METHODS: From January 1, 2012 to December 31, 2021, 226 consecutive patients who presented with PI on abdominal CT from any bowel segment were included. Variables at the time of the CT were retrospectively extracted from medical charts. CT examinations were blindly analyzed by two independent radiologists. The third reader classified all disagreement of bowel enhancement in three categories: (1) normal bowel enhancement; (2) doubtful bowel wall enhancement; (3) absent bowel wall enhancement. Multivariable logistic regression analysis was performed. Concomitant bowel ischemia was defined as requirement of bowel resection specifically due to ischemic lesion in operated patients and death from bowel ischemia in non-operated patients. RESULTS: Overall, 78/226 (35%) patients had PI associated with concomitant bowel ischemia. At multivariate analysis, Only absence or doubtful bowel wall enhancement was associated with concomitant bowel ischemia (OR = 167.73 95%CI [23.39-4349.81], P < 0,001) and acute mesenteric ischemia associated with PP (OR = 67.94; 95%CI [5.18-3262.36], P < 0.009). Among the 82 patients who underwent a laparotomy for suspected bowel ischemia, rate of non-therapeutic laparotomy increased from 15/59 (25%), 2/6 (50%) and 16/17 (94%) when bowel wall enhancement was absent, doubtful and normal respectively. CONCLUSION: Absence of enhancement of the bowel wall is the primary feature associated with concomitant bowel ischemia. It should be carefully assessed when PI is detected to avoid non-therapeutic laparotomy.

Resilience after severe critical illness: a prospective, multicentre, observational study (RESIREA).

BACKGROUND: Critical-illness survivors may experience post-traumatic stress disorder (PTSD) and quality-of-life impairments. Resilience may protect against psychological trauma but has not been adequately studied after critical illness. We assessed resilience and its associations with PTSD and quality of life, and also identified factors associated with greater resilience. METHODS: This prospective, multicentre, study in patients recruited at 41 French ICUs was done in parallel with the NUTRIREA-3 trial in patients given mechanical ventilation and vasoactive amines for shock. Three months to one year after intensive-care-unit admission, survivors completed the Connor-Davidson Resilience Scale (CD-RISC-25), Impact of Event-Revised scale for PTSD symptoms (IES-R), SF-36 quality-of-life scale, Multidimensional Scale of Perceived Social Support (MSPSS), and Brief Illness Perception Questionnaire (B-IPQ). RESULTS: Of the 382 included patients, 203 (53.1%) had normal or high resilience (CD-RISC-25 ≥ 68). Of these resilient patients, 26 (12.8%) had moderate to severe PTSD symptoms (IES-R ≥ 24) vs. 45 (25.4%) patients with low resilience (p = 0.002). Resilient patients had higher SF-36 scores. Factors independently associated with higher CD-RISC-25 scores were higher MSPSS score indicating stronger social support (OR, 1.027; 95%CI 1.008-1.047; p = 0.005) and lower B-IPQ scores indicating a more threatening perception of the illness (OR, 0.973; 95%CI 0.950-0.996; p = 0.02). CONCLUSIONS: Resilient patients had a lower prevalence of PTSD symptoms and higher quality of life scores, compared to patients with low resilience. Higher scores for social support and illness perception were independently associated with greater resilience. Thus, our findings suggest that interventions to strengthen social support and improve illness perception may help to improve resilience. Such interventions should be evaluated in trials with PTSD mitigation and quality-of-life improvement as the target outcomes.

Should we perform decompressive laparotomy during severe acute pancreatitis with intra-abdominal hypertension below 25 mmHg: Only the gut knows.

We suggest that during severe acute pancreatitis (SAP) with intra-abdominal hypertension, practitioners should consider decompressive laparotomy, even with intra-abdominal pressure (IAP) below 25 mmHg. Indeed, in this setting, non-occlusive mesenteric ischemia (NOMI) may occur even with IAP below this cutoff and lead to transmural necrosis if abdominal perfusion pressure is not promptly restored. We report our experience of 18 critically ill patients with SAP having undergone decompressive laparotomy of which one third had NOMI while IAP was mostly below 25 mmHg.

Oxygenation management during veno-arterial ECMO support for cardiogenic shock: a multicentric retrospective cohort study.

BACKGOUND: Hyperoxemia is common and associated with poor outcome during veno-arterial extracorporeal membrane oxygenation (VA ECMO) support for cardiogenic shock. However, little is known about practical daily management of oxygenation. Then, we aim to describe sweep gas oxygen fraction (FSO2), postoxygenator oxygen partial pressure (PPOSTO2), inspired oxygen fraction (FIO2), and right radial arterial oxygen partial pressure (PaO2) between day 1 and day 7 of peripheral VA ECMO support. We also aim to evaluate the association between oxygenation parameters and outcome. In this retrospective multicentric study, each participating center had to report data on the last 10 eligible patients for whom the ICU stay was terminated. Patients with extracorporeal cardiopulmonary resuscitation were excluded. Primary endpoint was individual mean FSO2 during the seven first days of ECMO support (FSO2 mean (day 1-7)). RESULTS: Between August 2019 and March 2022, 139 patients were enrolled in 14 ECMO centers in France, and one in Switzerland. Among them, the median value for FSO2 mean (day 1-7) was 70 [57; 79] % but varied according to center case volume. Compared to high volume centers, centers with less than 30 VA-ECMO runs per year were more likely to maintain FSO2 ≥ 70% (OR 5.04, CI 95% [1.39; 20.4], p = 0.017). Median value for right radial PaO2 mean (day 1-7) was 114 [92; 145] mmHg, and decreased from 125 [86; 207] mmHg at day 1, to 97 [81; 133] mmHg at day 3 (p < 0.01). Severe hyperoxemia (i.e. right radial PaO2 ≥ 300 mmHg) occurred in 16 patients (12%). PPOSTO2, a surrogate of the lower body oxygenation, was measured in only 39 patients (28%) among four centers. The median value of PPOSTO2 mean (day 1-7) value was 198 [169; 231] mmHg. By multivariate analysis, age (OR 1.07, CI95% [1.03-1.11], p < 0.001), FSO2 mean (day 1-3)(OR 1.03 [1.00-1.06], p = 0.039), and right radial PaO2 mean (day 1-3) (OR 1.03, CI95% [1.00-1.02], p = 0.023) were associated with in-ICU mortality. CONCLUSION: In a multicentric cohort of cardiogenic shock supported by VA ECMO, the median value for FSO2 mean (day 1-7) was 70 [57; 79] %. PPOSTO2 monitoring was infrequent and revealed significant hyperoxemia. Higher FSO2 mean (day 1-3) and right radial PaO2 mean (day 1-3) were independently associated with in-ICU mortality.

Prediction of esophagogastroduodenoscopy therapeutic usefulness for in-ICU suspected upper gastrointestinal bleeding: the SUGIBI score study.

BACKGROUND: Suspected upper gastrointestinal bleeding (SUGIB) is a common issue during ICU stay. In the absence of specific guidelines on the indication and timing of esophagogastroduodenoscopy (EGD), there is substantial variability in EGD indication depending on accessibility and clinical presentation. This study aimed to investigate factors associated with the need for per-EGD hemostatic therapy and to create a score predicting therapeutic benefit of emergency bedside EGD in ICU patients with SUGIB. METHODS: We conducted a retrospective study in our ICU to identify factors associated with the need for hemostatic procedure during EGD performed for SUGIB. From this observational cohort, we derived a score predicting the need for hemostasis during EGD, the SUGIBI score. This score was subsequently validated in a retrospective multicenter cohort. RESULTS: Two hundred fifty-five patients not primarily admitted for GI bleeding who underwent a bedside EGD for SUGIB during their ICU stay were analyzed. The preeminent EGD indication were anemia (79%), melena (19%), shock (14%), and hematemesis (13%). EGD was normal in 24.7% of cases, while primary lesions reported were ulcers (23.1%), esophagitis (18.8%), and gastritis (12.5%). Only 12.9% of patients underwent hemostatic endotherapy during EGD. A SUGIBI score < 4 had a negative predictive value of 95% (91-99) for hemostatic endotherapy [AUC of 0.81; 0.75-0.91 (p < 0.0001)]. The SUGIBI score for predicting the need for an EGD-guided hemostatic procedure was next validated in a multicenter cohort with an AUC of 0.75 (0.66-0.85) (p < 0.0001), a score < 4 having a negative predictive value of 95% (92-97). CONCLUSIONS: Our study shows that the therapeutic usefulness of bedside emergency EGD for SUGIB in critically ill patients is limited to a minority of patients. The SUGIBI score should help clinicians stratify the probability of a therapeutic EGD.

Plasma citrulline concentration and plasma LPS detection among critically ill patients a prospective observational study.

PURPOSE: Gut can be a source of sepsis but sepsis itself can induce gut dysfunction. We aimed to study whether plasma citrulline, a marker of enterocyte mass, was correlated with plasma lipopolysaccharide, a potential marker of bacterial translocation among critically ill patients. MATERIALS AND METHODS: Critically ill patients admitted to the ICU. Plasma citrulline and plasma LPS concentration and activity were measured at ICU admission. Patients were compared according to the presence of sepsis at ICU admission. RESULTS: 109 critically ill patients, with SOFA score 8 [6-12], were prospectively included. Sixty six patients (61%) had sepsis at ICU admission. There was no correlation between plasma citrulline concentration and plasma LPS concentration or activity. However, sepsis at ICU admission was associated with a lower plasma citrulline concentration (13.4 µmol.L-1 vs 21.3 µmol.L-1, p = 0.02). Plasma LPS activity was significantly higher among patients with abdominal sepsis compared to patients with extra-abdominal sepsis (1.04 EU/mL vs 0.63, p = 0.01). CONCLUSIONS: Plasma citrulline is not associated with the level of plasma LPS but is strongly decreased among septic patients. Detection of LPS is ubiquitous among critically ill patients but abdominal sepsis is associated with increased plasma LPS activity compared to extra-abdominal sepsis.

Quantifying iodine concentration in the normal bowel wall using dual-energy CT: influence of patient and contrast characteristics.

This study aimed to establish quantitative references of the normal bowel wall iodine concentration (BWIC) using dual energy CT (DECT). This single-center retrospective study included 248 patients with no history of gastrointestinal disease who underwent abdominal contrast-enhanced DECT between January and April 2022. The BWIC was normalized by the iodine concentration of upper abdominal organs (BWICorgan,) and the iodine concentration (IC) of the aorta (BWICaorta). BWIC decreased from the stomach to the rectum (mean 2.16 ± 0.63 vs. 2.19 ± 0.63 vs. 2.1 ± 0.58 vs. 1.67 ± 0.47 vs. 1.31 ± 0.4 vs. 1.18 ± 0.34 vs. 0.94 ± 0.26 mgI/mL for the stomach, duodenum, jejunum, ileum, right colon, left colon and rectum, respectively; P < 0.001). By multivariate analysis, BWIC was associated with a higher BMI (OR:1.01, 95% CI 1.00-1.02, P < 0.001) and with a higher injected contrast dose (OR: 1.51; 95% CI 1.36-1.66, P < 0.001 and 2.06; 95% CI 1.88-2.26, P < 0.001 for 500 mgI/kg and 600 mgI/kg doses taking 400 mgI/kg dose as reference). The BWICorgan was shown independent from patients and contrast-related variables while the BWICaorta was not. BWIC varies according to bowel segments and is dependent on the total iodine dose injected. It shall be normalized with the IC of the upper abdominal organs.

Short-term mortality prediction using a combination of clinical and CT features: Refining the prognosis of critically ill patients in shock.

PURPOSE: To assess the predictive value of combining CT and clinical findings for predicting 10-day mortality in critically ill patients in shock. MATERIALS AND METHODS: From January 1, 2018, to December 31, 2021, 289 consecutives critically ill patients in shock who underwent a contrast enhanced CT were included. Variables at the time of the CT were retrospectively extracted from medical charts. CT examinations were blindly analyzed by two independent radiologists. Multivariable analysis was performed, combining clinical and CT features. A simple survival score for 10-day mortality prediction was built and validated in a further independent external cohort of 70 patients. RESULTS: 10-day mortality rate was 135/289 (47%) in the study sample. At multivariate analysis, catecholamine infusion (OR = 2.11; 95%CI [1.21-4.18], P = 0.011), lactates level > 5 mmol/l (OR = 3.54; 95%CI [1.94-6.54], P < 0.001); total bilirubin > 50 mg/l (OR = 1.79 CI 95% [1.03-3.13], P = 0.039); small bowel dilation (OR = 1.82; 95%CI [1.01-3.32], P = 0.047); diffuse kidney infarction (OR = 2.76; 95%CI [1.26-6.37], P = 0.013) and superior mesentery artery < 5 mm (OR = 1.96; 95%CI [1.10-3.49], P = 0.021) were associated with 10-days mortality. The AUC of the combined model was 0.79; 95%CI [0.74-0.85] in the study sample and 0.87; 95%CI [0.71-0.91] in the validation cohort. CONCLUSION: The combination of CT imaging features and clinical data should emerge as a novel approach to predict short-term mortality in critically ill patients in shock.

Coma With Hyperammonemia in a Patient With Kwashiorkor.

We describe a case of coma-related hyperammonemia in a woman presenting with severe edematous malnutrition (Kwashiorkor-like), without underlying hepatic disease. Our main hypothesis is that the patient developed a functional urea cycle disorder, due to the inability to synthesize N-acetylglutamate which is the activator of the first enzymes (carbamoyl phosphate synthetase) of urea cycle, in a context of severe deficiency of essential amino acids and of acetyl-CoA. Severe hyperammonemia is a medical emergency exposing to the risk of cerebral edema. Urgent treatment should interrupt protein intake, stimulate protein anabolism, and remove ammonia from the blood using renal replacement therapy and ammonia scavengers. Hyperammonemia should be searched in case of unexplained coma, even among patients without hepatic disorder, in particular among young patients. Hyperammonemia should also be searched among patients with severe protein-calorie malnutrition.

Low versus standard calorie and protein feeding in ventilated adults with shock: a randomised, controlled, multicentre, open-label, parallel-group trial (NUTRIREA-3).

BACKGROUND: The optimal calorie and protein intakes at the acute phase of severe critical illness remain unknown. We hypothesised that early calorie and protein restriction improved outcomes in these patients, compared with standard calorie and protein targets. METHODS: The pragmatic, randomised, controlled, multicentre, open-label, parallel-group NUTRIREA-3 trial was performed in 61 French intensive care units (ICUs). Adults (≥18 years) receiving invasive mechanical ventilation and vasopressor support for shock were randomly assigned to early nutrition (started within 24 h after intubation) with either low or standard calorie and protein targets (6 kcal/kg per day and 0·2-0·4 g/kg per day protein vs 25 kcal/kg per day and 1·0-1·3 g/kg per day protein) during the first 7 ICU days. The two primary endpoints were time to readiness for ICU discharge and day 90 all-cause mortality. Key secondary outcomes included secondary infections, gastrointestinal events, and liver dysfunction. The trial is registered on ClinicalTrials.gov, NCT03573739, and is completed. FINDINGS: Of 3044 patients randomly assigned between July 5, 2018, and 8 Dec 8, 2020, eight withdrew consent to participation. By day 90, 628 (41·3%) of 1521 patients in the low group and 648 (42·8%) of 1515 patients in the standard group had died (absolute difference -1·5%, 95% CI -5·0 to 2·0; p=0·41). Median time to readiness for ICU discharge was 8·0 days (IQR 5·0-14·0) in the low group and 9·0 days (5·0-17·0) in the standard group (hazard ratio [HR] 1·12, 95% CI 1·02 to 1·22; p=0·015). Proportions of patients with secondary infections did not differ between the groups (HR 0·85, 0·71 to 1·01; p=0·06). The low group had lower proportions of patients with vomiting (HR 0·77, 0·67 to 0·89; p<0·001), diarrhoea (0·83, 0·73 to 0·94; p=0·004), bowel ischaemia (0·50, 0·26 to 0·95; p=0·030), and liver dysfunction (0·92, 0·86-0·99; p=0·032). INTERPRETATION: Compared with standard calorie and protein targets, early calorie and protein restriction did not decrease mortality but was associated with faster recovery and fewer complications. FUNDING: French Ministry of Health.

Increased blood lactate during enteral nutrition in the critically ill: associations and treatment options.

PURPOSE OF REVIEW: To evaluate the significance of blood lactate increase during enteral nutrition in the critically ill, and to propose diagnostic and therapeutic strategies. RECENT FINDINGS: Acute mesenteric ischemia occurs in approximately 1% of critically ill patients treated with catecholamine. Recent literature suggests that enteral nutrition is a risk factor of acute mesenteric ischemia, in particular in case of low cardiac output, by a mechanism of nonocclusive mesenteric ischemia. The association of clinical, biological, and computed tomography imaging might help to evaluate the reversibility of acute mesenteric ischemia. SUMMARY: As enteral nutrition induces an increased metabolic work of the gut, the inadequation between oxygen delivery and demand exposes the gut to a phenomenon of nonocclusive mesenteric ischemia. Before initiation of enteral nutrition,, and before each increase of the enteral nutrition dose, the risk factors of nonocclusive mesenteric ischemia should be searched in order to prevent it. While under enteral nutrition, increased lactate concentration while receiving enteral nutrition requires the urgent search for nonocclusive mesenteric ischemia, and the adaptation of enteral nutrition (reduction, stop, and/or switch to parenteral nutrition or tolerate early nutrient restriction). Early signs of nonocclusive mesenteric ischemia should be searched in order to allow for a rapid diagnosis, before development of irreversible transmural necrosis. After the diagnosis of acute mesenteric ischemia, improving the balance between oxygen demand and delivery to the gut, evaluating the reversibility of the gut ischemia, and performing urgent resection in case of irreversible transmural necrosis should be the main objectives. After the resolution of acute mesenteric ischemia, the benefit risk analysis of enteral nutrition reintroduction should be evaluated.

Outcomes and predictors of delayed endoscopic biliary drainage for severe acute cholangitis due to choledocholithiasis in an intensive care unit.

BACKGROUND: Acute cholangitis (AC) is an infection of the biliary tract secondary to biliary obstruction requiring biliary drainage through endoscopic retrograde cholangiopancreatography. This study aims to compare the outcome between the early and delayed ERCP in patients with severe AC. METHODS: Patient with severe AC due to choledocholithiasis admitted to intensive care unit were included. Early ERCP was defined was as ERCP performed within 24 h following hospital admission. Propensity-score matching was used to reduce the imbalance between groups. The primary outcome was 30-day mortality. Secondary outcomes included length of hospital and ICU stay, onset or persistent organ failure. RESULTS: The delayed ERCP group had a higher mortality rate at 30 days (45,5 versus 13%, <0.001) and at 1 year (59,7% versus 15,6%, p <0.001). Delayed ERCP had also a higher rate of respiratory adverse events (54,5 versus 27,8%, p = 0,002), longer ICU (7.41 versus 4.61, p = 0,004) and hospital (11,88 versus 9,22, p = 0,042) length of stay. Predictors of delayed ERCP were cardiac arrythmias, liver disease, creatinine value and white blood cell count at baseline. CONCLUSIONS: Delays in ERCP for patients with severe AC appear to be associated with higher mortality rate and prolonged ICU and hospital stays.

Abdominal atherosclerosis is not a risk factor of nonocclusive mesenteric ischemia among critically ill patients: a propensity matching study.

BACKGROUND: Although risk factors of occlusive acute mesenteric ischemia are well known, triggering factors of nonocclusive mesenteric ischemia (NOMI) remain unclear. Alongside to the known risk factors for NOMI, the role of atherosclerosis is not fully elucidated. The purpose of our study was to evaluate whether abdominal atherosclerosis is a risk factor for NOMI. METHODS: From January 2018 to December 2021, all consecutive patients admitted to the intensive care unit who underwent contrast-enhanced CT for suspicion of NOMI were evaluated for inclusion. Clinical and biological data at the time of the CT scan were retrospectively extracted from medical charts and reviewed by a single radiologist. The cohorts were matched by a 1:1 propensity score based on the patient clinical, biological data, and abdominal CT features associated with NOMI. Noncontrast CT acquisitions were used to calculate calcium scores of the abdominal aorta, celiac trunk, superior mesenteric artery (SMA), and common iliac artery according to the Agatston method. Analyses were performed before and after propensity score matching. RESULTS: Among the 165 critically ill patients included, 59 (36%) had NOMI. Before matching analysis, the SMA and total abdominal Agatston calcium scores were not different between patients without and with NOMI (52.00 [IQR = 0, 473] vs. 137.00 [IQR = 0, 259], P = 0.857, respectively, and 7253 [IQR = 1220, 21738] versus 5802 [IQR = 2075, 15,084]; P = 0.723). The results were similar after matching 38 patients with NOMI and 38 without: 153 [IQR = 0, 665] versus 85 [IQR = 0, 240] (P = 0.312) for the SMA calcium score, and 7915 [IQR = 1812, 21561] versus 4139 [IQR = 1440, 9858] (P = 0.170) for the total abdominal Agatston calcium score. CONCLUSION: Our results suggest that atherosclerosis is not a risk factor for NOMI in critically ill patients.

Optimizing PO2 during peripheral veno-arterial ECMO: a narrative review.

During refractory cardiogenic shock and cardiac arrest, veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is used to restore a circulatory output. However, it also impacts significantly arterial oxygenation. Recent guidelines of the Extracorporeal Life Support Organization (ELSO) recommend targeting postoxygenator partial pressure of oxygen (PPOSTO2) around 150 mmHg. In this narrative review, we intend to summarize the rationale and evidence for this PPOSTO2 target recommendation. Because this is the most used configuration, we focus on peripheral VA-ECMO. To date, clinicians do not know how to set the sweep gas oxygen fraction (FSO2). Because of the oxygenator's performance, arterial hyperoxemia is common during VA-ECMO support. Interpretation of oxygenation is complex in this setting because of the dual circulation phenomenon, depending on both the native cardiac output and the VA-ECMO blood flow. Such dual circulation results in dual oxygenation, with heterogeneous oxygen partial pressure (PO2) along the aorta, and heterogeneous oxygenation between organs, depending on the mixing zone location. Data regarding oxygenation during VA-ECMO are scarce, but several observational studies have reported an association between hyperoxemia and mortality, especially after refractory cardiac arrest. While hyperoxemia should be avoided, there are also more and more studies in non-ECMO patients suggesting the harm of a too restrictive oxygenation strategy. Finally, setting FSO2 to target strict normoxemia is challenging because continuous monitoring of postoxygenator oxygen saturation is not widely available. The threshold of PPOSTO2 around 150 mmHg is supported by limited evidence but aims at respecting a safe margin, avoiding both hypoxemia and severe hyperoxemia.

Nicotine patches in patients on mechanical ventilation for severe COVID-19: a randomized, double-blind, placebo-controlled, multicentre trial.

PURPOSE: Epidemiologic studies have documented lower rates of active smokers compared to former or non-smokers in symptomatic patients affected by coronavirus disease 2019 (COVID-19). We assessed the efficacy and safety of nicotine administered by a transdermal patch in critically ill patients with COVID-19 pneumonia. METHODS: In this multicentre, double-blind, placebo-controlled trial conducted in 18 intensive care units in France, we randomly assigned adult patients (non-smokers, non-vapers or who had quit smoking/vaping for at least 12 months) with proven COVID-19 pneumonia receiving invasive mechanical ventilation for up to 72 h to receive transdermal patches containing either nicotine at a daily dose of 14 mg or placebo until 48 h following successful weaning from mechanical ventilation or for a maximum of 30 days, followed by 3-week dose tapering by 3.5 mg per week. Randomization was stratified by centre, non- or former smoker status and Sequential Organ Function Assessment score (< or ≥ 7). The primary outcome was day-28 mortality. Main prespecified secondary outcomes included 60-day mortality, time to successful extubation, days alive and free from mechanical ventilation, renal replacement therapy, vasopressor support or organ failure at day 28. RESULTS: Between November 6th 2020, and April 2nd 2021, 220 patients were randomized from 18 active recruiting centers. After excluding 2 patients who withdrew consent, 218 patients (152 [70%] men) were included in the analysis: 106 patients to the nicotine group and 112 to the placebo group. Day-28 mortality did not differ between the two groups (30 [28%] of 106 patients in the nicotine group vs 31 [28%] of 112 patients in the placebo group; odds ratio 1.03 [95% confidence interval, CI 0.57-1.87]; p = 0.46). The median number of day-28 ventilator-free days was 0 (IQR 0-14) in the nicotine group and 0 (0-13) in the placebo group (with a difference estimate between the medians of 0 [95% CI -3-7]). Adverse events likely related to nicotine were rare (3%) and similar between the two groups. CONCLUSION: In patients having developed severe COVID-19 pneumonia requiring invasive mechanical ventilation, transdermal nicotine did not significantly reduce day-28 mortality. There is no indication to use nicotine in this situation.