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.

Quality of oncological resection criteria in minimally invasive esophagectomy.

BACKGROUND: Even though minimally invasive esophageal surgery (MIE) is spreading, questions remain regarding its oncological outcomes. The aim of this study was to assess the quality of oncological resection criteria in MIE. METHODS: All patients undergoing a two-way Ivor Lewis esophagectomy for esophageal or junctional cancer between 2010 and 2020 in a single tertiary upper gastrointestinal surgery ward were analyzed retrospectively. The following oncological criteria were analyzed: lymph node (LN) harvest and location, positive lymph node rate, margins, and R0 rates. They were compared between the MIE group (thoracoscopy + laparoscopy) and the hybrid group (H/O, thoracotomy + laparoscopy). RESULTS: Among the 240 patients included, 34 (14%) had MIE and 206 a hybrid esophagectomy. Main surgical indication was lower thoracic adenocarcinoma and the rate of neoadjuvant treatments administered (chemotherapy or chemoradiotherapy) was comparable between both groups (p = 1.0). LN harvest was significantly higher in the MIE group (31 ± 9 vs. 28 ± 9, p = 0.04) as well as thoracic LN harvest (14 ± 7 vs. 11 ± 5, p = 0.002). When analyzing patients according to T stage and response to neoadjuvant treatments, patients with T1 and T2 tumors and patients with a poor pathological response (TRG3, 4, 5) had a significantly higher LN harvest when undergoing a minimally invasive approach (p = 0.021 and p = 0.01, respectively). Positive LN rates (1.26 ± 3.63 in the MIE group vs. 1.60 ± 2.84 in the H/O group, p = 0.061), R0 rates (97% vs. 98.5%, p = 0.46) as well as proximal (p = 0.083), distal (p = 0.063), and lateral (p = 0.15) margins were comparable between both approaches. CONCLUSION: MIE seems oncologically safe and may even be better than the open approach in terms of LN harvest especially in patients with T1 and T2 tumors and in poor responders.

Intravenous immunoglobulins in patients with COVID-19-associated moderate-to-severe acute respiratory distress syndrome (ICAR): multicentre, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a major complication of COVID-19 and is associated with high mortality and morbidity. We aimed to assess whether intravenous immunoglobulins (IVIG) could improve outcomes by reducing inflammation-mediated lung injury. METHODS: In this multicentre, double-blind, placebo-controlled trial, done at 43 centres in France, we randomly assigned patients (1:1) receiving invasive mechanical ventilation for up to 72 h with PCR confirmed COVID-19 and associated moderate-to-severe ARDS to receive either IVIG (2 g/kg over 4 days) or placebo. Random assignment was done with a web-based system and was stratified according to the participating centre and the duration of invasive mechanical ventilation before inclusion in the trial (<12 h, 12-24 h, and >24-72 h), and treatment was administered within the first 96 h of invasive mechanical ventilation. To minimise the risk of adverse events, the IVIG administration was divided into four perfusions of 0·5 g/kg each administered over at least 8 hours. Patients in the placebo group received an equivalent volume of sodium chloride 0·9% (10 mL/kg) over the same period. The primary outcome was the number of ventilation-free days by day 28, assessed according to the intention-to-treat principle. This trial was registered on ClinicalTrials.gov, NCT04350580. FINDINGS: Between April 3, and October 20, 2020, 146 patients (43 [29%] women) were eligible for inclusion and randomly assigned: 69 (47%) patients to the IVIG group and 77 (53%) to the placebo group. The intention-to-treat analysis showed no statistical difference in the median number of ventilation-free days at day 28 between the IVIG group (0·0 [IQR 0·0-8·0]) and the placebo group (0·0 [0·0-6·0]; difference estimate 0·0 [0·0-0·0]; p=0·21). Serious adverse events were more frequent in the IVIG group (78 events in 22 [32%] patients) than in the placebo group (47 events in 15 [20%] patients; p=0·089). INTERPRETATION: In patients with COVID-19 who received invasive mechanical ventilation for moderate-to-severe ARDS, IVIG did not improve clinical outcomes at day 28 and tended to be associated with an increased frequency of serious adverse events, although not significant. The effect of IVIGs on earlier disease stages of COVID-19 should be assessed in future trials. FUNDING: Programme Hospitalier de Recherche Clinique.

Relevance of blood loss as key indicator of the quality of surgical care in laparoscopic liver resection for colorectal liver metastases.

BACKGROUND: The development of laparoscopic liver resection has led to the hypothesis that intraoperative blood loss may be a key indicator of surgical care quality. This study assessed short- and long-term results of patients according to three levels of intraoperative blood loss during laparoscopic liver resection for colorectal liver metastasis. METHODS: All patients who underwent laparoscopic liver resection for colorectal liver metastasis between 2000 and 2018 were included. Difficulty of laparoscopic liver resection was defined according to the Institut Mutualiste Montsouris classification. Three levels of the extent of intraoperative blood loss were defined: massive (≥1,000 mL), substantial (≥75th percentile of intraoperative blood loss within each grade of difficulty), and normal intraoperative blood loss. RESULTS: During study period, 317 patients underwent laparoscopic liver resection for colorectal liver metastasis. Among them, 213 (67.2%), 80 (25.2%), and 24 (7.6%) patients had normal, substantial, and massive intraoperative blood loss, respectively. Twenty-six patients (8.2%) required transfusion. Massive intraoperative blood loss came from a major hepatic vein in 54% of cases and were managed by laparoscopy in 83% of the cases. Laparoscopic liver resection difficulty grade (odds ratio = 3.15; P = .053) and number of colorectal liver metastasis (odds ratio = 1.24; P = .020) were independently associated with massive intraoperative blood loss. Risks factors for substantial intraoperative blood loss were bi-lobar colorectal liver metastasis (odds ratio = 3.12; P = .033) and sinusoidal obstruction syndrome (odds ratio = 3.27; P = .004). The level of intraoperative blood loss was not associated with severe complications nor overall and disease-free survival. Requirement of transfusion was associated with severe complications (odds ratio = 7.27; P = .002) and decreased 1-, 3-, and 5-year overall survival (87%, 68%, and 61% vs 95%, 88%, and 79%; P = .042). CONCLUSION: The extent of intraoperative blood loss did not affect short- and long-term results of laparoscopic liver resection for colorectal liver metastasis. Massive intraoperative blood loss was often incidental and, 83% of the time, manageable by laparoscopy. Rather than intraoperative blood loss, transfusion is a better relevant indicator of laparoscopic liver resection surgical quality.

Liver resection for extra-pancreatic biliary cancer: what is the role of laparoscopic approach?

BACKGROUND: Laparoscopic liver resection (LLR) has evolved over time, yet its role in extra-pancreatic biliary cancer has been limited due to several factors. We aimed to evaluate the short-term outcome of LLR in extra-pancreatic biliary tract cancer. METHODS: From January 2002 to 2016, all patients who underwent LLR for extra-pancreatic biliary tract cancer including gallbladder cancer (GBC), intra-hepatic cholangiocarcinoma (ICC), and peri-hilar cholangiocarcinoma (PHC) with curative intent (R0 or R1) at Institute Mutualiste Montsouris were identified from prospectively collected databases. Patient characteristics, and perioperative outcomes, were analyzed in all three groups. RESULTS: A total of 35 patients were included: 10 with GBC, 14 with ICC, and 11 with PHC. There were 19 (54%) women and median age was 71 years. Median operative time was 240 min, and estimated blood loss was 200 ml. Conversion to an open procedure was more common in patients with PHC (45% vs. 7% for ICC and 0% for GBC, p = 0.010). R0 resection was achieved in 10 (100%), 12 (86%), and 8 (73%) patients in GBC, ICC, and PHC groups, respectively (p = 0.204). Postoperative morbidity was reported in 19 (54%) patients of whom 12 (34%) had minor complications. Postoperative mortality was reported in 4 (11%) patients; one (7%) in GBC group, one (7%) in ICC group, and two (18%) in PHC, p = 0.681. Median hospital stay was 11 days. CONCLUSIONS: The present series suggests that LLR is feasible in GBC, challenging but achievable in ICC but unsuitable for the moment in PHC.

Laparoscopic extended liver resection: are postoperative outcomes different?

BACKGROUND: Although laparoscopic major hepatectomy (LMH) is becoming increasingly common in specialized centers, data regarding laparoscopic extended major hepatectomies (LEMH) and their outcomes are limited. The aim of this study was to compare the perioperative characteristics and postoperative outcomes of LEMH to standard LMH. METHODS: All patients who underwent purely laparoscopic anatomical right or left hepatectomy and right or left trisectionectomy between February 1998 and January 2016 are enrolled. Demographic, clinicopathological, and perioperative factors were collected prospectively and analyzed retrospectively. Perioperative characteristics and postoperative outcomes in LEMH were compared to those of standard LMH. RESULTS: Among 195 patients with LMH, 47 (24.1%) underwent LEMH, colorectal liver metastases representing 66.7% of all indications. Preoperative portal vein embolization was undertaken in 31 (15.9%) patients. Despite more frequent vascular clamping, blood loss was higher in LEMH group (400 vs. 214 ml; p = 0.006). However, there was no difference in intraoperative transfusion requirements. Thirty-one patients experienced liver failure with no differences between LMH and LEMH groups. Postoperative mortality was comparable in the two groups [3 (2.5%) LMH patients vs. 2 (5%) LEMH patients (p = 0.388)]. Overall morbidity was higher in the LEMH group [49 LMH patients (41.5%) vs. 24 LEMH patients (60%) (p = 0.052)]. Patients treated with left LEMH experienced more biliary leakage (p = 0.011) and more major pulmonary complications (p = 0.015) than left LMH. CONCLUSION: LEMH is feasible at the price of important morbidity, with manageable and acceptable outcomes. These exigent procedures require high-volume centers with experienced surgeons.

Postoperative Bleeding After Laparoscopic Pancreaticoduodenectomy: the Achilles' Heel?

BACKGROUND: Laparoscopic pancreaticoduodenectomy (LPD) is technically demanding, and its impact on postoperative outcomes remains controversial. OBJECTIVE: To compare short-term outcomes between laparoscopic versus open pancreaticoduodenectomy (OPD) in order to assess the safety of LPD. METHODS: From 2002 to 2014, all consecutive patients undergoing LPD or OPD at two tertiary centers were retrospectively analyzed. Patients were matched for demographics, comorbidities, pathological diagnosis, and pancreatic texture. Results for the two groups were compared for postoperative outcomes. RESULTS: Sixty-five LPD were performed and compared to 290 OPD. In the whole population, postoperative pancreatic fistula (PF) was higher in the LPD group, but the proportion of ampullary adénocarcinoma (25 vs. 10%, p = 0.004) and soft pancreatic parenchyma (52 vs. 38%, p = 0.001) were higher in the LDP group. After matching (n = 65), LPD was associated with longer operative time (429 vs. 328 min, p < 0.001) and lower blood loss (370 vs. 515 mL, p = 0.047). The PF rate and its severity were similar (33 vs. 27%, p = 0.439, p = 0.083) in the two groups. However, both complications (78 vs. 71%, p = 0.030) and major complications (40 vs. 23%, p = 0.033) were more frequent in the LPD group. LPD patients experience more postoperative bleeding (21 vs. 14%, p = 0.025) compared to their open counterparts. In multivariate analysis, perioperative transfusion (OR = 5 IC 95% (1.5-16), p = 0.008), soft pancreas (OR = 2.5 IC 95% (1.4-4.6), p = 0.001), and ampullary adenocarcinoma (OR = 2.6 IC 95% (1.2-5.6), p = 0.015) were independent risks factors of major complications. CONCLUSION: Despite lower blood loss and lower intraoperative transfusion, LPD leads to higher rate of postoperative complications with postoperative bleeding in particular.

Impact of intraoperative blood loss on the short-term outcomes of laparoscopic liver resection.

BACKGROUND: Intraoperative blood loss is one of the predictors of outcome of open hepatectomy. But the impact of blood loss in laparoscopic hepatectomy (LH) on postoperative outcomes is poorly understood. The aim of this study is to analyze the association between blood loss and postoperative outcomes after LH. METHODS: A retrospective analysis of prospectively maintained database of patients undergoing LH from 1995 to 2016 was performed. The data were divided into two groups based on the extent of blood loss: Group 1 (<250 ml) and Group 2 (≥250 ml). The basic characteristics and postoperative outcomes were compared between these groups. RESULTS: A total of 504 patients underwent 611 LH (Group 1: 414 and Group 2: 197). The mean age was 62.4 years. The most common indication was liver secondaries (71.7%). Major hepatectomy was performed in 37% cases. Mean operative time was 225 ± 110.5 min and estimated blood loss was 239 ± 399.4 ml (range 0-4500 ml). Group 2 had significantly higher number of patients with malignant lesions undergoing major hepatectomy, anatomical resection with higher requirement for blood transfusion, and longer hospital stay. The incidence of conversion rate, overall complications including liver failure, renal failure, and postoperative mortality, was significantly higher in Group 2. However, the bile leak rate was similar in the two groups. CONCLUSION: Intraoperative blood loss is most frequent in patients undergoing major LH. Blood loss ≥250 ml during LH may adversely affect the postoperative outcomes.

Quality of life after complicated elective surgery requiring intensive care.

OBJECTIVE: To evaluate outcomes of patients admitted to the ICU for complications after elective surgery and to assess perceived quality of life (pQOL) in survivors. DESIGN: Two-year prospective case-control study. SETTING: Twelve-bed ICU in a university-affiliated hospital. PATIENTS: Patients admitted to the ICU for a complication following elective surgery were included. Six months after discharge, pQOL was assessed using the Nottingham Health Profile (NHP). Results were compared to those of matched controls without complications. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Of the 182 patients, 124 were alive after 6 months, among whom 116 had 6-month data and 104 of these had matched controls. Overall pQOL as assessed by the global NHP score was similar in both groups (median, 0.82 and 0.87 in cases and controls; P=0.24). NHP subscores showed significantly worse pain ( P=0.03) and physical impairment ( P=0.02) in the ICU patients. In the multivariate analysis, pQOL was better in patients with cancer as the reason for surgery ( P=0.05). Severity of illness at inclusion had no influence on subsequent pQOL, but cardiovascular dysfunction was associated with decreased energy ( P=0.04). CONCLUSIONS: Although overall pQOL was satisfactory after 6 months, patients admitted to the ICU for postoperative complications had worse pain and physical impairment than controls. Whether these outcomes could be improved by early physiotherapy and aggressive pain management deserves investigation.