Insulin and glycolysis dependency of cardioprotection by nicotinamide riboside.

Decreased nicotinamide adenine dinucleotide (NAD+) levels contribute to various pathologies such as ageing, diabetes, heart failure and ischemia-reperfusion injury (IRI). Nicotinamide riboside (NR) has emerged as a promising therapeutic NAD+ precursor due to efficient NAD+ elevation and was recently shown to be the only agent able to reduce cardiac IRI in models employing clinically relevant anesthesia. However, through which metabolic pathway(s) NR mediates IRI protection remains unknown. Furthermore, the influence of insulin, a known modulator of cardioprotective efficacy, on the protective effects of NR has not been investigated. Here, we used the isolated mouse heart allowing cardiac metabolic control to investigate: (1) whether NR can protect the isolated heart against IRI, (2) the metabolic pathways underlying NR-mediated protection, and (3) whether insulin abrogates NR protection. NR protection against cardiac IRI and effects on metabolic pathways employing metabolomics for determination of changes in metabolic intermediates, and 13C-glucose fluxomics for determination of metabolic pathway activities (glycolysis, pentose phosphate pathway (PPP) and mitochondrial/tricarboxylic acid cycle (TCA cycle) activities), were examined in isolated C57BL/6N mouse hearts perfused with either (a) glucose + fatty acids (FA) ("mild glycolysis group"), (b) lactate + pyruvate + FA ("no glycolysis group"), or (c) glucose + FA + insulin ("high glycolysis group"). NR increased cardiac NAD+ in all three metabolic groups. In glucose + FA perfused hearts, NR reduced IR injury, increased glycolytic intermediate phosphoenolpyruvate (PEP), TCA intermediate succinate and PPP intermediates ribose-5P (R5P) / sedoheptulose-7P (S7P), and was associated with activated glycolysis, without changes in TCA cycle or PPP activities. In the "no glycolysis" hearts, NR protection was lost, whereas NR still increased S7P. In the insulin hearts, glycolysis was largely accelerated, and NR protection abrogated. NR still increased PPP intermediates, with now high 13C-labeling of S7P, but NR was unable to increase metabolic pathway activities, including glycolysis. Protection by NR against IRI is only present in hearts with low glycolysis, and is associated with activation of glycolysis. When activation of glycolysis was prevented, through either examining "no glycolysis" hearts or "high glycolysis" hearts, NR protection was abolished. The data suggest that NR's acute cardioprotective effects are mediated through glycolysis activation and are lost in the presence of insulin because of already elevated glycolysis.

Anaesthetic efficacy and postinduction hypotension with remimazolam compared with propofol: a multicentre randomised controlled trial.

Remimazolam, a short-acting benzodiazepine, may be used for induction and maintenance of total intravenous anaesthesia, but its role in the management of patients with multiple comorbidities remains unclear. In this phase 3 randomised controlled trial, we compared the anaesthetic efficacy and the incidence of postinduction hypotension during total intravenous anaesthesia with remimazolam vs. propofol. A total of 365 patients (ASA physical status 3 or 4) scheduled for elective surgery were assigned randomly to receive total intravenous anaesthesia with remimazolam (n = 270) or propofol (n = 95). Primary outcome was anaesthetic effect, quantified as the percentage of time with Narcotrend® Index values ≤ 60, during surgery (skin incision to last skin suture), with a non-inferiority margin of -10%. Secondary outcome was the incidence of postinduction hypotensive events. Mean (SD) percentage of time with Narcotrend Index values ≤ 60 during surgery across all patients receiving remimazolam (93% (20.7)) was non-inferior to propofol (99% (4.2)), mean difference (97.5%CI) -6.28% (-8.89-infinite); p = 0.003. Mean (SD) number of postinduction hypotension events was 62 (38.1) and 71 (41.1) for patients allocated to the remimazolam and propofol groups, respectively; p = 0.015. Noradrenaline administration events (requirement for a bolus and/or infusion) were also lower in patients allocated to remimazolam compared with propofol (14 (13.5) vs. 20 (14.6), respectively; p < 0.001). In conclusion, in patients who were ASA physical status 3 or 4, the anaesthetic effect of remimazolam was non-inferior to propofol.

Effects of surgery and general anaesthesia on sleep-wake timing: CLOCKS observational study.

Surgery and general anaesthesia have the potential to disturb the body's circadian timing system, which may affect postoperative outcomes. Animal studies suggest that anaesthesia could induce diurnal phase shifts, but clinical research is scarce. We hypothesised that surgery and general anaesthesia would result in peri-operative changes in diurnal sleep-wake patterns in patients. In this single-centre prospective cohort study, we recruited patients aged ≥18 years scheduled for elective surgery receiving ≥30 min of general anaesthesia. The Munich Chronotype Questionnaire and Pittsburgh Sleep Quality Index were used to determine baseline chronotype, sleep characteristics and sleep quality. Peri-operative sleeping patterns were logged. Ninety-four patients with a mean (SD) age of 52 (17) years were included; 56 (60%) were female. The midpoint of sleep (SD) three nights before surgery was 03.33 (55 min) and showed a phase advance of 40 minutes to 02.53 (67 min) the night after surgery (p < 0.001). This correlated with the midpoint of sleep three nights before surgery and was not associated with age, sex, duration of general anaesthesia or intra-operative dexamethasone use. Peri-operatively, patients had lower subjective sleep quality and worse sleep efficiency. Disruption started from one night before surgery and did not normalise until 6 days after surgery. We conclude that there is a peri-operative phase advance in midpoint of sleep, confirming our hypothesis that surgery and general anaesthesia disturb the circadian timing system. Patients had decreased subjective sleep quality, worse sleep efficiency and increased daytime fatigue.

Enhanced PeriOperative Care and Health protection programme for the prevention of surgical site infections after elective abdominal surgery (EPO2CH): statistical analysis plan of a randomised controlled multicentre superiority trial.

BACKGROUND: Surgical site infections (SSI) are frequent complications after elective abdominal surgery. We designed the Enhanced PeriOperative Care and Health Protection programme (EPO2CH) care bundle, comprising of intraoperative high fractional inspired oxygen; intraoperative goal-directed fluid therapy; active preoperative, intraoperative and postoperative warming; glucose control and treatment of hyperglycaemia (> 10 mmol L- 1) in diabetics as well as non-diabetics; and wound irrigation before closure using an aqueous antiseptic. We hypothesise that EPO2CH added to standard care reduces the incidence of SSI compared to standard care alone for elective abdominal surgery. METHODS: This trial is designed as an open label, pragmatic randomised controlled parallel-group multicentre superiority trial. The primary endpoint is the incidence of SSI, defined by the Centers for Disease Control and prevention, within 30 days after surgery. The incidence of SSI is assessed using the Dutch national complication register and medical chart review. Secondary endpoints include the SSI incidence within 90 days, incidence of anastomotic leakage at 30 and 90 days, the incidence of incisional hernia within 1 year, mortality within 1 year and 5 years, quality of life, health and disability, and cost-effectiveness. Primarily, an intention-to-treat analysis will be performed to estimate the relative risk using a log binomial model. If not feasible, a logistic regression will be used to estimate the odds ratio. A per-protocol analysis will also be performed. Furthermore, the attributive effect of the distinct interventions will be explored. DISCUSSION: The results of the EPO2CH trial will determine if the EPO2CH bundle is effective to prevent SSI incidence for patients undergoing elective abdominal surgery. Details of the statistical analysis are described in this Statistical Analysis Plan (SAP). TRIAL REGISTRATION: Registration number: Dutch Trial Register Trial NL5572 . Registered on March 3, 2016. SAP version: V1.0, January 8, 2020. This SAP has been written based on study protocol V10.

Cost-effectiveness of immediate total-body CT in patients with severe trauma (REACT-2 trial).

BACKGROUND: The effect of immediate total-body CT (iTBCT) on health economic aspects in patients with severe trauma is an underreported issue. This study determined the cost-effectiveness of iTBCT compared with conventional radiological imaging with selective CT (standard work-up (STWU)) during the initial trauma evaluation. METHODS: In this multicentre RCT, adult patients with a high suspicion of severe injury were randomized in-hospital to iTBCT or STWU. Hospital healthcare costs were determined for the first 6 months after the injury. The probability of iTBCT being cost-effective was calculated for various levels of willingness-to-pay per extra patient alive. RESULTS: A total of 928 Dutch patients with complete clinical follow-up were included. Mean costs of hospital care were €25 809 (95 per cent bias-corrected and accelerated (bca) c.i. €22 617 to €29 137) for the iTBCT group and €26 155 (€23 050 to €29 344) for the STWU group, a difference per patient in favour of iTBCT of €346 (€4987 to €4328) (P = 0.876). Proportions of patients alive at 6 months were not different. The proportion of patients alive without serious morbidity was 61.6 per cent in the iTBCT group versus 66.7 per cent in the STWU group (difference -5.1 per cent; P = 0.104). The probability of iTBCT being cost-effective in keeping patients alive remained below 0.56 for the whole group, but was higher in patients with multiple trauma (0.8-0.9) and in those with traumatic brain injury (more than 0.9). CONCLUSION: Economically, from a hospital healthcare provider perspective, iTBCT should be the diagnostic strategy of first choice in patients with multiple trauma or traumatic brain injury.

Association of intraoperative hypotension with postoperative morbidity and mortality: systematic review and meta-analysis.

BACKGROUND: Intraoperative hypotension, with varying definitions in literature, may be associated with postoperative complications. The aim of this meta-analysis was to assess the association of intraoperative hypotension with postoperative morbidity and mortality. METHODS: MEDLINE, Embase and Cochrane databases were searched for studies published between January 1990 and August 2018. The primary endpoints were postoperative overall morbidity and mortality. Secondary endpoints were postoperative cardiac outcomes, acute kidney injury, stroke, delirium, surgical outcomes and combined outcomes. Subgroup analyses, sensitivity analyses and a meta-regression were performed to test the robustness of the results and to explore heterogeneity. RESULTS: The search identified 2931 studies, of which 29 were included in the meta-analysis, consisting of 130 862 patients. Intraoperative hypotension was associated with an increased risk of morbidity (odds ratio (OR) 2.08, 95 per cent confidence interval 1.56 to 2.77) and mortality (OR 1.94, 1.32 to 2.84). In the secondary analyses, intraoperative hypotension was associated with cardiac complications (OR 2.44, 1.52 to 3.93) and acute kidney injury (OR 2.69, 1.31 to 5.55). Overall heterogeneity was high, with an I2 value of 88 per cent. When hypotension severity, outcome severity and study population variables were added to the meta-regression, heterogeneity was reduced to 50 per cent. CONCLUSION: Intraoperative hypotension during non-cardiac surgery is associated with postoperative cardiac and renal morbidity, and mortality. A universally accepted standard definition of hypotension would facilitate further research into this topic.

Intravenous acetaminophen does not have an opioid sparing effect in Emergency Department patients with painful conditions.

BACKGROUND: Pain in the Emergency Department is common and is frequently treated with opioids. Due to the opioid epidemic, it is clinically helpful to decrease opioid usage. The purpose of this study was to evaluate opioid requirement in Emergency Department patients with painful conditions who receive intravenous acetaminophen. METHODS: In this prospective cohort study, patients aged 18 years and older and treated with opioids in the acute phase were included. Patients receiving additional intravenous acetaminophen were compared to patients who did not. Primary outcome was opioid requirement, measured in Morphine Equivalent Units (MEU) during Emergency Department stay. Secondary outcomes were opioid requirement after discharge; decrease in pain scores; occurrence of adverse events and patient satisfaction. RESULTS: A total of 116 patients were included of whom 76 received intravenous acetaminophen. Opioid consumption in the acute phase was not significantly different (p=0.53) between patients receiving (10.0 MEU (IQR 7.5; 15.0)) and those not receiving acetaminophen: 10.0 MEU (IQR 7.1; 15.0). After discharge these numbers were 15.0 MEU (IQR 7.5; 30.0) versus 30.0 MEU (IQR 15.0; 43.8), respectively (p=0.059). In both groups median NRS pain scores decreased from 9.0 to 4.0 and >80% of patients were satisfied regarding pain treatment. Nine minor adverse events were recorded, equally divided among the groups. CONCLUSIONS: The additional use of intravenous acetaminophen did not decrease opioid requirement in adult patients with acute pain during Emergency Department stay. There was a trend towards decreased opioid requirement during 24 h after discharge.

Paravertebral catheter versus EPidural analgesia in Minimally invasive Esophageal resectioN: a randomized controlled multicenter trial (PEPMEN trial).

BACKGROUND: Thoracic epidural analgesia is the standard postoperative pain management strategy in esophageal cancer surgery. However, paravertebral block analgesia may achieve comparable pain control while inducing less side effects, which may be beneficial for postoperative recovery. This study primarily aims to compare the postoperative quality of recovery between paravertebral catheter versus thoracic epidural analgesia in patients undergoing minimally invasive esophagectomy. METHODS: This study represents a randomized controlled superiority trial. A total of 192 patients will be randomized in 4 Dutch high-volume centers for esophageal cancer surgery. Patients are eligible for inclusion if they are at least 18 years old, able to provide written informed consent and complete questionnaires in Dutch, scheduled to undergo minimally invasive esophagectomy with two-field lymphadenectomy and an intrathoracic anastomosis, and have no contra-indications to either epidural or paravertebral analgesia. The primary outcome is the quality of postoperative recovery, as measured by the Quality of Recovery-40 (QoR-40) questionnaire on the morning of postoperative day 3. Secondary outcomes include the QoR-40 questionnaire score Area Under the Curve on postoperative days 1-3, the integrated pain and systemic opioid score and patient satisfaction and pain experience according to the International Pain Outcomes (IPO) questionnaire, and cost-effectiveness. Furthermore, the groups will be compared regarding the need for additional rescue medication on postoperative days 0-3, technical failure of the pain treatment, duration of anesthesia, duration of surgery, total postoperative fluid administration day 0-3, postoperative vasopressor and inotrope use, length of urinary catheter use, length of hospital stay, postoperative complications, chronic pain at six months after surgery, and other adverse effects. DISCUSSION: In this study, it is hypothesized that paravertebral analgesia achieves comparable pain control while causing less side-effects such as hypotension when compared to epidural analgesia, leading to shorter postoperative length of stay on a monitored ward and superior quality of recovery. If this hypothesis is confirmed, the results of this study can be used to update the relevant guidelines on postoperative pain management for patients undergoing minimally invasive esophagectomy. TRIAL REGISTRATION: Netherlands Trial Registry, NL8037. Registered 19 September 2019.

International multicentre review of perioperative management and outcome for catecholamine-producing tumours.

BACKGROUND: Surgery for catecholamine-producing tumours can be complicated by intraoperative and postoperative haemodynamic instability. Several perioperative management strategies have emerged but none has been evaluated in randomized trials. To assess this issue, contemporary perioperative management and outcome data from 21 centres were collected. METHODS: Twenty-one centres contributed outcome data from patients who had surgery for phaeochromocytoma and paraganglioma between 2000 and 2017. The data included the number of patients with and without α-receptor blockade, surgical and anaesthetic techniques, complications and perioperative mortality. RESULTS: Across all centres, data were reported on 1860 patients with phaeochromocytoma or paraganglioma, of whom 343 underwent surgery without α-receptor blockade. The majority of operations (78·9 per cent) were performed using minimally invasive techniques, including 16·1 per cent adrenal cortex-sparing procedures. The cardiovascular complication rate was 5·0 per cent overall: 5·9 per cent (90 of 1517) in patients with preoperative α-receptor blockade and 0·9 per cent (3 of 343) among patients without α-receptor blockade. The mortality rate was 0·5 per cent overall (9 of 1860): 0·5 per cent (8 of 517) in pretreated and 0·3 per cent (1 of 343) in non-pretreated patients. CONCLUSION: There is substantial variability in the perioperative management of catecholamine-producing tumours, yet the overall complication rate is low. Further studies are needed to better define the optimal management approach, and reappraisal of international perioperative guidelines appears desirable.

ANTECEDENTES: La cirugía de los tumores productores de catecolaminas puede complicarse por la inestabilidad hemodinámica intraoperatoria y postoperatoria. Se han propuesto distintas estrategias de manejo perioperatorio, pero ninguna ha sido evaluada en ensayos aleatorizados. Para evaluar este tema, se han recogido los datos de los resultados y del manejo perioperatorio contemporáneo de 21 centros. MÉTODOS: Veintiún centros aportaron datos de los resultados de los pacientes operados por feocromocitoma y paraganglioma entre 2000-2017. Los datos incluyeron el número de pacientes con y sin bloqueo del receptor α, las técnicas quirúrgicas y anestésicas, las complicaciones y la mortalidad perioperatoria. RESULTADOS: Los centros en su conjunto aportaron datos de 1.860 pacientes con feocromocitoma y paraganglioma, de los cuales 343 pacientes fueron intervenidos sin bloqueo del receptor α. La gran mayoría (79%) de las cirugías se realizaron utilizando técnicas mínimamente invasivas, incluido un 17% de procedimientos con preservación de la corteza suprarrenal. La tasa de complicaciones cardiovasculares fue de 5,0% en total; 5,9% (90/1517) en pacientes con bloqueo preoperatorio de los receptores α y 0,9% (3/343) en pacientes no pretratados. La mortalidad global fue del 0,5% (9/1860); 0,5% (8/1517) en pacientes pretratados y 0,3% (1/343) en pacientes no tratados previamente. CONCLUSIÓN: Existe una variabilidad sustancial en el manejo perioperatorio de los tumores productores de catecolaminas, aunque la tasa global de complicaciones es baja. Este estudio brinda la oportunidad para efectuar comparaciones sistemáticas entre estrategias de prácticas terapéuticas variables. Se necesitan más estudios para definir mejor el enfoque de manejo óptimo y parece conveniente volver a evaluar las guías internacionales perioperatorias.

Ultrasound guided supra-inguinal Fascia Iliaca Compartment Blocks in hip fracture patients: An alternative technique.

INTRODUCTION: In the Emergency Department, regional anesthesia is increasingly used in elderly patients with hip fractures. An example is a Fascia Iliaca Compartment Block (FICB). Traditionally, this block is administered below the inguinal ligament. There is no Emergency Department data regarding effectivity of an alternative, more cranial approach above the inguinal ligament. The objective was to determine analgesic effects of an ultrasound-guided supra-inguinal FICB in hip fracture patients in the Emergency Department. METHODS: This case series included all Emergency Department hip fracture patients who were treated with a supra-inguinal FICB during a period of 10 months. All data were recorded prospectively. Primary study outcome was decrease in Numerical Rating Scale (NRS) pain scores 60 min after the FICB. Secondary outcomes included the proportion of patients achieving 1.5 NRS points decrease at 60 min; NRS differences at 30 and 120 min compared to baseline; need for additional analgesia and occurrence of adverse events. RESULTS: A total of 22 patients were included in the study. At 60 min median NRS pain scores decreased from 6.0 to 3.0 (p < 0.001). Of all patients, a total of 59% achieved a decrease in 1.5 NRS points after 60 min. Median pain scores at 30 and 120 min were 4.0 (Interquartile Range (IQR) 2.0-5.0) and 2.5 (IQR 0.8-3.0). Seven patients (31.8%) required additional opioid analgesia after the FICB. No adverse events were recorded. CONCLUSION: An ultrasound-guided supra-inguinal FICB decreases NRS pain scores in hip fracture patients both clinically relevant and statistically significantly after 60 min. CLINICAL TRIAL REGISTRATION: The study was registered in the ISRCTN database (ISRCTN74920258).

[Postoperative remote monitoring]. / Postoperatives "remote monitoring".

During the course of surgical interventions, complications mostly occur in the postoperative period. Slight clinical indications can be observed, which precede a significant deterioration of the patient's condition. On the general ward vital parameters, such as heart and breathing frequencies are measured every 4-8 h. Even if the monitoring of critically ill patients is increased to every 2 h and the measurement of vital functions takes 10 min, the patient is only monitored for 120 min in a 24 h period and remains postoperatively on the general ward without monitoring for 22 out of 24 h. New wireless monitoring systems are available to continuously register some vital functions with the aid of wearable sensors. These systems can alert and alarm ward personnel if the patient's condition deteriorates. Although the optimal monitoring system does not yet exist and implementation of these new wireless monitoring systems might involve some risks, these new methods offer a great opportunity to optimize surveillance of postoperative patients on the general ward.

The use of a machine-learning algorithm that predicts hypotension during surgery in combination with personalized treatment guidance: study protocol for a randomized clinical trial.

BACKGROUND: Intraoperative hypotension is associated with increased morbidity and mortality. Current treatment is mostly reactive. The Hypotension Prediction Index (HPI) algorithm is able to predict hypotension minutes before the blood pressure actually decreases. Internal and external validation of this algorithm has shown good sensitivity and specificity. We hypothesize that the use of this algorithm in combination with a personalized treatment protocol will reduce the time weighted average (TWA) in hypotension during surgery spent in hypotension intraoperatively. METHODS/DESIGN: We aim to include 100 adult patients undergoing non-cardiac surgery with an anticipated duration of more than 2 h, necessitating the use of an arterial line, and an intraoperatively targeted mean arterial pressure (MAP) of > 65 mmHg. This study is divided into two parts; in phase A baseline TWA data from 40 patients will be collected prospectively. A device (HemoSphere) with HPI software will be connected but fully covered. Phase B is designed as a single-center, randomized controlled trial were 60 patients will be randomized with computer-generated blocks of four, six or eight, with an allocation ratio of 1:1. In the intervention arm the HemoSphere with HPI will be used to guide treatment; in the control arm the HemoSphere with HPI software will be connected but fully covered. The primary outcome is the TWA in hypotension during surgery. DISCUSSION: The aim of this trial is to explore whether the use of a machine-learning algorithm intraoperatively can result in less hypotension. To test this, the treating anesthesiologist will need to change treatment behavior from reactive to proactive. TRIAL REGISTRATION: This trial has been registered with the NIH, U.S. National Library of Medicine at ClinicalTrials.gov, ID: NCT03376347 . The trial was submitted on 4 November 2017 and accepted for registration on 18 December 2017.

Patient blood management in the cardiac surgical setting: An updated overview.

In cardiac surgical patients it is a complex challenge to find the ideal balance between anticoagulation and hemostasis. Preoperative anemia and perioperative higher transfusion rates are related to increased morbidity and mortality. Patient blood management (PBM) is an evidence based patient specific individualized protocol used in the perioperative setting in order to reduce perioperative bleeding and transfusion rates and to improve patient outcomes. The three pillars of PBM in cardiac surgery consist of optimization of preoperative erythropoiesis and hemostasis, minimizing blood loss, and improving patient specific physiological reserves. This narrative review focuses on the challenges with special emphasis on PBM in the preoperative phase and intraoperative transfusion management and hemostasis in cardiac surgery patients. It is a "must" that PBM is a collaborative effort between anesthesiologists, surgeons, perfusionists, intensivists and transfusion laboratory teams. This review represents an up to date overview over "PBM in cardiac surgery patients".

Effect of Intraoperative High Positive End-Expiratory Pressure (PEEP) With Recruitment Maneuvers vs Low PEEP on Postoperative Pulmonary Complications in Obese Patients: A Randomized Clinical Trial.

Importance: An intraoperative higher level of positive end-expiratory positive pressure (PEEP) with alveolar recruitment maneuvers improves respiratory function in obese patients undergoing surgery, but the effect on clinical outcomes is uncertain. Objective: To determine whether a higher level of PEEP with alveolar recruitment maneuvers decreases postoperative pulmonary complications in obese patients undergoing surgery compared with a lower level of PEEP. Design, Setting, and Participants: Randomized clinical trial of 2013 adults with body mass indices of 35 or greater and substantial risk for postoperative pulmonary complications who were undergoing noncardiac, nonneurological surgery under general anesthesia. The trial was conducted at 77 sites in 23 countries from July 2014-February 2018; final follow-up: May 2018. Interventions: Patients were randomized to the high level of PEEP group (n = 989), consisting of a PEEP level of 12 cm H2O with alveolar recruitment maneuvers (a stepwise increase of tidal volume and eventually PEEP) or to the low level of PEEP group (n = 987), consisting of a PEEP level of 4 cm H2O. All patients received volume-controlled ventilation with a tidal volume of 7 mL/kg of predicted body weight. Main Outcomes and Measures: The primary outcome was a composite of pulmonary complications within the first 5 postoperative days, including respiratory failure, acute respiratory distress syndrome, bronchospasm, new pulmonary infiltrates, pulmonary infection, aspiration pneumonitis, pleural effusion, atelectasis, cardiopulmonary edema, and pneumothorax. Among the 9 prespecified secondary outcomes, 3 were intraoperative complications, including hypoxemia (oxygen desaturation with Spo2 ≤92% for >1 minute). Results: Among 2013 adults who were randomized, 1976 (98.2%) completed the trial (mean age, 48.8 years; 1381 [69.9%] women; 1778 [90.1%] underwent abdominal operations). In the intention-to-treat analysis, the primary outcome occurred in 211 of 989 patients (21.3%) in the high level of PEEP group compared with 233 of 987 patients (23.6%) in the low level of PEEP group (difference, -2.3% [95% CI, -5.9% to 1.4%]; risk ratio, 0.93 [95% CI, 0.83 to 1.04]; P = .23). Among the 9 prespecified secondary outcomes, 6 were not significantly different between the high and low level of PEEP groups, and 3 were significantly different, including fewer patients with hypoxemia (5.0% in the high level of PEEP group vs 13.6% in the low level of PEEP group; difference, -8.6% [95% CI, -11.1% to 6.1%]; P < .001). Conclusions and Relevance: Among obese patients undergoing surgery under general anesthesia, an intraoperative mechanical ventilation strategy with a higher level of PEEP and alveolar recruitment maneuvers, compared with a strategy with a lower level of PEEP, did not reduce postoperative pulmonary complications. Trial Registration: ClinicalTrials.gov Identifier: NCT02148692.

Correction to: Protective ventilation with high versus low positive end-expiratory pressure during one-lung ventilation for thoracic surgery (PROTHOR): study protocol for a randomized controlled trial.

After publication of the original article [1], the authors have notified us that two of the collaborator first and last names have been inverted in the "PROTHOR Investigators" table.

Safety of epidural drugs: a narrative review.

INTRODUCTION: Epidural analgesia is a popular approach to postoperative and labor pain. Neurotoxicity and drug-specific systemic side effects can occur after epidural administration. As an increasing number of epidural drugs are studied and clinically applied, drug efficacy and safety evaluation are crucial. AREAS COVERED: In this narrative review, the authors provide a thorough overview on the safety of the most widely used epidural drugs, focusing on potential neurotoxicity, side effects, and complications in the adult, non-pregnant population. A combined text and MeSH heading search strategy was used to identify relevant publications. EXPERT OPINION: The search for the ideal epidural medication has resulted in a surplus of drug combinations with extensive heterogeneity amongst studies, while the value of investigating these is not always evident. Epidural drugs pose a potential threat of neurotoxicity and other side effects. Consequently, we should pursue safe epidural drug administration to patients and refrain from drugs with minimal proven benefit. Also, studies should compare epidural with systemic application. Because why use a drug epidurally, which can be safely used systemically? Future research should focus on providing solid evidence regarding efficacy of epidural analgesia compared to new and already existing modalities and optimizing presently used medicinal regimens.

Markers of Pulmonary Oxygen Toxicity in Hyperbaric Oxygen Therapy Using Exhaled Breath Analysis.

INTRODUCTION: Although hyperbaric oxygen therapy (HBOT) has beneficial effects, some patients experience fatigue and pulmonary complaints after several sessions. The current limits of hyperbaric oxygen exposure to prevent pulmonary oxygen toxicity (POT) are based on pulmonary function tests (PFT), but the limitations of PFT are recognized worldwide. However, no newer modalities to detect POT have been established. Exhaled breath analysis in divers have shown volatile organic compounds (VOCs) of inflammation and methyl alkanes. This study hypothesized that similar VOCs might be detected after HBOT. METHODS: Ten healthy volunteers of the Royal Netherlands Navy underwent six HBOT sessions (95 min at 253 kPa, including three 5-min "air breaks"), i.e., on five consecutive days followed by another session after 2 days of rest. At 30 min before the dive, and at 30 min, 2 and 4 h post-dive, exhaled breath was collected and followed by PFT. Exhaled breath samples were analyzed using gas chromatography-mass spectrometry (GC-MS). After univariate tests and correlation of retention times, ion fragments could be identified using a reference database. Using these fragments VOCs could be reconstructed, which were clustered using principal component analysis. These clusters were tested longitudinally with ANOVA. RESULTS: After GC-MS analysis, eleven relevant VOCs were identified which could be clustered into two principal components (PC). PC1 consisted of VOCs associated with inflammation and showed no significant change over time. The intensities of PC2, consisting of methyl alkanes, showed a significant decrease (p = 0.001) after the first HBOT session to 50.8%, remained decreased during the subsequent days (mean 82%), and decreased even further after 2 days of rest to 58% (compared to baseline). PFT remained virtually unchanged. DISCUSSION: Although similar VOCs were found when compared to diving, the decrease of methyl alkanes (PC2) is in contrast to the increase seen in divers. It is unknown why emission of methyl alkanes (which could originate from the phosphatidylcholine membrane in the alveoli) are reduced after HBOT. This suggests that HBOT might not be as damaging to the pulmonary tract as previously assumed. Future research on POT should focus on the identified VOCs (inflammation and methyl alkanes).