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PURPOSE: Obstructive sleep apnea (OSA) is highly prevalent but mostly undiagnosed in obese patients scheduled for bariatric surgery. To prevent cardiopulmonary complications, many clinics perform preoperative OSA screening. Consequently, adequate adherence to continuous positive airway pressure (CPAP) therapy is essential but challenging. We aimed to evaluate CPAP adherence and its influence on postoperative outcomes.METHODS: In a prospective multicenter cohort study, we compared different perioperative strategies for handling undiagnosed OSA in bariatric patients. In this subgroup analysis, patients newly diagnosed with OSA were compared to those with pre-existing OSA. We assessed inadequate CPAP adherence, defined as RESULTS: In total, 272 patients with newly diagnosed OSA (67.4%) and 132 patients with pre-existing OSA (32.6%) were included. Before surgery, 41 newly diagnosed patients used CPAP inadequately, compared to 5 patients with pre-existing OSA (15% vs. 4%, p = 0.049). Six months after surgery, inadequate CPAP use increased to 73% for newly diagnosed patients and 39% for patients with pre-existing OSA, respectively (p CONCLUSION: Inadequate CPAP adherence is higher in bariatric patients newly diagnosed with OSA when compared to patients with pre-existing OSA. Strategies to increase CPAP adherence may be valuable when considering routine OSA screening and CPAP therapy in patients undergoing bariatric surgery. Further studies are needed to improve current guidelines on perioperative OSA management of obese patients.TRIAL REGISTRATION: POPCORN study, registered at Netherlands Trial Register, https://www.trialregister.nl/trial/6805 . ID no: 6805.

This study investigated the impact of laparoscopic or open resection of locally advanced colonic cancer on the incidence and severity of adhesions evaluated by laparoscopy at 18 months, primarily intended to evaluate peritoneal recurrence. Open surgery was identified as an independent risk factor for adhesions, but not intraperitoneal chemotherapy.

Contains fulltext : 220654.pdf (Publisher’s version ) (Open Access) In this prospective study, we examined the pharmacokinetics of 1 and 2 mg/kg liposomal amphotericin B in 16 morbidly obese individuals (104-177 kg). Body size had no effect on clearance. We recommend a fixed dose in patients ≥100 kg (ie, 300 or 500 mg rather than the current dose of 3 and 5 mg/kg, respectively). Clinical Trials Registration NCT02320604.

Background Although the sleeve gastrectomy (SG) has good short-term results, it comes with a significant number of patients requiring revisional surgery because of insufficient weight loss or functional complications. Objective To investigate the effectiveness of the single anastomosis duodenoileal bypass (SADI-S) versus the Roux-en-Y gastric bypass (RYGB) on health outcomes in (morbidly) obese patients who had previously undergone SG, with up to 5 years of follow-up. Methods Data from patients who underwent revisional SADI-S or RYGB after SG were retrospectively compared on indication of surgery, weight loss, quality of life, micronutrient deficiencies, and complications. Results From 2007 to 2017, 141 patients received revisional laparoscopic surgery after SG in three specialized Dutch bariatric hospitals (SADI-S n=63, RYGB n=78). Percentage total weight loss following revisional surgery at 1, 2, 3, 4, and 5 years was 22%, 24%, 22%, 18%, and 15% for SADI-S and 10%, 9%, 7%, 8%, and 2% for RYGB (P Conclusion Conversion of SG to SADI-S leads to significantly more total weight loss compared to RYGB surgery with no difference in quality of life scores, complication rates, or micronutrient deficiencies. When GERD in sleeve patients has to be resolved, RYGB provides adequate outcomes. Graphical abstract

Background The prevalence of obesity has shown a dramatic increase over recent decades. Obesity is associated with underdosing of antimicrobial drugs for prophylaxis and treatment. Posaconazole is a broad-spectrum triazole antifungal drug licensed for prophylaxis and treatment of invasive fungal infections. It is unclear how posaconazole should be dosed in obese patients. Methods We performed a prospective study investigating the pharmacokinetics of posaconazole in morbidly obese (n = 16) and normal-weight (n = 8) subjects, with a weight ranging between 61.4 and 190 kg, after a 300 or 400 mg IV dose. Population pharmacokinetic modelling was used to assess the effect of body size on posaconazole pharmacokinetics. ClinicalTrials.gov Identifier: NCT03246386. Results Total body weight best predicted changes in CL and V. Model-based simulations demonstrated that, for treatment of fungal infections, a daily IV dose of 300 mg will result in a PTA of ≥90% in individuals up to 140 kg, after which both twice daily loading and the daily maintenance dose should be increased to 400 mg. For prophylaxis, a 300 mg IV dose is adequate in patients up to 190 kg. Conclusions Body size has a significant impact on posaconazole CL and V, resulting in a lower exposure in obese subjects compared with normal-weight subjects. For therapeutic use of posaconazole, a dose increase is required in patients above 140 kg. For prophylaxis, a 300 mg IV dose is adequate. For oral treatment, these recommendations can act as a starting point followed by therapeutic drug monitoring.

Contains fulltext : 202593.pdf (Publisher’s version ) (Closed access) OBJECTIVES: The rising pandemic of obesity means an increasing number of obese patients who require antimicrobial therapy for serious infections. Micafungin is an echinocandin drug frequently used as therapy or prophylaxis for fungal infections, predominantly with Candida species. In order to maximize the efficacy of micafungin in obese patients, the dose that corresponds to optimal exposure for each obese individual needs to be identified. METHODS: We performed a prospective study in 16 obese and 8 normal-weight healthy subjects with a weight ranging from 61.5-184 kg (ClinicalTrials.gov Identifier: NCT03102658). A population pharmacokinetic model was developed and used to simulate several dosing regimens to evaluate the PTA for relevant MICs to define the optimal dose using the pharmacokinetic/pharmacodynamic target of an AUC/MIC ratio above 5000. RESULTS: Total body weight was found to be most predictive for CL and V. Simulations showed that a 100 mg dose results in a PTA of >90% in patients weighing 125 kg infected with a Candida species with an MIC of 0.016 mg/L. For an MIC of 0.032 mg/L, a 300 mg maintenance dose is recommended above 125 kg weight. Furthermore, we demonstrate that patients can benefit from a loading dose (i.e. twice the maintenance dose). CONCLUSIONS: We present easy-to-use dose recommendations for obese patients, based on both weight and target MIC, that result in adequate exposure in patients with body weight up to 190 kg.

Background Sleeve gastrectomy (SG) has become the most performed bariatric procedure to induce weight loss worldwide. Unfortunately, a significant portion of patients show insufficient weight loss or weight regain after a few years. Objective To investigate the effectiveness of the single anastomosis duodenoileal (SADI) bypass versus the Roux-en-Y gastric bypass (RYGB) on health outcomes in morbid obese patients who had undergone SG previously, with up to 2 years of follow-up. Methods From 2007 to 2017, 140 patients received revisional laparoscopic surgery after SG in four specialized Dutch bariatric hospitals. Data was analyzed retrospectively and included comparisons for indication of surgery, vitamin/mineral deficiencies, and complications; divided into short-, medium-term. To compare weight loss, linear regression and linear mixed models were used. Results Conversion of a SG to SADI was performed in 66 patients and to RYGB in 74 patients. For patients in which additional weight loss was the main indication for surgery, SADI achieved 8.7%, 12.4%, and 19.4% more total body weight loss at 6, 12, and 24 months compared to RYGB (all p

Background While in vitro and animal studies have shown reduced cytochrome P450 (CYP) 3A activity due to obesity, clinical studies in (morbidly) obese patients are scarce. As CYP3A activity may influence both clearance and oral bioavailability in a distinct manner, in this study the pharmacokinetics of the CYP3A substrate midazolam were evaluated after semi-simultaneous oral and intravenous administration in morbidly obese patients, and compared with healthy volunteers. Methods Twenty morbidly obese patients [mean body weight 144 kg (range 112–186 kg) and mean body mass index 47 kg/m2 (range 40–68 kg/m2)] participated in the study. All patients received a midazolam 7.5 mg oral and 5 mg intravenous dose (separated by 159 ± 67 min) and per patient 22 samples over 11 h were collected. Data from 12 healthy volunteers were available for a population pharmacokinetic analysis using NONMEM®. Results In the three-compartment model in which oral absorption was characterized by a transit absorption model, population mean clearance (relative standard error %) was similar [0.36 (4 %) L/min], while oral bioavailability was 60 % (13 %) in morbidly obese patients versus 28 % (7 %) in healthy volunteers (P

Background Discrimination between simple and perforated appendicitis in patients with suspected appendicitis may help to determine the therapy, timing of surgery and risk of complications. The aim of this study was to estimate the accuracy of magnetic resonance imaging (MRI) in distinguishing between simple and perforated appendicitis, and to compare MRI against ultrasound imaging with selected additional (conditional) use of computed tomography (CT). Methods Patients with clinically suspected appendicitis were identified prospectively at the emergency department of six hospitals. Consenting patients underwent MRI, but were managed based on findings at ultrasonography and conditional CT. Radiologists who evaluated the MRI were blinded to the results of ultrasound imaging and CT. The presence of perforated appendicitis was recorded after each evaluation. The final diagnosis was assigned by an expert panel based on perioperative data, histopathology and clinical follow-up after 3 months. Results MRI was performed in 223 of 230 included patients. Acute appendicitis was the final diagnosis in 118 of 230 patients, of whom 87 had simple and 31 perforated appendicitis. MRI correctly identified 17 of 30 patients with perforated appendicitis (sensitivity 57 (95 per cent confidence interval 39 to 73) per cent), whereas ultrasound imaging with conditional CT identified 15 of 31 (sensitivity 48 (32 to 65) per cent) (P = 0·517). All missed diagnoses of perforated appendicitis were identified as simple acute appendicitis with both imaging protocols. None of the MRI features for perforated appendicitis had a positive predictive value higher than 53 per cent. Conclusion MRI is comparable to ultrasonography with conditional use of CT in identifying perforated appendicitis. However, both strategies incorrectly classify up to half of all patients with perforated appendicitis as having simple appendicitis. Triage of appendicitis based on imaging for conservative treatment is inaccurate and may be considered unsafe for decision-making. Presented to a scientific meeting of the Association of Surgeons of the Netherlands, Veldhoven, The Netherlands, May 2012; published in abstract form as Br J Surg 2012; 99(Suppl 7): S6

In absence of specific dosing guidelines, the optimal dose of low molecular weight heparins for thrombosis prophylaxis in morbidly obese patients (BMI>40 kg/m(2)) remains unknown. In order to guide dosing in this patient group, a pharmacodynamics model is developed for nadroparin in morbidly obese and non-obese patients using anti-Xa levels as an endpoint, thereby characterizing the influence of excessive body weight on different pharmacodynamic model parameters.\nTwenty-eight morbidly obese and seven non-obese patients receiving 5700 IU and 2850 IU subcutaneous (s.c.) nadroparin for surgery, respectively, were included with a mean total body weight (TBW) of 135 kg (range 72-252 kg). Up to 11 anti-Xa levels were collected from the start until 24 h after nadroparin administration. Population pharmacodynamic modelling with covariate analysis was performed using NONMEM.\nIn a two-compartment pharmacodynamic model with baseline endogenous anti-Xa levels, the effect of nadroparin was found to be delayed and could be best described using a transit compartment. TBW was the most predictive covariate for clearance (CL=23.0 mL/min × (TBW/70)), while lean body weight (LBW) proved the most predictive covariate for central volume of distribution (V1=7.0 L × (LBW/60)).\nA pharmacodynamic model was developed characterizing anti-Xa levels after s.c. administration of nadroparin in patients weighing between 72 and 252 kg with TBW and LBW as the major determinants for clearance and volume of distribution, respectively.\nPURPOSE\nMETHODS\nRESULTS\nCONCLUSIONS

Signet ring cell cancer (SRCC) patients have a poor oncologic outcome. The aim of this study was to determine whether the potential drawbacks of hyperthermic intraperitoneal chemotherapy (HIPEC) outweigh the benefits in patients with peritoneally metastasized SRCC.Patients with peritoneal carcinomatosis (PC) of colorectal origin referred to two tertiary centers between April 2005 and December 2013 were identified and retrospectively analyzed. Data were compared between SRCC histology and other differentiations.Three-hundred-fifty-one patients were referred for CRS+HIPEC among which 20 (5.7%) patients were identified with SRCC histology. CRS + HIPEC was performed in 16 of these 20 (80%) and 252 out of the 331 remaining patients (76.1%). A higher proportion of patients in the SRCC-group were diagnosed with N2 stage (62.5% vs. 36.1%, P=0.04). A macroscopic complete resection was achieved in 87.5% and 97.2% respectively (P=0.04). Median survival was 14.1 months compared to 35.1 months (P0.01). Recurrence occurred in 68.8% of the SRCC patients and in 43.7% of the other histology patients (P=0.05).Patients with SRCC and PC treated with CRS+HIPEC have a poor median survival only slightly reaching over 1 year. In the presence of other relative contraindications, SRCC histology should refrain a surgeon from performing CRS and HIPEC.

BACKGROUND: Morbidly obese patients (BMI 40 kg/m(2)) are at increased risk for venous thromboembolism, especially after surgery. Despite limited evidence, morbidly obese patients are often administered a double dose of nadroparin for thromboprophylaxis compared to non-obese patients. The aim of this study was to evaluate the influence of different body size descriptors on anti-Xa levels after a double dose of nadroparin (5,700 IU) in morbidly obese patients. METHODS: In 27 morbidly obese patients with a mean total body weight of 148 kg (range 107-260 kg), anti-Xa levels were determined peri-operatively until 24 h after administration of a subcutaneous dose of 5,700 IU of nadroparin. RESULTS: Anti-Xa level 4 h after administration (A(4h), mean 0.22 ± 0.07 IU/ml) negatively correlated strongly with lean body weight (r = -0.66 (p 0.001)) and moderately with total body weight (r = -0.56 (p = 0.003)) and did not correlate with body mass index (r = -0.26 (p = 0.187)). The area under the anti-Xa level-time curve from 0 to 24 h (AUA(0-24h), mean 2.80 ± 0.97 h IU/ml) correlated with lean body weight (r = -0.63 (p = 0.007)), but did not correlate with total body weight (r = -0.44 (p = 0.075)) or body mass index (r = -0.10 (p = 0.709)). CONCLUCIONS: Following a subcutaneous dose of nadroparin 5,700 IU, A(4h) and AUA(0-24h) were found to negatively correlate strongly with lean body weight. From these results, individualized dosing of nadroparin based on lean body weight should be considered in morbidly obese patients.

Background and Objectives: In view of the increasing prevalence of morbidly obese patients, the influence of excessive total bodyweight (TBW) on the pharmacokinetics and pharmacodynamics of propofol was characterized in this study using bispectral index (BIS) values as a pharmacodynamic endpoint. Methods: A population pharmacokinetic and pharmacodynamic model was developed with the nonlinear mixed-effects modelling software NONMEM VI, on the basis of 491 blood samples from 20 morbidly obese patients (TBW range 98–167 kg) and 725 blood samples from 44 lean patients (TBW range 55–98 kg) from previously published studies. In addition, 2246 BIS values from the 20 morbidly obese patients were available for pharmacodynamic analysis. Results: In a three-compartment pharmacokinetic model, TBW proved to be the most predictive covariate for clearance from the central compartment (CL) in the 20 morbidly obese patients (CL 2.33L/min × [TBW/70]^[0.72]). Similar results were obtained when the morbidly obese patients and the 44 lean patients were analysed together (CL 2.22 L/min × [TBW/70]^[0.67]). No covariates were identified for other pharmacokinetic parameters. The depth of anaesthesia in the morbidly obese patients was adequately described by a two-compartment biophase-distribution model with a sigmoid maximum possible effect (Emax) pharmacodynamic model (concentration at half-maximum effect [EC50] 2.12 mg/L) without covariates. Conclusion: We developed a pharmacokinetic and pharmacodynamic model of propofol in morbidly obese patients, in which TBW proved to be the major determinant of clearance, using an allometric function with an exponent of 0.72. For the other pharmacokinetic and pharmacodynamic parameters, no covariates could be identified.

To describe the results of 100 endoscopic posterior retroperitoneal adrenalectomies performed in the University Medical Center Utrecht, the Netherlands.Descriptive, retrospective.In the period August 1997-March 2008 100 endoscopic posterior retroperitoneal adrenalectomies were performed in the University Medical Center Utrecht. Data were collected retrospectively on patients, operations, complications and course following the procedure.In this period 88 unilateral and 6 bilateral EPRA procedures were performed in 94 patients. The most common indications for unilateral EPRA were pheochromocytoma (33), Cushing's syndrome (16) and Conn's syndrome (20). Preoperative diagnosis involved clinical examination, hormonal analysis and radiological imaging. Mean operative time was 110 min and showed a clear learning curve. The mean intraoperative blood loss was 30 ml. The median size of the lesions was 2.8 cm (range: 0.4-7.5). Conversion to open surgery was necessary in 2 patients. No major intraoperative complications occurred. Postoperative complications occurred in 7 patients, of which 2 were severe and 5 were mild. Surgical reintervention was required in 1 patient. Median postoperative stay was 3 days.In experienced hands endoscopic posterior retroperitoneal adrenalectomy appears to be a safe and effective treatment for adrenal gland lesions.

Major hepatic resections are still associated with considerable morbidity. Gut-derived bacteria and bacterial endotoxin are considered to play a central role in the pathophysiology of complications. Experimental studies suggest that bactericidal/permeability-increasing protein (BPI), which has both antibacterial and endotoxin-neutralising properties, can reduce postoperative complications.A phase II, double-blind, placebo-controlled, multicentre, dose escalation trial was conducted in patients undergoing major liver resection, and clinical outcome, infectious complications, plasma amino acid patterns, coagulation and fibrinolytic cascade systems and neutrophil functions were compared between the two treatment groups and an extra group of patients undergoing major abdominal non-hepatic surgery.Drug administration in this patient group was safe, and resulted in a significant reduction of infectious complications. Furthermore, beneficial effects were found in the postoperative amino acid ratio and fibrinolytic cascades, and rBPI21 preserved leukocyte functions.Administration of rBPI21 in patients undergoing major liver resection is well tolerated and results in improvement of both clinical and biochemical parameters.

Although Kupffer cells (KCs) are capable of producing important growth-stimulating cytokines, their role in liver regeneration following partial hepatectomy (PH) remains poorly understood.In the present study liver regeneration was studied after KC-depletion by intravenous administration of liposome-encapsulated dichloromethylene-diphosphonate (C12MDP), a method known to physically eliminate KCs. Furthermore, splenectomy was performed one week prior to PH to exclude the effect of C12MDP-liposomes on macrophage populations in the spleen.KC-depletion was confirmed in cryostat liver sections stained with the monoclonal antibody ED2, a marker for resident tissue macrophages. Forty-eight hours after PH, the cumulative hepatocyte DNA synthesis, as determined in liver sections by the hepatocyte bromodeoxyuridine labeling index, was significantly decreased in KC-depleted rats when compared to control-rats. The weight of the remnant liver, expressed as a percentage of the initial liver weight, was significantly less at 96 h after PH in KC-depleted rats. KC-depletion abolished the hepatic interleukin-6 (IL-6) and interleukin-10 (IL-10) mRNA synthesis and decreased hepatic expression of tumor necrosis factor-alpha (TNF-alpha), hepatocyte growth factor (HGF) and transforming growth factor-beta1(TGF-beta1) mRNA after PH, as was assessed by reverse-transcriptase polymerase chain reaction (RT-PCR). Moreover, at 4 h after PH the systemic release of IL-6 was significantly decreased in KC-depleted rats.We conclude that KCs are important for hepatocyte regeneration after PH. Delayed liver regeneration in KC-depleted rats can be explained, at least in part, by an imbalanced hepatic cytokine expression, thereby suppressing important growth-stimulating cytokines.