Jens Neudecker

Efficacy of stapler versus hand-sewn closure after distal pancreatectomy (DISPACT): a randomised, controlled multicentre trial

BACKGROUND The ideal closure technique of the pancreas after distal pancreatectomy is unknown. We postulated that standardised closure with a stapler device would prevent pancreatic fistula more effectively than would a hand-sewn closure of the remnant. METHODS This multicentre, randomised, controlled, parallel group-sequential superiority trial was done in 21 European hospitals. Patients with diseases of the pancreatic body and tail undergoing distal pancreatectomy were eligible and were randomly assigned by central randomisation before operation to either stapler or hand-sewn closure of the pancreatic remnant. Surgical performance was assessed with intraoperative photo documentation. The primary endpoint was the combination of pancreatic fistula and death until postoperative day 7. Patients and outcome assessors were masked to group assignment. Interim and final analysis were by intention to treat in all patients in whom a left resection was done. This trial is registered, ISRCTN18452029. FINDINGS Between Nov 16, 2006, and July 3, 2009, 450 patients were randomly assigned to treatment groups (221 stapler; 229 hand-sewn closure), of whom 352 patients (177 stapler, 175 hand-sewn closure) were analysed. Pancreatic fistula rate or mortality did not differ between stapler (56 [32%] of 177) and hand-sewn closure (49 [28%] of 175; OR 0·84, 95% CI 0·53–1·33; p=0·56). One patient died within the fi rst 7 days after surgery in the hand-sewn group; no deaths occurred in the stapler group. Serious adverse events did not differ between groups. INTERPRETATION Stapler closure did not reduce the rate of pancreatic fistula compared with hand-sewn closure for distal pancreatectomy. New strategies, including innovative surgical techniques, need to be identified to reduce this adverse outcome. FUNDING German Federal Ministry of Education and Research.

Influenza A Viruses Target Type II Pneumocytes in the Human Lung

Abstract Background. Highly pathogenic avian H5N1 influenza viruses preferentially infect alveolar type II pneumocytes in human lung. However, it is unknown whether this cellular tropism contributes to high viral virulence because the primary target cells of other influenza viruses have not been systematically studied. Methods. We provide the first comparison of the replication, tropism, and cytokine induction of human, highly pathogenic avian influenza A virus subtype H5N1 and other animal influenza A viruses in primary human lung organ cultures. Results. Subytpe H5N1 and human-adapted subtype H1N1 and H3N2 viruses replicated efficiently in the lung tissue, whereas classic swine and low-pathogenicity avian viruses propagated only poorly. Nevertheless, all viruses examined were detected almost exclusively in type II pneumocytes, with a minor involvement of alveolar macrophages. Infection with avian viruses that have a low and high pathogenicity provoked a pronounced induction of cytokines and chemokines, while human and pandemic H1N1-2009 viruses triggered only weak responses. Conclusions. These findings show that differences in the pathogenic potential of influenza A viruses in the human lung cannot be attributed to a distinct cellular tropism. Rather, high or low viral pathogenicity is associated with a strain-specific capacity to productively replicate in type II pneumocytes and to cope with the induced cytokine response.

Effectiveness of triclosan-coated PDS Plus versus uncoated PDS II sutures for prevention of surgical site infection after abdominal wall closure: the randomised controlled PROUD trial

BACKGROUND Postoperative surgical site infections are one of the most frequent complications after open abdominal surgery, and triclosan-coated sutures were developed to reduce their occurrence. The aim of the PROUD trial was to obtain reliable data for the effectiveness of triclosan-coated PDS Plus sutures for abdominal wall closure, compared with non-coated PDS II sutures, in the prevention of surgical site infections. METHODS This multicentre, randomised controlled group-sequential superiority trial was done in 24 German hospitals. Adult patients (aged ≥18 years) who underwent elective midline abdominal laparotomy for any reason were eligible for inclusion. Exclusion criteria were impaired mental state, language problems, and participation in another intervention trial that interfered with the intervention or outcome of this trial. A central web-based randomisation tool was used to randomly assign eligible participants by permuted block randomisation with a 1:1 allocation ratio and block size 4 before mass closure to either triclosan-coated sutures (PDS Plus) or uncoated sutures (PDS II) for abdominal fascia closure. The primary endpoint was the occurrence of superficial or deep surgical site infection according to the Centers for Disease Control and Prevention criteria within 30 days after the operation. Patients, surgeons, and the outcome assessors were masked to group assignment. Interim and final analyses were by modified intention to treat. This trial is registered with the German Clinical Trials Register, number DRKS00000390. FINDINGS Between April 7, 2010, and Oct 19, 2012, 1224 patients were randomly assigned to intervention groups (607 to PDS Plus, and 617 to PDS II), of whom 1185 (587 PDS Plus and 598 PDS II) were analysed by intention to treat. The study groups were well balanced in terms of patient and procedure characteristics. The occurrence of surgical site infections did not differ between the PDS Plus group (87 [14·8%] of 587) and the PDS II group (96 [16·1%] of 598; OR 0·91, 95% CI 0·66-1·25; p=0·64). Serious adverse events also did not differ between the groups-146 of 583 (25·0%) patients treated with PDS Plus had at least one serious adverse event, compared with 138 of 602 (22·9%) patients treated with PDS II; p=0·39). INTERPRETATION Triclosan-coated PDS Plus did not reduce the occurrence of surgical site infection after elective midline laparotomy. Innovative, multifactorial strategies need to be developed and assessed in future trials to reduce surgical site infections. FUNDING Johnson & Johnson Medical Limited.

Emerging Human Middle East Respiratory Syndrome Coronavirus Causes Widespread Infection and Alveolar Damage in Human Lungs

Acknowledgment: The authors are grateful to Rosalind Simmonds, the staff within the Nuclear Medicine and Histopathology Department at Addenbrooke’s Hospital, and the Wellcome Trust Clinical Research Facility, Cambridge. They acknowledge the help of the Histopathology Departments at the Royal Brompton and Princess Alexandra Hospitals. They also thank the Cambridge Biomedical Research Centre and BRC Core Biochemistry Assay Laboratory and acknowledge the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network. The study was approved by Cambridgeshire Research Ethics Committee (09/H0308/ 119) and the Administration of Radioactive Substances Advisory Committee of the UK (83/3130/25000).

The Novel Human Influenza A(H7N9) Virus Is Naturally Adapted to Efficient Growth in Human Lung Tissue

ABSTRACT A novel influenza A virus (IAV) of the H7N9 subtype has been isolated from severely diseased patients with pneumonia and acute respiratory distress syndrome and, apparently, from healthy poultry in March 2013 in Eastern China. We evaluated replication, tropism, and cytokine induction of the A/Anhui/1/2013 (H7N9) virus isolated from a fatal human infection and two low-pathogenic avian H7 subtype viruses in a human lung organ culture system mimicking infection of the lower respiratory tract. The A(H7N9) patient isolate replicated similarly well as a seasonal IAV in explanted human lung tissue, whereas avian H7 subtype viruses propagated poorly. Interestingly, the avian H7 strains provoked a strong antiviral type I interferon (IFN-I) response, whereas the A(H7N9) virus induced only low IFN levels. Nevertheless, all viruses analyzed were detected predominantly in type II pneumocytes, indicating that the A(H7N9) virus does not differ in its cellular tropism from other avian or human influenza viruses. Tissue culture-based studies suggested that the low induction of the IFN-β promoter correlated with an efficient suppression by the viral NS1 protein. These findings demonstrate that the zoonotic A(H7N9) virus is unusually well adapted to efficient propagation in human alveolar tissue, which most likely contributes to the severity of lower respiratory tract disease seen in many patients. IMPORTANCE Humans are usually not infected by avian influenza A viruses (IAV), but this large group of viruses contributes to the emergence of human pandemic strains. Transmission of virulent avian IAV to humans is therefore an alarming event that requires assessment of the biology as well as pathogenic and pandemic potentials of the viruses in clinically relevant models. Here, we demonstrate that an early virus isolate from the recent A(H7N9) outbreak in Eastern China replicated as efficiently as human-adapted IAV in explanted human lung tissue, whereas avian H7 subtype viruses were unable to propagate. Robust replication of the H7N9 strain correlated with a low induction of antiviral beta interferon (IFN-β), and cell-based studies indicated that this is due to efficient suppression of the IFN response by the viral NS1 protein. Thus, explanted human lung tissue appears to be a useful experimental model to explore the determinants facilitating cross-species transmission of the H7N9 virus to humans. Humans are usually not infected by avian influenza A viruses (IAV), but this large group of viruses contributes to the emergence of human pandemic strains. Transmission of virulent avian IAV to humans is therefore an alarming event that requires assessment of the biology as well as pathogenic and pandemic potentials of the viruses in clinically relevant models. Here, we demonstrate that an early virus isolate from the recent A(H7N9) outbreak in Eastern China replicated as efficiently as human-adapted IAV in explanted human lung tissue, whereas avian H7 subtype viruses were unable to propagate. Robust replication of the H7N9 strain correlated with a low induction of antiviral beta interferon (IFN-β), and cell-based studies indicated that this is due to efficient suppression of the IFN response by the viral NS1 protein. Thus, explanted human lung tissue appears to be a useful experimental model to explore the determinants facilitating cross-species transmission of the H7N9 virus to humans.

Comparison of EORTC Quality of Life Core Questionnaire (EORTC-QLQ-C30) and Gastrointestinal Quality of Life Index (GIQLI) in patients undergoing elective colorectal cancer resection

BackgroundEORTC-QLQ-C30 questionnaires and GIQLI questionnaires are used to evaluate post-operative quality of life (QoL). It was not clear whether results of both instruments are comparable. Therefore, the level of agreement between both QoL questionnaires was evaluated in patients undergoing elective colorectal cancer resection.MethodsPre-operatively, 7 and 30 days after surgery 116 patients answered the EORTC-QLQ-C-30 and the GIQLI questionnaires in random order. Individual questions with similar content from each questionnaire were compared. Data for global QoL, physical (PF), emotional (EF) and social function (SF) were linearly transformed to fit a scale from 0 to 100. Data from the two instruments were correlated and the level of agreement between them was calculated according to the method of Bland and Altman.ResultsA total of 308 data sets [(pre-op. n=116; 7th pod n=101; 30th post-operative day (pod) n=91)] were evaluated. Both instruments detected a reversible reduction of QoL after surgery and gave inferior results for patients with conditions known to impair QoL. EORTC-QLQ-C30 was more sensitive than GIQLI. The correlation between the two questionnaires for global QoL, PF and EF was good (r=0.53–0.66, p<0.01), but no correlation for SF was detected (r=−0.44, p=0.44). Linearly transformed scores from the two instruments differed considerably from −13 (95%CI −51 to 24) points (QoL) to 10 (−38 to 58) points (PF).ConclusionAlthough EORTC-QLQ-C30 scores and GIQLI scores from patients undergoing elective colorectal cancer surgery did correlate well, the level of agreement between the two instruments was quite low. Perioperative QoL data from the two instruments cannot be compared with each other.

Streptococcus pneumoniae-induced regulation of cyclooxygenase-2 in human lung tissue

The majority of cases of community-acquired pneumonia are caused by Streptococcus pneumoniae and most studies on pneumococcal host interaction are based on cell culture or animal experiments. Thus, little is known about infections in human lung tissue. Cyclooxygenase-2 and its metabolites play an important regulatory role in lung inflammation. Therefore, we established a pneumococcal infection model on human lung tissue demonstrating mitogen-activated protein kinase (MAPK)-dependent induction of cyclooxygenase-2 and its related metabolites. In addition to alveolar macrophages and the vascular endothelium, cyclooxygenase-2 was upregulated in alveolar type II but not type I epithelial cells, which was confirmed in lungs of patients suffering from acute pneumonia. Moreover, we demonstrated the expression profile of all four E prostanoid receptors at the mRNA level and showed functionality of the E prostanoid4 receptor by cyclic adenosine monophosphate production. Additionally, in comparison to previous studies, cyclooxygenase-2/prostaglandin E2 related pro- and anti-inflammatory mediator regulation was partly confirmed in human lung tissue after pneumococcal infection. Overall, cell type-specific and MAPK-dependent cyclooxygenase-2 expression and prostaglandin E2 formation in human lung tissue may play an important role in the early phase of pneumococcal infections.

Prevention of abdominal wound infection (PROUD trial, DRKS00000390): study protocol for a randomized controlled trial

BackgroundWound infection affects a considerable portion of patients after abdominal operations, increasing health care costs and postoperative morbidity and affecting quality of life. Antibacterial coating has been suggested as an effective measure to decrease postoperative wound infections after laparotomies. The INLINE metaanalysis has recently shown the superiority of a slowly absorbable continuous suture for abdominal closure; with PDS plus® such a suture has now been made available with triclosan antibacterial coating.Methods/DesignThe PROUD trial is designed as a randomised, controlled, observer, surgeon and patient blinded multicenter superiority trial with two parallel groups and a primary endpoint of wound infection during 30 days after surgery. The intervention group will receive triclosan coated polydioxanone sutures, whereas the control group will receive the standard polydioxanone sutures; abdominal closure will otherwise be standardized in both groups. Statistical analysis is based on intention-to-treat population via binary logistic regression analysis, the total sample size of n = 750 is sufficient to ensure alpha = 5% and power = 80%, an interim analysis will be carried out after data of 375 patients are available.DiscussionThe PROUD trial will yield robust data to determine the effectiveness of antibacterial coating in one of the standard sutures for abdominal closure and potentially lead to amendment of current guidelines. The exploration of clinically objective parameters as well as quality of life holds immediate relevance for clinical management and the pragmatic trial design ensures high external validity.Trial RegistrationThe trial protocol has been registered with the German Clinical Trials Register (DRKS00000390).

Systematic evaluation of different approaches for minimizing hemodynamic changes during pneumoperitoneum

BackgroundCapnoperitoneum (CP) compromises hemodynamic function during laparoscopy. Three therapeutic concepts were evaluated with an aim to minimize the hemodynamic reaction to CP: First, a controlled increase of intrathoracic blood volume (ITBV) by intravenous fluids; second, partially reduced sympathetic activity by the β1-blocker esmolol; and third, a decrease in mean arterial pressure (MAP) by the vasodilator sodium nitroprusside.MethodsFor this study, 43 pigs were assigned to treatment with fluid and sodium nitroprusside (group A) or with esmolol (group B). In both groups, the pigs were assigned to head-up, head-down, or supine position, resulting in three different subgroups. Invasive hemodynamic monitoring was established including left heart catheter and cardiac oxygen lung water determination (COLD) measurements. Measurements were documented before CP with the animals in supine position, after induction of a 14-mmHg CP with the animals in each body position, after a 10% reduction in MAP by vasodilation, and after an increase in ITBV of about 30% by infusion of 6% hydroxyethylstarch solution.ResultsIncreasing ITBV improved hemodynamic function in all body positions during CP. Esmolol reduced cardiac output and myocardial contractility. Sodium nitroprusside did not improve hemodynamic function in any body position.ConclusionsOptimizing volume load is effective for minimizing hemodynamic changes during CP in the head-up and in head-down positions. In general, β1-blockers cannot be recommended because they might additionally compromise myocardial contractility and suppress compensatory reaction of the sympathetic nerve system. Vasodilation has not improved hemodynamic parameters during CP.

Article originalRéhabilitation rapide en chirurgie colique : résultats d'une étude prospectiveFast track rehabilitation in colonic surgery: results of a prospective trial

Objective. – In elective large bowel surgery the incidence of general complications with standard perioperative care is up to 27%. Hospital discharge occurs 10 to 15 days after a conventional or laparoscopic colonic resection. The aim of a fast track management is to reduce the number of general complications and the length of hospital stay. Material and methods. – We prospectively evaluated a multimodal protocol in our service utilizing a combined thoracic epidural analgesia, an early mobilization and oral nutrition to accelerate postoperative recovery after elective colonic surgery. Results. – One hundred thirty-two consecutive patients aged an average of 66 years (range 22–88) were operated by laparotomy (n =71) or laparoscopy (n =61) and treated with the fast track rehabilitation protocol. Surgical complications occurred in 15 patients (11 %), four of these had an anastomotique leakage (3%). General complications occurred in 11 patients (8 %), the mortality was 1 %. The median length of hospital stay was four days (range 3–77) and 14 patients (11%) had to be readmitted. Conclusion. – Application of a fast track rehabilitation protocol lowered the number of general complications and reduced the duration of hospital stay in our study.