Dominique Lisa Birrer

Background: Hepatic surgery rests on the unique, however limited regenerative capacity of the liver. Metabolic duties may be a key factor regulating proliferative abilities of hepatocytes. During regeneration, division of labor leads to spatial separation of proliferation from metabolic tasks, suggesting these opposing activities compete for space. Here, we exploited two-stage-hepatectomy mouse models to explore whether metabolic needs constrain the regenerative capacity of the liver. Materials and methods: Mice were subjected to sham or associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) surgery (a two-stage-hepatectomy renowned for accelerated regeneration), which leaves one fast-regenerating lobe (FLR) plus portally ligated lobes (LLs) that do not grow but have an intact arteriocentral flow. FLR and LLs were analyzed by omics approaches. Functional surgery was applied to create ALPPS variants with differing metabolic capacity. Results: The FLR and the adjacent LL displayed a similar metabolite profile which however completely diverged during the major FLR growth phase. Combined transcriptomics-metabolomics and histology assigned proliferative activities explicitly to the FLR, while LLs were enriched with metabolic tasks, establishing macroscopic division of labor. In ALPPS variants differing in ligated volume, FLR growth was increased or reduced with gain or loss of metabolic capacity, respectively, revealing control of regeneration through metabolic duties. Notably, FLRs of slow-growing variants had upregulated metabolic activities, reflecting plastic adaptation to the increased metabolic pressure coming with little ligated volume. Transcriptomics disclosed macroscopic division of labor also in human ALPPS regeneration. Conclusion: LLs act as auxiliary livers after ALPPS, enabling the FLR to focus on growth. Our findings demonstrate the functional requirement for division of labor during regeneration. This transient division roots on plastic behavior of the different lobes during ALPPS regeneration and reveals how metabolic needs define the liver’s regenerative capacity.

BACKGROUND: When Cox regression models are used to analyse time-to-event data, the proportional hazard assumption (PHA) must be reassured to obtain valid results. Transparent reporting of the statistics used is therefore essential to interpret research. This study aimed to assess the quality of statistical reporting and testing of the PHA in subgroup analysis of surgical randomised controlled trials (RCTs). METHODS: All published articles (see appendix 1) in the top quartile (25%) of surgical journals from 2019 to 2021 were screened in a literature review according to the ClarivateTM journal citation report impact factor. Subgroup analyses of surgical RCT data that used Cox models were identified. Statistical reporting was rated using a previously established 12-item PHA Reporting Score as our primary endpoint. For original surgical publications, the PHA was formally tested on reconstructed time-to-event data from Kaplan-Meier estimators. Methodological reporting quality was rated according to the CONSORT statement. Digitalisation was only possible in studies where a Kaplan-Meier estimator including numbers at risk per time interval was published. All results from the subgroup analyses were compared to primary surgical RCT reports and benchmark RCTs using Cox models published in the New England Journal of Medicine and The Lancet. RESULTS: Thirty-two studies reporting secondary subgroup analyses on surgical RCT data using Cox models were identified. Statistical reporting of surgical subgroup publications was significantly inferior compared to original benchmark publications: median PHA Reporting Score 50% (interquartile range [IQR]: 39 to 58) vs 58% (IQR: 42 to 67), p <0.001. The subgroups did not differ in comparison to primary surgical RCTs: median PHA Reporting Score 50% (IQR: 39 to 58) vs 42% (IQR: 33 to 58), p = 0.286. Adherence to the CONSORT reporting standards did significantly differ between subgroup studies and benchmark publications (p <0.001) as well as between subgroup studies and primary surgical RCT reports: 13 (12.5 to 14) vs 13 (IQR: 11 to 13), p = 0.042. CONCLUSION: Statistical methodological reporting of secondary subgroup analyses from surgical RCTs was inferior to benchmark publications but not worse than primary surgical RCT reports. A comprehensive statistical review process and statistical reporting guidelines might help improve the reporting quality.

Background Centralisation of highly specialised medicine (HSM) has changed practice and outcome in pancreatic surgery (PS) also in Switzerland. Fewer hospitals are allowed to perform pancreatic surgery according to nationally defined cut-offs. Objective We aimed to examine trends in PS in Switzerland. First, to assess opinions and expected trends among Swiss pancreatic surgeons in regard of PS practice and second, to assess the evolution of PS performance in Switzerland by a nationwide retrospective analysis. Methods First, a 26-item survey among all surgeons who performed PS in 2016 in Switzerland was performed. Then, nationwide data from 1998 to 2018 from all hospitals performing PS was analysed including centre volume, perioperative morbidity and mortality, surgical indications and utilisation of minimally invasive pancreatic surgery (MIPS). The national cut-off for regulatory accredited volume centres (AVC) was ≥ 12. Additionally, an international benchmark definition for high volume (≥ 20 surgeries/year) was used. Results Among 25 surgeons from 15 centres (response rate 51%), the survey revealed agreement that centralisation is important to improve perioperative outcomes. Respondents agreed on a minimum case load per surgeon or centre. Within the nationwide database, 8534 pancreatic resections were identified. Most resections were performed for pancreatic ductal adenocarcinoma (58.9%). There was a significant trend towards centralisation of PS with fewer non-accredited volume centres (nAVC) (36 in 1998 and 17 in 2018, p < 0.001) and more AVC (2 in 1998 and 18 in 2018, p < 0.001). A significantly higher adjusted mortality after pancreatoduodenectomy (PD) was observed in low-volume compared to high-volume hospitals (OR 1.45 [95% CI 1.15–1.84], p = 0.002) and a similar trend compared among AVC and nAVC (OR 1.25 [95% CI 0.98–1.60], p = 0.072), while mortality after distal pancreatectomy (DP) was not influenced by centre volume. Conclusions Over the last two decades, centralisation of PS towards higher-volume centres was observed in Switzerland with a decrease of mortality after PD and low mortality after DP. Further centralisation is supported by most pancreatic surgeons. However, the ideal metric and outcome measures for the allocation of highly specialised medicine need further discussion to allow a fair and outcome-focused allocation.

Background: Rehabilitation strategies after abdominal surgery enhance recovery and improve outcome. A cornerstone of rehabilitation is respiratory physiotherapy with inspiratory muscle training to enhance pulmonary function. Pre-habilitation is the process of enhancing functional capacity before surgery in order to compensate for the stress of surgery and postoperative recovery. There is growing interest in deploying pre-habilitation interventions prior to surgery. The aim of this study is to assess the impact of preoperative inspiratory muscle training on postoperative overall morbidity. The question is, whether inspiratory muscle training prior to elective abdominal surgery reduces the number of postoperative complications and their severity grade. Methods: We describe a prospective randomized-controlled single-centre trial in a tertiary referral centre. The primary outcome is the Comprehensive Complication Index (CCI) at 90 days after surgery. The CCI expresses morbidity on a continuous numeric scale from 0 (no complication) to 100 (death) by weighing all postoperative complications according to the Clavien-Dindo classification for their respective severity. In the intervention group, patients will be instructed by physiotherapists to perform inspiratory muscle training containing of 30 breaths twice a day for at least 2 weeks before surgery using Power®Breathe KHP2. Depending on the surgical schedule, training can be extended up to 6 weeks. In the control group, no preoperative inspiratory muscle training will be performed. After the operation, both groups receive the same physiotherapeutic support. Discussion: Existing data about preoperative inspiratory muscle training on postoperative complications are ambiguous and study protocols are often lacking a clear design and a clearly defined endpoint. Most studies consist of multi-stage concepts, comprehensively supervised and long-term interventions, whose implementation in clinical practice is hardly possible. There is a clear need for randomized-controlled studies with a simple protocol that can be easily transferred into clinical practice. This study examines the effortless adjustment of the common respiratory physiotherapy from currently postoperative to preoperative. The external measurement by the device eliminates the diary listing of patients’ performances and allows the exercise adherence and thus the effect to be objectively recorded. Trial registration: ClinicalTrials.gov NCT04558151. Registered on September 15, 2020.

Background: The aim of this study was to evaluate if the time of day a cholecystectomy was performed affects in‐hospital complication rates and mortality.Methods: A national quality measurement database was retrospectively studied. Study period was 2010 to 2017. The inclusion criteria were operatively treated cholecystitis or another benign disease of the gallbladder. Further, the time of day the operation was performed must have been documented. We defined nighttime as all interventions performed between 7PM until 6AM. A total of 11′459 patients were included. Development of any complication during hospitalization and in‐hospital mortality was the main outcomes. The first part of the study was solely descriptive. In the second part, we applied a 1:1 case–control‐matching. A matched group of 274 pairs were further investigated.Results: Only 8.4% of the procedures were performed during nighttime. Complications occurred in 6.7% of all patients. We found twice as many complications in the nighttime group compared to the daytime group. Mortality was 0.56% during daytime and 0.52% during nighttime. In a matched‐pair analysis, however, we found no significant differences in the overall mortality rate nor in the occurrence of complications when comparing day‐ vs. nighttime operations.Conclusions: We found twice as many complications in the nighttime group (12%) compared to the daytime group (6.1%), mainly related to patient risk factors. In contrast to common apprehension, however, nighttime cholecystectomies were not associated with higher mortality rates.

Acute appendicitis is among the most common indications for emergency abdominal surgery. The risk of perforation might increase with a delay in treatment. Therefore, appendicitis is considered a surgical emergency, leading to appendectomies being frequently performed off-hours. However, numerous studies from other medical specialties have shown less favourable outcomes in patients admitted or treated off-hours than in those treated during regular working hours. The purpose of this study was to determine whether the time of day of the procedure and preoperative delay in appendectomy have significant impacts on morbidity and mortality rates. All appendectomies recorded in a prospective national quality measurement database (Arbeitsgemeinschaft für Qualitätssicherung in der Chirurgie (AQC)) between 2010 and 2017 were retrospectively analysed. The inclusion criteria were appendicitis (International Classification of Diseases diagnostic codes K35-K37), surgical treatment (appendectomy), and available information on the time of day the appendectomy was performed. We stratified patients into four groups according to the start of the operation-'MORNING' for surgeries started between 7:00 a.m. and 12:59 p.m., 'AFTERNOON' for surgeries started between 1:00 p.m. and 6:59 p.m., 'EVENING' for surgeries started between 7:00 p.m. and 11:59 p.m., and 'NIGHT' for surgeries started between midnight and 6:59 a.m. In a further analysis, we examined differences between patients who underwent surgery on the admission day and those who underwent surgery later. A total of 9224 patients with a mean age of 36 ± 19 years (54% men) were included and further analysed. The occurrence of any complication was the primary outcome, whereas in-hospital mortality was the secondary outcome. Variables were entered into bivariate and multivariate analyses. Of the appendectomies, 38% were performed during the afternoon, 31% in the evening, 18% in the morning, and 13% at night-time. Patients who underwent surgery at night had slightly lower American Society of Anesthesiologists scores, were more often managed as emergency cases (98% of the cases), had fewer comorbidities, and were more often covered by statutory instead of private health insurance than the other patients. Junior attending and resident surgeons performed 88% of all night-time operations. The average duration of surgery was not significantly longer in the night-time group than in the day-time groups. The overall complication rate was 4.7%, ranging from 3.5% in the 'NIGHT' group to 5.0% in the 'AFTERNOON' group. However, the differences between the groups were not significant. The in-hospital mortality rate was 0.12% (n = 11), ranging from 0.082% (n = 1) in the 'NIGHT' group to 0.17% (n = 5) in the 'EVENING' group. The timing of appendectomy was not associated with mortality. However, the rates of complications, in-hospital mortality, and conversion were all significantly higher in patients with a preoperative delay of >24 h. The time of day of performing an appendectomy does not seem have any significant effect on complication and mortality rates. However, a longer length of preoperative stay significantly increases the risk of complications and mortality. Night-time operations should be preferred over next-day surgery considering the equal perioperative risks observed in this study.