Impact of hypoalbuminemia on outcomes following pancreaticoduodenectomy: a NSQIP retrospective cohort analysis of 25,848 patients.

BACKGROUND: Efforts to preoperatively risk stratify and optimize patients before pancreaticoduodenectomy continue to improve outcomes. This study aims to determine the impact of hypoalbuminemia on outcomes following pancreaticoduodenectomy and outline optimal hypoalbuminemia cut-off values in this population. METHODS: The ACS-NSQIP (2016-2021) database was used to extract patients who underwent pancreaticoduodenectomy, comparing those with hypoalbuminemia (< 3.0 g/L) to those with normal albumin. Demographics and 30-day outcomes were compared. Multivariable modeling evaluated factors including hypoalbuminemia to characterize their independent effect on serious complications, and mortality. Optimal albumin cut-offs for serious complications and mortality were evaluated using receiver-operating characteristic curves. RESULTS: We evaluated 25,848 pancreaticoduodenectomy patients with 2712 (10.5%) having preoperative hypoalbuminemia. Patients with hypoalbuminemia were older (68.2 vs. 65.1; p < 0.0001), and were significantly more likely to be ASA class 4 or higher (13.9% vs. 6.7%; p < 0.0001). Patients with hypoalbuminemia had significantly more 30-day complications and after controlling for comorbidities hypoalbuminemia remained a significant independent factor associated with 30-day serious complications (OR 1.80, p < 0.0001) but not mortality (OR 1.37, p = 0.152). CONCLUSIONS: Hypoalbuminemia plays a significant role in 30-day morbidity following pancreaticoduodenectomy. Preoperative albumin may serve as a useful marker for risk stratification and optimization.

Persistent hyperbilirubinemia following preoperative biliary stenting in patients undergoing anatomic hepatectomy predicts serious complications.

BACKGROUND: Biliary obstruction before liver resection is a known risk factor for post-operative complications. The aim of this study was to determine the impact of persistent hyperbilirubinemia following preoperative biliary drainage before liver resection. METHODS: The ACS-NSQIP (2016-2021) database was used to extract patients with cholangiocarcinoma who underwent anatomic liver resection with preoperative biliary drainage comparing those with persistent hyperbilirubinemia (> 1.2 mg/dL) to those with resolution. Patient characteristics and outcomes were compared with bivariate analysis. Multivariable modeling evaluated factors including persistent hyperbilirubinemia to evaluate their independent effect on serious complications, liver failure, and mortality. RESULTS: We evaluated 463 patients with 217 (46.9%) having hyperbilirubinemia (HB) despite biliary stenting. Bivariate analysis demonstrated that patients with HB had a higher rate of serious complications than those with non-HB (80.7% vs 70.3%; P = 0.010) including bile leak (40.9% vs 31.8%; P = 0.045), liver failure (26.7% vs 17.9%; P = 0.022), and bleeding (48.4% vs 36.6%; P = 0.010). Multivariable analysis demonstrated that persistent HB was independently associated with serious complications (OR 1.88, P = 0.020) and mortality (OR 2.39, P = 0.049) but not post-operative liver failure (OR 1.65, P = 0.082). CONCLUSIONS: Failed preoperative biliary decompression is a predictive factor for post-operative complications and mortality in patients undergoing hepatectomy and may be useful for preoperative risk stratification.

Long-term outcomes after normothermic machine perfusion in liver transplantation-Experience at a single North American center.

Normothermic machine perfusion (NMP) has emerged as a valuable tool in the preservation of liver allografts before transplantation. Randomized trials have shown that replacing static cold storage (SCS) with NMP reduces allograft injury and improves graft utilization. The University of Alberta's liver transplant program was one of the early adopters of NMP in North America. Herein, we describe our 7-year experience applying NMP to extend preservation time in liver transplantation using a "back-to-base" approach. From 2015 to 2021, 79 livers were transplanted following NMP, compared with 386 after SCS only. NMP livers were preserved for a median time of minutes compared with minutes in the SCS cohort (P < .0001). Despite this, we observed significantly improved 30-day graft survival (P = .030), although there were no differences in long-term patient survival, major complications, or biliary or vascular complications. We also found that although SCS time was strongly associated with increased graft failure at 1 year in the SCS cohort (P = .006), there was no such association among NMP livers (P = .171). Our experience suggests that NMP can safely extend the total preservation time of liver allografts without increasing complications.

Trends in types of graduate degrees and research output for academic general surgeons in Canada.

SummaryThe proportion of general surgeons with graduate degrees in Canada is increasing. We sought to evaluate the types of graduate degree held by surgeons in Canada, and whether differences in publication capacity exist. We evaluated all general surgeons working at English-speaking Canadian academic hospitals to determine the types of degrees achieved, changes over time and research output associated with each degree. We identified 357 surgeons, of whom 163 (45.7 %) had master's degrees and 49 (13.7 %) had PhDs. Achievement of graduate degrees increased over time, with more surgeons earning master's degrees in public health (MPH), clinical epidemiology and education (MEd), and fewer master's degrees in science (MSc) or PhDs. Most publication metrics were similar by degree type, but surgeons with PhDs published more basic science research than those with clinical epidemiology, MEd or MPH degrees (2.0 v. 0.0, p < 0.05); surgeons with clinical epidemiology degrees published more first-author articles than surgeons with MSc degrees (2.0 v. 0.0, p = 0.007). An increasing number of general surgeons hold graduate degrees, with fewer pursuing MSc and PhD degrees, and more holding MPH or clinical epidemiology degrees. Research productivity is similar for all groups. Support to pursue diverse graduate degrees could enable a greater breadth of research.

Cost-utility analysis of normothermic machine perfusion compared to static cold storage in liver transplantation in the Canadian setting.

To estimate the incremental cost-effectiveness of a liver transplant program that utilizes normothermic machine perfusion (NMP) alongside static cold storage (SCS) compared to SCS alone (control). A Markov model compared strategies (NMP vs. control) using 1-year cycle lengths over a 5-year time horizon from the public healthcare payer perspective. Primary micro-costing data from a single center retrospective trial were applied along with utility values from literature sources. Transition probabilities were deduced using the retrospective trial cohort, local transplant data, and supplemented with literature values. Scenario and probabilistic sensitivity analysis (PSA) were conducted. The NMP strategy was cost-effective in comparison to the control strategy, which was dominated. The mean cost for NMP was $456 455 (2021 US$) and the control was $519 222. The NMP strategy had greater incremental quality-adjusted life years (QALYs) gains over 5 years compared to the control, with 3.48 versus 3.17, respectively. The overarching results remained unchanged in scenario analysis. In PSA, NMP was cost-effective in 63% of iterations at a willingness-to-pay threshold of $40 941. The addition of NMP to a liver transplant program results in greater QALY gains and is cost-effective from the public healthcare payer perspective.

Use of the Molecular Adsorbent Recirculating System in Acute Liver Failure: Results of a Multicenter Propensity Score-Matched Study.

OBJECTIVES: The molecular adsorbent recirculating system removes water-soluble and albumin-bound toxins and may be beneficial for acute liver failure patients. We compared the rates of 21-day transplant-free survival in acute liver failure patients receiving molecular adsorbent recirculating system therapy and patients receiving standard medical therapy. DESIGN: Propensity score-matched retrospective cohort analysis. SETTING: Tertiary North American liver transplant centers. PATIENTS: Acute liver failure patients receiving molecular adsorbent recirculating system at three transplantation centers (n = 104; January 2009-2019) and controls from the U.S. Acute Liver Failure Study Group registry. INTERVENTIONS: Molecular adsorbent recirculating system treatment versus standard medical therapy (control). MEASUREMENTS AND MAIN RESULTS: One-hundred four molecular adsorbent recirculating system patients were propensity score-matched (4:1) to 416 controls. Using multivariable conditional logistic regression adjusting for acute liver failure etiology (acetaminophen: n = 248; vs nonacetaminophen: n = 272), age, vasopressor support, international normalized ratio, King's College Criteria, and propensity score (main model), molecular adsorbent recirculating system was significantly associated with increased 21-day transplant-free survival (odds ratio, 1.90; 95% CI, 1.07-3.39; p = 0.030). This association remained significant in several sensitivity analyses, including adjustment for acute liver failure etiology and propensity score alone ("model 2"; molecular adsorbent recirculating system odds ratio, 1.86; 95% CI, 1.05-3.31; p = 0.033), and further adjustment of the "main model" for mechanical ventilation, and grade 3/4 hepatic encephalopathy ("model 3"; molecular adsorbent recirculating system odds ratio, 1.91; 95% CI, 1.07-3.41; p = 0.029). In acetaminophen-acute liver failure (n = 51), molecular adsorbent recirculating system was associated with significant improvements (post vs pre) in mean arterial pressure (92.0 vs 78.0 mm Hg), creatinine (77.0 vs 128.2 µmol/L), lactate (2.3 vs 4.3 mmol/L), and ammonia (98.0 vs 136.0 µmol/L; p ≤ 0.002 for all). In nonacetaminophen acute liver failure (n = 53), molecular adsorbent recirculating system was associated with significant improvements in bilirubin (205.2 vs 251.4 µmol/L), creatinine (83.1 vs 133.5 µmol/L), and ammonia (111.5 vs 140.0 µmol/L; p ≤ 0.022 for all). CONCLUSIONS: Treatment with molecular adsorbent recirculating system is associated with increased 21-day transplant-free survival in acute liver failure and improves biochemical variables and hemodynamics, particularly in acetaminophen-acute liver failure.

Surgical outcomes and quality of life following exercise-based prehabilitation for hepato-pancreatico-biliary surgery: A systematic review and meta-analysis.

BACKGROUND: Hepato-pancreatico-biliary (HPB) patients experience significant risk of preoperative frailty. Studies assessing preventative prehabilitation in HPB populations are limited. This systematic review and meta-analysis evaluates outcomes for HPB patients treated with exercise prehabilitation. DATA SOURCES: A comprehensive search of MEDLINE (via Ovid), Embase (Ovid), Scopus, Web of Science Core Collection, Cochrane Library (Wiley), ProQuest Dissertations, Theses Global, and Google Scholar was conducted with review and extraction following PRISMA guidelines. Included studies evaluated more than 5 adult HPB patients undergoing ≥ 7-day exercise prehabilitation. The primary outcome was postoperative length of stay (LOS); secondary outcomes included complications, mortality, physical performance, and quality of life. RESULTS: We evaluated 1778 titles and abstracts and selected 6 (randomized controlled trial, n = 3; prospective cohort, n = 1; retrospective cohort, n = 2) that included 957 patients. Of those, 536 patients (56.0%) underwent exercise prehabilitation and 421 (44.0%) received standard care. Patients in both groups were similar with regards to important demographic factors. Prehabilitation was associated with a 5.20-day LOS reduction (P = 0.03); when outliers were removed, LOS reduction decreased to 1.85 days and was non-statistically significant (P = 0.34). Postoperative complications (OR = 0.70; 95% CI: 0.39 to 1.26; P = 0.23), major complications (OR = 0.83; 95% CI: 0.60 to 1.14; P = 0.24), and mortality (OR = 0.67; 95% CI: 0.17 to 2.70; P = 0.57) were similar. Prehabilitation was associated with improved strength, cardiopulmonary function, quality of life, and alleviated sarcopenia. CONCLUSIONS: Exercise prehabilitation may reduce LOS and morbidity following HPB surgery. Studies with well-defined exercise regimens are needed to optimize exercise prehabilitation outcomes.

A framework for role allocation in education, research and leadership services in Canadian academic divisions of general surgery: a modified Delphi consensus.

BACKGROUND: Moving toward a funding standard similar to that for clinical services for roles essential to the functioning of education, research and leadership services within divisions of general surgery is necessary to strengthen divisional resilience. We aimed to identify roles and underlying tasks in these services central to sustainable functioning of Canadian academic divisions of general surgery. METHODS: Between June 2018 and October 2020, we used a 4-step modified Delphi method (online survey, face-to-face nominal group technique [n = 12], semistructured telephone interview [n = 8] and nominal group technique [n = 12]) to achieve national consensus from an expert panel of all 17 heads of academic divisions of general surgery in Canada on the roles and accompanying tasks essential to education, research and leadership services within an academic division of general surgery. We used 70% agreement to determine consensus. RESULTS: The expert panel agreed that a framework for role allocation in education, research and leadership services was relevant and necessary. Consensus was reached for 7 roles within the educational service, 3 roles within the research service and 5 roles within the leadership service. CONCLUSION: Our framework represents a national consensus that defines role standards for education, research and leadership services in Canadian academic divisions of general surgery. The framework can help divisions build resiliency, and enable sustained and deliberate advances in these services.

Recommendations for the Management of Incidental Pancreatic Findings in Adults by the Canadian Association of Radiologists Incidental Findings Working Group.

The Canadian Association of Radiologists Incidental Findings Working Group consists of both academic subspecialty and general radiologists and is tasked with adapting and expanding upon the American College of Radiology incidental findings white papers to more closely apply to Canadian practice patterns, particularly more comprehensively dealing with the role of ultrasound and pursuing more cost-effective approaches to the workup of incidental findings without compromising patient care. Presented here are the 2021 Canadian guidelines for the management of pancreatic incidental findings. Topics covered include anatomic variants, fatty atrophy, pancreatic calcifications, ductal ectasia, and management of incidental pancreatic cysts.

Addressing organ shortages: progress in donation after circulatory death for liver transplantation

Reducing wait list mortality among patients awaiting liver transplantation remains a substantial challenge because of organ shortage. In efforts to expand the donor pool there has been a trend toward increased use of donation after circulatory death (DCD) liver grafts. However, these marginal grafts are prone to higher complication rates, particularly biliary complications. In addition, many procured DCD livers are then deemed unsuitable for transplant. Despite these limitations, DCD grafts represent an important resource to address the current organ shortage, and as such there are research efforts directed toward improving the use of and outcomes for transplantation of these grafts. We review the current progress in DCD liver transplantation.

La réduction du nombre de personnes en attente d'une greffe de foie qui décèdent avant la transplantation demeure un défi important en raison de la pénurie d'organes. On remarque actuellement une tendance à la hausse dans l'utilisation de greffons de foie provenant de don après décès circulatoire (DDC) dans le but d'élargir le bassin de donneurs. Ces greffons marginaux sont toutefois associés à des taux de complications plus élevés, particulièrement pour ce qui est des complications biliaires. De plus, de nombreux foies obtenus à la suite d'un DDC sont jugés inadmissibles à la greffe. Malgré ces restrictions, les greffons provenant de DDC représentent une importante ressource pour atténuer la pénurie d'organes. Des initiatives de recherche sont donc actuellement en cours dans le but d'améliorer leur taux d'utilisation et les issues des transplantations. Nous analysons ici l'état actuel des progrès pour les transplantations de foie provenant de DDC.

The Impact of Muscle and Adipose Tissue on Long-term Survival in Patients With Stage I to III Colorectal Cancer.

BACKGROUND: Computed tomography-derived body composition parameters are emerging prognostic factors in colorectal cancer. OBJECTIVE: This study aimed to determine the roles of sarcopenia, myosteatosis, and obesity as independent and overlapping parameters in stage I to III colorectal cancer. DESIGN: This is a retrospective cohort study from a prospectively collected database. Multivariate Cox proportional hazards models were performed to assess the associations between body composition parameters and survival. SETTINGS: All patients were seen in a tertiary care cancer center. PATIENTS: Adult patients with stage I to III colorectal cancer, undergoing curative resection from 2007 to 2009, were included. INTERVENTION: Computed tomography-derived quantification of skeletal muscle and adipose tissues was used to determine population-specific cutoffs for sarcopenia, myosteatosis, and total adiposity. MAIN OUTCOME MEASURES: Primary outcome measures were overall, recurrence-free, and cancer-specific survival. RESULTS: In the 968 patients included, there were a total of 254 disease recurrences and 350 deaths. Body mass index and CT-derived measures of adiposity did not result in worse survival outcomes. Sarcopenia was independently predictive of worse overall (HR, 1.45; 95% CI, 1.16-1.84), recurrence-free (HR, 1.32; 95% CI, 1.00-1.75), and cancer-specific survival (HR, 1.46; 95% CI, 1.09-1.94) in a multivariate model. Myosteatosis was also independently predictive of overall survival (HR, 1.53; 95% CI, 1.19-1.97). In a model considering joint effects of sarcopenia and myosteatosis, the presence of both predicted the worst overall (HR, 2.23; 95% CI, 1.62-3.06), recurrence-free (HR, 1.53; 95% CI, 1.06-2.21), and cancer-specific survival (HR, 2.40; 95% CI, 1.69-3.42) in a multivariate model. LIMITATIONS: The limitations of this study are inherent in retrospective observational studies. CONCLUSIONS: Sarcopenia and myosteatosis are independent predictors of worse survival in stage I to III colorectal cancer, and their joint effect is highly predictive of reduced overall, recurrence-free, and cancer-specific survival. See Video Abstract at http://links.lww.com/DCR/A923.

Downstaging prior to liver transplantation for hepatocellular carcinoma: advisable but at the price of an increased risk of cancer recurrence - a retrospective study.

The use of downstaging prior to liver transplantation for hepatocellular carcinoma (HCC) still needs refinement. This study included patients with HCC listed for transplantation according to the Total Tumour Volume (TTV) ≤115 cm3 and alpha fetoprotein (AFP) ≤400 ng/ml criteria, with and without previous downstaging. Overall, 455 patients were listed, and 286 transplanted. Post-transplant follow-up was 38.5 ± 1.7 months. Patients downstaged to TTV115/AFP400 (n = 29) demonstrated similar disease-free survivals (DFS, 74% vs. 80% at 5 years, P = 0.949), but a trend to more recurrences (14% vs. 5.8%, P = 0.10) than those always within TTV115/AFP400 (n = 257). Similarly, patients downstaged to Milan criteria (n = 80) demonstrated similar DFS (76% vs. 86% at 5 years, P = 0.258), but more recurrences (11% vs. 1.7%, P = 0.001) than those always within Milan (n = 177). Among patients downstaged to Milan, those originally beyond TTV115/AFP400 (n = 27) had similar outcomes as those originally beyond Milan, but within TTV115/AFP400 (n = 53). However, the likelihood of being within Milan at transplant was lower for patients with more advanced original HCCs (P < 0.0001). Overall, despite an expected increase in post-transplant HCC recurrence, similar survivals can be achieved with and without downstaging, using the TTV115/AFP400 transplantation criteria, and including patients with advanced original HCCs. Downstaging should continue to be performed.

Barriers to the Interpretation of Body Composition in Colorectal Cancer: A Review of the Methodological Inconsistency and Complexity of the CT-Defined Body Habitus.

BACKGROUND: Measurement of body composition by computed tomography (CT) is an advancing field. Sarcopenia, myosteatosis, and visceral obesity (VO) have been identified as predictive of survival in colorectal cancer (CRC). We performed a systematic review of contemporary studies to characterize this association and highlight methodological inconsistencies. METHODS: MEDLINE and PubMed were queried for articles published from January 2000 on, with populations of resectable CRC and with CT-measured body composition and survival data. The study quality was assessed by two independent reviewers using the Newcastle-Ottawa Scale. RESULTS: Twenty studies met inclusion criteria, with a total of 8895 patients. Only two of the studies scored as high quality and nine as moderate quality. The remaining nine studies scored as low quality. Ten studies considered sarcopenia and 12 considered visceral obesity (VO). Cutoff points to define sarcopenia, myosteatosis, and VO were identified by optimal stratification, quartiles, or median values. The prevalence of sarcopenia varied from 15 to 60%, which based on study population and cutoff value used. Sarcopenia was associated with worse overall and disease-free survival in eight of the included studies. Myosteatosis was considered in three studies with a prevalence of 19-78%. It was significantly predictive of worse overall and disease-free survival in all three studies. VO had a prevalence of 14-70% and was inconsistently predictive of survival outcomes. CONCLUSIONS: There is a lack of methodological consistency within the currently published literature. Despite this, sarcopenia and myosteatosis, but not VO, are consistently associated with worse survival outcomes, when population and cancer-specific cutoffs are utilized.

Synergy of glucagon-like peptide-2 and epidermal growth factor coadministration on intestinal adaptation in neonatal piglets with short bowel syndrome.

Glucagon-like peptide-2 (GLP-2) and epidermal growth factor (EGF) treatment enhance intestinal adaptation. To determine whether these growth factors exert synergistic effects on intestinal growth and function, GLP-2 and EGF-containing media (EGF-cm) were administered, alone and in combination, in neonatal piglet models of short bowel syndrome (SBS). Neonatal Landrace-Large White piglets were block randomized to 75% midintestinal [jejunoileal (JI) group] or distal intestinal [jejunocolic (JC) group] resection or sham control, with 7-day infusion of saline (control), intravenous human GLP-2 (11 nmol·kg-1·day-1) alone, enteral EGF-cm (80 µg·kg-1·day-1) alone, or GLP-2 and EGF-cm in combination. Adaptation was assessed by intestinal length, histopathology, Üssing chamber analysis, and real-time quantitative PCR of intestinal growth factors. Combined EGF-cm and GLP-2 treatment increased intestinal length in all three surgical models (P < 0.01). EGF-cm alone selectively increased bowel weight per length and jejunal villus height in the JI group only. The JC group demonstrated increased intestinal weight and villus height (P < 0.01) when given either GLP-2 alone or in combination with EGF-cm, with no effect of EGF-cm alone. Jejunal permeability of mannitol and polyethylene glycol decreased with combination therapy in both SBS groups (P < 0.05). No difference was observed in fat absorption or body weight gain. IGF-1 mRNA was differentially expressed in JI vs. JC piglets with treatment. Combined treatment with GLP-2 and EGF-cm induced intestinal lengthening and decreased permeability, in addition to the trophic effects of GLP-2 alone. Our findings demonstrate the benefits of novel combination GLP-2 and EGF treatment for neonatal SBS, especially in the JC model representing most human infants with SBS.NEW & NOTEWORTHY Glucagon-like peptide-2 (GLP-2) and epidermal growth factor (EGF) are intestinotrophic, with demonstrated benefit in both animal models and human studies of short bowel syndrome (SBS). The current research shows that over and above known trophic effects, the combination of GLP-2 and EGF synergistically lengthens the bowel in neonatal piglet models of SBS. Most notable benefit occurred with resection of the terminal ileum, the common clinical anatomy seen in neonatal SBS and associated with least de novo lengthening postsurgery.

Cardiopulmonary resuscitation with chest compressions during sustained inflations: a new technique of neonatal resuscitation that improves recovery and survival in a neonatal porcine model.

BACKGROUND: Guidelines on neonatal resuscitation recommend 90 chest compressions (CCs) and 30 manual inflations (3:1) per minute in newborns. The study aimed to determine whether CC s during sustained inflations (SIs) improves the recovery of asphyxiated newborn piglets in comparison with coordinated 3:1 resuscitation. METHODS AND RESULTS: Term newborn piglets (n=8/group) were anesthetized, intubated, instrumented, and exposed to 45-minute normocapnic hypoxia followed by asphyxia. Piglets were randomly assigned to receive either 3:1 resuscitation (3:1 group) or CCs during SIs (SI group) when the heart rate decreased to 25% of baseline. Piglets randomly assigned to the SI group received SIs with a pressure of 30 cm H2O for 30 s. During the SI, CCs at a rate of 120/min were provided. SI was interrupted after 30 s for 1 s before a further 30-s SI was provided. CCs were continued throughout SIs. CCs and SI were continued until the return of spontaneous circulation. Continuous respiratory parameters, cardiac output, mean systemic and pulmonary artery pressures, and regional blood flows were measured. Mean (standard deviation) time for return of spontaneous circulation was significantly reduced in SI group versus 3:1 group (32 [11] s versus 205 [113] s, respectively). In the SI group, administration of oxygen and epinephrine was significantly lower, whereas minute ventilation and exhaled CO2 were significantly increased. The SI group had significantly higher mean systemic and pulmonary arterial pressures during resuscitation in comparison with the 3:1 group (51 [10] versus 31 [5] mm Hg; 41[7] versus 31 [7] mm Hg, respectively; all P<0.05), with improved cardiac output and carotid blood flow. CONCLUSIONS: Combining CCs and SIs significantly improved the return of spontaneous circulation with better hemodynamic recovery in asphyxiated newborn piglets in comparison with standard coordinated 3:1 resuscitation.

Postresuscitation administration of doxycycline preserves cardiac contractile function in hypoxia-reoxygenation injury of newborn piglets*.

OBJECTIVE: Cardiac injury is common in asphyxiated neonates and is associated with matrix metalloproteinase-2 activation. Although studies have demonstrated the cardioprotective effects of matrix metalloproteinase inhibition, this has not been tested in clinically translatable models of hypoxia-reoxygenation injury. We aimed to elucidate the effect of doxycycline, a matrix metalloproteinase inhibitor, on cardiac injury and functional recovery in a swine model of neonatal hypoxia-reoxygenation. DESIGN: Thirty-three newborn piglets were acutely instrumented for continuous monitoring of cardiac output and systemic arterial pressure. After stabilization, normocapnic alveolar hypoxia (10-15% oxygen) was instituted for 2 hours followed by 4 hours of normoxic reoxygenation. Piglets were blindly, block randomized to receive IV boluses of normal saline (control) and doxycycline at 5 minutes of reoxygenation (n = 7/group). Sham-operated piglets (n = 5) received no hypoxia-reoxygenation. Markers of myocardial injury (plasma and myocardial tissue troponin I; myocardial lactate) and oxidative stress (lipid hydroperoxides) were measured by enzyme-linked immunosorbent assay and Western blot. Myocardial matrix metalloproteinase-2 activity was quantified by gelatin zymography and immunoprecipitation. SETTING: University animal laboratory. SUBJECTS: Piglets (1-4 d old, weighing 1.4-2.5 kg). INTERVENTIONS: IV doxycycline (3, 10, or 30 mg/kg) given during resuscitation. MEASUREMENTS AND MAIN RESULTS: Hypoxic piglets had cardiogenic shock (cardiac output 58% ± 1% of baseline), hypotension (systemic arterial pressure 31 ± 1 mm Hg), and acidosis (pH 7.02 ± 0.02). Doxycycline improved cardiac and stroke volume index with no chronotropic effect in doxycycline-treated piglets compared with controls. Systemic arterial pressure was higher and the pulmonary artery pressure/systemic arterial pressure ratio was lower in doxycycline groups, with reduced levels of markers of myocardial injury and oxidative stress in doxycycline-treated piglets compared with controls. Negative correlations were found between markers of myocardial injury (plasma troponin I, myocardial lactate) and functional recovery and between myocardial tissue and plasma troponin I. Doxycycline-treated piglets had lower myocardial matrix metalloproteinase-2 activity compared with controls. CONCLUSIONS: Postresuscitation administration of doxycycline attenuates cardiac injury and improves functional recovery in newborn piglets with hypoxia-reoxygenation.

Cyclosporine A Does Not Mitigate Liver Ischemia/Reperfusion Injury in an Ex Vivo Porcine Model of Donation After Circulatory Death.

BACKGROUND Ischemia/reperfusion injury (IRI) is an inherent problem in organ transplantation, owing to the obligate period of ischemia that organs must endure. Cyclosporine A (CsA), though better know as an immunosuppressant, has been shown to mitigate warm IRI in a variety of organ types, including the liver. However, there is little evidence for CsA in preventing hepatic IRI in the transplant setting. MATERIAL AND METHODS In the present study, we tested the effect of CsA on hepatic IRI in a large-animal ex vivo model of donation after circulatory death (DCD). Porcine donors were pre-treated with either normal saline control or 20 mg/kg of CsA. Animals were subject to either 45 or 60 minutes of warm ischemia before hepatectomy, followed by 2 or 4 hours of cold storage prior to reperfusion on an ex vivo circuit. Over the course of a 12-hour perfusion, perfusion parameters were recorded and perfusate samples and biopsies were taken at regular intervals. RESULTS Peak perfusate lactate dehydrogenase was significantly decreased in the lower-ischemia group treated with CsA compared to the untreated group (4220 U/L [3515-5815] vs 11 305 [10 100-11 674]; P=0.023). However, no difference was seen between controls and CsA-treated groups on other parameters in perfusate alanine or asparagine aminotransferase (P=0.912, 0.455, respectively). Correspondingly, we found no difference on midpoint histological injury score (P=0.271). CONCLUSIONS We found minimal evidence that CsA is protective against hepatic IRI in our DCD model.

Evaluating Islet Cell Isolation and Transplantation From Donors Following Medical Assistance in Dying.

Background: Limited information is available regarding outcomes of islet cell isolation (ICI) and transplantation (ITx) using medical assistance in dying (MAiD) donors. We aimed to assess the feasibility and outcomes of ICI and ITx in MAiD donors. Methods: ICI and ITx from MAiD were compared with donation after circulatory death (DCD) type III between 2016 and 2023. Differences of isolated islet equivalents (IEQs), numeric viability and other quantitative in vitro metabolic measures were assessed. Results: Overall, 81 ICIs were available of whom 34 (42%) and 47 (58%) from MAiD and DCD-III, respectively. There were no differences of pancreas and digested tissue weight and islets viability among the 2 groups; however, cold ischemic time was longer in MAiD (11.5 versus 9.1 h; P = 0.021). The IEQ (P < 0.001) and percent trapped (P < 0.001) were higher in the DCD-III; however, MAiD islets demonstrated a higher purity (P = 0.020). Overall, 15 ITx were performed of whom 3 (8.8%) and 12 (25.5%) from MAiD and DCD-III, respectively (P = 0.056). Patients had a median fasting C-peptide of 0.51 ng/mL (interquartile range, 0.30-0.76 nmol/L), with no differences between groups (MAiD = 0.52 versus DCD-III = 0.51; P = 0.718). The median HbA1c was 6.2% (interquartile range, 5.7%-7%) (MAiD = 6.3% versus DCD-III = 6.1%; P = 0.815) and BETA2 scores (MAiD = 7.4 versus DCD-III = 12.8; P = 0.229) did not differ. Conclusions: ICI from MAiD donor pancreas may be successfully transplanted with comparable outcomes to DCD-III and may be used for research. These results justify additional efforts to consider MAiD as another valuable source of grafts for ITx. Further multicenter studies and larger clinical experience are needed to validate our findings.

Incidence, management and outcomes in hepatic artery complications after paediatric liver transplantation: protocol of the retrospective, international, multicentre HEPATIC Registry.

INTRODUCTION: Hepatic artery complications (HACs), such as a thrombosis or stenosis, are serious causes of morbidity and mortality after paediatric liver transplantation (LT). This study will investigate the incidence, current management practices and outcomes in paediatric patients with HAC after LT, including early and late complications. METHODS AND ANALYSIS: The HEPatic Artery stenosis and Thrombosis after liver transplantation In Children (HEPATIC) Registry is an international, retrospective, multicentre, observational study. Any paediatric patient diagnosed with HAC and treated for HAC (at age <18 years) after paediatric LT within a 20-year time period will be included. The primary outcomes are graft and patient survivals. The secondary outcomes are technical success of the intervention, primary and secondary patency after HAC intervention, intraprocedural and postprocedural complications, description of current management practices, and incidence of HAC. ETHICS AND DISSEMINATION: All participating sites will obtain local ethical approval and (waiver of) informed consent following the regulations on the conduct of observational clinical studies. The results will be disseminated through scientific presentations at conferences and through publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: The HEPATIC registry is registered at the ClinicalTrials.gov website; Registry Identifier: NCT05818644.

Postresuscitation cyclosporine treatment attenuates myocardial and cardiac mitochondrial injury in newborn piglets with asphyxia-reoxygenation.

OBJECTIVES: Cardiovascular dysfunction occurs in the majority of asphyxiated neonates and has been suggested to be a major cause of neonatal morbidity and mortality. We previously demonstrated that cyclosporine A treatment during resuscitation can significantly improve cardiovascular performance in asphyxiated newborn piglets. However, the mechanisms through which cyclosporine elicits its protective effect in neonates have not yet been fully characterized. We hypothesized that cyclosporine A treatment would attenuate myocardial and cardiac mitochondrial injury during the resuscitation of asphyxiated newborn piglets. DESIGN: After acute instrumentation, piglets received normocapnic alveolar hypoxia (10% to 15% oxygen) for 2 hours followed by reoxygenation with 100% oxygen (0.5 hr) and then 21% oxygen (3.5 hr). At 4 hours of reoxygenation, plasma troponin level, left ventricle myocardial levels of lipid hydroperoxides, cytochrome-c, and mitochondrial aconitase activity were determined. SETTING: Neonatal asphyxia and reoxygenation. SUBJECTS: Twenty-four newborn (1-4 days old) piglets. INTERVENTIONS: Piglets were randomized to receive an IV bolus of cyclosporine A (10 mg/kg) or normal saline (placebo, control) at 5 minutes of reoxygenation (n=8/group). Sham-operated piglets (n=8) underwent no asphyxia-reoxygenation. MEASUREMENTS AND MAIN RESULTS: Asphyxiated piglets treated with cyclosporine had lower plasma troponin and myocardial lipid hydroperoxides levels (vs. controls, both p<0.05, analysis of variance). Cyclosporine treatment also improved mitochondrial aconitase activity and attenuated the rise in cytosol cytochrome-c level (vs. controls, all p<0.05). The improved mitochondrial function significantly correlated with cardiac output (p<0.05, Spearman rank-correlation test). CONCLUSIONS: We demonstrate that the postresuscitation administration of cyclosporine attenuates myocardial and cardiac mitochondrial injury in asphyxiated newborn piglets following resuscitation.