Anna J. Dare

A systematic review of experimental treatments for mitochondrial dysfunction in sepsis and multiple organ dysfunction syndrome

Sepsis and multiple organ dysfunction syndrome (MODS) are major causes of morbidity and mortality in the intensive care unit. Recently mitochondrial dysfunction has been proposed as a key early cellular event in critical illness. A growing body of experimental evidence suggests that mitochondrial therapies are effective in sepsis and MODS. The aim of this article is to undertake a systematic review of the current experimental evidence for the use of therapies for mitochondrial dysfunction during sepsis and MODS and to classify these mitochondrial therapies. A search of the MEDLINE and PubMed databases (1950 to July 2009) and a manual review of reference lists were conducted to find experimental studies containing data on the efficacy of mitochondrial therapies in sepsis and sepsis-related MODS. Fifty-one studies were included in this review. Five categories of mitochondrial therapies were defined-substrate provision, cofactor provision, mitochondrial antioxidants, mitochondrial reactive oxygen species scavengers, and membrane stabilizers. Administration of mitochondrial therapies during sepsis was associated with improvements in mitochondrial electron transport system function, oxidative phosphorylation, and ATP production and a reduction in cellular markers of oxidative stress. Amelioration of proinflammatory cytokines, caspase activation, and prevention of the membrane permeability transition were reported. Restoration of mitochondrial bioenergetics was associated with improvements in hemodynamic parameters, organ function, and overall survival. A substantial body of evidence from experimental studies at both the cellular and the organ level suggests a beneficial role for the administration of mitochondrial therapies in sepsis and MODS. We expect that mitochondrial therapies will have an increasingly important role in the management of sepsis and MODS. Clinical trials are now required.

Additive effect of pretransplant obesity, diabetes, and cardiovascular risk factors on outcomes after liver transplantation

The effects of pretransplant obesity, diabetes mellitus (DM), coronary artery disease (CAD), and hypertension (HTN) on outcomes after liver transplantation (LT) are controversial. Questions have also been raised about the appropriateness of the body mass index (BMI) for assessing obesity in patients with end‐stage liver disease. Both issues have implications for organ allocation in LT. To address these questions, we undertook a cohort study of 202 consecutive patients (2000‐2010) undergoing LT at a national center in New Zealand. BMI and body fat percentage (%BF) values (dual‐energy X‐ray absorptiometry) were measured before transplantation, and the methods were compared. The influence of pretransplant risk variables (including obesity, DM, CAD, and HTN) on the 30‐day postoperative event rate, length of hospital stay, and survival were analyzed. There was agreement between the calculated BMI and the measured %BF for 86.0% of the study population (κ coefficient = 0.73, 95% confidence interval = 0.61‐0.85), and this was maintained across increasing Model for End‐Stage Liver Disease scores. Obesity was an independent risk factor for the postoperative event rate [count ratio (CR) = 1.03, P < 0.001], as was DM (CR = 1.4, P < 0.001). Obesity with concomitant DM was the strongest predictor of the postoperative event rate (CR = 1.75, P < 0.001) and a longer hospital stay (5.81 days, P < 0.01). Independent metabolic risk factors had no effect on 30‐day, 1‐year, or 5‐year patient survival. In conclusion, BMI is an adequate tool for assessing obesity‐associated risk in LT. Early post‐LT morbidity is highest for patients with concomitant obesity and DM, although these factors do not appear to influence recipient survival. Liver Transpl 20:281‐290, 2014.

Training the intern: The value of a pre-intern year in preparing students for practice

Aims: To evaluate the clinical and professional development that occurs during a New Zealand trainee intern year in preparation for the first house officer role. Methods: A quantitative questionnaire was distributed to all trainee interns (year 6) and year 5 medical students in New Zealand at the end of the 2007 academic year. This survey assessed self-reported competency and performance across clinical, professional and role development domains. Results: Response rate was 65% (457/702). Compared to year 5 students, trainee interns reported significantly greater competence and performance levels across all three domains. The greatest improvement occurred in the independent performance of procedural skills (trainee interns: 77%, year 5: 35%, p < 0.001) and clinical tasks (trainee interns: 94%, year 5: 56%, p < 0.001) and in the level of clinical responsibility taken (p < 0.001). At the end of the trainee intern year, 92% of students felt prepared to be a junior doctor, versus only 53% at the end of their 5th year (p < 0.0001). Conclusions: The trainee intern year is important in preparing graduates for the intern role. The year affords increased responsibility and practical experience, whilst retaining an educational focus, facilitating the move from competence towards performance. Preparedness for practice was substantially higher following the New Zealand trainee intern year than has been reported with other pre-intern placements.

Critical Care of the Potential Organ Donor

Organ transplantation represents one of the great success stories of 20th century medicine. However, its continued success is greatly limited by the shortage of donor organs. This has led to an increased focus within the critical care community on optimal identification and management of the potential organ donor. The multi-organ donor can represent one of the most complex intensive care patients, with numerous competing physiological priorities. However, appropriate management of the donor not only increases the number of organs that can be successfully donated but has long-term implications for the outcomes of multiple recipients. This review outlines current understandings of the physiological derangements seen in the organ donor and evaluates the available evidence for management strategies designed to optimize donation potential and organ recovery. Finally, emerging management strategies for the potential donor are discussed within the current ethical and legal frameworks permitting donation after both brain and circulatory death.

Early organ-specific mitochondrial dysfunction of jejunum and lung found in rats with experimental acute pancreatitis

INTRODUCTION Multiple organ dysfunction is the main cause of death in severe acute pancreatitis. Primary mitochondrial dysfunction plays a central role in the development and progression of organ failure in critical illness. The present study investigated mitochondrial function in seven tissues during early experimental acute pancreatitis. METHODS Twenty-eight male Wistar rats (463 ± 2 g; mean ± SEM) were studied. Group 1 (n= 8), saline control; Group 2 (n= 6), caerulein-induced mild acute pancreatitis; Group 3 (n= 7) sham surgical controls; and Group 4 (n= 7), taurocholate-induced severe acute pancreatitis. Animals were euthanased at 6 h from the induction of acute pancreatitis and mitochondrial function was assessed in the heart, lung, liver, kidney, pancreas, duodenum and jejunum by mitochondrial respirometry. RESULTS Significant early mitochondrial dysfunction was present in the pancreas, lung and jejunum in both models of acute pancreatitis, however, the Heart, liver, kidney and duodenal mitochondria were unaffected. CONCLUSIONS The present study provides the first description of early organ-selective mitochondrial dysfunction in the lung and jejunum during acute pancreatitis. Research is now needed to identify the underlying pathophysiology behind the organ selective mitochondrial dysfunction, and the potential benefits of early mitochondrial-specific therapies in acute pancreatitis.

Appraisal of donor steatosis in liver transplantation: a survey of current practice in Australia and New Zealand

Correspondence: Adam Bartlett New Zealand Liver Transplant Unit, Level 15, Support Building, Auckland City Hospital, 2 Park Road, Grafton, Auckland 1023, New Zealand Tel +64 21 241 4647 Fax +64 9 375 4345 Email a.bartlett@auckland.ac.nz Background: Hepatic steatosis is increasingly encountered among organ donors. Currently, there is no consensus guideline as to the type or degree of donor steatosis considered acceptable for liver transplantation (LT), and little is known about local practices in this area. The aim of this survey was to evaluate current clinical practices amongst liver transplant surgeons in Australia and New Zealand (ANZ) in the evaluation and use of steatotic donor livers in LT. Methods: An anonymous online twelve-question survey was emailed to all practicing LT surgeons in ANZ (n = 23) in January 2010. Results: The response rate was 83%. Estimated prevalence of steatosis in donor livers was between 40% and 60%. In determining suitability for LT, 90% of respondents reported rejecting organs with “severe” steatosis based on visual and palpation grounds alone. A total of 68% sought further histological assessment if the donor liver looked bad and there were risk factors for steatosis. The majority of respondents performed only one biopsy of the liver (79%), using hematoxylin and eosin staining for fat assessment (53%). There was wide variation in the upper limit of steatosis considered to be acceptable for LT (40%–80% steatosis). A total of 21% of respondents still considered microvesicular steatosis a risk factor for primary graft nonfunction. Conclusion: This survey highlights the significant variation in the appraisal and use of steatotic grafts by LT surgeons in ANZ. Accurate evaluation and judicious use of mild and moderately steatotic grafts is required if we are to utilize the available donor pool best.

Ob/ob mouse livers show decreased oxidative phosphorylation efficiencies and anaerobic capacities after cold ischemia.

Background Hepatic steatosis is a major risk factor for graft failure in liver transplantation. Hepatic steatosis shows a greater negative influence on graft function following prolonged cold ischaemia. As the impact of steatosis on hepatocyte metabolism during extended cold ischaemia is not well-described, we compared markers of metabolic capacity and mitochondrial function in steatotic and lean livers following clinically relevant durations of cold preservation. Methods Livers from 10-week old leptin-deficient obese (ob/ob, n = 9) and lean C57 mice (n = 9) were preserved in ice-cold University of Wisconsin solution. Liver mitochondrial function was then assessed using high resolution respirometry after 1.5, 3, 5, 8, 12, 16 and 24 hours of storage. Metabolic marker enzymes for anaerobiosis and mitochondrial mass were also measured in conjunction with non-bicarbonate tissue pH buffering capacity. Results Ob/ob and lean mice livers showed severe (>60%) macrovesicular and mild (<30%) microvesicular steatosis on Oil Red O staining, respectively. Ob/ob livers had lower baseline enzymatic complex I activity but similar adenosine triphosphate (ATP) levels compared to lean livers. During cold storage, the respiratory control ratio and complex I-fueled phosphorylation deteriorated approximately twice as fast in ob/ob livers compared to lean livers. Ob/ob livers also demonstrated decreased ATP production capacities at all time-points analyzed compared to lean livers. Ob/ob liver baseline lactate dehydrogenase activities and intrinsic non-bicarbonate buffering capacities were depressed by 60% and 40%, respectively compared to lean livers. Conclusions Steatotic livers have impaired baseline aerobic and anaerobic capacities compared to lean livers, and mitochondrial function indices decrease particularly from after 5 hours of cold preservation. These data provide a mechanistic basis for the clinical recommendation of shorter cold storage durations in steatotic donor livers.

Challenges and Opportunities in the Provision of Surgical Care in Vanuatu: A Mixed Methods Analysis

BackgroundThe Pacific island nation of Vanuatu faces a number of challenges in delivering surgical care to its population. We aimed to understand and document the barriers, opportunities and required actions to improve surgical care in the country using a mixed methods analysis which incorporated the perspectives of local health stakeholders.MethodsA baseline quantitative assessment of surgical capacity in Vanuatu was carried out using the WHO situational analysis tool. Twenty semi-structured interviews were then conducted on the two main islands (Efate and Espiritu Santo) with surgeons, allied health staff, health managers, policy-makers and other key stakeholders, using a grounded theory qualitative case study methodology. Initial informants were identified by purposive sampling followed by snowball sampling until theoretical saturation was reached. Interviews were open and axially coded with subsequent thematic analysis.ResultsVanuatu faces deficits in surgical infrastructure, equipment and human resources, especially in the rural provinces. Geographic isolation, poverty and culture—including the use of traditional medicine and low health literacy—all act as barriers to patients accessing timely surgical care. Issues with governance, human resourcing and perioperative care were commonly identified by stakeholders as key challenges facing surgical services. Increasing outreach clinics, developing efficient referral systems, building provincial surgical capacity and undertaking locally led research were identified as key actions that can improve surgical care.ConclusionDocumenting locally identified challenges and opportunities for surgical care in Vanuatu is an important first step towards developing formal strategies for improving surgical services at the country level.

Effect of Hepatic Steatosis on Bioenergetic Function During HepaticIschemia-reperfusion: A Systematic Review

Background: The impact of hepatic steatosis on bioenergetics following hepatic ischemia-reperfusion injury (IRI) remains controversial and is associated with variable reports on its outcome. Large numbers of studies have been published examining the relationship between hepatic steatosis and cellular bioenergetics following hepatic IRI. This sys- tematic review evaluates these studies. Methods: An electronic search of the Medline and Embase databases (January 1946 to June 2012) was performed to select studies that reported relevant outcomes in animal models or patients with hepatic steatosis subjected to IRI. Results: A total of 489 articles were identified, of which 63 animal studies met the predefined criteria and were included in the study. There was large variation in the type of animal model, duration and type of IRI utilized and histological de- scription of hepatic steatosis. Bioenergetic impairments appear to increase the susceptibility of steatotic livers to IRI. The most common impairment was decreased adenosine triphosphate recovery with increased oxidative stress following IRI. Impaired mitochondrial function play a key role in the susceptibility of steatotic livers to IRI. Conclusions: Animals with >30% hepatic steatosis have been shown to have poor outcome following IRI. Despite limita- tions of different experimental models and inconsistency in histological description, impaired mitochondrial function and bioenergetics appear to be important mediators in the decreased tolerance of steatotic livers to IRI. Future studies need to be consistent and clinically relevant to further improve our understanding of this issue.