A Systematic Review of Donor Serum Sodium Level and Its Impact on Transplant Recipients.

BACKGROUND: An important aspect of donor management is the optimization of serum sodium levels. OBJECTIVE: To perform a systematic review to determine the effects of donor sodium levels on heart, lung, kidney, and pancreas graft function, recipient mortality, and to identify the optimal donor serum sodium target. METHODS: We searched MEDLINE, Cochrane, Guideline databases, and trial registries from 1946 to May 2019 for studies investigating the effects of donor serum sodium levels on transplant outcomes in all non-hepatic organs. A two-step independent review process was used to identify relevant articles based on inclusion/exclusion criteria. We describe the results narratively, assess the risk of bias, and apply GRADE methodology to evaluate the certainty in the evidence. RESULTS: We included 18 cohort studies in our final analysis (n=28,007). 3 of 4 studies demonstrated an association between donor serum sodium and successful organ transplantation. 5 studies reported no association with graft function, while 6 studies did. 5 studies reported on recipient survival, 3 of which suggested donor sodium is unlikely to be associated with recipient survival. The included studies had serious risk of bias, and the certainty in evidence was deemed to be very low. CONCLUSION: In low risk of bias studies, donor sodium dysregulation is unlikely to affect kidney graft function or mortality of heart and kidney recipients, but the certainty in the evidence is very low due to inconsistency and imprecision. Further research is required to refine the serum sodium target range, quantify the dose-response curve, and identify organs most vulnerable to sodium dysregulation.

Canadian Guidelines for Controlled Pediatric Donation After Circulatory Determination of Death-Summary Report

OBJECTIVES: Create trustworthy, rigorous, national clinical practice guidelines for the practice of pediatric donation after circulatory determination of death in Canada. METHODS: We followed a process of clinical practice guideline development based on World Health Organization and Canadian Medical Association methods. This included application of Grading of Recommendations Assessment, Development, and Evaluation methodology. Questions requiring recommendations were generated based on 1) 2006 Canadian donation after circulatory determination of death guidelines (not pediatric specific), 2) a multidisciplinary symposium of national and international pediatric donation after circulatory determination of death leaders, and 3) a scoping review of the pediatric donation after circulatory determination of death literature. Input from these sources drove drafting of actionable questions and Good Practice Statements, as defined by the Grading of Recommendations Assessment, Development, and Evaluation group. We performed additional literature reviews for all actionable questions. Evidence was assessed for quality using Grading of Recommendations Assessment, Development, and Evaluation and then formulated into evidence profiles that informed recommendations through the evidence-to-decision framework. Recommendations were revised through consensus among members of seven topic-specific working groups and finalized during meetings of working group leads and the planning committee. External review was provided by pediatric, critical care, and critical care nursing professional societies and patient partners. RESULTS: We generated 63 Good Practice Statements and seven Grading of Recommendations Assessment, Development, and Evaluation recommendations covering 1) ethics, consent, and withdrawal of life-sustaining therapy, 2) eligibility, 3) withdrawal of life-sustaining therapy practices, 4) ante and postmortem interventions, 5) death determination, 6) neonatal pediatric donation after circulatory determination of death, 7) cardiac and innovative pediatric donation after circulatory determination of death, and 8) implementation. For brevity, 48 Good Practice Statement and truncated justification are included in this summary report. The remaining recommendations, detailed methodology, full Grading of Recommendations Assessment, Development, and Evaluation tables, and expanded justifications are available in the full text report. CONCLUSIONS: This process showed that rigorous, transparent clinical practice guideline development is possible in the domain of pediatric deceased donation. Application of these recommendations will increase access to pediatric donation after circulatory determination of death across Canada and may serve as a model for future clinical practice guideline development in deceased donation

Time to loss of brain function and activity during circulatory arrest.

PURPOSE: Brain function during the dying process and around the time of cardiac arrest is poorly understood. To better inform the clinical physiology of the dying process and organ donation practices, we performed a scoping review of the literature to assess time to loss of brain function and activity after circulatory arrest. MATERIALS AND METHODS: Medline and Embase databases were searched from inception to June 2014 for articles reporting the time interval to loss of brain function or activity after loss of systemic circulation. RESULTS: Thirty-nine studies met selection criteria. Seven human studies and 10 animal studies reported that electroencephalography (EEG) activity is lost less than 30seconds after abrupt circulatory arrest. In the setting of existing brain injury, with progressive loss of oxygenated circulation, loss of EEG may occur before circulatory arrest. Cortical evoked potentials may persist for several minutes after loss of circulation. CONCLUSION: The time required to lose brain function varied according to clinical context and method by which this function is measured. Most studies show that clinical loss of consciousness and loss of EEG activity occur within 30seconds after abrupt circulatory arrest and may occur before circulatory arrest after progressive hypoxia-ischemia. Prospective clinical studies are required to confirm these observations.

Lifetime probabilities of needing an organ transplant versus donating an organ after death.

The lifetime probabilities of becoming a deceased organ donor and requiring or receiving an organ transplant are unknown. An actuarial analysis was performed in a representative Canadian sample. Using Canadian organ donation data 1999-2007, provincial waiting list and population census data, actuarial rates were produced that provide the probabilities, by age band and gender, of (1) becoming a deceased organ donor, (2) needing an organ transplant and (3) receiving all organs needed. Regardless of age, the lifetime probability of needing a transplant for males is approximately twice that of females. Depending on age, Canadians are five to six times more likely to need an organ transplant than to become a deceased organ donor. The lifetime probabilities of not receiving a required organ transplant, expressed as a percentage of individuals on the waiting list, ranges from approximately 30% at birth, 20 years and 40 years to approximately 40% at 60 years. Across provinces and genders, Canadians at all ages are much more likely to need an organ transplant than to become an organ donor. Approximately one-third of those in need of a transplant will never receive one. How this information may influence organ donation decisions is currently under study.

A systematic review of autoresuscitation after cardiac arrest.

OBJECTIVE: There is a lack of consensus on how long circulation must cease for death to be determined after cardiac arrest. The lack of scientific evidence concerning autoresuscitation influences the practice of organ donation after cardiac death. We conducted a systematic review to summarize the evidence on the timing of autoresuscitation. DATA SOURCES: Electronic databases were searched from date of first issue of each journal until July 2008. STUDY SELECTION: Any original study reporting autoresuscitation, as defined by the unassisted return of spontaneous circulation after cardiac arrest, was considered eligible. Reports of electrocardiogram activity without signs of return of circulation were excluded. DATA EXTRACTION: For each study case, we extracted patient characteristics, duration of cardiopulmonary resuscitation, terminal heart rhythms, time to unassisted return of spontaneous circulation, monitoring, and outcomes. DATA SYNTHESIS: A total of 1265 citations were identified and, of these, 27 articles describing 32 cases of autoresuscitation were included (n = 32; age, 27-94 yrs). The studies came from 16 different countries and were considered of very-low quality (case reports or letters to the editor). All 32 cases reported autoresuscitation after failed cardiopulmonary resuscitation, with times ranging from a few seconds to 33 mins; however, continuity of observation and methods of monitoring were highly inconsistent. For the eight studies reporting continuous electrocardiogram monitoring and exact times, autoresuscitation did not occur beyond 7 mins after failed cardiopulmonary resuscitation. No cases of autoresuscitation in the absence of cardiopulmonary resuscitation were reported. CONCLUSIONS: These findings suggest that the provision of cardiopulmonary resuscitation may influence autoresuscitation. In the absence of cardiopulmonary resuscitation, as may apply to controlled organ donation after cardiac death after withdrawal of life-sustaining therapies, autoresuscitation has not been reported. The provision of cardiopulmonary resuscitation, as may apply to uncontrolled organ donation after cardiac death, may influence observation time. However, existing evidence is limited and is consequently insufficient to support or refute the recommended waiting period to determine death after a cardiac arrest, strongly supporting the need for prospective studies in dying patients.

Long-term pulmonary sequelae of severe bronchopulmonary dysplasia.

OBJECTIVE: To evaluate the long-term pulmonary sequelae of survivors of bronchopulmonary dysplasia (BPD) of sufficient severity to have required supplemental oxygen for at least 1 month after term. STUDY DESIGN: Fifteen patients with a mean age of 1.1 years were matched to preterm infants of similar gestational age and age at time of study. Pulmonary function testing included spirometry, plethysmographic lung volumes, carbon monoxide diffusion capacity, and in 9 of 15 subjects with BPD, measurement of lung static elastic recoil pressures. RESULTS: The subjects with BPD had a mean expiratory volume in 1 second (FEV1) of 64% +/- 21% predicted (4 had an FEV1 < 50% predicted) compared with 85% +/- 11% (P < .01) for the preterm children in the control group. Subjects with BPD had a significant degree of gas trapping with a residual volume to total lung capacity ratio of 37% +/- 13% compared with 25% +/- 4% for the control group (P < .01). An inverse relationship was seen between the FEV1 and the time on supplemental oxygen (r = -0.84, P < .0001), with 3 of the 4 children whose FEV1 was < 50% requiring oxygen for more than 900 days. Those with the greatest degree of airflow limitation and gas trapping had the greatest abnormalities in both shape and position of the pressure volume curves of the lung. CONCLUSION: Severe BPD may result in moderate to severe long-term abnormalities in pulmonary function tests.

Activity levels and the relationship to lung function and nutritional status in children with cystic fibrosis.

Cystic fibrosis is characterized by chronic obstructive lung disease and malnutrition. Previous studies have shown that nutritional status and lung function are limiting factors for exercise capacity. A reduced exercise capacity may in turn diminish activity levels. We evaluated whether the total time spent somewhat active (e.g., walking) or active (e.g., biking), as reported by the Habitual Activity Estimation Scale, was related to lung function, as evaluated by forced expiratory volume in one second (%predicted FEV1), and nutritional status, measured as body mass percentile, in 36 children with cystic fibrosis, aged 6 to 16 years. The Habitual Activity Estimation Scale questionnaires were completed by the parents for children younger than 12 years of age and by both the parent and the child, independently, for those 12 years and older. Patients had a body mass percentile of 99 +/- 15.2% and % predicted FEV1 of 85.7 +/- 20, with no differences between boys (15/36) and girls (21/36). Boys spent 8.1 hours and girls spent 7.5 hours (P > 0.1) being at least somewhat active. These values are similar to those reported for healthy boys and girls. In patients with significant lung disease (%predicted FEV1, < or = 75; n = 11), activity level (the time spent somewhat active or active) was related to nutritional status (r = 0.675; P = 0.02) but not to lung function (r = 0.21; P > 0.1). Activity level reported by patients 12 years of age and older was on average 24.1% higher (P < 0.05) than that reported by their parents, but the two reportings were related (r = 0.758; P = 0.004). These results suggest that activity level may be restricted by nutritional status in those patients with significant air flow limitation. We suggest that improving the nutritional status of cystic fibrosis patients may prevent decreases in activity levels and quality of life of these affected children.

Exercise ability in survivors of severe bronchopulmonary dysplasia.

There is limited information concerning the exercise performance of long-term survivors of bronchopulmonary dysplasia (BPD), and much of what is available pertains to those with relatively mild disease. The present study was undertaken to describe exercise responses in patients with a history of severe BPD, defined as those patients with a clinical and radiographic diagnosis of BPD who required supplemental oxygen at least until they were 44 wk postconceptual age and who were discharged home on oxygen. Fifteen children with a history of severe BPD were matched for gestational age with 15 children who had previously had respiratory distress syndrome but who did not develop BPD (Prem). These Prem control children were subsequently compared with 13 healthy control children born at term (Control) who were of similar postnatal age. Participants underwent pulmonary function testing, progressive exercise testing on a cycle ergometer, and a steady-state exercise test with cardiac output determined by CO2-rebreathing. Despite the patients with BPD having a lower FEV1 than those in the Prem group, who had lower values than the Control group (BPD, 64 +/- 21%; Prem, 85 +/- 11%; Control, 95 +/- 8%), the exercise capacity did not differ between the BPD and the Prem and between the Prem and the Control groups (BPD, 84 +/- 15%; Prem, 81 +/- 17%; Control, 91 +/- 12%). However, the BPD patients used a greater percentage of their ventilatory reserve (VEmax/40 FEV1: BPD, 93 +/- 20%; Prem, 67 +/- 12%; Control, 59 +/- 13%). Of the four patients with BPD who had significant oxygen desaturation with exercise, three had the lowest values for FEV1. Cardiac output was appropriate for oxygen consumption in most patients.

Estimation of mixed venous PCO2 for determination of cardiac output in children.

STUDY OBJECTIVES: Cardiac output (Q) can be estimated noninvasively during exercise by employing CO2-rebreathing techniques (equilibrium and exponential) to estimate the oxygenated mixed venous PCO2 (PvCO2). It has been found in adults and children that the equilibrium method underestimates Q as a result of overestimation of PvCO2, unless PvCO2 is "downstream corrected." In adults, it has been found that the exponential method does not require downstream correction and yields values similar to those obtained by the equilibrium method with downstream correction. The objectives of this study were as follows: to test whether the exponential method gives similar results to the equilibrium method with downstream correction in children; to verify that downstream correction is required in children; and to test whether a single equation could be used in adults and children to predict Q from oxygen consumption (VO2). DESIGN: Descriptive. SETTING: Exercise laboratory of a university hospital. PARTICIPANTS: 23 children (16 boys, 7 girls) with a mean age of 11.0 +/- 1.9 years (7.1 to 13.9 years), and 12 adults (7 men, 5 women) with a mean age of 33.6 +/- 7.2 years (24 to 48 years). INTERVENTIONS: While performing steady-state exercise on an ergometer, PvCO2 was determined in 14 children using both the equilibrium and exponential methods, and in all other subjects using the equilibrium method alone. MEASUREMENTS AND RESULTS: For the 14 children who underwent testing by both the equilibrium and exponential methods, the uncorrected equilibrium PvCO2 was significantly different from both the corrected PvCO2 and the exponential PvCO2. We found a strong relationship between Q (L/min), calculated using the downstream corrected values of PvCO2, and VO2 (L/min) (r2 = 0.95), and this relationship was similar to that obtained by dye dilution in other studies. When weight was included, it was determined that one equation could be used for children and adults: Q (L/min) = 1.42 + 5.80.VO2 (L/min) + 0.06.wt (kg), r2 = 0.97, SEY = 0.67. CONCLUSIONS: CO2-rebreathing techniques can be used to determine Q in children; the exponential method gives values that are similar to the equilibrium method with the downstream correction; and one prediction can be used for Q in adults and children.

Accuracy of measurements of small changes in soft-tissue mass by dual-energy x-ray absorptiometry.

OBJECTIVE: To assess the ability of dual-energy x-ray absorptiometry (DXA) to measure accurately small changes in lean soft-tissue mass. DXA has recently been suggested as an accurate, noninvasive method of analysis of body composition. DESIGN: Experimental use of DXA to assess human body composition before and after rapid saline infusion. PARTICIPANTS: Six healthy men. OUTCOME MEASURES: Weight measurements, DXA scanning results and skinfold thicknesses taken on the first day of the experiment and on the second day, before and after rapid saline infusion. RESULTS: After the infusion, the subjects' weight increased by a mean 2.26 kg (standard deviation 0.199 kg). At each of the four readings, there was a strong correlation between weight and DXA-derived total mass (r = 0.999) and between skinfold-derived fat-free mass and DXA-derived lean mass (r = 0.941 to 0.957). Following infusion, no differences were found between the measured and theoretical (i.e., preinfusion value plus weight change) values for total mass (p = 22), lean soft-tissue mass (p = 0.10) and lean mass (p = 0.09). The bias was -0.669 (95% confidence interval [CI] 0.18 to -1.49) for total mass, -0.65 (95% CI 0.16 to -1.47) for lean soft-tissue mass, and -0.14 (95% CI 0.11 to -0.38) for lean mass. CONCLUSIONS: DXA is an improvement over- previous dual-energy technologies and appears to provide sufficient accuracy to detect small (less than 2.5 kg) changes in mass in individual, healthy men, over a short period and under non-steady-state conditions. Therefore, DXA may also be of practical use for longitudinal assessment of weight change.

Effect of analyzer on determination of mixed venous PCO2 and cardiac output during exercise.

Cardiac output (CO) during exercise can be determined noninvasively by using the indirect Fick CO2-rebreathing technique. CO2 measurements for this technique are usually performed with an infrared analyzer (IA) or mass spectrometer (MS). However, IA CO2 measurements are susceptible to underreading in the face of high O2 concentrations because of collision broadening. We compared an IA (Ametek model CD-3A) with a MS (Marquette model MGA-1100) to see the effect this would have on mixed venous PCO2 (PVCO2) and CO measurements. After calibration with room air and a gas mixture of 5% CO2-12% O2-83% N2, both devices were tested with three different gas mixtures of CO2 in O2. For each gas mixture, IA gave lower CO2 values than did the MS (4.1% CO2: IA, 3.85 +/- 0.01% and MS, 4.13 +/- 0.01%; 9.2% CO2: IA, 8.44 +/- 0.07% and MS, 9.19 +/- 0.01%; 13.8% CO2: IA, 12.57 +/- 0.15% and MS, 13.82 +/- 0.01%). Warming and humidifying the gases did not alter the results. The IA gave lower values than did the MS for eight other medical gases in lower concentrations of O2 (40-50%). Equilibrium and exponential rebreathing procedures were performed. Values determined by the IA were > 10% higher than those determined by the MS for both rebreathing methods. We conclude that all IAs must be checked for collision broadening if they are to be used in environments where the concentration of O2 is > 21%. If collision broadening is present, then either a special high O2-CO2 calibration curve must be constructed, or the IA should not be used for both arterial PCO2 and PVCO2 estimates because it may produce erroneously low PVCO2 values, with resultant overestimation of CO.

Cyclosporine A blockade of the induction of ornithine decarboxylase activity as a cause of failure of islet cell proliferation and differentiation.

Maintenance of islet cell mass may be one factor that contributes to long-term islet allograft viability. It is important, therefore, to determine whether transplant-related events, such as immunosuppression, interfere with the regenerative capacity of the hormone-producing cellular elements of the islet. To investigate this possibility, we utilized a well-characterized model of islet cell growth in which partial obstruction of the hamster pancreatic duct leads to the induction of duct epithelial cell proliferation in association with endocrine cell differentiation and new islet formation. These changes appear to be mediated by a specific trophic activity (TA) that can be extracted from the pancreas following obstruction. Since the trophic effects of many growth factors are mediated through the polyamine pathway, we postulated that the trophic effect of TA is associated with the induction of ornithine decarboxylase (ODC) activity, the rate-limiting step in polyamine biosynthesis. The effect of TA on pancreatic ODC activity was studied alone, and after pretreatment with cyclosporine A (CsA), an immunosuppressive agent that is known to inhibit ODC activity. Eight h following the administration of TA, pancreatic ODC activity increased approximately 6-fold. Pretreatment with CsA for 7 d at a daily dose of 20 mg/kg prevented the induction of pancreatic ODC activity. We conclude that, in this model, CsA can block islet cell proliferation, and that this may be mediated by inhibition of TA-stimulated ODC activity.

A simple isokinetic cycle for measurement of leg muscle function.

The measurement of net pedaling torque during isokinetic cycling allows for the evaluation of leg muscle strength and work capacity over fixed time intervals. However, the expense and difficulty of constructing an isokinetic cycle have limited the widespread application of this useful research tool. We have modified a simple commercially available isokinetic cycle that uses hydraulics to maintain pedaling velocity. A strain gauge on the flywheel axle strut measures the torsion on the strut caused by pedaling. To evaluate this device, seven healthy subjects (3 males and 4 females) were each tested twice at 60, 90, and 120 rpm for peak power during a 10-s sprint and at 100 rpm for total work performed during a 30-s sprint. These results were compared with predicted values for age, height, and sex developed on a more complicated isokinetic cycle. Subjects also performed a progressive cycle ergometry test. For the group, peak power was 97.30 +/- 12.64% of predicted (males 883.70 +/- 202.76 W; females 657.00 +/- 66.42 W) and work output was 107.70 +/- 15.75% of predicted (males 15.50 +/- 2.85 kJ; females 11.70 +/- 2.17 kJ), whereas maximal progressive exercise capacity was 126.40 +/- 25.84% (males 245.30 +/- 56.58 W; females 212.30 +/- 35.49 W). The relatively lower work values generated on this cycle (compared with the maximal progressive exercise capacity) can be attributed to the location of the strain gauge, resulting in measurement of effective work output on the flywheel.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclosporine and islet mass--implications for islet transplantation.

Cyclosporine (CsA) is an inhibitor of ornithine decarboxylase (ODC), a key enzymatic step in cell proliferation. The purpose of this study was to determine the effect of CsA on islet cell mass. Partial obstruction (PDO) of the hamster pancreas is an established model of islet cell differentiation and proliferation in which regeneration is mediated by the induction of trophic activity (TA) that can be extracted from the pancreas. In Part 1 of these studies, hamsters were randomized to (i) Control (n = 5); (ii) PDO alone (n = 5); (iii) PDO + CsA (20 mg/kg ip daily) (n = 5); (iv) CsA alone (n = 5). On Day 21, 1 hr prior to sacrifice, animals received tritiated thymidine, 2 microCi/g body wt ip. Pancreata were excised for analysis of islet cell mass (No. islets/mm2) by morphometry and of cell proliferation (islet cell labeling index) by autoradiography. In Part 2 of these studies, hamsters were randomized to receive CsA (n = 34), as in Part 1, or saline (n = 30). After 7 days, animals received 1 ml of TA ip and were sacrificed after 0, 6, 8, and 10 hr. The pancreata were excised and determinations made of organ weight, DNA content, and ODC bioactivity (pmole/CO2/hr/mg DNA). Data (mean +/- SEM) were analyzed by ANOVA. In Part 1, the number of islets/mm2 in the PDO group was increased two-fold compared to control animals, those receiving CsA, and those undergoing PDO with CsA (2.4 +/- 0.1 vs 1.1 +/- 0.0, 1.4 +/- 0.2, 1.2 +/- 0.1, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Role of cardiac work in regulating myocardial biochemical characteristics.

The purpose of this study was to determine the extent to which functional demand regulates the biochemical character and enzyme capacities of the rat myocardium. Hearts from donor rats were heterotopically transplanted onto the abdominal aorta and inferior vena cava of isogenic recipients. The procedure results in a perfused but nonpumping heart that has a reduced heart rate (HR) and performs essentially no stroke work (SW). After 30 days, metabolic enzyme activities (phosphorylase, 6-phosphofructokinase, citrate synthase, and 3-hydroxyacyl-CoA dehydrogenase) were significantly lower (40-60%) in the nonworking heart. Specific sarcoplasmic reticulum Ca2(+)-adenosinetriphosphatase (ATPase) activity was unchanged, but activity per gram of heart was 41% lower. Myosin isozymes were 58% V1, 21% V2, and 21% V3 in the nonworking heart compared with 100% V1 in the working heart. Myosin and myofibrillar ATPase activities each decreased by 28%. These findings suggest that both HR and SW play major and specific roles in regulating myocardial biochemical capacities and determining the myosin phenotype.