Publications by authors named "David L Bigam"

85 Publications

Liver Transplantation in Locally Unresectable, Undifferentiated Embryonal Cell Sarcoma.

Transplant Direct 2021 Feb 15;7(2):e654. Epub 2021 Jan 15.

Department of Surgery, Section of Hepatobiliary, Pancreatic and Transplant Surgery, University of Alberta Hospital, Edmonton, AB, Canada.

Background: Undifferentiated embryonal cell sarcoma (UESL) of the liver is the third most common malignant liver disease of childhood presenting as a rapidly enlarging intraabdominal mass. This systematic review explores the practicality of liver transplantation as a viable option in the treatment armamentarium for locally advanced undifferentiated embryonal cell sarcoma.

Methods: A systematic review of the literature was performed using Medline and Embase, from inception of databases to December 31, 2018. Keywords and MeSH headings used were embryonal sarcoma, mesenchymal sarcoma, and liver transplant. Reviews and manuscripts with incomplete data were excluded.

Results: Twenty-eight patients had orthotopic liver transplantation (OLT) as a curative treatment option. The median age at presentation was 8 and 27 years in the pediatric and adult population, respectively, with a similar male to female ratio. A majority of the patients presented with abdominal pain, palpable mass, and a normal alpha-feto-protein. The median tumor size was 15 cm mainly affecting the right lobe (62%) of the liver. Eighty-two percent of the patients underwent primary OLT and 5 patients had salvage OLT. One death (3.6%) was due to initial misdiagnosis and management for hepatoblastoma. Recurrence was noted in 7.1% of the population. The median follow-up was noted to be 28.5 months. The documented survival rate post-liver transplant for UESL was 96%.

Conclusions: Based on available data and the very positive results therein, liver transplantation is a practical and justifiable use of a scarce resource as a treatment option for locally unresectable, undifferentiated embryonal cell sarcoma. The authors propose (accepting existence of different proposals) neoadjuvant therapy before curative resection, and if not achievable, then liver transplantation followed by adjuvant chemotherapy is an option for suitable candidates. For recurrent tumors after surgical resection, adjuvant therapy with salvage liver transplantation is an option.
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http://dx.doi.org/10.1097/TXD.0000000000001106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817332PMC
February 2021

The Actual Operative Costs of Liver Transplantation and Normothermic Machine Perfusion in a Canadian Setting.

Pharmacoecon Open 2020 Nov 15. Epub 2020 Nov 15.

Department of Surgery, University of Alberta, 8440 112 St, Edmonton, AB, T6G 2B7, Canada.

Background: Liver transplantation is an effective treatment for end-stage liver disease. However, waiting lists continue to lengthen as demand exceeds supply. Use of extended criteria donors has helped but is associated with increased rates of complications. The application of normothermic machine perfusion (NMP) has been shown to be protective, especially in more marginal grafts. Despite this benefit, no cost-effectiveness studies have been published.

Objective: This study serves as a prelude to a cost-effectiveness analysis of the costs of liver procurement, transplantation, and machine perfusion in a Canadian setting.

Methods: The total costs were calculated for 106 in-province procurements, the set cost for 237 out-of-province procurements, and 343 liver transplantations. These costs include overheads, supplies, anaesthesia technologist and nursing salaries, and physician billings. Base and modified costs for all procedures were calculated, with consideration of physician billing modifiers. The total cost per run of NMP was calculated, with a range based on variations in the exchange rates for Great British pounds (₤) to Canadian dollars ($Can), year 2019 values.

Results: Costs were $Can30,770.22 for in-province and $Can44,636.73 for out-of-province liver procurement and transplantation. These increased to $Can35,659.22 and 48,076.18 when considering modifiers. The minimum cost per NMP run was $Can18,593.02.

Conclusions: Although the cost per run is substantial, NMP could potentially lead to cost savings by decreasing night-time salary premiums, complications, and patient length of stay. A formal cost-effectiveness study of NMP in liver transplantation is underway to help clarify the financial benefit or burden of this new technology.
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http://dx.doi.org/10.1007/s41669-020-00241-8DOI Listing
November 2020

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

Can J Surg 2020 03 20;63(2):E135-E141. Epub 2020 Mar 20.

From the Department of Surgery, Division of General Surgery, University of Alberta Hospital, Edmonton, Alta. (Nostedt, Shapiro, Bigam); the Department of Physiology, University of Alberta, Edmonton, Alta. (Freed); and the Department of Surgery, Division of Cardiac Surgery, University of Alberta, Alberta Heart Institute, Edmonton, Alta. (Freed).

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.
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http://dx.doi.org/10.1503/cjs.005519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828961PMC
March 2020

Avoiding initial hypothermia does not improve liver graft quality in a porcine donation after circulatory death (DCD) model of normothermic perfusion.

PLoS One 2019 6;14(8):e0220786. Epub 2019 Aug 6.

Department of Surgery, Division of General Surgery, University of Alberta, Edmonton AB, Canada.

Background: Normothermic machine perfusion (NMP) of liver grafts donated after circulatory death (DCD) has shown promise in large animal and clinical trials. Following procurement, initial flush with a cold preservation solution is the standard of care. There is concern that initial cooling followed by warming may exacerbate liver injury, and the optimal initial flush temperature has yet to be identified. We hypothesize that avoidance of the initial cold flush will yield better quality liver grafts.

Methods: Twenty-four anaesthetized pigs were withdrawn from mechanical ventilation and allowed to arrest. After 60-minutes of warm ischemia to simulate a DCD procurement, livers were flushed with histidine-tryptophan-ketoglutarate (HTK) at 4°C, 25°C or 35°C (n = 4 per group). For comparison, an adenosine-lidocaine crystalloid solution (AD), shown to have benefit at warm temperatures in heart perfusions, was also used (n = 4 per group). During 12-hours of NMP, adenosine triphosphate (ATP), lactate, transaminase levels, and histological injury were determined. Bile production and hemodynamics were monitored continuously.

Results: ATP levels recovered substantially following 1-hour of NMP reaching pre-ischemic levels by the end of NMP with no difference between groups. There was no difference in peak aspartate aminotransferase (AST) or in lactate dehydrogenase (LDH). Portal vein resistance was lowest in the 4°C group reaching significance after 2 hours (0.13 CI -0.01,0.277, p = 0.025). Lactate levels recovered promptly with no difference between groups. Comparison to AD groups showed no statistical difference in the abovementioned parameters. On electron microscopy the HTK4°C group had the least edema with mean cell thickness of 2.92μm (p = 0.41) while also having the least sinusoidal dilatation with a mean diameter of 5.36μm (p = 0.04). For AD, the 25°C group had the lowest mean cell thickness at 3.14μm (p = 0.09).

Conclusions: Avoidance of the initial cold flush failed to demonstrate added benefit over standard 4°C HTK in this DCD model of liver perfusion.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0220786PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684160PMC
March 2020

Clearance of transaminases during normothermic ex situ liver perfusion.

PLoS One 2019 24;14(4):e0215619. Epub 2019 Apr 24.

Department of Surgery, University of Alberta, Edmonton, Canada.

Background: One of the most promising applications of liver normothermic machine perfusion (NMP) is the potential to directly assess graft viability and injury. In most NMP studies, perfusate transaminases are utilized as markers of graft injury. Our aim was to further elucidate the metabolism of transaminases by healthy porcine livers during NMP, specifically whether such livers could clear circuit perfusate transaminases.

Methods: A highly concentrated transaminase solution was prepared from homogenized liver, with an aspartate aminotransferase (AST) level of 107,427 U/L. Three livers in the treatment group were compared to three controls, during 48 hours of NMP. In the treatment group, the circuit perfusate was injected with the transaminase solution to artificially raise the AST level to a target of 7,500 U/L. Perfusate samples were taken at two-hour intervals and analyzed for biochemistry until NMP end. Graft oxygen consumption and vascular parameters were monitored.

Results: Compared to controls, treated perfusions demonstrated abrupt elevations in transaminase levels (p>0.0001) and lactate dehydrogenase (LDH) (p>0.0001), which decreased over time, but never to control baseline. Liver function, as demonstrated by lactate clearance and oxygen consumption was not different between groups. The treatment group demonstrated a higher portal vein resistance (p = 0.0003), however hepatic artery resistance was similar. Treated livers had higher bile production overall (p<0.0001).

Conclusions: Addition of high levels of transaminases and LDH to a healthy porcine liver during ex situ perfusion results in progressive clearance of these enzymes, suggesting preserved liver metabolism. Such tolerance tests may provide valuable indicators of prospective graft function.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215619PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481840PMC
January 2020

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

Dis Colon Rectum 2019 05;62(5):549-560

Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.

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.
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http://dx.doi.org/10.1097/DCR.0000000000001352DOI Listing
May 2019

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

Transpl Int 2019 02 10;32(2):163-172. Epub 2018 Sep 10.

Division of Transplantation, Department of Surgery, University of Alberta, Edmonton, AB, Canada.

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 cm 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.
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http://dx.doi.org/10.1111/tri.13337DOI Listing
February 2019

Normothermic Ex Vivo Machine Perfusion for Liver Grafts Recovered from Donors after Circulatory Death: A Systematic Review and Meta-Analysis.

HPB Surg 2018 23;2018:6867986. Epub 2018 Apr 23.

Department of Surgery, Division of General Surgery, University of Alberta Hospital, 2D4.41 W.M.C, 8440-112 St., Edmonton, AB, Canada T6G 2B7.

As a result of donation after circulatory death liver grafts' poor tolerance to cold storage, there has been increasing research interest in normothermic machine perfusion. This study aims to systematically review the current literature comparing normothermic perfusion to cold storage in donation after circulatory death liver grafts and complete a meta-analysis of published large animal and human studies. A total of nine porcine studies comparing cold storage to normothermic machine perfusion for donation after circulatory death grafts were included for analysis. There was a significant reduction in AST (mean difference -2291 U/L, CI (-3019, -1563); ≤ 0.00001) and ALT (mean difference -175 U/L, CI (-266, -85); = 0.0001), for normothermic perfusion relative to static cold storage, with moderate ( = 61%) and high ( = 96%) heterogeneity, respectively. Total bile production was also significantly higher (mean difference = 174 ml, CI (155, 193); ≤ 0.00001). Further research focusing on standardization, performance of this technology following periods of cold storage, economic implications, and clinical trial data focused on donation after circulatory death grafts will be helpful to advance this technology toward routine clinical utilization for these grafts.
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http://dx.doi.org/10.1155/2018/6867986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5937385PMC
April 2018

Determination of Minimal Hemoglobin Level Necessary for Normothermic Porcine Ex Situ Liver Perfusion.

Transplantation 2018 08;102(8):1284-1292

Department of Surgery, University of Alberta, Edmonton, Canada.

Background: In current studies of ex situ liver perfusion there exists considerable variability in perfusate composition, including the type of oxygen carrier. Herein, we aim to clarify the minimal hemoglobin level necessary during normothermic porcine ex situ liver perfusion.

Methods: Livers procured from 35 to 45 kg domestic pigs were connected to our experimental ex situ circuit (n = 10). In the treatment group, perfusate was sequentially diluted hourly to predetermined hemoglobin levels. At the end of each hemoglobin dilution, perfusate samples were analyzed for liver transaminases, lactate dehydrogenase (LD), total bilirubin, and lactate levels. Liver oxygen consumption was measured. In the control group, livers were perfused continually for a duration of 24 hours at target hemoglobin levels of 30 and 20 g/L.

Results: Rising liver transaminases, significantly higher lactate (P < 0.001), and LD levels (P < 0.001) were noted at lower perfusate hemoglobin levels in the treatment group. Liver oxygen utilization (P < 0.001) and hepatic artery oxygen delivery (P < 0.001) were significantly lower at lower hemoglobin levels, whereas liver vessel resistance remained relatively constant. Histology demonstrated increasing parenchymal damage at lower hemoglobin levels. In control livers, higher perfusate transaminases, higher lactate, and LD levels were noted at a perfusion hemoglobin level of 20 g/L.

Conclusions: Ex situ liver function decompensated during perfusion between a mean hemoglobin level of 30 to 20 g/L, as evidenced by notably rising lactate and LD levels. This study demonstrates optimal hemoglobin concentration during normothermic ex situ liver perfusion to ensure a fully metabolically functioning graft.
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http://dx.doi.org/10.1097/TP.0000000000002272DOI Listing
August 2018

Ex situ liver perfusion: Organ preservation into the future.

Transplant Rev (Orlando) 2018 07 5;32(3):132-141. Epub 2018 Apr 5.

Department of Surgery, University of Alberta, 2D4.43 Walter D MacKenzie Health Sciences Centre, 8440 112 St, Edmonton, Alberta T6G2B7, Canada; Members of the Canadian National Transplant Research Program (CNTRP), 2D4.43 Walter D MacKenzie Health Sciences Centre, 8440 112 St, Edmonton, Alberta T6G2B7, Canada. Electronic address:

In recent years, remarkable progress has occurred in the development of technologies to support ex situ liver perfusion. Building upon extensive preclinical studies in large animal models, pilot and randomized clinical trials have been initiated, and preliminary outcomes suggest more optimal protection of both standard and extended criteria liver grafts. There currently exists an incredible opportunity and need to further refine this technology, determine appropriate viability measures to predict usable liver grafts, and to explore potent protective additive strategies to further optimize the quality of extended criteria organs. These findings will have major bearing in expanding the limited liver donor pool, and may save lives where up to a quarter of listed patients die on wait-lists. Herein we offer a brief overview of the history and current status of ex situ liver perfusion, and discuss future directions that will likely have major impact on the practice of clinical liver transplantation.
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http://dx.doi.org/10.1016/j.trre.2018.03.002DOI Listing
July 2018

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

Ann Surg Oncol 2018 May 27;25(5):1381-1394. Epub 2018 Feb 27.

Department of Medical Oncology, Cross Cancer Institute, Edmonton, AB, Canada.

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.
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http://dx.doi.org/10.1245/s10434-018-6395-8DOI Listing
May 2018

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

Am J Physiol Gastrointest Liver Physiol 2017 Apr 19;312(4):G390-G404. Epub 2017 Jan 19.

Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.

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·day) alone, enteral EGF-cm (80 μg·kg·day) 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 ( < 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 ( < 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 ( < 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. 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.
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http://dx.doi.org/10.1152/ajpgi.00281.2016DOI Listing
April 2017

Diaphragmatic Hernia After Living Donor Right Hepatectomy: Proposal for a Screening Protocol.

Transplant Direct 2016 Jul 2;2(7):e84. Epub 2016 Jun 2.

Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.

Background: Living donor hepatectomy (LDH) is increasingly being used to improve access to liver transplantation for those with end-stage liver disease. Although recipient outcomes are equivalent, donor complication rates range from 10% to 41%. A rare, but potentially serious complication is occurrence of a diaphragmatic hernia (DH), of which 9 cases have been reported so far in the literature. The purpose of this work was to review the clinical impact of DH post-LDH, including risk factors (RF) in hope of mitigating impact.

Methods: A literature review was performed identifying all previous reports of post-operative DH in living liver donors. Demographic and outcome data were gathered to help identify RF. We also report 2 cases from our own institution.

Results: Reported incidences range from 0.6% to 2.3%, of which the majority are delayed (≥19 months). Obstruction or intestinal strangulation was present in 45%, 60% of whom required an intestinal resection. The most common RF was right lobe donation.

Conclusions: Postoperative DH is a rare but serious complication of LDH. The major RFs are right lobe donation and potentially conditions resulting in increased intraabdominal pressure. Diaphragmatic hernia frequently lead to intestinal obstruction and strangulation and should be repaired when identified. The implementation of a screening protocol for early identification could lead to repair before the development of complications. We propose the addition of screening chest x-ray to follow-up protocols to aid in the identification and subsequent repair of postoperative DH. Such a practice could hopefully reduce the clinical impact of this complication.
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http://dx.doi.org/10.1097/TXD.0000000000000596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5087565PMC
July 2016

Differential Effects on Intestinal Adaptation Following Exogenous Glucagon-Like Peptide 2 Therapy With and Without Enteral Nutrition in Neonatal Short Bowel Syndrome [Formula: see text].

JPEN J Parenter Enteral Nutr 2017 02 28;41(2):156-170. Epub 2016 Sep 28.

1 Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.

Background: We aim to study the efficacy of exogenously administered glucagon-like peptide 2 (GLP-2) on intestinal adaptation in 2 preclinical models of neonatal short bowel syndrome (SBS) according to remnant intestinal anatomy, with and without ileum. Furthermore, we aim to determine if this adaptive effect was potentiated with enteral nutrition (EN).

Methods: Neonatal piglets were block-randomized to 75% mid-intestinal (JI group, retains ileum) or distal-intestinal (JC group, has no ileum) resection or no resection (sham control) and GLP-2 treatment (11 nmol/kg/d) or saline control for 7 days. Piglets received nutrition support, either 100% parenteral nutrition (PN; 0% EN, n = 32 in total) or 80% PN + 40% EN (n = 28 in total). Adaptation was assessed by morphological and histological changes, as well as RT quantitative polymerase chain reaction of nutrient transporters and tight junctional proteins and fat absorption. Data are analyzed by 3-way analysis of variance (ANOVA) and 2-way ANOVA per EN level.

Results: GLP-2 treatment lengthened villi, deepened crypts, and improved intestinal weight in the remnant intestine of JC piglets. EN was a more potent adaptive stimulus for JI piglets. Small intestinal lengthening occurred only in the JI group, when given EN. There was no difference in total fat absorption and messenger RNA expression of nutrient transporters and tight junctional proteins.

Conclusions: GLP-2 administration augmented structural adaptation in JC piglets with distal intestinal resection. Given JI anatomy, further stimulation by GLP-2 treatment over innate adaptation and stimulation by EN was modest and restricted to ileum. The differential effect of GLP-2 in neonatal SBS, depending on remnant anatomy, has important implications for clinical translation and planning of clinical trials.
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http://dx.doi.org/10.1177/0148607116665812DOI Listing
February 2017

On the horizon: trophic peptide growth factors as therapy for neonatal short bowel syndrome.

Expert Opin Ther Targets 2016 Jul 1;20(7):819-30. Epub 2016 Mar 1.

d Departments of Physiology and Medicine , University of Toronto , Toronto , ON , Canada.

Introduction: Short bowel syndrome (SBS) occurs more commonly in human neonates than in adults. There are currently no approved therapeutic agents aimed directly at stimulating intestinal adaptation in this population.

Areas Covered: A brief review of SBS and intestinal adaptation is first presented. We then present candidate peptide growth factors that are suggested to augment intestinal adaptation in SBS, with a particular focus on glucagon-like peptide-2, as well as insulin-like growth factor-1 and epidermal growth factor. The normal physiology of these peptides and our understanding of their roles in intestinal adaptation are discussed. We further consider the roles of these peptides in the ontogeny of the gastrointestinal tract and we present the limited preclinical data on the effects of administering these peptides in neonatal SBS.

Expert Opinion: The clinical translation of trophic peptide therapies in neonatal SBS will require several challenges to be overcome. The optimal dose, timing and route of administration for the likely peptide, or combination of peptides, to be administered will be paramount. Despite their cost to patient care, trophic peptides have shown promise in preclinical models of neonatal SBS and may be especially beneficial for neonates that lack remnant ileum and suffer from irreversible intestinal failure.
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http://dx.doi.org/10.1517/14728222.2016.1146695DOI Listing
July 2016

Exhaled CO2 Parameters as a Tool to Assess Ventilation-Perfusion Mismatching during Neonatal Resuscitation in a Swine Model of Neonatal Asphyxia.

PLoS One 2016 14;11(1):e0146524. Epub 2016 Jan 14.

Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.

Background: End-tidal CO2 (ETCO2), partial pressure of exhaled CO2 (PECO2), and volume of expired CO2 (VCO2) can be continuously monitored non-invasively to reflect pulmonary ventilation and perfusion status. Although ETCO2 ≥14 mmHg has been shown to be associated with return of an adequate heart rate in neonatal resuscitation and quantifying the PECO2 has the potential to serve as an indicator of resuscitation quality, there is little information regarding capnometric measurement of PECO2 and ETCO2 in detecting return of spontaneous circulation (ROSC) and survivability in asphyxiated neonates receiving cardiopulmonary resuscitation (CPR).

Methods: Seventeen newborn piglets were anesthetized, intubated, instrumented, and exposed to 45-minute normocapnic hypoxia followed by apnea to induce asphyxia. Protocolized resuscitation was initiated when heart rate decreased to 25% of baseline. Respiratory and hemodynamic parameters including ETCO2, PECO2, VCO2, heart rate, cardiac output, and carotid artery flow were continuously measured and analyzed.

Results: There were no differences in respiratory and hemodynamic parameters between surviving and non-surviving piglets prior to CPR. Surviving piglets had significantly higher ETCO2, PECO2, VCO2, cardiac index, and carotid artery flow values during CPR compared to non-surviving piglets.

Conclusion: Surviving piglets had significantly better respiratory and hemodynamic parameters during resuscitation compared to non-surviving piglets. In addition to optimizing resuscitation efforts, capnometry can assist by predicting outcomes of newborns requiring chest compressions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0146524PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4713087PMC
July 2016

Doxycycline attenuates renal injury in a swine model of neonatal hypoxia-reoxygenation.

Shock 2015 Jan;43(1):99-105

Departments of *Surgery, †Laboratory Medicine and Pathology, ‡Pharmacology, and §Pediatrics, University of Alberta, Edmonton, Alberta, Canada.

Acute kidney injury in asphyxiated neonates is common. The renal protective effects of doxycycline, a known matrix metalloproteinase (MMP) inhibitor, have been demonstrated in rat ischemic-reperfusion models of injury. These effects have not been tested in large-animal models designed to reflect true clinical scenarios of neonatal hypoxia-reoxygenation (H-R). Newborn piglets were surgically instrumented for hemodynamic monitoring and subjected to 2 h of hypoxia followed by 4 h of normoxic reoxygenation. Piglets were blindly randomized to receive i.v. saline or doxycycline (3, 10, or 30 mg/kg) 5 min into reoxygenation (n = 7 per group). Sham-operated piglets (n = 5) received no H-R. Renal injury was investigated by histologic examination and measuring serum creatinine, urinary N-acetyl-D-glucosaminidase activity and renal tissue lactate with enzyme-linked immunosorbent assay. Renal tissue oxidative stress (lipid hydroperoxides) and total MMP-2 activity were measured with enzyme-linked immunosorbent assay and gelatin zymography, respectively. Piglets treated with doxycycline had significantly improved cardiac index, systemic arterial pressure, renal artery blood flow, and oxygen delivery, with no difference observed in heart rate compared with controls. The H-R piglets had significantly higher urinary N-acetyl-D-glucosaminidase activity, renal tissue lipid hydroperoxides, lactate, and MMP-2 activity, which were attenuated to varied degrees in a dose-related manner in piglets treated with doxycycline (P = 0.08 to P < 0.05). Serum creatinine and histologic features of H-R were not different among groups. Postresuscitation administration of doxycycline improved renal perfusion, attenuated renal injury, and reduced tissue oxidative stress and MMP-2 activity in a clinically translatable newborn swine model of H-R.
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http://dx.doi.org/10.1097/SHK.0000000000000257DOI Listing
January 2015

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

Crit Care Med 2014 Apr;42(4):e260-9

1Department of Surgery, University of Alberta, Edmonton, AB, Canada. 2Department of Pharmacology, University of Alberta, Edmonton, AB, Canada. 3Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada. 4Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.

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.
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http://dx.doi.org/10.1097/CCM.0000000000000135DOI Listing
April 2014

3:1 compression to ventilation ratio versus continuous chest compression with asynchronous ventilation in a porcine model of neonatal resuscitation.

Resuscitation 2014 Feb 22;85(2):270-5. Epub 2013 Oct 22.

Department of Pediatrics, University of Alberta, Edmonton, Canada; Neonatal Research Unit, Royal Alexandra Hospital, Edmonton, Canada; Department of Surgery, University of Alberta, Edmonton, Canada.

Objective: In contrast to the resuscitation guidelines of children and adults, guidelines on neonatal resuscitation recommend synchronized 90 chest compressions with 30 manual inflations (3:1) per minute in newborn infants. The study aimed to determine if chest compression with asynchronous ventilation improves the recovery of bradycardic asphyxiated newborn piglets compared to 3:1 Compression:Ventilation cardiopulmonary resuscitation (CPR).

Intervention And Measurements: Term newborn piglets (n=8/group) were anesthetized, intubated, instrumented and exposed to 45-min normocapnic hypoxia followed by asphyxia. Protocolized resuscitation was initiated when heart rate decreased to 25% of baseline. Piglets were randomized to receive resuscitation with either 3:1 compressions to ventilations (3:1C:V CPR group) or chest compressions with asynchronous ventilations (CCaV) or sham. Continuous respiratory parameters (Respironics NM3(®)), cardiac output, mean systemic and pulmonary artery pressures, and regional blood flows were measured.

Main Results: Piglets in 3:1C:V CPR and CCaV CPR groups had similar time to return of spontaneous circulation, survival rates, hemodynamic and respiratory parameters during CPR. The systemic and regional hemodynamic recovery in the subsequent 4h was similar in both groups and significantly lower compared to sham-operated piglets.

Conclusion: Newborn piglets resuscitated by CCaV had similar return of spontaneous circulation, survival, and hemodynamic recovery compared to those piglets resuscitated by 3:1 Compression:Ventilation ratio.
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http://dx.doi.org/10.1016/j.resuscitation.2013.10.011DOI Listing
February 2014

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

Circulation 2013 Dec 2;128(23):2495-503. Epub 2013 Oct 2.

Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada (G.M.S., MO., T.-F.L., P.-Y.C.); Neonatal Research Unit, Royal Alexandra Hospital, Edmonton, Alberta, Canada (G.M.S., M.O., S.C., S.Q., P.-Y.C.); Department of Pediatrics, Medical University Graz, Graz, Austria (G.M.S.); Department of Surgery, University of Alberta, Edmonton, Alberta, Canada (J.L., D.L.B., P.-Y.C.); and Faculty of Science, University of Alberta, Edmonton, Alberta, Canada (S.C.).

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.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.113.002289DOI Listing
December 2013

Effects of post-resuscitation administration with sodium hydrosulfide on cardiac recovery in hypoxia-reoxygenated newborn piglets.

Eur J Pharmacol 2013 Oct 18;718(1-3):74-80. Epub 2013 Sep 18.

Departments of Surgery, University of Alberta, Edmonton, Alberta, Canada; Departments of Pediatrics, University of Alberta, Edmonton, Alberta, Canada. Electronic address:

Hydrogen sulfide may protect multiple organ systems against ischemic-reperfusion injuries. It is unknown if treatment with sodium hydrosulfide (NaHS, a hydrogen sulfide donor) will improve myocardial function and minimize oxidative stress in hypoxic-reoxygenated newborn piglets. Mixed breed piglets (1-5 day, 1.5-2.5 kg) were anesthetized and acutely instrumented for the measurement of systemic, pulmonary and regional (carotid, superior mesenteric and renal) hemodynamics and blood gas parameters. The piglets were induced with normocapnic alveolar hypoxia (10-15% oxygen, 2h) followed by reoxygenation with 100% (1h) then 21% oxygen (3h). At 10 min of reoxygenation, either NaHS (10mg/kg, 5 ml) or saline (5 ml) was administered intravenously for 30 min (5 min bolus followed by 25 min of continuous infusion) in a blinded, block-randomized fashion (n = 7/group). Plasma lactate and troponin I levels and tissue markers of myocardial oxidative stress were also determined. Two hours hypoxia caused cardiogenic shock (45 ± 3% of respective normoxic baseline), reduced regional perfusion with metabolic acidosis (pH 6.94 ± 0.02). NaHS infusion significantly improved recovery of cardiac index (84 ± 3% vs. 72 ± 5% in controls), systemic oxygen delivery (84 ± 3% vs. 72 ± 5% in controls) and systemic oxygen consumption (102 ± 5% vs. 84 ± 6% in controls) at 4h of reoxygenation. NaHS had no significant effect on systemic and pulmonary blood pressures, regional blood flows, plasma lactate and troponin I levels. The myocardial glutathionine ratio was reduced in piglets treated with NaHS (vs. controls, P<0.05). Post-resuscitation administration of NaHS improves cardiac function and systemic perfusion and attenuates myocardial oxidative stress in newborn piglets following hypoxia-reoxygenation.
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http://dx.doi.org/10.1016/j.ejphar.2013.09.017DOI Listing
October 2013

Pharmacokinetic characterization of intravenous cyclosporine treatment for cardioprotection during resuscitation of asphyxiated newborn piglets.

Pediatr Crit Care Med 2013 Mar;14(3):e156-62

Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.

Objectives: Cyclosporine treatment, as a single intravenous bolus, during resuscitation has been shown to attenuate myocardial injury in asphyxiated newborn piglets. However, the pharmacokinetics of cyclosporine treatment for cardioprotection in newborns has not been studied. We aimed to assess the pharmacokinetics of a single intravenous cyclosporine treatment during resuscitation of asphyxiated newborn piglets and compare these parameters with healthy newborn piglets.

Design: Newborn piglets were acutely instrumented and normocapnic alveolar hypoxia was induced for 2 hours followed by 4 hours of reoxygenation. Piglets were block-randomized to receive a single intravenous bolus of cyclosporine (2.5-25 mg/kg) (n = 8 per group). Eight piglets underwent no hypoxia-reoxygenation and received 10 mg/kg cyclosporine at the corresponding time point. Plasma cyclosporine and troponin concentrations during reoxygenation period were determined by high-pressure liquid chromatography and enzyme-linked immunosorbent assay, respectively. Noncompartmental methods were used to calculate the pharmacokinetic parameters. Cyclosporine concentrations and pharmacokinetic parameters were analyzed by one-way analysis of variance.

Setting: University animal laboratory.

Subjects: Piglets (1-4 days old, weighing 1.4-2.5 kg).

Interventions: Intravenous cyclosporine (2.5, 10, or 25 mg/kg) given during resuscitation.

Measurements And Main Results: In the hypoxic-reoxygenated piglets, the plasma AUC(0-4 hrs) and C(max) of cyclosporine at reoxygenation were in the following rank order: 25 > 10 > 2.5 mg/kg treatment (p < 0.001 between groups, analysis of variance). Plasma AUC(0-4 hrs) and C(max) in piglets treated with cyclosporine at 25 mg/kg was associated with increased plasma troponin levels, a marker of myocardial injury, relative to piglets treated with 2.5 and 10 mg/kg. Asphyxiated newborn piglets had higher clearance and lower AUC(0-∞), but similar AUC(0-4 hrs), steady-state volume of distribution, and mean residence time compared with those of healthy newborn piglets.

Conclusions: This is the first study to demonstrate the pharmacokinetics of intravenous cyclosporine treatment during resuscitation of asphyxiated newborn piglets, which did not appear to different from that of healthy piglets.
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http://dx.doi.org/10.1097/PCC.0b013e318271f475DOI Listing
March 2013

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

Crit Care Med 2013 Apr;41(4):1069-74

Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.

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.
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http://dx.doi.org/10.1097/CCM.0b013e3182746704DOI Listing
April 2013

A comparison of combination dopamine and epinephrine treatment with high-dose dopamine alone in asphyxiated newborn piglets after resuscitation.

Pediatr Res 2013 Apr 23;73(4 Pt 1):435-42. Epub 2013 Jan 23.

Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.

Background: When asphyxiated neonates require additional cardiovascular support to moderate doses of dopamine infusion, controversy exists on the differential hemodynamic effects of two approaches (adding a second inotrope vs. increasing dopamine dosage). We hypothesized that high-dose dopamine (HD) would be detrimental to systemic and regional perfusion as compared with dopamine and epinephrine (D + E) combination therapy using a swine model of neonatal hypoxia-reoxygenation (H-R).

Methods: Twenty-seven piglets (1-4 d, 1.5-2.5 kg) were used for continuous monitoring of systemic arterial pressure (mean arterial pressure, MAP) and pulmonary arterial pressure (PAP), cardiac output (cardiac index, CI), and carotid (carotid artery flow index, CAFI), superior mesenteric (superior mesenteric artery flow index), and renal arterial flows. H-R piglets underwent 2 h of hypoxia followed by 2 h of reoxygenation before drug infusion (2 h).

Results: The hemodynamics of H-R piglets deteriorated gradually after reoxygenation. HD and D + E infusions improved CI similarly (both groups vs. control; P < 0.05). Both regimens increased MAP (P < 0.05) but not PAP, with decreased PAP/MAP ratio in D + E piglets. Both regimens improved CAFI and superior mesenteric artery flow index, with decreased mesenteric vascular resistance in HD-treated piglets. No significant effect on renal perfusion was observed.

Conclusion: In H-R newborn piglets treated with a moderate dose of dopamine, adding epinephrine or further increasing dopamine improved systemic hemodynamics similarly; these treatments have differential effects on the pulmonary and mesenteric circulations.
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http://dx.doi.org/10.1038/pr.2013.17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4972577PMC
April 2013

Cyclosporine treatment reduces oxygen free radical generation and oxidative stress in the brain of hypoxia-reoxygenated newborn piglets.

PLoS One 2012 9;7(7):e40471. Epub 2012 Jul 9.

Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.

Oxygen free radicals have been implicated in the pathogenesis of hypoxic-ischemic encephalopathy. It has previously been shown in traumatic brain injury animal models that treatment with cyclosporine reduces brain injury. However, the potential neuroprotective effect of cyclosporine in asphyxiated neonates has yet to be fully studied. Using an acute newborn swine model of hypoxia-reoxygenation, we evaluated the effects of cyclosporine on the brain, focusing on hydrogen peroxide (H(2)O(2)) production and markers of oxidative stress. Piglets (1-4 d, 1.4-2.5 kg) were block-randomized into three hypoxia-reoxygenation experimental groups (2 h hypoxia followed by 4 h reoxygenation) (n = 8/group). At 5 min after reoxygenation, piglets were given either i.v. saline (placebo, controls) or cyclosporine (2.5 or 10 mg/kg i.v. bolus) in a blinded-randomized fashion. An additional sham-operated group (n = 4) underwent no hypoxia-reoxygenation. Systemic hemodynamics, carotid arterial blood flow (transit-time ultrasonic probe), cerebral cortical H(2)O(2) production (electrochemical sensor), cerebral tissue glutathione (ELISA) and cytosolic cytochrome-c (western blot) levels were examined. Hypoxic piglets had cardiogenic shock (cardiac output 40-48% of baseline), hypotension (mean arterial pressure 27-31 mmHg) and acidosis (pH 7.04) at the end of 2 h of hypoxia. Post-resuscitation cyclosporine treatment, particularly the higher dose (10 mg/kg), significantly attenuated the increase in cortical H(2)O(2) concentration during reoxygenation, and was associated with lower cerebral oxidized glutathione levels. Furthermore, cyclosporine treatment significantly attenuated the increase in cortical cytochrome-c and lactate levels. Carotid blood arterial flow was similar among groups during reoxygenation. Conclusively, post-resuscitation administration of cyclosporine significantly attenuates H(2)O(2) production and minimizes oxidative stress in newborn piglets following hypoxia-reoxygenation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0040471PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3392221PMC
April 2013

Infusing sodium bicarbonate suppresses hydrogen peroxide accumulation and superoxide dismutase activity in hypoxic-reoxygenated newborn piglets.

PLoS One 2012 22;7(6):e39081. Epub 2012 Jun 22.

Department of Neonatology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.

Background: The effectiveness of sodium bicarbonate (SB) has recently been questioned although it is often used to correct metabolic acidosis of neonates. The aim of the present study was to examine its effect on hemodynamic changes and hydrogen peroxide (H(2)O(2)) generation in the resuscitation of hypoxic newborn animals with severe acidosis.

Methods: Newborn piglets were block-randomized into a sham-operated control group without hypoxia (n = 6) and two hypoxia-reoxygenation groups (2 h normocapnic alveolar hypoxia followed by 4 h room-air reoxygenation, n = 8/group). At 10 min after reoxygenation, piglets were given either i.v. SB (2 mEq/kg), or saline (hypoxia-reoxygenation controls) in a blinded, randomized fashion. Hemodynamic data and blood gas were collected at specific time points and cerebral cortical H(2)O(2) production was continuously monitored throughout experimental period. Plasma superoxide dismutase and catalase and brain tissue glutathione, superoxide dismutase, catalase, nitrotyrosine and lactate levels were assayed.

Results: Two hours of normocapnic alveolar hypoxia caused cardiogenic shock with metabolic acidosis (PH: 6.99 ± 0.07, HCO(3)(-): 8.5 ± 1.6 mmol/L). Upon resuscitation, systemic hemodynamics immediately recovered and then gradually deteriorated with normalization of acid-base imbalance over 4 h of reoxygenation. SB administration significantly enhanced the recovery of both pH and HCO(3-) recovery within the first hour of reoxygenation but did not cause any significant effect in the acid-base at 4 h of reoxygenation and the temporal hemodynamic changes. SB administration significantly suppressed the increase in H(2)O(2) accumulation in the brain with inhibition of superoxide dismutase, but not catalase, activity during hypoxia-reoxygenation as compared to those of saline-treated controls.

Conclusions: Despite enhancing the normalization of acid-base imbalance, SB administration during resuscitation did not provide any beneficial effects on hemodynamic recovery in asphyxiated newborn piglets. SB treatment also reduced the H(2)O(2) accumulation in the cerebral cortex without significant effects on oxidative stress markers presumably by suppressing superoxide dismutase but not catalase activity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0039081PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3382246PMC
March 2013

Early versus delayed cyclosporine treatment in cardiac recovery and intestinal injury during resuscitation of asphyxiated newborn piglets.

Intensive Care Med 2012 Jul 10;38(7):1215-23. Epub 2012 May 10.

Department of Surgery, University of Alberta, Edmonton, AB, Canada.

Purpose: We previously demonstrated that treating asphyxiated newborn piglets with cyclosporine immediately following resuscitation can improve cardiac and intestinal recovery. However, immediate treatment may not be feasible for a large portion of neonates delivered in peripheral or rural hospitals. Therefore, our objective was to determine if delayed cyclosporine treatment remained effective in treating neonatal asphyxia. We hypothesized that early and delayed cyclosporine treatment would improve cardiac and intestinal recovery during resuscitation of asphyxiated newborn piglets.

Methods: Thirty piglets (1-4 days old) were instrumented for continuous monitoring of cardiac output and mesenteric hemodynamics. After stabilization, normocapnic alveolar hypoxia (10-15 % oxygen) was instituted for 2 h followed by reoxygenation with 100 % oxygen for 0.5 h, then 21 % for 5.5 h. Piglets were block-randomized to receive either intravenous bolus of cyclosporine A (10 mg/kg) or normal saline (control) at 5 or 120 min of reoxygenation (early or delayed, respectively; n = 8/group). Myocardial and intestinal lactate concentrations as well as histological examinations were determined.

Results: Hypoxic piglets had cardiogenic shock (cardiac output 52 ± 1 % of baseline, mean arterial pressure 32 ± 1 mmHg) and acidosis (pH 6.98 ± 0.1). Although both cyclosporine treatments improved cardiac output (p < 0.05 vs. controls), only early cyclosporine treatment improved stroke volume and systemic oxygen delivery (p < 0.05 vs. controls). Left ventricle and intestinal lactate were lowered in both cyclosporine-treated groups (p < 0.05 vs. controls). Early, but not delayed, cyclosporine treatment also attenuated intestinal injury (p < 0.05 vs. controls).

Conclusion: This study demonstrates that treating asphyxiated newborn piglets with cyclosporine within 2 h of resuscitation is effective with superior cardioprotection and intestinal injury attenuation with early treatment.
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http://dx.doi.org/10.1007/s00134-012-2577-1DOI Listing
July 2012

Therapeutic strategies to protect the immature newborn myocardium during resuscitation following asphyxia.

Can J Physiol Pharmacol 2012 Jun 17;90(6):689-95. Epub 2012 Apr 17.

Department of Surgery, University of Alberta, Edmonton, AB T6G 2R3, Canada.

Perinatal asphyxia contributes to over one million newborn deaths worldwide annually, and may progress to multiorgan failure. Cardiac dysfunction, of varying severity, is seen in 50%-70% of asphyxiated newborns. Resuscitation is necessary to restore oxygenation to deprived tissues, including the heart. However, reoxygenation of asphyxiated newborns may lead to generation of reactive oxygen species (ROS) and further myocardial damage, termed reperfusion injury. The newborn heart is especially vulnerable to oxidative stress and reperfusion injury due to immature antioxidant defense mechanisms and increased vulnerability to apoptosis. Currently, newborn myocardial protective strategies are aimed at reducing the generation of ROS through controlled reoxygenation, boosting antioxidant defenses, and attenuating cellular injury via mitochondrial stabilization.
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http://dx.doi.org/10.1139/y2012-041DOI Listing
June 2012

Milrinone is preferred to levosimendan for mesenteric perfusion in hypoxia-reoxygenated newborn piglets treated with dopamine.

Pediatr Res 2012 Mar 11;71(3):241-6. Epub 2012 Jan 11.

Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.

Introduction: There is little information regarding the comparative hemodynamic effects of adding milrinone or levosimendan to dopamine infusion in hypoxia-reoxygenated (H-R) newborns.

Results: Severely hypoxic piglets had cardiogenic shock with depressed cardiac index (CI) and mean arterial pressure (MAP). The hemodynamics deteriorated gradually after initial recovery upon reoxygenation. Heart rate and CI improved with milrinone (D+M) and levosimendan (D+L) administration (P < 0.05 vs. control). Both regimens improved carotid arterial flow and carotid vascular resistance; D+M additionally improved superior mesentric arterial flow (all P < 0.05 vs. control). No effect was found on renal arterial flow or elevated lactate state with either regimen. D+M piglets also had a lower myocardial oxidized/reduced glutathione ratio (P < 0.05 vs. control).

Discussion: In conclusion, adding milrinone or levosimendan to dopamine similarly improved systemic hemodynamics in H-R newborn piglets. Milrinone also improved mesenteric perfusion and attenuated myocardial oxidative stress.

Methods: Twenty-eight piglets (1-4 d, 1.5-2.5 kg) were instrumented for continuous monitoring of systemic MAP and pulmonary arterial pressure (PAP), CI, and carotid, superior mesenteric, and renal arterial flows. Piglets were randomized with blinding to sham-operated, H-R control (saline), and H-R dopamine (10 μg/kg/min) with D+M or D+L groups. H-R piglets underwent H-R followed by 2 h of drug infusion after reoxygenation. Tissue was collected for biochemical/oxidative stress testing and histological analysis.
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http://dx.doi.org/10.1038/pr.2011.48DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4972574PMC
March 2012

The role of cyclosporine in the treatment of myocardial reperfusion injury.

Shock 2012 Apr;37(4):341-7

Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.

Myocardial injury in adult, pediatric, and newborn patients is a leading cause of mortality and morbidity. Although the underlying etiologies are different among patient populations, the sequence of initial ischemic-hypoxic injury followed by secondary myocardial reperfusion injury is relatively consistent. Overall infarct size is important because it is believed to be a key determinant of mortality. The detrimental effects of myocardial reperfusion have been proposed to be at least partially related to the formation of mitochondrial permeability transition pore (MPTP). The MPTP is a nonspecific pore, which forms during myocardial reperfusion and allows the release of apoptotic signaling molecules and may also lead to cellular necrosis. Cyclosporine A has been shown to be a potent inhibitor of the MPTP, leading to its study as a potential treatment to limit myocardial reperfusion injury. Multiple adult animal models have demonstrated the protective effects of cyclosporine in ischemia-reperfusion. A recent human pilot clinical trial also reported reduced myocardial injury and infarct size in patients treated with cyclosporine intravenously before percutaneous coronary intervention for ST-elevation myocardial infarction. Despite the paucity of evidence of cyclosporine A demonstrating myocardial protection in pediatric and newborn patients, the existing animal experimental results are promising.
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http://dx.doi.org/10.1097/SHK.0b013e31824bc9abDOI Listing
April 2012