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Intraperitoneal 1.5% Delflex improves intestinal blood flow in necrotizing enterocolitis ARTICLE in JOURNAL OF SURGICAL RESEARCH · APRIL 2013 Impact Factor: 1.94 · DOI: 10.1016/j.jss.2013.04.007 · Source: PubMed
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Intraperitoneal 1.5% Delflex improves intestinal blood flow in necrotizing enterocolitis Sarah K. Walker, MD,a Paul J. Matheson, PhD,a,b Matthew T. Schreiner, BS,a Jason W. Smith, MD, PhD,a R. Neal Garrison, MD,a,b and Cynthia D. Downard, MD, MMSca,* a b
Hiram C. Polk, Jr., MD, Department of Surgery, University of Louisville, Louisville, Kentucky Department of Research, Robley Rex Veterans Affairs Medical Center, Louisville, Kentucky
article info
abstract
Article history:
Background: Necrotizing enterocolitis (NEC) alters intestinal microvascular control mecha-
Received 3 January 2013
nisms causing significant vasoconstriction. Our prior work with intraperitoneal 2.5%
Received in revised form
dextrose solution demonstrated increased intestinal perfusion in experimentally induced
28 March 2013
NEC. In the current study, we examine whether a buffered solution with lower glucose and
Accepted 4 April 2013
osmolar loads similarly increases intestinal blood flow. We hypothesized that buffered
Available online 28 April 2013
1.5% dextrose solution would increase ileal blood flow compared with baseline in NEC. Methods: We randomly assigned pregnant Sprague-Dawley rats to control (n ¼ 103) or NEC
Keywords:
(n ¼ 123) groups, by litter. We induced NEC by previously published methods. Control pups
Necrotizing enterocolitis
were vaginally delivered and dam-fed. We used laser Doppler flowmetry to evaluate
Rat
perfusion in the terminal ileum at 12, 24, 48, 72, or 96 h after delivery at baseline and after
Ileum
application of topical 1.5% dextrose solution. We evaluated differences between groups
Laser Doppler flow
and time points by analysis of variance and Tukey post hoc test.
Hyperglycemia
Results: Baseline blood flow in the terminal ileum increased with gestational age in both
Hypovolemia
groups (P < 0.05). Control groups had significantly greater baseline blood flow than NEC
Direct peritoneal resuscitation
groups (P < 0.05), and topical application of buffered 1.5% dextrose solution increased blood flow compared with baseline in both groups at all time points (P < 0.05). Conclusions: Topical 1.5% dextrose solution significantly enhanced blood flow in the terminal ileum to the same degree as 2.5% dextrose solution. Thus, the use of buffered 1.5% dextrose solution might be more beneficial in treating clinical NEC, because it places a lower glucose and osmotic load on NEC-injured intestine. ª 2013 Elsevier Inc. All rights reserved.
1.
Introduction
Necrotizing enterocolitis (NEC) is the most frequent cause of gastrointestinal emergencies in infants [1]. It affects mostly premature neonates, and carries a mortality rate of
approximately 15%e30% [2,3]. Although many cases of NEC can be managed medically, close to 40% of NEC patients have severe disease that necessitates surgical intervention [4]. The exact pathophysiology of NEC is still unclear, but it is believed to be multifactorial [5]. Risk factors most commonly associated
Presented at the 2013 Annual Scientific Meeting of the Association for Academic Surgery in New Orleans, Louisiana, February 7, 2013. * Corresponding author. Division of Pediatric Surgery, Hiram C. Polk, Jr., MD, Department of Surgery, University of Louisville, 315 East Broadway Ste 565, Louisville, KY 40202. Tel.: þ1 502 629 8630; fax: þ1 502 583 9735. E-mail address:
[email protected] (C.D. Downard). 0022-4804/$ e see front matter ª 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jss.2013.04.007
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Fig. 1 e Experimental timeline. We randomized pups to feeding protocol by litter to the control group, which were delivered vaginally and dam-fed, or to the NEC group, which were delivered by caesarian at 12 h prematurity and underwent gastric gavage feedings and stressors every 12 h. Pups were anesthetized by inhaled isoflurane and underwent ileum laser Doppler flow studies at 12, 24, 48, 72, or 96 h post-birth. We recorded baseline blood flow over 5 min and then topically applied 1.5% or 2.5% Delflex to the ileum and recorded blood flow 1, 5, and 10 min later. C-section [ caesarian delivery; N2 [ nitrogen gas; NBF [ 10% neutral-buffered formalin for histopathology samples; BL [ baseline laser Doppler blood flow.
with NEC include prematurity, low birth weight, and formula feeds [3,6e11]. Studies suggest that the intestinal ischemia seen in NEC is the result of nitric oxide (NO) and endothelin-1 dysregulation [12,13]. Decreased endothelial NO synthase activity and a resultant decrease in NO production have also been demonstrated in neonates with NEC [14]. Our laboratory has previously demonstrated that vasoconstriction is a key step in the development of NEC [15]. Thus, interventions that improve newborn intestinal blood flow may prove effective in the treatment of NEC. We have previously shown that direct peritoneal resuscitation (DPR), in which commercially available peritoneal dialysis solution is topically applied to the intestine as an adjunct to conventional resuscitation, improves intestinal blood flow in a hemorrhagic shock rat model and improves outcomes in humans undergoing damage control laparotomy for trauma [16,17]. In translating this treatment to neonates, we have also demonstrated that DPR using a buffered 2.5% dextrose peritoneal dialysis solution (2.5% Delflex; Fresenius USA, Ogden, UT) improves intestinal hypoperfusion seen in experimental NEC [18]. Because of concerns regarding hyperglycemia and hypovolemia with use of a hyperosmolar
solution in the peritoneum, we hypothesized that buffered 1.5% Delflex would similarly increase intestinal blood flow in an animal model of NEC, but cause less hyperglycemia than 2.5% Delflex solution.
2.
Methods
All studies were conducted at the Robley Rex Veterans Affairs Medical Center in Louisville, Kentucky, and were approved by the Institutional Animal Care and Use Committee and Research Safety Committee before the initiation of experiments. Timed-pregnant Sprague-Dawley rat dams (Harlan, Indianapolis, IN) were housed in the Association for Assessment and Accreditation of Laboratory Animal Care Internationaleaccredited Veterinary Medical Unit for at least 1 wk before the study and were allowed ad libitum access to water and commercial rat diet (LabDiet 5001; PMI Nutrition International, LLC, Brentwood, MO). Litters were randomized to caesarian delivery under carbon dioxide anesthesia 24 h before the expected date of delivery or vaginal delivery. We
360
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assigned caesarian pups to NEC groups, and they underwent the NEC-inducing protocol for 12, 24, 48, 72, or 96 h postdelivery; vaginally delivered pups were assigned to control groups at matching time points. Figure 1 shows the experimental time line for the studies. We induced NEC as previously described [15,19e26]. Briefly, NEC pups underwent intermittent stress consisting of intragastric gavage feeding with formula (200 kcal/kg/d) every 4 h, hypoxia (100% nitrogen gas for 60 s) and hypothermia (4 C for 10 min) every 12 h, and a single oral dose of lipopolysaccharide (2 mg/kg, Salmonella enterica serotype typhimurium; Sigma Chemical Co., St. Louis, MO) at 12 h of life. The NEC formula was composed of cow milkebased Similac 60/40 (20 g; Ross Pediatrics, Columbus, OH) dissolved into Esbilac, a liquid canine formula (100 mL; Pet-Ag, New Hampshire, IL). Gavage feedings (0.1 mL) were started at 2 h post-delivery and advanced every 24 h by at least 0.05 mL to a maximum delivery of 0.4 mL per feed at 96 h of life. A neonatal incubator maintained body temperature at 37.0 C 0.5 C, and incubator temperature, room temperature, and room humidity were continuously monitored. Control pups were dam-fed ad libitum in the same climate-controlled room that housed the NEC pup incubator. We measured laser Doppler perfusion in the ileum of all pups using a PeriFlux system (Perimed AB, Ja¨rfa¨lla, Sweden), as previously described [18,26]. Briefly, pups inhaled isoflurane anesthetic at an induction dose of 3.5% and subsequent maintenance dose of 1.5% on 2 L/min oxygen to obtain a deep surgical plane of anesthesia. A transverse abdominal incision allowed access to the peritoneum. We evaluated gross appearance and color of the intestines and recorded them as normal, distended, gaseous, hemorrhagic, perforated, and/or necrotic. Any gross blood or stool was noted and flushed from the peritoneum with pre-warmed normal saline (37.0 C), and a seven-site integrating laser Doppler flow probe was placed on the ileum. We verified placement by visual inspection for the duration of the protocol. After a 20-min equilibration period, ileal perfusion with topical warmed “no glucose” normal saline was recorded at two time points 10 min apart. Inclusion criterion was ileal blood flow stability with subsequent readings with
