Direct peritoneal resuscitation reduces intestinal permeability after brain death.

BACKGROUND: The profound inflammatory response associated with brain death is frequently cited as the reason organs procured from brain dead donors are associated with worse graft function. The intestine releases inflammatory mediators in other types of shock, but its role is brain death has not been well-studied. Direct peritoneal resuscitation (DPR) improves visceral organ blood flow and reduces inflammation after hemorrhagic shock. We hypothesized that use of DPR would maintain intestinal integrity and reduce circulating inflammatory mediators after brain death. METHODS: Brain death was induced in male Sprague-Dawley rats by inserting a 4F Fogarty catheter into the epidural space and slowly inflating it. After herniation, rats were resuscitated with normal saline to maintain a mean arterial pressure of 80 mm Hg and killed with tissue collected immediately (time 0), or 2 hours, 4 hours, or 6 hours after brain death. Randomly selected animals received DPR via an intraperitoneal injection of 30-mL commercial peritoneal dialysis solution. RESULTS: Levels of proinflammatory cytokines, including IL-1ß and IL-6, as well as high-mobility group box 1 protein and heat shock protein 70, were all increased after brain death and decreased with DPR. Fatty acid binding protein and lipopolysaccharide, both markers of intestinal injury, were increased in the serum after brain death and decreased with DPR. Immunohistochemistry staining for zona occludin-1 showed decreased intestinal tight junction integrity after brain death, which improved with DPR. CONCLUSIONS: Intestinal permeability increases after brain death, and this contributes to the increased inflammation seen throughout the body. Using DPR prevents intestinal ischemia and helps preserve intestinal integrity. This suggests that using this novel therapy as an adjunct to the resuscitation of brain dead donors has the potential to reduce inflammation and potentially improve the quality of transplanted organs.

Randomized Controlled Trial Evaluating the Efficacy of Peritoneal Resuscitation in the Management of Trauma Patients Undergoing Damage Control Surgery.

BACKGROUND: Peritoneal resuscitation (PR) represents a unique modality of treatment for severely injured trauma patients requiring damage control surgery. These data represent the outcomes of a single institution randomized controlled trial into the efficacy of PR as a management option in these patients. STUDY DESIGN: From 2011 to 2015, one hundred and three patients were enrolled in a prospective randomized controlled trial evaluating the use of PR in the treatment of patients undergoing damage control surgery compared with conventional resuscitation (CR) alone. Patient demographics, clinical variables, and outcomes were collected. Univariate and multivariate analysis was performed with a priori significance at p ≤ 0.05. RESULTS: After initial screening, 52 patients were randomized to the PR group and 51 to the CR group. Age, sex, initial pH, and mechanism of injury were used for randomization. Method of abdominal closure was standardized across groups. Time to definitive abdominal closure was reduced in the PR group compared with the CR group (4.1 ± 2.2 days vs 5.9 ± 3.5 days; p ≤ 0.002). Volume of resuscitation and blood products transfused in the initial 24 hours was not different between the groups. Primary fascial closure rate was higher in the PR group (83% vs 66%; p ≤ 0.05). Intra-abdominal complications were lower in the PR compared with the CR group (8% vs 18%), with abscess formation rate (3% vs 14%; p < 0.05) being significant. Patients in the PR group had a lower 30-day mortality rate, despite similar Injury Severity Scores (13% vs 28%; p = 0.06). CONCLUSIONS: Peritoneal resuscitation enhances management of damage control surgery patients by reducing time to definitive abdominal closure, intra-abdominal infections, and mortality rates.

Direct Peritoneal Resuscitation Alters Hepatic miRNA Expression after Hemorrhagic Shock.

BACKGROUND: MicroRNAs (miRNAs) are small segments of noncoding RNA that regulate gene expression and protein function, and therefore are key regulators of cellular processes including those of the inflammatory cascade after hemorrhagic shock (HS). We have previously shown that direct peritoneal resuscitation (DPR), as an adjunct to traditional IV fluid resuscitation, improves visceral blood flow and reduces pro-inflammatory cytokines released during HS. The effects of DPR on hepatic miRNA (miR) expression patterns after resuscitated HS are not known. STUDY DESIGN: Male Sprague-Dawley rats were divided into 3 groups: sham (no HS); conventional resuscitation (CR; HS, then resuscitated with shed blood and 2 volumes of saline); and DPR (CR plus 30 mL peritoneal dialysis solution). Animals were sacrificed at 4 hours, and miRNAs were measured using reverse transcription polymerase chain reaction. RESULTS: Use of DPR downregulated 68 of 92 hepatic miRNAs compared with only 2 of 92 upregulated when compared with CR alone, p < 0.01). Specifically, miR-9-5p, miR-122-5p, and miR-146, which regulate NFκB, were downregulated 4.1-, 3.4-, and 0.86-fold, respectively; miR-29a and miR-126 were upregulated 0.88- and 3.7-fold when DPR was compared with CR. CONCLUSIONS: Adding DPR downregulated most hepatic miRNAs compared with CR alone. Some miRNAs were affected more significantly, suggesting that although this clinical intervention causes a near-global downregulation of hepatic miRNA, it still targets specific inflammatory pathways. Use of DPR for resuscitation of patients in HS may reduce hepatic inflammation to improve patient outcomes after hemorrhage.

Machine perfusion: not just for marginal kidney donors.

Interest in machine perfusion (MP) for donated kidneys has markedly increased in the past decade as a means to improve graft function, although the donor populations in which it should be applied have not yet been resolved. All adults undergoing de-novo isolated kidney transplantation from standard-criteria donors in the UNOS database 2005 to 2011 were reviewed with the primary endpoint of delayed graft function (DGF), defined as dialysis within seven days of transplantation, in those who received kidneys that underwent MP versus cold storage (CS) alone. Three methods were used to control for differences between groups. Multivariable logistic regression was performed, adjusting for donor and recipient characteristics significantly associated with DGF. Rates were also compared in a cohort of propensity-matched MP vs CS recipients. Finally, a paired-kidney study was performed, where one kidney underwent MP and the contralateral underwent CS. There were 36,323 patients, with unadjusted DGF rates of 18.6 per cent (n = 1830/9882) and 22.4 per cent (n = 5931/26,441; P < 0.001) in the MP vs CS groups, respectively. After multivariable analysis, the odds ratio for DGF in the MP group was 0.59 (P < 0.001) versus CS. In the propensity-matched cohort, there were 8929 patients each in the MP and CS groups. DGF occurred in 16.8 per cent of the MP group vs 25.3 per cent with CS (P < 0.001, OR 0.59). In the paired-kidney study, rates of DGF were 16.7 per cent vs 24.3 per cent (P < 0.001) in the 1665 recipients each in the MP versus CS groups (OR 0.6). In conclusion, machine perfusion is beneficial in reducing DGF even when standard donors are utilized, and thus should not be limited to marginal kidneys.

Alterations in platelet-derived growth factor expression in the pathophysiology of necrotizing enterocolitis.

BACKGROUND: Necrotizing enterocolitis (NEC) involves impaired ileal blood flow due to alterations in vascular tone control and intestinal angiogenesis. Platelet-derived growth factor (PDGF) is a mediator of normal angiogenesis in intestinal epithelium. We hypothesized that gene dysregulation during experimental NEC results in altered PDGF expression. METHODS: Sprague-Dawley rats were randomized to groups by litter. Controls were delivered vaginally and dam-fed. NEC groups were delivered prematurely by cesarean section and subjected to an established NEC protocol. Ileum was obtained at 0, 12, 24, 48, 72, and 96 h of life from all animals (N = 108 animals). Western blot analysis was carried out for every time point, and samples were evaluated by immunohistochemistry. Antibodies against PDGF-A, PDGF-B, and their receptors, PDGFR-α and PDGFR-ß, were used. Statistical analysis was performed using two-way analysis of variance with a priori P < 0.05. RESULTS: Ileal PDGF-A concentration was higher in controls versus NEC from 24-96 h of life. Its receptor, PDGFR-α, was low in concentration in both groups at all time points. PDGF-B concentration was increased in controls at 24 and 72 h of life but decreased at the 48-h mark. Its receptor, PDGFR-ß, was also low in both groups at 12 and 24 h but increased in controls at 48 and 72 h. CONCLUSIONS: These data support our hypothesis that PDGF and PDGF receptor expression are altered in experimental NEC. Dysregulation of PDGF during intestinal maturation could contribute to the development of NEC. Further investigation into this pathway could yield new therapeutic targets for this devastating disease.

Addition of direct peritoneal lavage to human cadaver organ donor resuscitation improves organ procurement.

BACKGROUND: Brain dead organ donors have altered central hemodynamic performance, impaired hormone physiology, exaggerated systemic inflammatory response, end-organ microcirculatory dysfunction, and tissue hypoxia. A new treatment, direct peritoneal resuscitation (DPR), stabilizes vital organ blood flow after conventionally resuscitated shock to improve these derangements. STUDY DESIGN: A prospective case-control study of adjunctive DPR compared 26 experimental patients (brain dead organ donors) to 52 controls (protocolized conventionally resuscitated donors). Actual organ procurement rates were compared with the Scientific Registry of Transplant Recipient predicted organ yield per patient. Achievement of donor management goals and effective hepatic blood flow were recorded. RESULTS: Fourteen of 26 (53.8%) patients treated with DPR achieved all donor management goals compared with 17 of 52 (32.7%) patients treated with conventionally resuscitated (odds ratio = 2.4; 95% CI, 0.92-6.3; p = 0.06). Patients treated with DPR were more than 2 times as likely to achieve final pO2 >100 on 40% FiO2 compared with controls (odds ratio = 2.8; 95% CI, 1-7.69; p = 0.03). Also, DPR-treated patients required less IV crystalloid during the first 12 hours of management (DPR: 3,167 ± 1,893 mL vs 4,154 ± 2,100 mL; p = 0.046) and required less vasopressor agents at 12 hours post resuscitation (odds ratio = 7.7; 95% CI, 0.82-42; p = 0.02). Direct peritoneal resuscitation patients had enhanced effective hepatic blood flow and significantly higher organs transplanted per donor rates compared with controls (3.7 ± 1.7 vs 3.1 ± 1.3; p = 0.024). CONCLUSIONS: Direct peritoneal resuscitation reduced IV fluid requirement and IV pressor use as well as increased hepatic blood flow and organs transplanted per donor. Direct peritoneal resuscitation studies show it to be a safe, effective method to augment organ donor resuscitation and additional large-scale trials should be conducted to validate these findings.

Application of prostaglandin E2 improves ileal blood flow in NEC.

PURPOSE: Indomethacin, a nonselective prostaglandin inhibitor used to treat patent ductus arteriosus, is associated with intestinal perforation inducing an NEC-like illness. We sought to define the contribution of prostaglandin E2 (PG E2) and its receptor EP4 to intestinal blood flow regulation in premature neonates with NEC. METHODS: Newborn Sprague-Dawley rats were randomized by litter to undergo experimental NEC induction or to serve as a CONTROL. At 48hours of age, intestinal laser Doppler blood flow was assessed at baseline and after intraperitoneal administration of indomethacin, PG E2, EP4 antagonist, or EP4 agonist. Data were analyzed using a 2-way ANOVA with post hoc Tukey-Kramer correction. RESULTS: At baseline, NEC animals had lower intestinal blood flow than controls. Indomethacin, PG E2 and EP4 agonist all increased ileal blood flow, but PG E2 and EP4 agonist increased blood flow the most in NEC pups. EP4 antagonist decreased intestinal perfusion in both groups. CONCLUSION: The above evidence suggests the importance of PG E2 and EP4 in regulation of neonatal intestinal blood flow. Since indomethacin treatment of patent ductus arteriosus in the premature infant is associated with an increased risk of intestinal perforation owing to compromised blood flow, PG E2 supplementation might provide intestinal protection if administered simultaneously with indomethacin.

Direct peritoneal resuscitation improves inflammation, liver blood flow, and pulmonary edema in a rat model of acute brain death.

BACKGROUND: Brain death in organ donors alters central hemodynamic performance, impairs physiology, exaggerates inflammation, and causes end-organ microcirculatory dysfunction and hypoxia. A new treatment, direct peritoneal resuscitation (DPR), might improve these derangements in acute brain death (ABD). STUDY DESIGN: We studied a standardized rodent model of brain death with matched controls to assess the efficacy of DPR as a resuscitation strategy after ABD. Anesthetized Sprague-Dawley rats were randomized as follows: ABD (supradural balloon inflation) with minimal IV fluid (IVF; 2 mL/h, n = 12); ABD + adequate IVF (5 mL/h, n = 12); ABD with aggressive IVF (goal: mean arterial pressure [MAP] >80 mmHg, n = 15); or ABD + IVF + DPR (goal: MAP >80 mmHg, n = 12). Ventilation support, IVF, and DPR were started at loss of reflexes, and MAP, heart rate, and effective hepatic blood flow were recorded. RESULTS: High IVF and DPR prevented mortality (0%) compared with low IVF (81.8%) or mid IVF (16.7%). Effective hepatic blood flow was decreased in low and mid IVF (2.8 ± 0.3 mL/min/g body weight and 4.0 ± 0.5 mL/min/g body weight, respectively) vs baseline, but was stable in high IVF (6.2 ± 0.5 mL/min/g body weight; NS) or improved with DPR (8.6 ± 0.7 mL/min/g body weight). The high-IVF group had significant organ edema, which was prevented in the DPR group. The mid-IVF and low-IVF groups had higher serum markers of organ injury compared with high-IVF or DPR groups. The high-IVF group had elevated inflammatory cytokines compared with the DPR group. CONCLUSIONS: Direct peritoneal resuscitation improved survival and effective hepatic blood flow, required less IVF to stabilize blood pressure, prevented organ edema, and normalized fluid electrolyte balance compared with IVF-alone groups. Direct peritoneal resuscitation in animals reduced inflammatory response after ABD compared with IVF-alone controls. These data suggest a potential role for DPR in organ donors to stabilize donors and possibly increase the number of organs suitable for transplantation per donor.

Increased hepatic blood flow during enteral immune-enhancing diet gavage requires intact enterohepatic bile cycling.

OBJECTIVES: Total hepatic blood flow (HBF) via the hepatic artery and portal vein is highly dependent on gastrointestinal perfusion. During postprandial hyperemia, intestinal blood flow depends on nutrient composition, gastrointestinal location, and time. Immune-enhancing diets (IEDs) containing n-3 polyunsaturated fatty acids (PUFAs) selectively augment blood flow in the ileum at 60-120 min via a bile-dependent mechanism. My colleagues and I hypothesized that liver blood flow would be similarly affected by IEDs containing n-3 PUFAs. METHODS: Mean arterial blood pressure, heart rate, and effective HBF (galactose clearance) were measured in anesthetized male Sprague-Dawley rats after gastric gavage of either a control diet (CD, Boost, Novartis) or an IED (Impact, Nestle Nutrition), with or without bile-duct ligation (BDL), and with or without supplemental bile (bovine, dried, unfractionated). Significance was assessed by 2-way ANOVA for repeated measures with the Tukey-Kramer honestly significant difference test. RESULTS: Compared with baseline levels, a CD increased HBF (peak at 40 min , *P < 0.05) whereas an IED increased HBF in two distinct peaks at 40 min (*P < 0.05) and 120 min (*P < 0.05), but BDL prevented both the early (CD and IED, †P < 0.05) and late peaks (IED, †P < 0.05). Bile supplementation in the CD + BDL or IED + BDL groups restored neither the CD peak nor the early or late IED peaks. CONCLUSIONS: HBF during absorptive intestinal hyperemia is modulated by a mechanism that requires an intact enterohepatic circulation. The early peaks at 40 min (CD or IED) were prevented by BDL, even though fat absorption in the proximal gut occurs by bile-independent direct absorption. Bile supplementation with the diet (CD + BDL or IED + BDL) was insufficient to restore HBF hyperemia, which implies that a relationship exists between intestinal and hepatic blood flow that is not solely dependent on bile-mediated intestinal fat absorption and bile recirculation.

Intraperitoneal 1.5% Delflex improves intestinal blood flow in necrotizing enterocolitis.

BACKGROUND: Necrotizing enterocolitis (NEC) alters intestinal microvascular control mechanisms causing significant vasoconstriction. Our prior work with intraperitoneal 2.5% dextrose solution demonstrated increased intestinal perfusion in experimentally induced NEC. In the current study, we examine whether a buffered solution with lower glucose and osmolar loads similarly increases intestinal blood flow. We hypothesized that buffered 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 = 103) or NEC (n = 123) groups, by litter. We induced NEC by previously published methods. Control pups were vaginally delivered and dam-fed. We used laser Doppler flowmetry to evaluate perfusion in the terminal ileum at 12, 24, 48, 72, or 96 h after delivery at baseline and after application of topical 1.5% dextrose solution. We evaluated differences between groups and time points by analysis of variance and Tukey post hoc test. RESULTS: Baseline blood flow in the terminal ileum increased with gestational age in both groups (P < 0.05). Control groups had significantly greater baseline blood flow than NEC 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.

To pump or not to pump: a comparison of machine perfusion vs cold storage for deceased donor kidney transplantation.

BACKGROUND: A recent multicenter European trial has demonstrated reduced rates of delayed graft function when kidneys undergo machine perfusion before transplantation. This study was undertaken to evaluate the impact of machine perfusion on early kidney transplant function in the United States. STUDY DESIGN: Retrospective review of United Network for Organ Sharing data from January 1, 2005 through March 31, 2011 was undertaken. Comparisons were made between kidneys that underwent machine perfusion (MP) vs cold storage (CS) alone in terms of delayed graft function (DGF). The analysis was performed in a cohort of MP and CS kidneys matched by propensity scoring, as well as in a cohort of paired kidneys from the same donor in which one underwent MP and the other underwent CS. Secondary end points analyzed included recipient length of stay after transplantation and graft survival. RESULTS: In the overall cohort, rates of DGF were similar for MP and CS kidneys (25.7% vs 25.0%; p = 0.082), likely due to preferential use of MP in marginal kidneys. In the propensity matched cohort, MP was associated with significantly lower rates of DGF compared with CS (21.1% vs 29.1%; p < 0.001). These findings were corroborated by the paired kidney analysis, in which DGF occurred in 19.7% of the MP group compared with 27.5% of the CS group (p < 0.001). There was no difference in the hazard for graft failure between the MP and CS group in the propensity matched analysis (hazard ratio = 0.98; p = 0.622) and in the paired kidney analysis (hazard ratio = 1.02; p = 0.839). CONCLUSIONS: Machine perfusion of deceased donor kidneys results in significantly decreased rates of DGF.

Fish oil increases blood flow in the ileum during chronic feeding in rats.

Benefits of enteral feeding with immune-enhancing diets (IEDs) depend on route, timing, and composition. We hypothesized that chronic enteral feeding with certain individual immunonutrients would enhance gastrointestinal blood flow. Male rats were fed a standard enteral diet supplemented with immunonutrients for 5 days before study. Groups were (1) standard rat chow, (2) liquid control diet (CD) alone (CD), (3) CD + fish oil, (4) CD + L-arginine, and (5) CD + RNA fragments. Whole organ blood flow distribution was measured by colorimetric microsphere technique in antrum, small intestine (in thirds), colon, liver, spleen, pancreas, and kidneys. Chronic feeding for 5 days with CD + fish oil increased blood flow in the distal third of the small intestine compared with CD alone, whereas feeding with CD + L-arginine decreased blood flow in the small intestine (all segments) compared with CD alone. Acute gavage of CD + L-arginine or CD + fish oil increased blood flow in the proximal and middle third of the small intestine compared with CD alone. Control diet + RNA increased blood flow in the proximal small intestine compared with CD alone. These findings support prior acute feeding studies with CD, CD + individual immunonutrients, or IED. Our current data suggest that blood flow benefits associated with fish oil persist during chronic feeding in rats. Enhanced gastrointestinal perfusion might partially explain the benefits of early enteral feeding with IEDs not seen with regular enteral diets and parenteral immunonutrient delivery.

Preservation of hepatic blood flow by direct peritoneal resuscitation improves survival and prevents hepatic inflammation following hemorrhagic shock.

Conventional resuscitation (CR) from hemorrhagic shock (HS) results in gut and liver hypoperfusion, organ and cellular edema, and vital organ injury. Adjunct direct peritoneal resuscitation (DPR) with dialysate prevents gut vasoconstriction, hypoperfusion, and injury. We hypothesized that DPR might also improve hepatocellular edema, inflammation, and injury. Anesthetized male SD rats were assigned to groups (n = 8/group): 1) sham (no HS); 2) HS (40% MAP/60 min) + intravenous fluid conventional resuscitation [CR; shed blood + 2 vol saline (SAL)/30 min]; 3) HS+CR+DPR (30 ml ip 2.5% glucose dialysate); or 4) HS+CR+SAL (30 ml ip saline). Histopathology showed lung and liver injury in HS+CR and HS+CR+SAL up to 24-h postresuscitation (post-RES) that was not in shams and which was prevented by adjunct DPR. Wet-to-dry weight ratios in HS+CR revealed organ edema formation that was prevented by adjunct DPR. HS+CR and HS+CR+SAL had 34% mortality by 24-h post-RES, which was absent with DPR (0%). Liver IFN-γ and IL-6 levels were elevated in CR compared with DPR or shams. TNF-α mRNA was upregulated in CR/sham and DPR/sham. IL-17 was downregulated in DPR/sham. CXCL10 mRNA was upregulated in CR/sham but downregulated in DPR/sham. Despite restored central hemodynamic performance after CR of HS, liver blood flow was compromised up to 24 h post-RES, and the addition of DPR restores and maintains liver perfusion at 24-h post-RES. DPR prevented liver injury, histological damage, and edema formation compared with CR alone. DPR provided a mitigating anti-inflammatory dampening of the systemic inflammatory response. In all, these effects likely account for improved survivorship in the DPR-treated group.

Intestinal microcirculatory flow alterations in necrotizing enterocolitis are improved by direct peritoneal resuscitation.

Vasoconstriction of the neonatal intestinal microvasculature is a central mechanistic event in development of necrotizing enterocolitis. We hypothesized that topical treatment of the intestine with dialysate fluid would ameliorate the vasoconstriction in necrotizing enterocolitis (NEC). NEC was induced in experimental groups. Control animals were delivered vaginally and dam-fed (control group). Neonatal pups underwent laser Doppler flow study of the terminal ileum to determine real-time blood flow in the intestinal microvasculature. After baseline flow was determined, dialysis solution was added to the peritoneal cavity and alterations in microcirculation were recorded. Baseline ileal blood flow in the control group was significantly higher than in NEC rat pups at 48 hours post delivery (P < 0.05), but not at 24 hours (P = NS). Ileal blood flow increased in all groups after adding dialysate (P < 0.05), improving ileal blood flow in the 48-hour NEC group and reaching the baseline level of the 48-hour control group (P < 0.05). Our data shows blood flow to be higher in 48-hour controls as compared with 24-hour controls suggesting a time-dependency in the development of intestinal vasoregulatory processes. All groups had an increase in blood flow with dialysate treatment. This may represent a novel initial therapy to improve intestinal ischemia in human necrotizing enterocolitis.

Maternal cigarette smoking and the development of necrotizing enterocolitis.

BACKGROUND: The maternal variables that affect fetal development and correlate with necrotizing enterocolitis (NEC), the most common gastrointestinal emergency in premature infants, are not well defined. We hypothesized that maternal risk factors were the primary determinant of future development of NEC. METHODS: Patients with NEC were identified from an established NICU database and were control-matched with 2 neonates treated at the same institution. The medical records of each patient during the NICU admission as well as the prenatal and delivery record of the patient's mother were reviewed. Perinatal data, including maternal smoking, maternal hypertension, maternal BMI, maternal gestational diabetes, conduct of labor and type of delivery, Apgar scores, types of feedings, and placental pathology, were examined, with P < .05 deemed significant. RESULTS: A total of 73 neonates diagnosed with NEC and 146 matched controls were identified. Medical records for each subject and their mothers were reviewed (438 records total). Maternal cigarette smoking was significantly associated with the future development of NEC (P = .02). Maternal gestational diabetes, maternal hypertension, formula feeding, and pathologic chorioamnionitis or uteroplacental insufficiency did not correlate with NEC. CONCLUSIONS: These data identified maternal cigarette smoking as the only risk factor that is associated with the development of NEC in premature infants. Our data imply that smoking delivers toxins and nicotine to the uterine microenvironment that can affect microvascular development and may predispose the fetus to future NEC.

Glucose-induced intestinal vasodilation via adenosine A1 receptors requires nitric oxide but not K(+)(ATP) channels.

BACKGROUND: Both nitric oxide (NO) and adenosine A1 receptor activation mediate microvascular vasodilation during intestinal glucose absorption. Our overall hypothesis is that adenosine triphosphate (ATP) utilization during glucose absorption would increase adenosine metabolite release, which acts on adenosine A1 receptors to alter endothelial production of NO and/or activate ATP-dependent potassium channels (K(+)(ATP)) to dilate intestinal microvessels. METHODS: Intravital videomicroscopy of the rat jejunum was used to record the vascular responses of inflow (termed 1A) arterioles, proximal (p3A), and distal (d3A) premucosal arterioles during exposure to isotonic glucose or mannitol solutions alone or in the presence of the selective nitric oxide synthase (NOS) inhibitor (L-NMMA), an adenosine A1 receptor antagonist (8-cyclopentyl-1,3-dipropylxanthine (DPCPX)), or a K(+)(ATP) channel inhibitor (glibenclamide). RESULTS: As expected, glucose exposure caused rapid dilation of both p3A and d3A arterioles, while mannitol exposure had no effect on microvascular diameters. Adenosine A1 receptor blockade completely prevented glucose-induced dilation of the premucosal arterioles. NOS inhibition significantly blunted the glucose-induced vasodilation of the premucosal arterioles, but had little effect in the mannitol group. Simultaneous application of both the NOS inhibitor and the adenosine A1 receptor antagonist gave the same reduction in glucose-induced dilation of the premucosal arterioles as the adenosine A1 receptor antagonist alone. Blockade of K(+)(ATP) channels with glibenclamide did not attenuate glucose-induced vasodilation of the premucosal arterioles. CONCLUSION: These data suggest that glucose-induced vasodilation of premucosal jejunal arterioles is mediated through adenosine A1 receptors, and NO at least partially mediates the adenosine A1 receptor-induced vasodilation. In addition, K(+)(ATP) channels are not involved in premucosal arteriolar vasodilation during intestinal glucose exposure.

Optimization of donor management goals yields increased organ use.

Multiple strategies have been used in an effort to increase the pool of organs for transplantation. Standardizing donor management has produced promising results. Donor management goals (DMGs) are now being used as end points of intensive care unit care during the prerecovery phase but no prospective results have been reported. Data from the United Network for Organ Sharing Region 11 were collected for successful achievement of eight common donor management goals (mean airway pressure [MAP], central venous pressure [CVP], pH, PaO2, sodium, glucose, single pressor use, and urine output) before organ recovery. Two time periods were studied with different panels of DMGs. The analysis identified the success rate of transplantation. Goals were stratified by their statistical correlation with the number of organs transplanted per donor (OTPD) in an effort to identify the most important parameter(s). Eight hundred five organ donors were studied with 2685 organs transplanted. DMGs were assessed through two phases of the study. Achieving DMGs rose from 18 to 66 per cent associated with significant improvement in OTPD (range, 2.96 to 3.45). The success of transplantation was primarily associated with limitations in vasopressor use and PaO2. Tight glucose control did affect the rate of pancreatic transplants. Thoracic organs were the most sensitive to DMGs with a 10- to 15-fold increase in lung transplantation when PaO2 rose above 100 mmHg. MAP, CVP, pH, sodium, and urine output had little effect on transplantation. Standardization of end points of donor management was associated with increased rates of transplantation. Surprisingly, not all standard goals are necessary for optimal organ use. The most significant parameters were the low use of vasopressor agents and oxygenation. Donor management strategies should strive to optimize these goals.

Direct peritoneal resuscitation accelerates primary abdominal wall closure after damage control surgery.

BACKGROUND: Damage control surgery is a staged approach to the trauma patient in extremis that improves survival, but leads to open abdominal wounds that are difficult to manage. We evaluated whether directed peritoneal resuscitation (DPR) when used as a resuscitation strategy in severely injured trauma patients with hemorrhagic shock requiring damage control surgery would affect the amount of and timing of resuscitation and/or show benefits in time to abdominal closure and reduction of intra-abdominal complications. STUDY DESIGN: A retrospective case-matched study of patients undergoing damage control surgery for hemorrhagic shock secondary to trauma between January 2005 and December 2008 was performed. Twenty patients undergoing standardized wound closure and adjunctive DPR were identified and matched to 40 controls by Injury Severity Score, age, gender, and mechanism of injury. A single early death was excluded because of inability to control ongoing hemorrhage. RESULTS: There were no differences in age, gender, or mechanism of injury between the groups. Injury Severity Score (35.07 +/- 17.1 versus DPR 34.95 +/- 16.95; p = 0.82) and packed red blood cell administration in 24 hours (23.8 +/- 14.35 U versus DPR 26.9 +/- 14.1 U; p = 0.43) were similar between the groups. Presenting pH was similar between the study group and the DPR group (7.24 +/- 0.13 d versus DPR 7.26 +/- 0.11; p = 0.8). Time to definitive abdominal closure was significantly less in the DPR group compared with controls (DPR: 4.35 +/- 1.6 d versus 7.05 +/- 3.31; p < 0.003). DPR also allowed for a higher rate of primary fascial closure, lower intra-abdominal complication rate, and lower rate of ventral hernia formation at 6 months. Adjunctive DPR afforded a definitive wound closure advantage compared with Wittmann patch closure techniques (DPR 4.35 +/- 1.6 versus Wittmann patch 6.375 +/- 1.3; p = 0.004). CONCLUSIONS: The addition of adjunctive DPR to the damage control strategy shortens the interval to definitive fascial closure without affecting overall resuscitation volumes. As a result, this mitigates intra-abdominal complications associated with open abdomen and damage control surgery and affords better patient outcomes.