Hydrogen sulfide improves intestinal recovery following ischemia by endothelial nitric oxide-dependent mechanisms.

Hydrogen sulfide (H2S) is an endogenous gasotransmitter that has vasodilatory properties. It may be a novel therapy for intestinal ischemia-reperfusion (I/R) injury. We hypothesized that 1) H2S would improve postischemic survival, mesenteric perfusion, mucosal injury, and inflammation compared with vehicle and 2) the benefits of H2S would be mediated through endothelial nitric oxide. C57BL/6J wild-type and endothelial nitric oxide synthase knockout (eNOS KO) mice were anesthetized, and a midline laparotomy was performed. Intestines were eviscerated, the small bowel mesenteric root identified, and baseline intestinal perfusion was determined using laser Doppler. Intestinal ischemia was established by temporarily occluding the superior mesenteric artery. Following ischemia, the clamp was removed, and the intestines were allowed to recover. Either sodium hydrosulfide (2 nmol/kg or 2 µmol/kg NaHS) in PBS vehicle or vehicle only was injected into the peritoneum. Animals were allowed to recover and were assessed for mesenteric perfusion, mucosal injury, and intestinal cytokines. P values < 0.05 were significant. H2S improved mesenteric perfusion and mucosal injury scores following I/R injury. However, in the setting of eNOS ablation, there was no improvement in these parameters with H2S therapy. Application of H2S also resulted in lower levels of intestinal cytokine production following I/R. Intraperitoneal H2S therapy can improve mesenteric perfusion, intestinal mucosal injury, and intestinal inflammation following I/R. The benefits of H2S appear to be mediated through endothelial nitric oxide-dependent pathways.NEW & NOTEWORTHY H2S is a gaseous mediator that acts as an anti-inflammatory agent contributing to gastrointestinal mucosal defense. It promotes vascular dilation, mucosal repair, and resolution of inflammation following intestinal ischemia and may be exploited as a novel therapeutic agent. It is unclear whether H2S works through nitric oxide-dependent pathways in the intestine. We appreciate that H2S was able to improve postischemic recovery of mesenteric perfusion, mucosal integrity, and inflammation. The beneficial effects of H2S appear to be mediated through endothelial nitric oxide-dependent pathways.

Direct peritoneal resuscitation improves mesenteric perfusion by nitric oxide dependent pathways.

BACKGROUND: Direct peritoneal resuscitation (DPR) has been shown to increase survival after intestinal ischemia and reperfusion injury (I/R). We have previously appreciated that minimum essential medium (MEM), a synthetic cell culture medium with bovine serum, glutamine, and antibiotics, contributes to these benefits. We hypothesized that (1) DPR using MEM as a dialysate would increase mesenteric perfusion, improve intestinal mucosal injury, and limit intestinal and hepatic inflammation after intestinal I/R and (2) these improvements would be dependent on endothelial nitric oxide pathways. METHODS: Eight-week-old C57Bl6J wild-type (WT) and eNOS Knock Out (eNOS KO) male mice were anesthetized and intestinal ischemia was induced for 60 min. After ischemia, 1 mL of phosphate buffered saline vehicle or MEM was injected into the abdominal cavity. Intestinal perfusion was reassessed after 48 h. Animals were then euthanized, and intestines and livers explanted for histologic and molecular analyses. RESULTS: DPR with MEM significantly improved mesenteric perfusion compared with vehicle (phosphate buffered saline) as measured by Laser Doppler Imaging (WT + MEM 91.58 ± 13.74%, WT + Vehicle 44.27 ± 11.93%, P < 0.05); however, these benefits were lost when endothelial nitric oxide signaling pathways were ablated (eNOS KO + MEM 21.72 ± 5.67 %, eNOS KO + Vehicle 45.24± 11.31%). WT mice treated with MEM also had significantly better preservation of their mucosal architecture (WT + MEM Mdn = 1.0, interquartile range [IQR] = 1.25, WT + Vehicle Mdn = 3.0, IQR = 2.0, P < 0.05). When we compared eNOS KO mice treated with either MEM or vehicle the protective effect of MEM disappeared (eNOS KO + MEM Mdn = 2.0, IQR = 2.25, eNOS KO + Vehicle Mdn = 2.0, IQR = 1.0 P > 0.05). Intestinal levels of interleukin (IL)-1ß were increased in WT animals treated with MEM compared with eNOS KOs, whereas concentrations of intestinal IL-6 were similar between groups. Hepatic levels of both IL-1ß and IL-6 were significantly elevated in eNOS KOs compared with WT treated with MEM. CONCLUSIONS: DPR with MEM has significant therapeutic potential for improving mesenteric perfusion, intestinal injury, and the local inflammatory response after intestinal I/R. These benefits appear to be dependent on nitric oxide signaling within the endothelium.

The utility of presacral drainage in penetrating rectal injuries in adult and pediatric patients.

BACKGROUND: With changing weaponry associated with injuries in civilian trauma, there is no clinical census on the utility of presacral drainage (PSD) in penetrating rectal injuries (PRIs), particularly in pediatric patients. METHODS: Patients with PRI from July 2004-June 2014 treated at two free-standing children's hospitals and two adult level 1 trauma centers were compared by age (pediatric patients ≤16 years) and PSD. A stratified analysis was performed based on age. The primary outcome was pelvic/presacral abscess. RESULTS: We identified 81 patients with PRI; 19 pediatric, 62 adult. Forty patients had PSD; only three pediatric patients had a drain. Adult patients were more likely to have sustained gunshot wounds (84%), whereas pediatric patients were more likely to sustain impalement injuries (59%). Pediatric patients were more likely to have distal extraperitoneal injuries (56% versus 27% in adults, P = 0.03). PSD was more common in adult patients (59% versus 14%, P = 0.0004), African-Americans (71% versus 11% Caucasian, P < 0.01), and those sustaining gun shot wounds (63% versus 18% impalement, P < 0.01); only race remained significant in stratified analysis for both adult and pediatric patients. There were three cases of pelvic/presacral abscess, all in the adult patients (P = 0.31); one patient with PSD and two without PSD (P = 0.58). In stratified analysis, there were no differences in any infectious complication between those with and without PSD. CONCLUSIONS: Pelvic/presacral abscess is a rare complication of PRI, especially in pediatric patients. PSD is not associated with decreased rates of infectious complications and may not be necessary in the treatment of PRI.

Mesenchymal stromal cell therapy for the treatment of intestinal ischemia: Defining the optimal cell isolate for maximum therapeutic benefit.

Intestinal ischemia is a devastating intraabdominal emergency that often necessitates surgical intervention. Mortality rates can be high, and patients who survive often have significant long-term morbidity. The implementation of traditional medical therapies to prevent or treat intestinal ischemia have been sparse over the last decade, and therefore, the use of novel therapies are becoming more prevalent. Cellular therapy using mesenchymal stromal cells is one such treatment modality that is attracting noteworthy attention in the scientific community. Several groups have seen benefit with cellular therapy, but the optimal cell line has not been identified. The purpose of this review is to: 1) Review the mechanism of intestinal ischemia and reperfusion injury, 2) Identify the mechanisms of how cellular therapy may be therapeutic for this disease, and 3) Compare various MSC tissue sources to maximize potential therapeutic efficacy in the treatment of intestinal I/R diseases.

Harvest tissue source does not alter the protective power of stromal cell therapy after intestinal ischemia and reperfusion injury.

BACKGROUND: Transplantation of mesenchymal stromal cells (MSCs) may be a novel treatment for intestinal ischemia. The optimal stromal cell source that could yield maximal protection after injury, however, has not been identified. We hypothesized that (1) MSCs would increase survival and mesenteric perfusion, preserve intestinal histologic architecture, and limit inflammation after intestinal ischemia and reperfusion (I/R) injury, and (2) MSCs harvested from different sources of tissue would have equivalent protective properties to the intestine after I/R inury. METHODS: Adult male mice were anesthetized, and a midline laparotomy was performed. The intestines were eviscerated, the small bowel mesenteric root was identified, and baseline intestinal perfusion was determined using laser Doppler imaging. Intestinal ischemia was established by temporarily occluding the superior mesenteric artery for 60 min with a noncrushing clamp. After ischemia, the clamp was removed and the intestines were allowed to recover. Before abdominal closure, 2 × 10(6) human umbilical cord-derived MSCs, bone marrow-derived MSCs, or keratinocytes in 250 µL of phosphate-buffered saline vehicle were injected into the peritoneum. Animals were allowed to recover for 12 or 24 h (perfusion, histology, and inflammatory studies) or 7 d (survival studies). Survival data was analyzed using the log-rank test. Perfusion was expressed as a percentage of the baseline, and 12- and 24-h data was analyzed using one-way analysis of variance and the Student t-test. Nonparametric data was compared using the Mann-Whitney U-test. A P value of <0.05 was considered statistically significant. RESULTS: All MSCs increased 7-d survival after I/R injury and were superior to vehicle and keratinocytes (P < 0.05). All MSCs increased mesenteric perfusion more than vehicle at 12 and 24 h after injury (P < 0.05). All MSCs provided superior perfusion compared with keratinocytes at 24 h after injury (P < 0.05). Administration of each MSC line improved intestinal histology after I/R injury (P < 0.05). Multiple proinflammatory chemokines were downregulated after the application of MSCs, suggesting a decreased inflammatory response after MSC therapy. CONCLUSIONS: Transplantation of MSCs after intestinal I/R injury, irrespective of a tissue source, significantly increases survival and mesenteric perfusion and at the same time limits intestinal damage and inflammation. Further studies are needed to identify the mechanism that these cells use to promote improved outcomes after injury.

Serotonin Surge: Intravenous Escitalopram as a Rare Cause of Drug-Induced Aplastic Anaemia.

Escitalopram is a commonly prescribed medication that has infrequently been implicated in drug-induced thrombocytopenia (DITP) but has never been associated with aplastic anaemia in the literature. We present an extremely rare case of hypoproliferative pancytopenia due to self-administered intravenous (IV) injection of escitalopram. The crux of this case is the unusual trilineage cytopenia. Our patient was managed with steroids and supportive care with subsequent clinical and blood count recovery. This case sheds light on this uncommon but important association. LEARNING POINTS: Escitalopram is an uncommon medication that could lead to drug-induced aplastic anaemia.The adverse effects of escitalopram on red cell, white cell and platelet counts may be exacerbated on intravenous administration of the medication.Timely diagnosis is vital for the effective treatment of severe aplastic anaemia, avoiding complications and preventing recurrence.

Comparison of accuracy of prediction of postoperative mortality and morbidity between a new, parsimonious risk calculator (SURPAS) and the ACS Surgical Risk Calculator.

BACKGROUND: The novel Surgical Risk Preoperative Assessment System (SURPAS) requires entry of five predictor variables (the other three variables of the eight-variable model are automatically obtained from the electronic health record or a table look-up), provides patient risk estimates compared to national averages, is integrated into the electronic health record, and provides a graphical handout of risks for patients. The accuracy of the SURPAS tool was compared to that of the American College of Surgeons Surgical Risk Calculator (ACS-SRC). METHODS: Predicted risk of postoperative mortality and morbidity was calculated using both SURPAS and ACS-SRC for 1,006 randomly selected 2007-2016 ACS National Surgical Quality Improvement Program (NSQIP) patients with known outcomes. C-indexes, Hosmer-Lemeshow graphs, and Brier scores were compared between SURPAS and ACS-SRC. RESULTS: ACS-SRC risk estimates for overall morbidity underestimated risk compared to observed postoperative overall morbidity, particularly for the highest risk patients. SURPAS accurately estimates morbidity risk compared to observed morbidity. CONCLUSIONS: SURPAS risk predictions were more accurate than ACS-SRC's for overall morbidity, particularly for high risk patients. SUMMARY: The accuracy of the SURPAS tool was compared to that of the American College of Surgeons Surgical Risk Calculator (ACS-SRC). SURPAS risk predictions were more accurate than those of the ACS-SRC for overall morbidity, particularly for high risk patients.

Initial Noninvasive Oxygenation Strategies in Subjects With De Novo Acute Hypoxemic Respiratory Failure.

BACKGROUND: De novo hypoxemic respiratory failure is defined as significant hypoxemia in the absence of chronic lung disease such as COPD, and excluding respiratory failure occurring in the immediate postoperative or postextubation period. We aimed to evaluate the efficacy of various oxygenation strategies including noninvasive ventilation (NIV), high-flow nasal cannula (HFNC), and conventional oxygen therapy in patients with de novo hypoxemic respiratory failure. METHODS: We performed electronic database searches of PubMed, Cochrane Library, and Embase from inception to December 2018 to include randomized controlled trials that compared various oxygenation strategies in cases of de novo hypoxemic respiratory failure occurring in adult subjects without a preexisting chronic lung disease and excluding respiratory failure in the immediate postoperative or postextubation periods. We performed a Bayesian network meta-analysis to calculate odds ratio (OR) and Bayesian 95% credible intervals (CrI). RESULTS: 16 studies were included, involving 2,180 subjects with a mean age of 61 ± 17 y (66% were male; 46% of the included subjects were treated with conventional oxygen, 27.8% were treated with NIV, and 25.8% were treated with HFNC). Compared to conventional oxygen, NIV was associated with reduced intubation rates (OR 0.42, 95% CrI 0.26-0.62) but no significant reduction in short-term (OR 0.73, 95% CrI 0.47-1.02) or long-term mortality (OR 0.60, 95% CrI 0.29-1.06). There was no significant difference between NIV and HFNC or between HFNC and conventional oxygen regarding all outcomes. In a sensitivity analysis, the results remained consistent after exclusion of studies that included subjects with respiratory failure secondary to cardiogenic pulmonary edema. CONCLUSION: Among subjects with hypoxemic respiratory failure, NIV was associated with a significant reduction in intubation rates but not short- or long-term mortality when compared to conventional oxygen therapy. There was no significant difference between NIV and HFNC or between HFNC and conventional oxygen regarding all outcomes.

Hydrogen Sulfide: A Potential Novel Therapy for the Treatment of Ischemia.

Hydrogen sulfide (H2S) is a novel signaling molecule most recently found to be of fundamental importance in cellular function as a regulator of apoptosis, inflammation, and perfusion. Mechanisms of endogenous H2S signaling are poorly understood; however, signal transmission is thought to occur via persulfidation at reactive cysteine residues on proteins. Although much has been discovered about how H2S is synthesized in the body, less is known about how it is metabolized. Recent studies have discovered a multitude of different targets for H2S therapy, including those related to protein modification, intracellular signaling, and ion channel depolarization. The most difficult part of studying hydrogen sulfide has been finding a way to accurately and reproducibly measure it. The purpose of this review is to: elaborate on the biosynthesis and catabolism of H2S in the human body, review current knowledge of the mechanisms of action of this gas in relation to ischemic injury, define strategies for physiological measurement of H2S in biological systems, and review potential novel therapies that use H2S for treatment.