Use of a 5-Item Modified Frailty Index for Assessing Outcomes After Hartmann's Reversal: An ACS-NSQIP Study.

BACKGROUND: Half of all patients with an end colostomy after sigmoid colectomy (Hartmann's procedure) never undergo Hartmann's reversal, frequently secondary to frailty. This retrospective cohort study evaluates the utility of a five-item modified frailty index (mFI-5) in predicting post-operative outcomes after Hartmann's reversal. METHODS: The National Surgery Quality Improvement Program (NSQIP) database captured patients with elective Hartmann's reversals from 2011 to 2020. Clinical covariates were evaluated with univariate analysis and modified Poisson regression to determine association with overall morbidity, overall mortality, and extended length of stay (eLOS) when categorized by mFI-5 score. RESULTS: 15,172 patients underwent elective Hartmann's reversal (91.6% open and 8.4% laparoscopic). Patients were grouped by mFI-5 score (0: 48.7%, 1: 38.2%, ≥ 2: 13.1%). Adjusted multivariable analysis showed frail patients (mFI-5≥2) had increased overall mortality (OR 2.23, 95% CI 1.21-4.11), morbidity (OR 1.23, 95% CI 1.12-1.35), and eLOS (OR 1.12, 95% 1.02-1.23). Among frail patients, a laparoscopic approach was associated with decreased overall morbidity (OR .64, 95% CI 0.56-.73) and decreased eLOS (OR .46, 95% CI 0.39-.54) when compared to open approach. DISCUSSION: An mFI-5 of ≥2 was associated with greater morbidity, mortality, and eLOS following Hartmann's reversal. However, there were no mortality or eLOS differences in patients with an mFI-5 of 1 and only a 14% increase in any morbidity, making these patients potentially good candidates for Hartmann's reversal. Furthermore, laparoscopic surgery was associated with a protective effect for overall morbidity and eLOS, potentially mitigating some of the risk associated with higher frailty scores.

Impact of Preoperative Factors in Patients With IBD on Postoperative Length of Stay: A National Surgical Quality Improvement Program-Inflammatory Bowel Disease Collaborative Analysis.

BACKGROUND: Patients with IBD are challenging to manage perioperatively because of disease complexity and multiple comorbidities. OBJECTIVE: To identify whether preoperative factors and operation type were associated with extended postoperative length of stay after IBD-related surgery, defined by 75th percentile or greater (n = 926; 30.8%). DESIGN: This was a cross-sectional study based on a retrospective multicenter database. SETTING: The National Surgery Quality Improvement Program-Inflammatory Bowel Disease Collaborative captured data from 15 high-volume sites. PATIENTS: A total of 3008 patients with IBD (1710 with Crohn's disease and 1291 with ulcerative colitis) with a median postoperative length of stay of 4 days (interquartile range, 3-7) from March 2017 to February 2020. MAIN OUTCOME MEASURES: The primary outcome was extended postoperative length of stay. RESULTS: On multivariable logistic regression, increased odds of extended postoperative length of stay were associated with multiple demographic and clinical factors (model p < 0.001, area under receiver operating characteristic curve = 0.85). Clinically significant contributors that increased postoperative length of stay were rectal surgery (vs colon; OR, 2.13; 95% CI, 1.52-2.98), new ileostomy (vs no ileostomy; OR, 1.50; 95% CI, 1.15-1.97), preoperative hospitalization (OR, 13.45; 95% CI, 10.15-17.84), non-home discharge (OR, 4.78; 95% CI, 2.27-10.08), hypoalbuminemia (OR, 1.66; 95% CI, 1.27-2.18), and bleeding disorder (OR, 2.42; 95% CI, 1.22-4.82). LIMITATIONS: Retrospective review of only high-volume centers. CONCLUSIONS: Patients with IBD who were preoperatively hospitalized, who had non-home discharge, and who underwent rectal surgery had the highest odds of extended postoperative length of stay. Associated patient characteristics included bleeding disorder, hypoalbuminemia, and ASA classes 3 to 5. Chronic corticosteroid, immunologic, small molecule, and biologic agent use were insignificant on multivariable analysis. See Video Abstract. IMPACTO DE LOS FACTORES PREOPERATORIOS EN PACIENTES CON ENFERMEDAD INFLAMATORIA INTESTINAL EN LA DURACIN DE LA ESTANCIA POSTOPERATORIA UN ANLISIS COLABORATIVO DEL PROGRAMA NACIONAL DE MEJORA DE LA CALIDAD QUIRRGICAENFERMEDAD INFLAMATORIA INTESTINAL: ANTECEDENTES:Los pacientes con enfermedad inflamatoria intestinal son difíciles de manejar perioperatoriamente debido a la complejidad de la enfermedad y a múltiples comorbilidades.OBJETIVO:Este estudio tuvo como objetivo identificar si los factores preoperatorios y el tipo de operación se asociaron con una estadía postoperatoria prolongada después de una cirugía relacionada con enfermedad inflamatoria intestinal, definida por el percentil 75 o mayor (n = 926, 30.8%).DISEÑO:Este fue un estudio transversal basado en una base de datos multicéntrica retrospectiva.ESCENARIO:Datos capturados de quince sitios de alto volumen en El Programa Nacional de Mejoramiento de la Calidad de la Cirugía-Enfermedad Intestinal Inflamatoria en colaboración.PACIENTES:Un total de 3,008 pacientes con enfermedad inflamatoria intestinal (1,710 con enfermedad de Crohn y 1,291 con colitis ulcerosa) con una mediana de estancia postoperatoria de 4 días (RIC 3-7) desde marzo de 2017 hasta febrero de 2020.PRINCIPALES MEDIDAS DE RESULTADO:El resultado primario fue la extensión de la estancia postoperatoria.RESULTADOS:En la regresión logística multivariable, el aumento de las probabilidades de prolongar la estancia postoperatoria se asoció con múltiples factores demográficos y clínicos (modelo p<0.001, área bajo la curva ROC - 0.85). Los contribuyentes clínicamente significativos que aumentaron la duración de la estancia postoperatoria fueron la cirugía rectal (frente al colon) (OR 2.13, IC del 95 %: 1.52 a 2.98), una nueva ileostomía (frente a ninguna ileostomía) (OR 1.50, IC del 95 %: 1.15 a 1.97), hospitalización preoperatoria (OR 13.45, IC 95% 10.15-17.84), alta no domiciliaria (OR 4.78, IC 95% 2.27-10.08), hipoalbuminemia (OR 1.66, IC 95% 1.27-2.18) y trastorno hemorrágico (OR 2.42, IC 95% 1.22-4.82).LIMITACIONES:Revisión retrospectiva de solo centros de alto volumen.CONCLUSIONES:Los pacientes con enfermedad inflamatoria intestinal que fueron hospitalizados antes de la operación, que tuvieron alta no domiciliaria y que se sometieron a cirugía rectal tuvieron las mayores probabilidades de prolongar la estancia postoperatoria. Las características asociadas de los pacientes incluyeron trastorno hemorrágico, hipoalbuminemia y clases ASA 3-5. El uso crónico de corticosteroides, inmunológicos, agentes de moléculas pequeñas y de agentes biológicos no fue significativo en el análisis multivariable. (Traducción-Dr. Jorge Silva Velazco ).

Early trauma-hemorrhage-induced splenic and thymic apoptosis is gut-mediated and toll-like receptor 4-dependent.

Immune depression after trauma-hemorrhage has been implicated as an important factor in the pathogenesis of sepsis and septic-organ failure. Although recent studies have implicated immune-cell apoptosis as an important factor in the evolution of this posttrauma immune-suppressed state, neither the initial triggers that induce this response nor the cellular pathways through which these triggering pathways act have been fully defined. Thus, the current study tests the hypothesis that acute splenic and thymic immune-cell apoptosis developing after trauma-hemorrhagic shock (T/HS) is due to gut-derived factors carried in intestinal lymph and that this T/HS lymph-induced immune depressed state is mediated through Toll-like receptor 4 (TLR4). The first set of experiments documented that T/HS caused both thymic and splenic immune-cell apoptosis as measured by TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) and caspase-3 immunohistochemistry and that this increase in apoptosis was totally abrogated by mesenteric lymph duct ligation. In subsequent experiments, mesenteric lymph collected from animals subjected to T/HS or trauma-sham shock were injected into TLR4-deficient (TLR4mut) mice or their wild-type (WT) littermates. Trauma-hemorrhagic shock, but not trauma-sham shock, lymph caused splenic apoptosis in the WT mice. However, the TLR4mut mice were resistant to T/HS lymph-induced splenic apoptosis. Furthermore, the WT, but not the TLR4mut mice developed splenic apoptosis after actual T/HS. In conclusion, gut-derived factors appear to initiate a sequence of events that leads to an acute increase in splenic and thymic immune-cell apoptosis, and this process is TLR4-dependent.

Role of lipase-generated free fatty acids in converting mesenteric lymph from a noncytotoxic to a cytotoxic fluid.

Recent studies have shown that mesenteric lymph plays a very important role in the development of multiple-organ dysfunction syndrome under critical conditions. Great efforts have been made to identify the biologically active molecules in the lymph. We used a trauma-hemorrhagic shock (T/HS) model and the superior mesenteric artery occlusion (SMAO) model, representing a global and a localized intestinal ischemia-reperfusion insult, respectively, to investigate the role of free fatty acids (FFAs) in the cytotoxicity of mesenteric lymph in rats. Lymph was collected before, during, and after (post) shock or SMAO. The post-T/HS and SMAO lymph, but not the sham lymph, manifested cytotoxicity for human umbilical vein endothelial cells (HUVECs). HUVEC cytotoxicity was associated with increased FFAs, especially the FFA-to-protein ratio. Addition of albumin, especially delipidated albumin, reduced this cytotoxicity. Lipase treatment of trauma-sham shock (T/SS) lymph converted it from a noncytotoxic to a cytotoxic fluid, and its toxicity correlated with the FFA-to-protein ratio in a fashion similar to that of the T/HS lymph, further suggesting that FFAs were the key components leading to HUVEC cytotoxicity. Analysis of lymph by gas chromatography revealed that the main FFAs in the post-T/HS or lipase-treated T/SS lymph were palmitic, stearic, oleic, and linoleic acids. When added to the cell culture at levels comparable to those in T/HS lymph, all these FFAs were cytotoxic, with linoleic acid being the most potent. In conclusion, this study suggests that lipase-generated FFAs are the key components resulting in the cytotoxicity of T/HS and SMAO mesenteric lymph.

Activation of toll-like receptor 4 is necessary for trauma hemorrhagic shock-induced gut injury and polymorphonuclear neutrophil priming.

Interactions of toll-like receptors (TLRs) with nonmicrobial factors play a major role in the pathogenesis of early trauma-hemorrhagic shock (T/HS)-induced organ injury and inflammation. Thus, we tested the hypothesis that TLR4 mutant (TLR4 mut) mice would be more resistant to T/HS-induced gut injury and polymorphonuclear neutrophil (PMN) priming than their wild-type littermates and found that both were significantly reduced in the TLR4 mut mice. In addition, the in vivo and ex vivo PMN priming effect of T/HS intestinal lymph observed in the wild-type mice was abrogated in TLR4 mut mice as well the TRIF mut-deficient mice and partially attenuated in Myd88 mice, suggesting that TRIF activation played a more predominant role than MyD88 in T/HS lymph-induced PMN priming. Polymorphonuclear neutrophil depletion studies showed that T/HS lymph-induced acute lung injury was PMN dependent, because lung injury was totally abrogated in PMN-depleted animals. Because the lymph samples were sterile and devoid of endotoxin or bacterial DNA, we investigated whether the effects of T/HS lymph was related to endogenous nonmicrobial TLR4 ligands. High-mobility group box 1 protein 1, heat shock protein 70, heat shock protein 27, and hyaluronic acid all have been implicated in ischemia-reperfusion-induced tissue injury. None of these "danger" proteins appeared to be involved, because their levels were similar between the sham and shock lymph samples. In conclusion, TLR4 activation is important in T/HS-induced gut injury and in T/HS lymph-induced PMN priming and lung injury. However, the T/HS-associated effects of TLR4 on gut barrier dysfunction can be uncoupled from the T/HS lymph-associated effects of TLR4 on PMN priming.

Testosterone depletion or blockade in male rats protects against trauma hemorrhagic shock-induced distant organ injury by limiting gut injury and subsequent production of biologically active mesenteric lymph.

BACKGROUND: We tested the hypothesis that testosterone depletion or blockade in male rats protects against trauma hemorrhagic shock-induced distant organ injury by limiting gut injury and subsequent production of biologically active mesenteric lymph. METHODS: Male, castrated male, or flutamide-treated rats (25 mg/kg subcutaneously after resuscitation) were subjected to a laparotomy (trauma), mesenteric lymph duct cannulation, and 90 minutes of shock (35 mm Hg) or trauma sham-shock. Mesenteric lymph was collected preshock, during shock, and postshock. Gut injury was determined at 6 hours postshock using ex vivo ileal permeability with fluorescein dextran. Postshock mesenteric lymph was assayed for biological activity in vivo by injection into mice and measuring lung permeability, neutrophil activation, and red blood cell deformability. In vitro neutrophil priming capacity of the lymph was also tested. RESULTS: Castrated and flutamide-treated male rats were significantly protected against trauma hemorrhagic shock (T/HS)-induced gut injury when compared with hormonally intact males. Postshock mesenteric lymph from male rats had a higher capacity to induce lung injury, Neutrophil (PMN) activation, and loss of red blood cell deformability when injected into naïve mice when compared with castrated and flutamide-treated males. The increase in gut injury after T/HS in males directly correlated with the in vitro biological activity of mesenteric lymph to prime neutrophils for an increased respiratory burst. CONCLUSIONS: After T/HS, gut protective effects can be observed in males after testosterone blockade or depletion. This reduced gut injury contributes to decreased biological activity of mesenteric lymph leading to attenuated systemic inflammation and distant organ injury.

ß2-Adrenoreceptors of regulatory lymphocytes are essential for vagal neuromodulation of the innate immune system.

The nervous system is classically organized into sympathetic and parasympathetic systems acting in opposition to maintain physiological homeostasis. Here, we report that both systems converge in the activation of ß2-adrenoceptors of splenic regulatory lymphocytes to control systemic inflammation. Vagus nerve stimulation fails to control serum TNF levels in either ß2-knockout or lymphocyte-deficient nude mice. Unlike typical suppressor CD25(+) cells, the transfer of CD4(+)CD25(-) regulatory lymphocytes reestablishes the anti-inflammatory potential of the vagus nerve and ß2-agonists to control inflammation in both ß2-knockout and nude mice. ß2-Agonists inhibit cytokine production in splenocytes (IC(50)≈ 1 µM) and prevent systemic inflammation in wild-type but not in ß2-knockout mice. ß2-Agonists rescue wild-type mice from established polymicrobial peritonitis in a clinically relevant time frame. Regulatory lymphocytes reestablish the anti-inflammatory potential of ß2-agonists to control systemic inflammation, organ damage, and lethal endotoxic shock in ß2-knockout mice. These results indicate that ß2-adrenoceptors in regulatory lymphocytes are critical for the anti-inflammatory potential of the parasympathetic vagus nerve, and they represent a potential pharmacological target for sepsis.

Trauma hemorrhagic shock-induced lung injury involves a gut-lymph-induced TLR4 pathway in mice.

BACKGROUND: Injurious non-microbial factors released from the stressed gut during shocked states contribute to the development of acute lung injury (ALI) and multiple organ dysfunction syndrome (MODS). Since Toll-like receptors (TLR) act as sensors of tissue injury as well as microbial invasion and TLR4 signaling occurs in both sepsis and noninfectious models of ischemia/reperfusion (I/R) injury, we hypothesized that factors in the intestinal mesenteric lymph after trauma hemorrhagic shock (T/HS) mediate gut-induced lung injury via TLR4 activation. METHODS/PRINCIPAL FINDINGS: The concept that factors in T/HS lymph exiting the gut recreates ALI is evidenced by our findings that the infusion of porcine lymph, collected from animals subjected to global T/HS injury, into naïve wildtype (WT) mice induced lung injury. Using C3H/HeJ mice that harbor a TLR4 mutation, we found that TLR4 activation was necessary for the development of T/HS porcine lymph-induced lung injury as determined by Evan's blue dye (EBD) lung permeability and myeloperoxidase (MPO) levels as well as the induction of the injurious pulmonary iNOS response. TRIF and Myd88 deficiency fully and partially attenuated T/HS lymph-induced increases in lung permeability respectively. Additional studies in TLR2 deficient mice showed that TLR2 activation was not involved in the pathology of T/HS lymph-induced lung injury. Lastly, the lymph samples were devoid of bacteria, endotoxin and bacterial DNA and passage of lymph through an endotoxin removal column did not abrogate the ability of T/HS lymph to cause lung injury in naïve mice. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that non-microbial factors in the intestinal mesenteric lymph after T/HS are capable of recreating T/HS-induced lung injury via TLR4 activation.

Anticoagulants influence the in vitro activity and composition of shock lymph but not its in vivo activity.

Many models of trauma-hemorrhagic shock (T/HS) involve the reinfusion of anticoagulated shed blood. Our recent observation that the anticoagulant heparin induces increased mesenteric lymph lipase activity and consequent in vitro endothelial cell cytotoxicity prompted us to investigate the effect of heparin-induced lipase activity on organ injury in vivo as well as the effects of other anticoagulants on mesenteric lymph bioactivity in vitro and in vivo. To investigate this issue, rats subjected to trauma-hemorrhage had their shed blood anticoagulated with heparin, the synthetic anticoagulant arixtra (fondaparinux sodium), or citrate. Arixtra, in contrast to heparin, did not increase lymph lipase activity or result in high levels of endothelial cytotoxicity. Yet, the arixtra-treated rats subjected to T/HS still manifested lung injury, neutrophil priming, and red blood cell dysfunction, which was totally abrogated by lymph duct ligation. Furthermore, the injection of T/HS mesenteric lymph, but not sham-shock lymph, collected from the arixtra rats into control mice recreated the pattern of lung injury, polymorphonucleocyte (PMN) priming, and red blood cell dysfunction observed after actual shock. Consistent with these observations, citrate-anticoagulated rats subjected to T/HS developed lung injury, and the injection of mesenteric lymph from the citrate-anticoagulated T/HS rats into control mice also resulted in lung injury. Based on these results, several conclusions can be drawn. First, heparin-induced increased mesenteric lymph lipase activity is not responsible for the in vivo effects of T/HS mesenteric lymph. Second, heparin should be avoided as an anticoagulant when studying the biology or composition of mesenteric lymph because of its ability to cause increases in lymph lipase activity that increase the in vitro cytotoxicity of these lymph samples.

Hypoxia-inducible factor plays a gut-injurious role in intestinal ischemia reperfusion injury.

Gut injury and loss of normal intestinal barrier function are key elements in the paradigm of gut-origin systemic inflammatory response syndrome, acute lung injury, and multiple organ dysfunction syndrome (MODS). As hypoxia-inducible factor (HIF-1) is a critical determinant of the physiological and pathophysiological response to hypoxia and ischemia, we asked whether HIF-1 plays a proximal role in the induction of gut injury and subsequent lung injury. Using partially HIF-1α-deficient mice in an isolated superior mesenteric artery occlusion (SMAO) intestinal ischemia reperfusion (I/R) injury model (45 min SMAO followed by 3 h of reperfusion), we showed a direct relationship between HIF-1 activation and intestinal I/R injury. Specifically, partial HIF-1α deficiency attenuated SMAO-induced increases in intestinal permeability, lipid peroxidation, mucosal caspase-3 activity, and IL-1ß mRNA levels. Furthermore, partial HIF-1α deficiency prevented the induction of ileal mucosal inducible nitric oxide synthase (iNOS) protein levels after SMAO and iNOS deficiency ameliorated SMAO-induced villus injury. Resistance to SMAO-induced gut injury was also associated with resistance to lung injury, as reflected by decreased levels of myeloperoxidase, IL-6 and IL-10 in the lungs of HIF-1α(+/-) mice. In contrast, a short duration of SMAO (15 min) followed by 3 h of reperfusion neither induced mucosal HIF-1α protein levels nor caused significant gut and lung injury in wild-type or HIF-1α(+/-) mice. This study indicates that intestinal HIF-1 activation is a proximal regulator of I/R-induced gut mucosal injury and gut-induced lung injury. However, the duration and severity of the gut I/R insult dictate whether HIF-1 plays a gut-protective or deleterious role.

Loss of the intestinal mucus layer in the normal rat causes gut injury but not toxic mesenteric lymph nor lung injury.

There is substantial evidence that gut barrier failure is associated with distant organ injury and systemic inflammation. After major trauma or stress, the factors and mechanisms involved in gut injury are unknown. Our primary hypothesis is that loss of the intestinal mucus layer will result in injury of the normal gut that is exacerbated by the presence of luminal pancreatic proteases. Our secondary hypothesis is that the injury produced in the gut will result in the production of biologically active mesenteric lymph and consequently distant organ (i.e., lung) injury. To test this hypothesis, five groups of rats were studied: 1) uninstrumented naive rats; 2) control rats in which a ligated segment of distal ileum was filled with saline; 3) rats with pancreatic proteases placed in their distal ileal segments; 4) rats with the mucolytic N-acetylcysteine (NAC) placed in their distal ileal segments; and 5) rats exposed to NAC and pancreatic proteases in their ileal segments. The potential systemic consequences of gut injury induced by NAC and proteases were assessed by measuring the biological activity of mesenteric lymph as well as gut-induced lung injury. Exposure of the normal intestine to NAC, but not saline or proteases, led to increased gut permeability, loss of mucus hydrophobicity, a decrease in the mucus layer, as well as morphological evidence of villous injury. Although proteases themselves did not cause gut injury, the combination of pancreatic proteases with NAC caused more severe injury than NAC alone, suggesting that once the mucus barrier is impaired, luminal proteases can injure the now vulnerable gut. Because comparable levels of gut injury caused by systemic insults are associated with gut-induced lung injury, which is mediated by biologically active factors in mesenteric lymph, we next tested whether this local model of gut injury would produce active mesenteric lymph or lead to lung injury. It did not, suggesting that gut injury by itself may not be sufficient to induce distant organ dysfunction. Therefore, loss of the intestinal mucus layer, especially in the presence of intraluminal pancreatic proteases, is sufficient to lead to injury and barrier dysfunction of the otherwise normal intestine but not to produce gut-induced distant organ dysfunction.

Estrogen receptor hormone agonists limit trauma hemorrhage shock-induced gut and lung injury in rats.

BACKGROUND: Acute lung injury (ALI) and the development of the multiple organ dysfunction syndrome (MODS) is a major cause of death in trauma patients. Earlier studies in trauma hemorrhagic shock (T/HS) have documented that splanchnic ischemia leading to gut inflammation and loss of barrier function is an initial triggering event that leads to gut-induced ARDS and MODS. Since sex hormones have been shown to modulate the response to T/HS and proestrous (PE) females are more resistant to T/HS-induced gut and distant organ injury, the goal of our study was to determine the contribution of estrogen receptor (ER)alpha and ERbeta in modulating the protective response of female rats to T/HS-induced gut and lung injury. METHODS/PRINCIPAL FINDINGS: The incidence of gut and lung injury was assessed in PE and ovariectomized (OVX) female rats subjected to T/HS or trauma sham shock (T/SS) as well as OVX rats that were administered estradiol (E2) or agonists for ERalpha or ERbeta immediately prior to resuscitation. Marked gut and lung injury was observed in OVX rats subjected to T/HS as compared to PE rats or E2-treated OVX rats subjected to T/HS. Both ERalpha and ERbeta agonists were equally effective in limiting T/HS-induced morphologic villous injury and bacterial translocation, whereas the ERbeta agonist was more effective than the ERalpha agonist in limiting T/HS-induced lung injury as determined by histology, Evan's blue lung permeability, bronchoalevolar fluid/plasma protein ratio and myeloperoxidase levels. Similarly, treatment with either E2 or the ERbeta agonist attenuated the induction of the intestinal iNOS response in OVX rats subjected to T/HS whereas the ERalpha agonist was only partially protective. CONCLUSIONS/SIGNIFICANCE: Our study demonstrates that estrogen attenuates T/HS-induced gut and lung injury and that its protective effects are mediated by the activation of ERalpha, ERbeta or both receptors.