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Sudden cardiac death is a major cause of cardiovascular mortality in the United States with 250,000-450,000 deaths annually. Transvenous Implantable Cardioverter-Defibrillator (ICD) has been conventionally used for both primary and secondary prevention of ventricular tachycardia or fibrillation (VT/VF). It is also associated with a high risk of complications like hemothorax, pneumothorax, cardiac tamponade, lead failure, and increased risk for infections. Subcutaneous ICD (S-ICD) poses as a viable alternative with reduced chances of complications. This manuscript aims to review S-ICD as an alternative to conventional transvenous ICD and its efficacy. We conducted a Medline search of "Subcutaneous," "ICD," "transvenous," and "ventricular tachycardia or fibrillation (VT/VF)" to identify pivotal trials published before June 2021, for inclusion in this review. Major practice guidelines, trial bibliographies, and pertinent reviews were examined to ensure the inclusion of relevant trials. The following section reviews data from pivotal trials to review the efficacy of S-ICD for the termination of VT/VF. The S- ICD system consists of a pulse generator positioned over the sixth rib between the midaxillary and anterior axillary line and a tripolar parasternal electrode with the proximal and distal sensing electrodes positioned adjacent to the xiphoid process and manubriosternal junction, respectively. The conversion of the efficacy of the S-ICD after the first shock ranges from 88%-90.1% and 98.2%-100% after 5 shocks based on the current evidence. The device also has a 99% complication-free rate at 180 days with no increased complications even in ESRD patients. The PRAETORIAN trial showed non-inferiority of the S-ICD to transvenous ICD concerning device-related complications or inappropriate shocks in patients. S-ICD has several advantages including no need for fluoroscopy for implantation, decreased risk of infections, complications, and evidence of safety even in high-risk populations like ESRD. The limitations include the inherent lack of pacing abnormalities, the increase in inappropriate shocks compared to transvenous ICD, and non-reliability if there are baseline T wave abnormalities, especially in the inferior leads. Thus, S-ICD can be considered as an alternative to transvenous ICD in patients with an indication for defibrillator therapy but with no indication for pacing., (Published by Elsevier Inc.)

31 Phosphorus magnetic resonance spectroscopy ( 31 P-MRS) has been shown to detect altered energetic status (e.g. the ratio of inorganic phosphate to phosphocreatine: Pi/PCr), intracellular acid-base status, and free intracellular magnesium ([Mg 2+ ]) in dystrophic muscle compared with unaffected muscle; however, the causes of these differences are not well understood. The purposes of this study were to examine 31 P-MRS indices of energetic status and sarcolemma integrity in young mdx mice compared with wild-type and to evaluate the effects of downhill running to induce muscle damage on 31 P-MRS indices in dystrophic muscle. In vivo 31 P-MRS spectra were acquired from the posterior hindlimb muscles in young (4-10 weeks of age) mdx (C57BL/10ScSn-DMDmdx) and wild-type (C57BL/10ScSnJ) mice using an 11.1-T MR system. The flux of phosphate from PCr to ATP was estimated by 31 P-MRS saturation transfer experiments. Relative concentrations of high-energy phosphates were measured, and intracellular pH and [Mg 2+ ] were calculated. 1 H 2 O-T 2 was measured using single-voxel 1 H-MRS from the gastrocnemius and soleus using a 4.7-T MR system. Downhill treadmill running was performed in a subset of mice. Young mdx mice were characterized by elevated 1 H 2 O-T 2 (p < 0.01) , Pi/PCr (p = 0.02), PCr to ATP flux (p = 0.04) and histological inflammatory markers (p < 0.05) and reduced (p < 0.01) [Mg 2+ ] compared with wild-type. Furthermore, 24 h after downhill running, an increase (p = 0.02) in Pi/PCr was observed in mdx and wild-type mice compared with baseline, and a decrease (p < 0.001) in [Mg 2+ ] and a lower (p = 0.048) intracellular [H + ] in damaged muscle regions of mdx mice were observed, consistent with impaired sarcolemma integrity. Overall, our findings demonstrate that 31 P-MRS markers of energetic status and sarcolemma integrity are altered in young mdx compared with wild-type mice, and these indices are exacerbated following downhill running., (© 2021 John Wiley & Sons, Ltd.)

Background: Hypercholesterolemia and sickle cell disease (SCD) impair endothelium-dependent vasodilation by dissimilar mechanisms. Hypercholesterolemia impairs vasodilation by a low-density lipoprotein (LDL)-dependent mechanism. SCD has been characterized as a chronic state of inflammation in which xanthine oxidase (XO) from ischemic tissues increases vascular superoxide anion (O2*-) generation. Recent reports indicate that apolipoprotein (apo) A-1 mimetics inhibit atherosclerosis in LDL receptor-null (Ldlr-/-) mice fed Western diets. Here we hypothesize that L-4F, an apoA-1 mimetic, preserves vasodilation in hypercholesterolemia and SCD by decreasing mechanisms that increase O2*- generation., Methods and Results: Arterioles were isolated from hypercholesterolemic Ldlr-/- mice and from SCD mice that were treated with either saline or L-4F (1 mg/kg per day). Vasodilation in response to acetylcholine was determined by videomicroscopy. Effects of L-4F on LDL-induced increases in endothelium-dependent O2*- generation were determined on arterial segments via the hydroethidine assay and on stimulated endothelial cell cultures via superoxide dismutase-inhibitable ferricytochrome c reduction. Effects of L-4F on XO bound to pulmonary arterioles and content in livers of SCD mice were determined by immunofluorescence. Hypercholesterolemia impaired vasodilation in Ldlr-/- mice, which L-4F dramatically improved. L-4F inhibited LDL-induced increases in O2*- in arterial segments and in stimulated cultures. SCD impaired vasodilation, increased XO bound to pulmonary endothelium, and decreased liver XO content. L-4F dramatically improved vasodilation, decreased XO bound to pulmonary endothelium, and increased liver XO content compared with levels in untreated SCD mice., Conclusions: These data show that L-4F protects endothelium-dependent vasodilation in hypercholesterolemia and SCD. Our findings suggest that L-4F restores vascular endothelial function in diverse models of disease and may be applicable to treating a variety of vascular diseases.

Background/purpose: The molecular and cellular events that regulate inflammatory lung injury, a major cause of morbidity in surgical patients, remain unclear. The authors hypothesize that nitric oxide (NO) plays an important role in regulating polymorphonuclear cell (PMN)-induced acute lung injury, and further, that attenuated expression of inducible nitric oxide synthase (iNOS) and therefore decreased production of NO by lung microvascular endothelial cells (LMVEC), accelerates inflammation and injury., Methods: LMVEC and aortic EC (AEC) from rat and human were stimulated with lipopolysaccharide (LPS) and cytokines; changes in iNOS mRNA expression and iNOS activity were determined. The role of NO in mediating inflammatory responses was evaluated by determining PMN adherence to LMVEC and lung tissue slices in the presence and absence of NOS inhibitors and NO donors. Human LMVEC and AEC were assessed by FACS analysis for ICAM-1 expression, because this is thought to be a critical determinant of PMN adherence., Results: When stimulated with endotoxin and cytokines, rat AEC monolayers express nearly 3-fold more iNOS mRNA than rat LMVEC. The low levels of LMVEC iNOS expression are associated with a 4-fold lower nitrite and nitrate production. Similar trends are seen in human endothelial cells. When iNOS activity was blocked, PMN adherence to tumor necrosis factor alpha (TNFalpha)/LPS-stimulated LMVEC was markedly increased. In contrast, adding a nitric oxide donor to endotoxin/cytokine-stimulated LMVEC monolayers reduced PMN adherence to near background levels. Similar responses were observed in vivo. Human lung microvascular endothelial cells show a substantially increased level of ICAM-1 upregulation when compared with similarly stimulated human aortic macrovascular endothelial cells., Conclusions: These data indicate that LMVEC express less iNOS and produce less NO than AEC. This lower expression and activity of iNOS in LMVEC may be linked to increased expression of ICAM-1. Because ICAM-1 has been shown to be essential for tight PMN adherence, these data suggest that relatively low iNOS expression in LMVEC may contribute to a propensity for the lung to be injured by activated PMNs., (Copyright 2001 by W.B. Saunders Company.)

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This study examines the effect of intestinal reperfusion injury (IIR) on renal blood flow and relates this temporally to changes in renal ATP levels and renal tubular function. Sprague-Dawley rats underwent 120 min of intestinal ischemia and 60 min of reperfusion (IIR). Renal blood flow was measured with radiolabeled microspheres and a Doppler flow probe. Renal dysfunction was quantitated by measuring inulin clearance and fractional excretion of sodium (FENa) in the isolated perfused organ. Renal tissue ATP levels were measured using a luciferase-luciferin assay. Sham-operated animals served as controls (SHAM). Renal blood flow was reduced by > 80% in the animals sustaining IIR when compared to baseline measurements (P < 0.05) or SHAM (P < 0.05). Temporally this reduction in renal blood flow was associated with a 25% reduction in tissue ATP levels (P < 0.05). The kidneys of animals sustaining IIR had a significantly greater FENa than did those of controls. These data support the notion that IIR is associated with a profound reduction in renal blood flow which is temporally related to reduced renal tissue ATP levels and renal tubular dysfunction.

Purpose: Nitric oxide (NO) is a major regulator of vascular tone, blood pressure, and blood flow, and plays a significant role in disease states associated with hemodynamic alterations. However, the role of NO in association with the effects of brain death (BD) has not yet been evaluated., Methods: In 17 mongrel dogs (23 to 31 kg), right atrial serum measurements of nitrite and L-arginine as well as NO ex vivo tissue nitrite extraction were performed at baseline (0), and 120, 240, and 360 minutes after BD. The hearts were instrumented with micromanometers, transonic flow probes, and ultrasonic dimension transducers to determine systolic function and to analyze the pulmonary vasculature flow characteristics by Fourier analysis. Brain death was induced by inflation of a subdurally placed balloon and validated neuropathologically. The results are expressed as mean and standard error of the mean (+/- SEM) (P < .05, paired t-test)., Results: Right and left ventricular function deteriorated significantly (P < .001) by 37% (+/- 10) and 22% (+/- 7) respectively following BD. Pulmonary and systemic vascular resistance as well as pulmonary impedance decreased significantly over 6 hours after BD. Pulsatile flow, a potent stimulant of NO release, converted significantly to more steady flow. Myocardial NO extraction values remained unchanged after BD and serum L-arginine decreased from 12.84 mu g/L (+/- 0.60) to 11.77 mu g/L (+/- 0.55)., Conclusions: The decreases in pulmonary and systemic vascular resistance, pulmonary impedance, and cardiac function associated with BD are not related to major changes in the NO pathway. NO may not play a key role in the early changes after BD.

Background: Intestinal ischemia-reperfusion injury (IIR) induces hepatic and pulmonary dysfunction and thus has been used as a model of multiple organ failure syndrome. This study examines the hypothesis that hepatic blood flow is markedly reduced in this injury model., Methods: Sprague-Dawley rats underwent 120 minutes of intestinal ischemia and 60 minutes of reperfusion (IIR). Hepatic blood flow was measured with radiolabeled microspheres and Doppler flow probes. Hepatic dysfunction was quantitated by measuring bile flow and serum alanine aminotransferase and hepatic tissue adenosine triphosphate levels. Sham-operated animals served as controls., Results: Intestinal ischemia reduced portal flow by 66% when compared with sham-operated animals (p = 0.0001) but had no effect on hepatic arterial flow. In contrast, reperfusion reduced hepatic artery flow by 80% when compared with controls (p = 0.002) with most of this change occurring within 5 minutes of reperfusion. IIR induced a 63% reduction in bile flow (p < 0.05), a fivefold rise in serum alanine aminotransferase level (p < 0.0002), and a 33% reduction in hepatic adenosine triphosphate level (p < 0.05)., Conclusions: These data suggest that IIR induces profound hepatic hypoperfusion, which is temporally related to acute hepatic dysfunction. This observation suggests that hepatic ischemia may contribute to IIR-induced liver injury.

This study examines the hypothesis that reduced splanchnic blood flow during intestinal reperfusion (IR) is associated with impaired release of the vasodilatory prostanoid PGI2. Sprague-Dawley rats underwent occlusion of the superior mesenteric artery (SMA) for 120 min and reperfusion for up to 60 min. SMA blood flow was measured by transonic flow probe and radiolabeled microspheres (141Ce and 103Ru). Sham-operated animals served as controls (SHAM). Splanchnic eicosanoid release was quantitated by measuring thromboxane B2 (TxB2, stable metabolite of TxA2), 6-keto-PGF1a (6-keto, stable metabolite of PGI2), and PGE2 within the portal vein (PV) and inferior vena cava (IVC) of animals sustaining IR and SHAM. SMA flow in IR animals was < 10% of baseline and 27% of SHAM when measured by transonic flow probe (8 +/- 2% and 29 +/- 3%, IR and SHAM, respectively, P < 0.05). Similar results were obtained when intestinal blood flow was measured with microspheres (0.33 +/- 0.12 vs 1.34 +/- 0.13 ml/min/g, IR vs SHAM, P < 0.05). The greatest change in IR-induced splanchnic eicosanoid release occurred with 6-keto. Following ischemia, 6-keto levels in the PV were twice those of SHAM (P < 0.05). Five minutes after reperfusion, PV 6-keto levels were 22 times those of controls (P < 0.05) and 4 times greater than those of the IVC (P < 0.05). By 60 min of reperfusion, levels of 6-keto were reduced to those in the IVC. These data support the hypothesis that splanchnic blood flow is critically reduced by severe IR.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: Previous data have shown that glutathione (GSH), an endogenous antioxidant, is converted to its oxidized form (GSSG) after oxidative ischemia-reperfusion events. As GSSG is toxic to cells and is extruded through an active mechanism dependent on intracellular GSSG levels, substance appears in plasma., Study Design: Single lung transplantation was performed upon 18 puppies, 3 to 5 kg, with a two hour ischemic time for the donor lung before reimplantation. Recipient animal plasma was obtained after anesthesia induction, pulmonary artery ligation, recipient pneumonectomy, reestablishment of blood flow to the donor lung, completion of transplant, and one, two, and three hours postoperatively. Donor lung bronchoalveolar lavage fluid (BALF) was obtained at the time of harvest, after perfusion of the donor lung with EuroCollins, immediately pretransplant, and after completion of the vascular anastomoses. Oxidized and total GSH levels in plasma and BALF samples were determined by a spectrophotometric assay., Results: After reimplantation of the ischemic donor lung, there was a statistically significant increase in both GSSG and GSH in plasma samples, and a statistically significant increase in GSSG in the BALF., Conclusions: Compartmental differences between arterial and venous plasma, as well as the increase in GSSG in the BALF, implicated the lung that was transplanted as the source of oxygen free radical generation and GSSG release. Plasma GSSG levels seem to provide a sensitive, noninvasive, repeatable measure of ongoing tissue response and oxygen free radical production.

This study examines the hypothesis that hydroxyl radical (OH.) generation during intestinal reperfusion activates the complement system forming the potent chemotaxin C5a. Anesthetized Sprague-Dawley rats underwent 120 min of intestinal ischemia and 60 min of reperfusion (IIR). Complement (C) activation was assessed by measuring total plasma C activity and C5a-related chemotaxis and leukoaggregation. Dimethylthiourea and the iron chelator deferoxamine were utilized to assess the role of the OH. in the activation of C in this model. Sham-operated animals served as controls. Total plasma C activity of animals sustaining IIR was 64% of controls (p < .05). Plasma of animals sustaining IIR induced greater chemotaxis and leukoaggregation than plasma from sham-operated groups (p < .05). Treatment of IIR plasma with anti-C5a antibody ameliorated the enhanced leukoaggregation characteristic of IIR plasma. Pretreatment with dimethylthiorea and deferoxamine prevented reperfusion-induced activation of complement and inhibited the chemotactic activity of plasma from IIR animals. These data are consistent with the hypothesis that IIR activates complement and that the OH. generated during reperfusion may be one mechanism by which C is activated in this injury model.

Multiple organ failure is the most common cause of death in critically ill patients in the United States. Acute respiratory failure is the most important single component of this clinical scenario, with a mortality risk > 50%. Key pathophysiologic events occur in the pulmonary microvasculature at the interface between circulating elements and the external environment. In particular, the response of the alveolar capillary endothelial cell is of fundamental importance in this injury process. A variety of clinical stimuli initiate a systemic inflammatory response that contributes to acute microvascular lung injury. Sepsis, trauma, thermal injury, acute pancreatitis, and ischemia-reperfusion injury are among these stimuli. The particular emphasis of this review is on events associated with intestinal ischemia-reperfusion, a common and important clinical event. The pathogenic mechanisms that lead to acute lung injury in this setting are not completely understood, although it is clear that neutrophil-endothelial interactions regulated by both humoral and local mediators are crucial. Oxygen-derived free radicals, proteases, cytokines, eicosanoids, endotoxin, complement activation products, and probably platelet activating factor and nitric oxide are involved as either signalling or effector molecules. The key cellular participants during the acute phase of injury are the polymorphonuclear neutrophil (PMN) and the microvascular endothelial cell. Each of these participants is considered with regard to phlogistic behavior and the potential for therapeutic intervention. Adherence of the neutrophil to the endothelium creates a microenvironment in which PMN-derived oxidants, proteases, and cationic proteins are discharged under conditions that lead to cellular injury. Loss of microvascular integrity results and pulmonary dysfunction follows. At present, we offer only nonspecific supportive care for patients with this problem. However, investigations into relevant molecular and cellular regulatory events offer important opportunities for directed therapy. We are now approaching the threshold for utilization of several new and specific approaches. While no single pharmacologic therapy is likely to be curative for this complex problem, it is probable that certain approaches will be of clinical benefit in the near future. This review is designed to provide a basis for understanding this evolution.

This study examines the hypothesis that whole gut irrigation with polyethylene glycol-electrolyte gavage solution (PEG-ELS) increases intravascular volume. Seventeen patients drank 6 to 8 liters of PEG-ELS in preparation for elective colonoscopy. The patients were weighed and serum electrolytes, albumin, hematocrit, blood urea nitrogen, and creatinine were obtained prior to the gavage and 8 hr following gavage. Plasma volume was measured before and after gavage using an isotope dilution technique involving 125I-human serum albumin. No patients developed symptoms of intravascular volume excess or depletion following gavage. There was no significant change in body weight, serum sodium, chloride, potassium, bicarbonate, blood urea nitrogen, or creatinine following gavage with PEG-ELS. When measured by the isotope dilution technique, the mean plasma volume increased from 3174 +/- 117 ml before gavage to 3365 +/- 160 ml following gavage (P = 0.03). This represented a mean percentage change in plasma volume of 5.88 +/- 2.4%. The percentage change in plasma volume associated with gavage ranged from -9.8 to +29.8%. This data supports the hypothesis that gavage with polyethylene glycol-electrolyte solution is associated with an increase in plasma volume. Although in most patients the increase in plasma volume is minimal, there is significant variability in this response, with some patients experiencing substantial increases in plasma volume.

Intestinal injury resulting from ischemia/reperfusion (I/R) is of fundamental importance in clinical pediatric surgery. I/R injury results from inadequate oxygen delivery as well as a secondary inflammatory response involving neutrophils and oxidants. This study was designed to evaluate a novel use for diclofenac sodium (DS), a nonsteroidal antiinflammatory agent, and to compare it with traditional antioxidants in this setting. Rats were subjected to intestinal ischemia followed by reperfusion. When killed, samples were obtained for measurement of intestinal myeloperoxidase (MPO), a measure of neutrophil sequestration, as well as for adenosine triphosphate (ATP) content, a marker of tissue injury. Animals exposed to I/R injury had significant neutrophil sequestration in the intestine by 120 minutes of ischemia, and this persisted after 60 minutes of reperfusion. DS pretreatment did not prevent neutrophil sequestration in the intestine. Analysis of intestinal ATP content demonstrated a decrease in intestinal ATP after 120 minutes of ischemia, and this did not change with 60 minutes of reperfusion. Pretreatment with DS significantly attenuated this intestinal ATP depletion. Furthermore, with 120 minutes of ischemia and 60 minutes of reperfusion, ATP preservation with DS pretreatment exceeded that obtained using the following conventional antioxidants: a xanthine-oxidase inhibitor (lodoxamide), deferoxamine, dimethysulfoxide, and superoxide dismutase plus catalase. DS has a significant cytoprotective effect for intestine subjected to I/R injury, exceeding that of conventional antioxidants. DS does not attenuate injury by preventing neutrophil influx into injured intestine.(ABSTRACT TRUNCATED AT 250 WORDS)

This study addresses the hypothesis that endotoxin (LPS) is an important proximal mediator of remote organ dysfunction following intestinal reperfusion. Sprague-Dawley rats underwent intestinal ischemia for 120 min followed by 60 min of reperfusion (IIR). Animals underwent pretreatment with polymyxin B (PMB, 200 micrograms, sc) or the induction of tolerance to LPS prior to assignment to the IIR or sham group. Controls received equal volumes of normal saline. Lung and intestinal injury was quantitated using an edema index. Bile flow was quantitated by measuring the volume of bile produced per 15 min. The intestinal edema index of IIR animals pretreated with PMB was nearly 50% less than that of saline-treated animals sustaining the same injury (P < 0.05). The induction of LPS tolerance reduced the edema index of IIR animals by 28% compared to the saline-treated IIR group (P < 0.05). Neither treatment reduced this parameter to that of sham-operated controls (P < 0.05). The lung edema index of animals pretreated with PMB was 50% of that of saline-treated IIR animals (P < 0.05). This remained significantly greater than that of sham-operated controls (P < 0.05). LPS tolerance did not affect the lung edema index of animals sustaining IIR. Bile flow rates following IIR were not significantly affected by PMB or LPS tolerance. These data do not support the hypothesis that LPS is an important proximal mediator of the remote organ injury associated with IIR. However, they do suggest that LPS may be one of many mediators responsible for this injury.

This study examines the relationship between hypovolemia and remote organ injury following intestinal reperfusion. Sprague-Dawley rats underwent intestinal ischemia (120 min) and reperfusion (90 min, IIR) or sham operation (CTL). The animals received normal saline (NS) at 0, 30, or 40 ml/kg/h intravenously. Lung and intestinal injury was quantitated using an edema index, and liver injury was assessed by measuring bile flow rates. The infusion of 40 ml/kg/h of NS attenuated the intestinal edema index of IIR animals nearly 50% (p < .05). Despite this improvement, this parameter remained nearly 10-fold greater than that of CTL (p < .05). The lung edema index was 70% greater in IIR animals receiving 30 and 40 ml/kg/h of NS than those not receiving NS. The infusion of 40 ml/kg/h of NS restored bile flow rates in IIR animals to that of CTL. These data suggest that hypovolemia may contribute to the intestinal and hepatic injury in this model. The lung injury is independent of hypovolemia.

Parenchymal injury following reperfusion of the donor lung remains a significant problem in clinical lung transplantation. It has been postulated that free oxygen radicals act as local mediators of this event, and that tissue oxidized glutathione levels which reflect local free oxygen radical production, may be useful as an indicator of this regional ischemia-reperfusion injury. The glutathione redox cycle plays a physiologically important role in the endogenous antioxidant defense system. Intracellular glutathione depletion has been shown to render cells vulnerable to oxidant mediated injury. Adequate glutathione stores may be vital in protecting the cell from oxidant injury, especially the relatively exposed pulmonary epithelial cells. Single lung transplantation was carried out in 10 3- to 5-kg mongrel puppies, with a standard 2-hour ischemic time for the donor lung prior to reimplantation. Four hours following transplantation, lung tissue was harvested from both the transplanted and native lung of the recipient animal, and compared to normal lung tissue from the donor animal. Tissue was prepared for histological evaluation and glutathione assay. Tissue glutathione levels were determined via a spectrophotometric assay. For determination of oxidized glutathione (GSSG), samples were prepared with 2-vinylpyridine and N-ethylmaleimide (NEM) to derivatize all reduced glutathione and leave only GSSG for measurement by the fluorometric assay.(ABSTRACT TRUNCATED AT 250 WORDS)

In this study we tested the hypothesis that neutrophil products are present in ischemic skin flaps and that they are abolished with preconditioning of the skin. Random back flaps were created on rats, and the sequential appearance of neutrophil products and tissue oxidants was measured in the skin flaps. These flaps had predictable skin necrosis (4.7 +/- 0.8 cm) in the distal ends, while preconditioned flaps had no skin necrosis. Neutrophil products were assayed by both histomorphometrics and myeloperoxidase assays. Lipid peroxidation products were measured to assess tissue oxidant production. These data demonstrate that there is an increase in myeloperoxidase activity in skin flaps that is statistically significantly greater in the distal ends of the flaps at 24 hours (p < 0.05). The lipid peroxidation products were statistically significantly elevated at 48 hours in the distal ends (p < 0.05). Preconditioning the skin as a bipedicled skin flap for 7 days and then dividing the distal attachment abolished neutrophil products and tissue oxidant activity in the skin flaps (p < 0.05). These data suggest that neutrophil products and oxidant production are increased in ischemic skin and that preconditioning of the flap markedly attenuates this response.

Cyclosporine immunosuppression remains vital for successful lung transplantation. Cyclosporine also functions as a membrane active biological response modifier and has been noted to have a variable effect on ischemia-reperfusion (I/R) injury in various tissues. Glutathione plays an important role in the endogenous antioxidant defense system; plasma oxidized glutathione (GSSG) levels are useful as a sensitive indicator of in vivo oxidant stress and I/R injury. Lung transplantation results in ischemia, followed by a period of reperfusion, potentially producing functional injury. This study was designed to evaluate the effect of cyclosporine on oxygen radical generation in a model of single-lung transplantation. Single-lung transplantation was performed in 12 mongrel puppies, with animals assigned to receive either intravenous or aerosolized cyclosporine. Arterial blood and bronchoalveolar lavage fluid (BALF) samples were obtained to determine GSSG levels via a spectrophotometric technique. Samples were obtained both prior to and following the revascularization of the transplanted lung. Whole blood and tissue cyclosporine levels were determined via an high-performance liquid chromatography technique 3 hr following the completion of the transplant. Aerosolized cyclosporine administration resulted in greatly decreased arterial plasma and BALF GSSG levels, whole blood cyclosporine levels, and equivalent tissue cyclosporine levels when compared to intravenous cyclosporine delivery. These findings support the hypothesis that the transplanted lung is a source of GSSG production and release into plasma. Additionally, these findings suggest that cyclosporine may have a direct antioxidant effect on pulmonary tissue, with this activity occurring at the epithelial surface, an area susceptible to oxidant injury.

Intestinal ischemia-reperfusion is a common clinical event associated with both clinical and experimental distant organ injury. In particular, the pulmonary microvasculature appears to be susceptible to injury resulting from systemic inflammatory mediator activation. This study was designed to evaluate the hypothesis that noncellular humoral factors associated with intestinal ischemia-reperfusion result in pulmonary endothelial cell adenosine triphosphate (ATP) depletion. Male Sprague-Dawley rats had intestinal ischemia induced by microvascular clip occlusion of the superior mesenteric artery (SMA) for 120 minutes. Reperfusion resulted from superior mesenteric artery clip removal. After reperfusion for 0, 15, or 30 minutes, plasma samples were obtained from the portal vein. Monolayers of cultured rat pulmonary artery endothelial cells then were incubated with the plasma samples. Adenosine triphosphate levels were determined using a luciferin-luciferase assay. A 51Cr-release assay using labeled endothelial cells was performed under identical conditions to assess cytotoxicity. Potential mechanisms of ATP depletion were evaluated by analysis of cellular energy charge and assessment of microfilament architecture. Endothelial cell ATP levels decreased from 2.23 +/- 0.16 x 10(-11) moles/microgram DNA in sham preparations to 1.23 +/- 0.09 x 10(-11) moles/microgram DNA (p < 0.001) after 4 hours in plasma from animals undergoing 120 minutes of intestinal ischemia. For plasma obtained after 15 minutes of reperfusion, the decrease in cellular ATP concentration persisted (1.23 +/- 0.27 x 10(-11) moles/microgram DNA, p < 0.001 vs. sham). After 30 minutes' reperfusion, cellular ATP levels increased only slightly after the 4-hour incubation (1.39 +/- 0.26 x 10(-11) moles/microgram DNA, p < 0.005 vs. sham). No significant cytotoxic injury occurred in any group when compared with controls. Cellular energy charge was unchanged, and microfilament architecture was preserved. These data confirm the hypothesis that humoral factors, independent of the neutrophil, result in endothelial cell ATP depletion without metabolic inhibition or cell death. Depletion of energy stores by noncellular humoral factors may represent an early event that predisposes the cell to more severe injury by other mediators of the endogenous inflammatory response.

Multiple organ failure (MOF) is known to follow systemic inflammatory mediator activation associated with intestinal ischemia-reperfusion injury. In particular, the pulmonary microvasculature appears to be susceptible to MOF-related injury. This study was designed to evaluate the hypothesis that non-cellular plasma factors associated with intestinal ischemia without reperfusion also mediate pulmonary endothelial cell injury. Male Sprague-Dawley rats had intestinal ischemia induced by microvascular clip occlusion of the superior mesenteric artery for 30, 60, 90, or 120 min. Following each period of ischemia, plasma samples were obtained from the protal vein. Time-matched sham-operated animals served as controls. Monolayers of cultured rat pulmonary artery endothelial cells were then incubated with the plasma samples and ATP levels determined using a luciferin-luciferase assay. A 51Cr-release assay using labeled endothelial cells was performed under identical conditions to assess cytotoxicity. Endothelial cell ATP levels were 1.99 +/- 0.23 x 10(-11) mole/micrograms DNA in sham preparations. After a 4-hr incubation in plasma from the 90 and 120 min ischemia groups, cellular ATP levels fell significantly to 1.07 +/- 0.23 x 10(-11) mole/micrograms DNA, respectively (P less than 0.005). No significant cytotoxic injury resulted from incubation with plasma from the 120 min group (1.0 +/- 0.4% versus 0.8 +/- 0.4% in sham group, P = NS). All animals survived 24 hr in the sham, 30, and 60 min groups. However, survival was 40 and 0% in the 90 and 120 min groups, respectively (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Reperfusion of ischemic intestine results in acute liver dysfunction characterized by hepatocellular enzyme release into plasma, reduction in bile flow rate, and neutrophil sequestration within the liver. The pathophysiology underlying this acute hepatic injury is unknown. This study was undertaken to determine whether oxidants are associated with the hepatic injury and to determine the relative value of several indirect methods of assessing oxidant exposure in vivo. Rats were subjected to a standardized intestinal ischemia-reperfusion injury. Hepatic tissue was assayed for lipid peroxidation products and oxidized and reduced glutathione. There was no change in hepatic tissue total glutathione following intestinal ischemia-reperfusion injury. Oxidized glutathione (GSSG) increased significantly following 30 and 60 min of reperfusion. There was no increase in any of the products of lipid peroxidation associated with this injury. An increase in GSSG within hepatic tissue during intestinal reperfusion suggests exposure of hepatocytes to an oxidant stress. The lack of a significant increase in products of lipid peroxidation suggests that the oxidant stress is of insufficient magnitude to result in irreversible injury to hepatocyte cell membranes. These data also suggest that the measurement of tissue GSSG may be a more sensitive indicator of oxidant stress than measurement of products of lipid peroxidation.

The pathogenesis of acute pancreatitis is incompletely defined, but the outcome is determined in part by an acute inflammatory process. Pancreatitis-associated inflammation appears to play a role in the local retroperitoneal injury as well as in the associated dysfunction of remote organs such as the lung. Tumor necrosis factor (TNF) appears to be a proximal mediator of the inflammatory response. In this study, anti-TNF antibody was administered to rats with caerulein-induced pancreatitis to determine if the observed increases in pancreatic and pulmonary microvascular permeability were related to plasma TNF activity. In contrast to the expected findings, blockade of TNF activity was found to increase the amount of edema formation in both the pulmonary and pancreatic microvascular beds. The mechanism is not known; however, blockade of TNF-induced down regulation of phagocytic cell activity, ablation of TNF-dependent feedback inhibition of other cytokines, failure of induction of endogenous antioxidant systems, or inactivation of the TNF control of microvascular tone are all possible explanations. This is potentially an important observation as clinical strategies are now being developed to modify the inflammatory response in ways presumed advantageous to an injured host.

Noninfectious obliterative cholangitis results from biliary tract inflammation in clinical conditions such as biliary atresia and sclerosing cholangitis. The purpose of this study was to develop an animal model of noninfectious biliary tract inflammation and fibrosis. An implantable osmotic pump was connected to a catheter placed into the gallbladder of hamsters. Phorbol myristate acetate (PMA) was infused into the biliary tract for periods of 6 hours to 28 days. After 7 days the animals developed neutrophil infiltration, cellular necrosis, and edema of the biliary ducts. After 14 days, the animals demonstrated intrahepatic cholestasis with bile duct fibrosis and acute and chronic inflammatory cell infiltration. By 28 days pronounced portal fibrosis was present, some of which created an early bridging cirrhosis pattern. In addition there was evidence of neocholangiogenesis. We conclude that long-term PMA infusion into the biliary tract generates an inflammatory response characterized by obliterative cholangitis and fibrosis, sharing many of the histologic features of human biliary atresia. This model may provide a relatively simple technique for investigating the process of nonpyogenic biliary tract inflammation.

Acute lung injury characterized by increased microvascular permeability is one feature of multiple-organ system failure and the adult respiratory distress syndrome. Intestinal ischemia-reperfusion injury has been linked to this type of acute lung injury. The purpose of these experiments was to examine the pathogenic mediators that link the two processes, with particular emphasis on the roles of endotoxin and tumor necrosis factor alpha (TNF alpha). Previously described characteristics of the acute lung injury in this rat model of intestinal ischemia-reperfusion include pulmonary neutrophil sequestration, depletion of lung tissue ATP, alveolar endothelial cell disruption, and increased microvascular permeability. Plasma levels of TNF in the systemic circulation of sham-operated animals and those with intestinal ischemic injury less than 60 minutes in duration were very low or undetectable. Intestinal ischemia for 120 minutes was associated with TNF elevation to 1.19 +/- 0.50 U/mL. Reperfusion for periods of 15 and 30 minutes generated 5- to 10-fold increases in circulating TNF levels (6.61 +/- 3.11 U/mL, p greater than 0.05 and 10.41 +/- 5.41 U/mL, p = 0.004 compared to sham); however this increase in circulating TNF was transient and largely cleared within 60 minutes after initiating reperfusion. Portal vein endotoxin levels were found to increase significantly before the appearance of TNF in systemic plasma, suggesting that gut-derived endotoxin may induce TNF release from hepatic macrophages into the systemic circulation. Anti-TNF antibody attenuated the increase in pulmonary microvascular permeability in this preparation but did not prevent pulmonary neutrophil sequestration. These observations suggest that endotoxin and TNF have pathogenic roles in this acute lung injury, but that mechanisms of adherence of neutrophils to endothelial cells independent of TNF may be involved. The accumulation of neutrophils in the lung but the prevention of a vascular permeability increase in the presence of antibody to TNF may imply an in vivo role for TNF in the process of neutrophil activation. These studies provide additional evidence of the importance of the endogenous inflammatory mediators in the development of systemic injury in response to local tissue injury.

Neutrophil-related, oxidant-mediated injury to the pulmonary microvasculature appears to follow endotoxemia, cutaneous thermal injury, and ischemia-reperfusion injury to the liver or intestine. Glutathione is an important endogenous intracellular oxygen radical scavenger. Plasma concentrations of oxidized glutathione (GSSG) reflect oxidant injury resulting from an overdose of certain oxidatively metabolized drugs. The purpose of this investigation was to evaluate plasma GSSG as an indicator of oxidant stress resulting from activation of the endogenous inflammatory response. An established model of neutrophil- and oxidant-related acute lung injury following intestinal ischemia and reperfusion in rats was used. Intestinal ischemia was induced by clip occlusion of the superior mesenteric artery (SMA) for 120 min. Reperfusion resulted from SMA clip removal. Following reperfusion for 0, 15, or 120 min, plasma GSSG levels in portal vein, inferior vena cava (IVC), and aorta were obtained. Plasma GSSG was undetectable in sham animals and those with intestinal ischemia alone. Following reperfusion, all plasma samples had significant elevations in GSSG. Aortic plasma GSSG after 15 min of reperfusion was significantly elevated compared to both portal vein and IVC plasma GSSG. These data suggest that oxidant stress after intestinal reperfusion is reflected by elevations in plasma GSSG. The step up in plasma GSSG across the pulmonary vascular bed, a site of known oxidant injury, suggests that plasma GSSG may be a useful marker of oxidant stress in vivo, particularly with regard to the pulmonary microvasculature. This simple in vivo approach to assessing oxidant stress related to inflammatory tissue injury may have the potential to be of significant use in the clinical setting.

Xanthine oxidase (XO)-derived oxygen radicals are thought to play an important role in the intestinal injury resulting from ischemia and reperfusion. In vitro data shows enhanced XO activity in the presence of histamine. Histamine is known to be released during intestinal ischemia and reperfusion. The purpose of this study was to evaluate the relationship between histamine and XO in vivo in intestinal ischemia/reperfusion injury. Using an established model of gut ischemia and reperfusion, portal venous plasma was obtained and assayed for histamine levels, XO activity, and xanthine dehydrogenase (XD) activity following injury. Intestinal ischemia for 120 minutes resulted in a 200% increase in plasma histamine levels (263.4 +/- 36.9 nmol/mL control, v 548.7 +/- 35.1 nmol/mL experimental, P less than .05). Reperfusion for 15 minutes resulted in a further increase in plasma histamine (to 658.3 +/- 33.9 nmol/mL), compared with 120 minutes of ischemia alone. No significant change in plasma XO activity resulted after simple ischemia for 120 minutes. However, XO activity doubled within 15 minutes of reperfusion of the ischemic intestine (6.37 +/- 0.53 nmol O2- per milliliter per minute v 3.12 +/- 0.25 nmol O2- per milliliter per minute, P less than .05). Reperfusion for 60 minutes resulted in the maximal observed increase in plasma XO activity (9.49 +/- 0.67 nmol O2- per milliliter per minute). Analysis of XD activity demonstrated no significant decrease compared with controls until 120 minutes of ischemia and 60 minutes of reperfusion (1.62 +/- 0.49 nmol uric acid per milliliter per minute at 60 minutes of reperfusion, versus 5.02 +/- 0.52 nmol uric acid per milliliter per minute control, P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

The large mass of fixed macrophages resident in the liver make it a potentially rich source of cytokines. We have previously demonstrated that an isolated and severe ischemia/reperfusion injury to the liver results in cytokine release, specifically tumor necrosis factor alpha, and that TNF is then involved in the development of pulmonary pathology. This study was designed to determine the kinetics of TNF release following varying periods of hepatic ischemia and to further investigate the acute lung injury that follows. Suprahepatic blood samples were obtained at serial time points following a 45-, 60-, 75-, or 90-min ischemic insult to a segment of the rat liver with subsequent reperfusion. Using a bioassay based on the WEHI 164 cell line, plasma TNF levels were measured in all experimental animals; sham-operated control animals had undetectable levels. Changes in pulmonary capillary permeability were then measured using a standard 125I-labeled albumin washout technique following a 90-min ischemic insult with subsequent reperfusion. A significant increase in the mean permeability index was observed 9 to 12 hr following hepatic reperfusion (.601 +/- 102 as compared with .114 +/- .085 in sham-operated controls, P less than 0.005). Animals treated with anti-TNF antiserum prior to the induction of hepatic ischemia had a significantly reduced pulmonary capillary leak compared to animals pretreated with rabbit serum without TNF-blocking properties (.184 +/- .029 versus .694 +/- 052 for the control serum, P less than 0.005). TNF release follows both moderate and severe ischemic injury to the liver and the results reported here implicate TNF as an important mediator of increased pulmonary capillary permeability. These experiments confirm previous histologic studies that demonstrated pulmonary edema and intra-alveolar hemorrhage following hepatic ischemia/reperfusion, with subsequent blockade of the histologic injury by pretreatment with anti-TNF antiserum.

Advances in chemotherapy have improved survival in patients with hematological malignancies, solid tumors, and have allowed for rapid progress in the field of organ transplantation. However, the frequency of opportunistic, specifically mycotic, infections has risen and provides a new challenge in the treatment of these patients. The following case report illustrates the need for early diagnosis and treatment and is the first known case reported of fatal hemorrhagic pancreatitis secondary to disseminated aspergillosis.

Cerulein-induced acute pancreatitis in rats is associated with acute lung injury characterized by increased pulmonary microvascular permeability, increased wet lung weights, and histologic features of alveolar capillary endothelial cell and pulmonary parenchymal injury. The alveolar capillary permeability index is increased 1.8-fold after a 3-hour injury (0.30 to 0.54, p less than 0.05). Gravimetric analysis shows a similar 1.5-fold increase in wet lung weights at 3 hours (0.35% vs. 0.51% of total body weight, p less than 0.05). Histologic features assessed by quantitative morphometric analysis include significant intra-alveolar hemorrhage (0.57 +/- 0.08 vs. 0.12 +/- 0.02 RBC/alveolus at 6 hours, p less than 0.001); endothelial cell disruption (28.11% vs. 4.3%, p less than 0.001); and marked, early neutrophil infiltration (7.45 +/- 0.53 vs. 0.83 +/- 0.18 PMN/hpf at 3 hours, p less than 0.001). The cerulein peptide itself, a cholecystokinin (CCK) analog, is naturally occurring and is not toxic and in several in vitro settings including exposure to pulmonary artery endothelial cells, Type II epithelial cells, and an ex vivo perfused lung preparation. The occurrence of this ARDS-like acute lung injury with acute pancreatitis provides an excellent experimental model to investigate mechanisms and mediators involved in the pathogenesis of ARDS.