Acute lung injury following pancreas ischaemia-reperfusion: role of xanthine oxidase.

BACKGROUND: Acute pancreatitis can lead to increased pulmonary vascular permeability and respiratory failure. Oxidants (and their generator, xanthine oxidase (XO)) play an important role in injuring the structural integrity of the pulmonary epithelium and endothelium, but their importance in the induction of acute lung injury following pancreas ischaemia-reperfusion (IR) has not been defined. MATERIALS AND METHODS: Rats (n = 48) received a regular or a tungsten (oxidoreductase inhibitor)-enriched diet for 14 days. Their isolated pancreases were then either perfused (controls) or made ischaemic (IR) for 40 min (12 replicates/group). This was followed by in-series pancreas plus normal isolated lung reperfusion for 15 min. Lungs only were subsequently perfused with the 15-min accumulated pancreas effluents for 45 min. RESULTS: Injury was induced in all IR pancreases as expressed by reperfusion pressure, wet-to-dry ratio and amylase and lipase concentrations. Tissue XO activity was high and reduced glutathione pool was low in the tungsten-free IR pancreases. Pulmonary plateau pressure increased by 46% and final PO(2)/FiO(2) decreased by 24%. Capillary pressure and weight rose two- to fourfold in lungs paired with IR non-treated pancreases. Twofold increases in bronchoalveolar lavage volume and contents, including XO, were also recorded in this group of lungs. Lungs exposed to tungsten-treated ischaemic pancreas effluents were minimally damaged and tissue XO content was low compared to controls. CONCLUSIONS: Ex-vivo acute pancreatitis induces acute lung injury via oxidants/antioxidants misbalance, which may be prevented by attenuating pancreas oxidative stress.

The midazolam-induced paradox phenomenon is reversible by flumazenil. Epidemiology, patient characteristics and review of the literature.

BACKGROUND AND OBJECTIVE: Midazolam may occasionally precipitate hostility and violence instead of tranquility. We characterized these episodes, their rate of occurrence, the potential paradoxical responders and possible predisposing circumstances among patients undergoing lower body surgery under spinal or epidural anaesthesia and midazolam sedation. PATIENTS AND METHODS: Fifty-eight patients who fulfilled the study entry criteria and who underwent surgery within a 3-month period in a large metropolitan, university-affiliated hospital were enrolled. Sedation and restlessness in all patients were controlled by midazolam administered intravenously by the attending anaesthesiologist; these parameters were later objectively confirmed by recorded actigrams. If "paradoxical" events occurred, flumazenil 0.1 mg 10 s-1 was injected until the aberrant behaviour ceased. Patients with paradoxical reactions were later compared with matched control patients selected from the study group to identify epidemiological characteristics. RESULTS: The incidence of paradoxical events was 10.2% (six out of 58 patients, confidence limits 2.3-18.3%) and they occurred 45-210 min after sedation started; the only independent predictor was an age older than that of the entire study group. The mean cumulative and per weight doses of midazolam were similar for both the experimental and the study groups of patients: 7.3 +/- 2.8 to 10.1 +/- 3.6 mg, and 0.1 +/- 0.04 to 0.12 +/- 0.05 mg kg-1. Flumazenil 0.2-0.3 mg (range 0.1-0.5 mg) effectively stopped the midazolam-induced paradoxical activity within 30 s and surgery continued uneventfully. CONCLUSIONS: Flumazenil completely reverses midazolam-induced paradoxical reactions and they are more frequent in older patients.

Selective attenuation of acute lung ventilatory injury by methylene blue after liver ischemia-reperfusion: a drug response study in an isolated perfused double organ model.

BACKGROUND: Liver transplantation-related ischemia-reperfusion (IR) is associated with the generation of stress oxidants that can spread damage remotely. Methylene blue (MB) had been shown to reduce lung neutrophils sequestration after in vivo intestinal IR and to have a dose-dependent potential for abrogating oxidant-induced ex vivo aortal ring reperfusion injury after liver IR. We now investigated MB's dose-dependent capabilities in preventing acute lung injury after the same liver IR. METHODS: Wistar rat livers (eight replicates/group) were perfused (control) with modified Krebs-Henseleit solution or put globally in no flow (IR) conditions for 2 hr. Separately prepared lungs were then paired with livers and "reperfused" (15 min) together. The livers were then removed, and the lungs were left to recirculate alone with the accumulated Krebs for 45 min. Three additional control and three IR groups were reperfused with Krebs containing 20, 40, or 60 mg/kg MB at concentrations of 42, 86, or 128 microM. RESULTS: All IR livers had hepatocellular and biochemical abnormalities compared with normal functions in the controls. Liver IR was associated with a 50%-75% increase in lung ventilation and perfusion pressures, vascular resistance and decreased compliance, and abnormal bronchoalveolar lavage (BAL) volume and content. Adding 42 and 86 microM MB selectively maintained normal the vascular parameters, intra-experimental lung weight gain, BAL indices, and wet-to-dry ratios. MB128 microM but not 42 or 86 microM best prevented IR-induced deterioration in lung ventilatory pressure and compliance. CONCLUSIONS: MB selectively affords maintenance of normal lung ventilatory versus vascular measures after liver ischemia-reperfusion. Its proposed differential mechanism of action is discussed.

Role of the molecular adsorbent recycling system (MARS) in the treatment of patients with acute exacerbation of chronic liver failure.

OBJECTIVE: To test the efficacy of the molecular adsorbent recycling system (MARS) in patients with acute exacerbation of chronic liver disease. DESIGN: A prospective case analysis. SETTING: A university-affiliated tertiary medical center. PATIENTS AND METHODS: We applied MARS to treat a consecutive series of eight patients with acute exacerbation of chronic liver disease. RESULTS: The overall survival rate was 62.5%. All patients demonstrated improvement with regard to their degree of encephalopathy. In three patients, intracranial pressure and jugular bulb oxygen saturation decreased and cerebral perfusion pressure increased after treatment institution. Patients' hyperdynamic state was attenuated, as demonstrated by elevation of systemic vascular resistance, mean arterial pressure, and parallel reduction in cardiac index. A prompt reduction in serum ammonia, bilirubin, and lactate levels was observed. There were no complications during the treatment period. CONCLUSIONS: Applying MARS treatments to patients with acute exacerbation of chronic liver disease can detoxify blood, improve cerebral circulation, and reduce brain edema, as reflected by the reduction in intracranial pressure and jugular bulb oxygen saturation values in our patients. A partial reversal of the characteristic hyperdynamic circulation was also achieved. Despite our encouraging results, further testing is needed to determine the reliability of the system.

Antagonization of TNF attenuates systemic hemodynamic manifestations of envenomation in a rat model of Vipera aspis snakebite.

OBJECTIVES: Tumor necrosis factor (TNF) has been reported as a mediator of local tissue injury following snake envenomation in an intact rat model. We investigated whether systemic release of TNF occurs following Vipera aspis envenomation. We further analyzed the possible connection between envenomation-related hemodynamic depression and TNF antagonization (TNF antibodies or soluble TNF receptor). DESIGN: A prospective, randomized, controlled experimental study using a rat model for snake envenomation. SETTINGS: A medical university hospital research laboratory. INTERVENTION: Eighty rats (300-400 g) were divided into four groups (n = 20): control and three experimental groups. Intramuscular injection of V. asis 500 microg/kg was administered to the three experimental groups: venom only (group 1), venom and 40 microg anti-TNF antibodies (group 2), venom and 250 microg soluble TNF receptor (p55-R; group 3). Hemodynamic parameters were monitored up to 4 h following venom injection. MEASUREMENTS AND RESULTS: A significant hemodynamic deterioration (reduction in heart rate and blood pressure) occurred 30 min following venom injection in group 1 compared to groups 2 and 3, where hemodynamic parameters remained stable throughout the 4 h observation period. Serum levels of TNF were detected 15 min after venom injection and peaked after 2 h at 485+/-12 pg/ml. CONCLUSIONS: The hemodynamic consequences of intramuscular injection of V. aspis venom can be blunted in a rat by systemic antagonization of TNF activity prior to venom injection. The poisonous hemodynamic effects of the V. aspis venom might be caused by systemic release of TNF.

Liver support systems.

In recent years liver transplantation was shown to be the only clinically effective method of treating acute or chronic hepatic failure due to various causes. However, this ultimate therapeutic approach is limited by the growing disparity between organ donation and the number of patients on the waiting list. Factors such as high cost, morbidity, and the need for lifelong immunosuppression accelerated the research on alternative methods to support the failing liver. Recently, new technologies incorporating hepatocytes and extracorporeal circulation devices were introduced for liver support. This review presents current knowledge on liver support systems and their role in the treatment of acute liver failure.

Xanthine oxidase and tumor necrosis factor alpha: possible mediators of remote tissue injury after viper envenomation.

BACKGROUND: Tumor necrosis factor is associated with various local and systemic inflammatory sequelae following snakebite. Xanthine oxidase is a principal mediator of remote tissue injury (e.g., lungs, heart, liver). OBJECTIVE: To investigate in a snakebite-like animal model the as yet unexplored role of TNF and XO in mediating organ damage following snakebite. METHODS: Sprague-Dawley rats were injected intramuscularly with a non-lethal 500 micrograms/kg dose of Vipera aspis venom (n = 10) or saline (n = 10). Blood pressure and heart rate were continuously monitored, TNF-alpha was measured in the blood, and total XO + xanthine dehydrogenase activity was assessed in various tissues. Lung histology and permeability indices were analyzed. RESULTS: Venom injection caused a significant (P < 0.05) reduction in both heart rate and invasive arterial pressure. The blood circulating TNF levels were significantly higher in the intoxicated group (P < 0.05 vs. saline group), with changes seen at 30 minutes from intoxication in both groups. Total XO + XDH activity in the kidney, lung and liver of the venom-injected group was significantly (P < 0.05) higher than in the saline group, while the activity in the heart was similar. CONCLUSIONS: The mediation of remote organ and hemodynamic changes following intramuscular injection of a non-lethal dose of Vipera aspis venom can be attributed partly to TNF and partly to XO. More research is needed to better understand the role of either compound and the time frame of their activity before specific antagonists can be introduced for snakebite management.

Kerosene-induced severe acute respiratory failure in near drowning: reports on four cases and review of the literature.

OBJECTIVE: The purpose of this study is to present an unusual respiratory and cardiovascular course after intoxication and near drowning in a river contaminated with kerosene. DESIGN: Case reports and review of the literature. SETTING: Intensive care unit of a university-affiliated hospital. PATIENTS: Four patients after near drowning. INTERVENTION: Supportive only. RESULTS: The four patients developed acute respiratory failure. Cardiomyopathy was present in three patients and a persistent hypokalemia in two patients. The onset of the symptoms was delayed, which led to underestimation of the severity of their illness. Two of the four patients died. The diagnosis of hydrocarbon intoxication was based on bronchoalveolar lavage results, neutrophilic alveolitis with the presence of lipid-laden macrophages, and evidence of lipoid pneumonia from the autopsy performed on one victim. One patient who clinically deteriorated and another who developed a severe restrictive pulmonary disorder were treated with corticosteroids, which were effective only in the latter patient. CONCLUSIONS: Acute kerosene intoxication in a near-drowning event often results in severe respiratory and cardiac failure, with a high fatality rate. Treatment with corticosteroids may lead to a rapid improvement in lung function.

Cross-sensitivity between isoflurane and diazepam: evidence from a bidirectional tolerance study in mice.

We examined in mice the effect of chronic diazepam treatment on the sensitivity to isoflurane, and that of repeated isoflurane exposure on the sensitivity to diazepam. Mice were divided into four groups: group 1, treated with diazepam, 10 mg/kg i.p. twice daily; group 2, vehicle-treated controls; group 3, exposed to 3% isoflurane for 25 min twice daily; and group 4, untreated controls. After 14 days the effect of the treatment was assessed. Twenty-four hours after the last 10 mg/kg diazepam treatment, groups 1 and 2 received diazepam, 5 mg/kg i.p., and were subjected to the horizontal wire test (HWT). All control mice but only 10% of the diazepam-treated mice failed the HWT. Groups 1 and 2 were then exposed to increasing concentrations of isoflurane. Diazepam-treated mice (group 1) lost the HWT at 0.7+/-0.7%, compared with 0.6+/-0.1% in controls (group 2) (P<0.001); the ED50 was 0.75% vs. 0.65%. Group 1 mice lost the righting reflex at 0.94+/-0.07% isoflurane vs. 0.87+/-0.06% in group 2 (P<0.01); the ED50 was 0.93% vs. 0.82%. Recovery time was 175+/-161 s in group 1 vs. 343+/-275 s in group 2 (P<0.02). Twenty-four hours after the last of the repeated exposures to isoflurane, we examined the responses of groups 3 and 4 to increasing concentrations of isoflurane. Mice in group 3 lost the righting reflex at 1.0+/-0.06% isoflurane vs. 0.9+/-0.04% in controls (group 4) (P<0.001); the ED50 was 0.96% vs. 0.85%. Recovery time was 113+/-124 s vs. 208+/-126 s in groups 3 and 4 (P<0.09). Diazepam, 3 mg/kg i.p. administered to groups 3 and 4, caused loss of the HWT reflex in 33% of group 3 mice and in 82% of controls (group 4) (P<0.001). It appears that prolonged exposure to both diazepam and isoflurane caused reduced sensitivity to each drug separately, as well as to the other drug. This finding may strengthen the theory that inhalational anesthetics may act via the same mechanism as the benzodiazepines.

[Severe heat stroke in an intensive care unit: course of the disease in the intensive care unit, and early and subsequent treatment results].

During the August 1998 heat wave in Tel Aviv we admitted many patients for acute heat-related illness; 6 had severe heat stroke and were admitted in critical condition. We describe their clinical courses during the first 5 days of hospitalization, including response to treatment and implications for future management of this disorder. The mean APACHE II score of the 6 was 30 +/- 3.5 and mean Glasgow Coma Scale rating 3.5 +/- 0.5; they were in hypovolemic shock and respiratory failure, necessitating mechanical ventilation. Despite early effective therapy (core temperature in all was reduced to less than 39 degrees C in less than 1 hour), there was 1 death (mortality 15%) and 4 required further intensive care for life-threatening multiple organ failure. During severe heat waves a significant number of referrals for acute heat-related illness must be anticipated, possibly overwhelming admission capacity of regional intensive-care units. Severe heat stroke complicated by multi-organ failure is not necessarily related to prior physical activity. Although important in determining prognosis, early treatment does not prevent severe complications. Mechanisms regulating body heat may remain disturbed for days following early treatment and apparent stabilization, mandating continued hospitalization.

[Injuries due to falls in urban buses: 100 consecutive cases].

We reviewed the charts of 100 consecutive emergency department (ED) cases of injuries in public buses (not due to actual traffic accidents) seen during 7 months in 1995. There were 29 males and 71 females with a mean age of 55.6 +/- 21.4 years, median 60, and range 13-91. 92 were discharged home directly from the ED. 3 were admitted to general surgical wards, and 1 each to the orthopedic, medical and neurosurgical wards, while 2 soldiers were sent for observation to a military clinic. There were 28 spinal column, 27 head and 25 chest injuries; 1 patient died. There were no significant differences in admissions during the months of the year. 58% of injuries occurred during normal working hours, with a peak incidence at about 1000 hrs. The most common cause was falling while standing, due to sudden acceleration/deceleration or sharp turns. There are 1900 buses in Tel Aviv which carry 1.1 million passengers daily and most of which are capable of significant acceleration. A high proportion of passengers travel standing, and elderly passengers are more liable to fall when the bus accelerates, decelerates or turns. We calculate a potential national yearly bus injury toll from falls of more than 1000, which often result in significant morbidity and even mortality. A national survey is now being planned.

Methylene blue prevents pulmonary injury after intestinal ischemia-reperfusion.

OBJECTIVE: To investigate the effect of methylene blue, an inhibitor of oxygen radicals, on lung injury caused by reperfusion of ischemic tissue. METHODS: Intestinal ischemia-reperfusion injury was induced in rats by clamping the superior mesenteric artery for 1 hour. Thereafter, the experimental group was administered 1% methylene blue intraperitoneally and the control group received saline. After 4 hours, pulmonary histopathologic features were assessed, and lung wet-weight to dry-weight ratios and tissue xanthine oxidase were determined. RESULTS: The control group suffered from severe pulmonary parenchymal damage, compared with slight damage in the experimental group. The number of sequestered neutrophils was significantly higher in the control group (319 +/- 60 polymorphonuclear cells per 10 high-power fields) than in the methylene blue-treated group (91 +/- 8 polymorphonuclear cells per 10 high-power fields; p < 0.001). The wet-weight to dry-weight ratio was significantly increased in the saline-treated rats compared with the methylene blue-treated group (6.19 +/- 0.28 vs. 5.07 +/- 0.21; p < 0.001). Xanthine oxidase activity was similar in both groups. CONCLUSION: Methylene blue attenuated lung injury after intestinal ischemia-reperfusion. Inhibition of oxygen free radicals may be the protective mechanism.

Permissive hypercapnia ventilation in patients with severe pulmonary blast injury.

OBJECTIVES: To describe our experience with the use of limited peak inspiratory pressure (PIP), volume-controlled ventilation, and permissive hypercapnia in patients with severe pulmonary blast injury. METHODS: Patients with pulmonary blast injury were ventilated using volume-controlled, synchronized intermittent mandatory ventilation. Whenever PIP exceeded 40 cm H2O, the tidal volume was decreased to maintain PIP at less than 40 cm H2O. Whenever the arterial pH fell below 7.2, the ventilator rate was increased in increments of 2 breaths per minute until the arterial pH rose to 7.25. RESULTS: Between 1994 and 1996, 17 patients with severe pulmonary blast injury (10 from enclosed space explosions and seven from open space ones), requiring mechanical ventilatory support were admitted to our intensive care unit. Four patients developed increasing PaCO2 levels (to 93 +/- 12 mm Hg) associated with the reduction in arterial pH that was corrected by increasing the ventilator rate. There was evidence of ventilator-induced pulmonary barotrauma. Of the 17 patients, 15 patients (88%) survived. CONCLUSIONS: Limited PIP in a volume-controlled ventilation is a useful and safe mode of mechanical ventilation in patients with pulmonary blast injury.

A risk-benefit assessment of flumazenil in the management of benzodiazepine overdose.

The worldwide expansion in the use of benzodiazepines has led to their frequent, and often inappropriate, use and to increase in their involvement in self-induced poisoning and iatrogenic overdosing. Flumazenil is a specific and competitive antagonist at the central benzodiazepine receptor, reversing all effects of benzodiazepine agonists without tranquillising or anticonvulsant actions. Incremental intravenous bolus injections of flumazenil 0.1 to 0.3 mg are the most effective and well tolerated in the diagnosis and treatment of pure benzodiazepine overdose; additional boluses or an infusion (0.3 to 0.5 mg/h) can be given to prevent patients from relapsing into coma. Intravenous flumazenil 10 to 20 micrograms/kg is effective in neonates and small children. Intramuscular, oral (20 to 25 mg 3 times daily or as required) and rectal administration may be used as alternatives in long term regimens. Patients with mixed-drug overdose require higher doses (up to 2 mg bolus, approximately equal to 1 mg/h infusion) to regain consciousness. Children and the elderly, chronically ill patients, and pregnant women and their fetuses all respond satisfactorily to flumazenil, but the usefulness of the drug in patients with hepatic encephalopathy and alcohol overdose is debatable. The use of flumazenil results in complete awakening with restoration of upper airway protective reflexes, thus enabling gastric lavage to be performed and transfer of the patient from the emergency room to another hospital department. Resumption of effective spontaneous respiration allows for expeditious extubation, weaning off mechanical ventilation or the avoidance of endotracheal intubation. While flumazenil is not associated with haemodynamic adverse effects, caution should be exercised when using this agent in patients who have co-ingested chloral hydrate to carbamazepine or whose ECG shows abnormalities typical to those seen after overdose with tricyclic antidepressants (TCAs); the use of flumazenil in the presence of these drugs can sometimes induce treatable cardiac dysrrhythmia. Flumazenil per se does not induce adverse effects. Coma reversal by flumazenil may cause mild, short-lived reactions caused by sudden awakening. Withdrawal symptoms in long term benzodiazepine users and seizures in patients who have taken an overdose of TCA or carbamazepine and a benzodiazepine can occur with flumazenil; these symptoms are avoidable by utilising slow flumazenil dose titration.

Gut decontamination reduces bowel ischemia-induced lung injury in rats.

OBJECTIVE: To evaluate the effects of gut decontamination on endotoxin, tumor necrosis factor (TNF) levels, and the associated lung injury in a rat model of bowel ischemia. SUMMARY BACKGROUND DATA: Gut ischemia induces disruption of the intestinal mucosal barrier, allowing translocation of bacteria and endotoxin into the blood, which may trigger a systemic inflammatory response and lung injury. METHODS: Thirty anesthetized rats were randomized into three groups: (1) ischemia-reperfusion (I/R) alone (a 60-min superior mesenteric artery occlusion and 4 h of reperfusion, n=10); (2) rats that underwent gut decontamination prior to ischemia (I/R+GD, n=10); and (3) control rats (sham operated, n=10). Serum levels of lipopolysaccharide (LPS) and TNF were measured at the end of the experiment. Lung permeability was measured using bovine serum albumin labeled with 125I, and organ injury was assessed histologically. RESULTS: One hour of bowel ischemia and 4 h of reperfusion (I/R) led to elevations of blood LPS and TNF levels of 0.33+/-0.005 EU/mL and 173+/-56 pg/mL, which were higher than the sham group (p<0.01). Gut decontamination (I/R+GD) significantly attenuated the LPS and TNF generation, 0.09+/-0.005 and 56.2+/-6 pg/mL (p<0.01). Lung injury as assessed by pulmonary permeability index was also reduced by gut decontamination, 2.1+/-0.42 vs 5.3+/-0.82 in the control group (p<0.03). Surprisingly no difference was detected in the number of pulmonary neutrophils in sequestration between the groups. CONCLUSIONS: Our data suggest that gut decontamination can reduce the generation of LPS, TNF, and the severity of lung damage that often follows ischemia and reperfusion of the intestine in rats.

Microbiological cultures of heart valves and valve tags are not valuable for patients without infective endocarditis who are undergoing valve replacement.

We evaluated the significance of the results of microbiological cultures of heart valves and identification tags from newly inserted prosthetic valves that were removed from patients with valvular heart disease; none of these patients had a preoperative diagnosis of endocarditis. We reviewed the charts of patients with positive cultures for evidence of infections before or after surgery. Cultures were positive for 11.9% of 219 valves (206 native valves and 13 prosthetic or bioprosthetic valves) and 11.6% of 224 tags. The most common isolates were coagulase-negative staphylococci. Typical agents of endocarditis--viridans streptococcus, Enterococcus faecalis, and Staphylococcus aureus--were cultured from five specimens, and Mycobacterium avium complex was identified in six valves. None of the patients with positive valve or tag cultures developed postsurgical endocarditis or wound infection. Findings on histopathologic examination of the valves were not consistent with endocarditis. We conclude that the results of cultures of valves from patients without preoperative diagnoses of endocarditis lack clinical significance, and positive tag cultures are not predictive of postsurgical infection. Positive cultures are most likely a result of contamination during surgery or thereafter.

Identification of defensin binding to C1 complement.

In human serum we found strong defensin binding to the complexes of activated C1 complement (C1) and C1 inhibitor (C1i). Purified C1q, activated C1 tetramer (r2s2) and C1i did not bind defensin. When r2s2 was dissociated by EDTA, only the activated C1s (C1s) bound defensin. Binding of defensins to C1 complement represents a newly recognized bridge between the complement- and phagocyte-mediated host defenses, and a potential mechanism for protecting infected tissue from cytotoxic injury by defensin.