Effect of preemptive intra-articular morphine and ketamine on pain after arthroscopic rotator cuff repair: a prospective, double-blind, randomized controlled study.

BACKGROUND: Rotator cuff tear is a leading etiology of shoulder pain and disability. Surgical treatment is indicated in patients with persistent pain who fail a trial of non-surgical treatment. Pain reduction following rotator cuff repair, particularly within the first 24-48 h, is a major concern to both doctors and patients. This study aimed to compare the postoperative antinociceptive additive effects of pre-incisional intra-articular (IA) ketamine when combined with morphine with two times the dose of morphine or saline. METHODS: In this prospective, randomized, double blind, controlled trial patients undergoing arthroscopic rotator cuff tear repair (ARCR) under general anesthesia were enrolled. Patients were randomly assigned to one of the three intervention groups. Twenty minutes prior to incision, morphine (20 mg/10 ml), ketamine (50 mg + morphine 10 mg/10 ml), or saline (0.9 % 10 ml) (n = 15/group), were administered to all patients. First 24 h postoperative analgesia consisted of intravenous patient controlled analgesia (IV-PCA) morphine and oral rescue paracetamol 1000 mg or oxycodone 5 mg. 24-h, 2-week and 3-month patient rated pain numeric rating scale (NRS) and analgesics consumption were documented. RESULTS: Patients' demographic and perioperative data were similar among all groups. The 24-h and the 2-week NRSs were significantly (p < 0.05) lower in both treatment groups compared to placebo, but were not significantly different between the two intervention groups. PCA-morphine and oral analgesics were consumed similarly among the groups throughout the study phases. CONCLUSIONS: Pre-incisional intra-articular morphine reduced pain in the first 2 weeks after arthroscopic rotator cuff repair. Further research is warranted to elucidate the optimal timing and dosing of IA ketamine and morphine for postoperative analgesic effects.

Metformin-associated lactic acidosis following acute kidney injury. Efficacious treatment with continuous renal replacement therapy.

INTRODUCTION: Metformin is a biguanide anti-hyperglycaemic drug. Metformin-associated lactic acidosis may sometimes be life-threatening. Continuous renal replacement therapy has been suggested as a method for resolving this extremely dangerous metabolic state. We describe the history of six patients admitted to the intensive care unit over a 28-month period in pre-shock conditions because of severe lactic acidosis, attributed to metformin-associated lactic acidosis, and successfully treated. METHODS: We reviewed the charts of six patients admitted to our intensive care unit between January 2008 and May 2010. After initial assessment, all patients were treated with continuous renal replacement therapy. Admission serum lactate and creatinine levels, pH, need for ventilatory and cardiovascular support, as well as continuous renal replacement therapy details and length of stay were reviewed. RESULTS: Admission pH levels of the six patients ranged between pH 6.63 and 7.0 and their serum lactate levels ranged between 12 and 27 mmol/l; the estimated creatinine clearance ranged between 6 and 24 ml min(-1) 1.73 m(-2) . All patients required vasoactive support and five required ventilatory support. Lactate levels decreased to near zero with continuous renal replacement therapy within 7-19 h in five of the patients whose intensive care unit length of stay ranged between 1 and 5 days. One patient's length of stay reached 11 days because of pneumonia, one died from multi-organ failure and another suffered permanent neurological damage following prolonged cardiopulmonary resuscitation before continuous renal replacement therapy was administered. All other patients recovered without sequellae. CONCLUSIONS: Accurate recognition of metformin-associated lactic acidosis and prompt initiation of haemodialysis are paramount steps towards rapid recovery. Large series reports and controlled studies may better determine the optimal duration and best dialysis technique in these patients.

New evidence for the role of TNF-alpha in liver ischaemic/reperfusion injury.

BACKGROUND: Tumour necrosis factor-alpha (TNF-alpha) plays a key role in causing ischaemia/reperfusion (I/R) injury. I/R also causes activation of xanthine oxidase and dehydrogenase (XDH + XO) system that, via generated free radicals, causes organ damage. We investigated the effect of ischaemia, reperfusion and non-ischaemic prolonged perfusion (NIP) on TNF-alpha and XDH + XO production in an isolated perfused rat liver model. MATERIALS AND METHODS: Rat livers underwent 150 min NIP (control group) or two hours of ischaemia followed by reperfusion (I/R group). TNF-alpha (TNF-alpha mRNA and protein level), XDH + XO production and bile secretion were determined in tissue and effluent at baseline, at 120 min of ischaemia, after 30 min of reperfusion (I/R group) and after 120 and 150 min of prolonged perfusion (control). RESULTS: Unexpectedly, neither ischaemia nor reperfusion had any effect on TNF-alpha production. TNF-alpha in effluent was 11 +/- 4.8 pg mL(-1) at baseline, 7 +/- 3.2 pg mL(-1) at the end of ischaemia, and 13 +/- 5.3 pg mL(-1) after 30 min of reperfusion. NIP, however, caused a significant increase of TNF-alpha synthesis and release. TNF-alpha effluent level after 120 and 150 min of perfusion was 392 +/- 78.7 pg mL(-1) and 408 +/- 64.3 pg mL(-1), respectively. TNF-alpha mRNA in tissue was also significantly elevated compared to baseline levels (1.31 +/- 0.2 P < 0.001 and 1.38 P < 0.002, respectively). Decrease of liver function (expressed by bile secretion) during I/R and NIP was accompanied by significant XDH + XO elevation. CONCLUSION: This is the first evidence that NIP, and not I/R, is the decisive trigger for TNF-alpha production. This study leads to a better understanding of pathogenesis of liver I/R and perfusion damage.

Cuffed oropharyngeal airway (COPA) placement is delayed by wearing antichemical protective gear.

BACKGROUND: Airway management, the first step in resuscitation, may entail special difficulties in mass casualty situations, even in experienced hands. Of the available airway devices, the cuffed oropharyngeal airway (COPA) appears the easiest one to insert, allowing a hands-free anaesthesiologist. A study was undertaken to evaluate the success of airway control with COPA when anaesthetists wore either surgical attire or antichemical protective gear. METHODS: Twelve anaesthetists with 2-5 years of residency inserted COPA in 24 anaesthetised patients in a random crossover prospective manner. The duration of airway management was measured from the time the device was grasped to obtaining a normal capnography recording; time to proper fixation was also recorded. RESULTS: Time to COPA placement was significantly shorter when the anaesthetists wore surgical attire than when they wore protective gear (28 (10) s vs 56 (34) s, p<0.05). Time to proper fixation of the COPA to patients' faces also differed significantly (19 (14) s with surgical attire vs 34 (16) s with protective gear, p<0.05). First-time COPA insertion failure was statistically similar in both groups. There was no hypoxaemia. CONCLUSIONS: Antichemical protective gear slowed proper placement of COPA and its fixation compared with surgical attire. COPA may be a temporarily useful device in non-conventional settings, but functional reassessment is required when injured patients reach medical facilities.

N-acetyl-L-cysteine for preventing lung reperfusion injury after liver ischemia-reperfusion: a possible dual protective mechanism in a dose-response study.

BACKGROUND: Acute lung reperfusion injury (ALI) frequently follows an ischemic event in another organ, such as organ transplantation. We recently demonstrated that lung priming with N-acetyl-L-cysteine (NAC) prevented liver ischemia-reperfusion (IR)-induced ALI pending on reduced glutathione (GSH) amount of replenishment. We now assessed the therapeutic effect of NAC-in preventing ALI caused by liver IR-if administered to the lung during liver reperfusion. PROCEDURES: Rat isolated livers were stabilized (30 min) and then perfused with modified Krebs-Henseleit solution (control, n=20) or made globally ischemic (IR, n=20) for 2 hr. Rat lungs were isolated separately, ventilated, and stabilized (30 min) with Krebs plus 5% bovine albumin. Pairs of liver and lung were then reperfused together for 15 min, followed by only lung recirculation with the liver effluent for another 45 min. Three more controls (n=20 each) and three ischemic groups (n=20 each) included lungs which were treated with 100, 150 or 225 mg x kg(-1) NAC (0.5, 0.74, or 1.1 mmol, respectively) during the 15-min liver and lung reperfusion period. RESULTS: Pulmonary artery and ventilatory pressures and vascular resistance increased by 60-80% of baseline, compliance decreased, and bronchoalveolar lavage volume and content were abnormally high in the IR-nontreated and the IR-100 lungs. Most parameters in IR-150 and IR-225 lungs remained almost similar to controls. Postinsult GSH content in IR-100, -150, and -225 lungs was at 20%, 110%, and 90% above the IR-nontreated lungs, respectively. CONCLUSIONS: Lung treatment with NAC during its reperfusion with IR liver effluent prevented ALI. Lung GSH replenishment accounted for lung protection, but its content did not correlate directly with grade of protection; NAC itself seemingly afforded lung protection as well.

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.

Cumulative damaging effect of liver hypoperfusion and cyclosporine a on the peribiliary capillary plexus: a study in an isolated dually perfused rat model.

BACKGROUND: Cyclosporine (CsA) is an essential posttransplantation immunosuppressive drug. It may cause hepatotoxicity, mostly cholestasis, by unknown mechanism. CsA causes nephrotoxicity mainly by increased vascular resistance. We investigated the effects of CsA on the peribiliary capillary plexus, in an isolated, dually perfused (i.e., via the hepatic artery and the portal vein) rat liver preparation. METHODS: After 30 min of stabilization with optimal flow (4 ml/min/g liver), four liver groups were perfused (control, n=5 each) and four groups were hypoperfused (n=5 each, 1 ml/min/g) for 120 min. This was followed by a 30-min optimal reperfusion phase, during which the controls and the hypoperfused groups were injected (60 sec) via the hepatic artery with CsA at high (3 mg/kg body weight in 1 ml) or low dose (0.03 mg/kg), cremophore (130 mg/kg), or saline (1 ml). A ninth group (n=5) underwent 2-hr ischemia and 30-min reperfusion to standardize liver damage. Dark nonradioactive microspheres (approximately 10 microm diameter) were injected via the hepatic artery 15 min after drug or saline injection. RESULTS: Neither of the two CsA doses, nor cremophore controls, nor hypoperfusion alone caused entrapment of microspheres in the peribiliary circulation as assessed by light microscopy; perfusion pressures and resistances were also not altered. Significant arteriolar impaction and vasculature engorgement occurred in the hypoperfused plus high-dose CsA livers; hypoperfusion plus low-dose CsA or cremophore groups were minimally tainted. Vascular notable obstruction was associated with 15-40% increase in portal and arterial perfusion pressures and resistances, 50% decrease in oxygen extraction, and increase in lactate/pyruvate ratio, hepatocellular damage, and wet-to-dry weight ratio. Such findings were superior to those detected in the ischemic livers. CONCLUSIONS: Acute single high-dose CsA injection, but not low-dose or cremophore, if combined with decreased flow, alters hepatic microcirculatory resistance. Possible correlations between such changes and clinical implications in organ transplantation are discussed.

Lung preconditioning with N-acetyl-L-cysteine prevents reperfusion injury after liver no flow-reflow: a dose-response study.

BACKGROUND: Circulating xanthine oxidase activity and the generated oxidants have been linked to lung reperfusion injury from no flow-reflow conditions in other organs after organ transplantation or surgery. N-acetyl-1-cysteine (NAC), an oxidant scavenger, promotes glutathione in its reduced form (GSH) that is depleted during ischemia. We have recently demonstrated its efficacy in protecting lungs from reperfusion injury if administered during reperfusion of postischemic liver. We now investigated whether preconditioning of lungs with NAC could attenuate lung respiratory or vascular derangement after no flow-reflow (ischemia-reperfusion, IR) and if this depends on lung GSH levels. METHODS: Rat isolated livers were stabilized and perfused with modified Krebs-Henseleit solution (KH) (control, n=12) or made ischemic (no flow, IR-0, n=12) for 2 hr. Meanwhile, lungs were isolated, ventilated, and stabilized (KH+bovine albumin 5%). Serial perfusion (15 min) of liver+lung pairs took place followed by lung only recirculation (45 min) with the accumulated solution. Another three controls and three ischemic groups included lungs treated during stabilization with NAC at 100 mg x kg(-1), 150 or 225 mg x kg(-1) (in 2.5, 3.7 or 5.5 mmol solutions, respectively). Results. Ischemic liver damage, expressed by circulating hepatocellular constituents, was associated with pulmonary artery and ventilatory pressure increases by 70-100% of baseline, abnormal wet-to-dry weight ratio, and abnormal bronchoalveolar lavage volume and content in the IR-0 (nontreated) and the IR-100 and IR-225 pretreated lungs. NAC-150 pretreatment afforded preservation for most parameters. GSH content in the IR-150 lung tissue was only 11% higher than that of IR-225, but 2-fold that in IR-0 and IR-100 GSH lungs. CONCLUSION: Lung preconditioning with NAC prevents reperfusion injury but not in a dose-related manner. Although enhanced GSH tissue content explains lung protection, GSH-independent NAC activity is another possibility.

Methylene blue abolishes aortal tone impairment induced by liver ischemia-reperfusion in a dose response manner: an isolated-perfused double-organ rat model study.

Liver ischemia-reperfusion (IR) generates remote organ reperfusion injury attributable to oxidative mediators. We tested the protective properties of methylene blue (MB) on aortal dysfunction. An ex vivo rat liver-aortal ring model was used to study the results of aortal exposure to post-ischemia (IR) hepatic effluent and its response to phenylephrine and isosorbide dinitrate in the absence or presence of increasing concentrations of MB in the effluent. Aortal incubation with IR effluents resulted in abnormal contraction. Ring's response to the vasoactive drugs was abnormally weak both during and following this exposure. Return to stabilization tone was irregular. MB (1.28 mM) best avoided overall dysfunction; 0.86 mM was partially effective, and 0.42 mM was ineffective. Nitrite/nitrate levels were similar to controls in the only IR 1.28 mM perfusate. Liver IR interferes with aortal tone and its response to vasoactive drugs, probably via oxidative interaction with nitric oxide. MB reverses these effects in a dose-dependent fashion.

Xanthine oxidoreductase release after descending thoracic aorta occlusion and reperfusion in rabbits.

Cardiopulmonary and other organ dysfunction often occurs after operation on the descending thoracic aorta. Though there are multiple causes of organ dysfunction in this setting, free radical injury may play a prominent role. Xanthine oxidoreductase, an enzyme that generates oxidants after exposure to ischemia, could be released from ischemic liver and intestine during reperfusion. To test this hypothesis, we created aortic occlusion in eight rabbits for 40 minutes by inflation of a 4F Fogarty balloon catheter in the descending thoracic aorta. Eight sham-operated rabbits served as a control group. Two hours of reperfusion followed removal of the balloon catheter. Hemodynamic and acid-base status were maintained near baseline values during reperfusion. Plasma samples were obtained for determination of the activity of the hepatocellular enzymes xanthine oxidoreductase, aspartate aminotransferase, alanine transferase, and lactate dehydrogenase. Plasma xanthine oxidoreductase activity increased significantly (p < 0.001) during reperfusion (729 +/- 140 microU/ml, mean +/- standard error of the mean) compared with baseline (132 +/- 18 microM/mL). The other enzymes followed a similar pattern of release. We report the release of xanthine oxidoreductase in an animal model that simulates the situation of human thoracic aorta operations. The oxidants produced by the circulating xanthine oxidoreductase observed during reperfusion would likely be toxic to vascular endothelium, potentially contributing to multiple organ dysfunction.

The use of flumazenil in the management of acute drug poisoning--a review.

The popularity and widespread availability of benzodiazepines (BZD) has led to their frequent abuse in intentional drug poisoning. Although mortality from pure BZD overdose is usually small, in elderly, debilitated patients, or when BZD are combined with other CNS depressant drugs, morbidity increases significantly and outcome may be fatal. Drug overdose is therefore a medical emergency necessitating close observation and support of vital functions. Recently, the specific BZD antagonist flumazenil (Anexate) has become clinically available and much experience in its usefulness has accumulated. The present review summarizes a total of 30 studies and reports published to date, involving approximately 760 intoxicated patients. Flumazenil was evaluated both in prehospital use as well as in emergency rooms or in intensive care units. The age of patients ranged from 4-90 years and doses of flumazenil varied between 0.3-10 mg, approximately 1 mg being the most frequently used. All patients intoxicated with only BZD returned to full consciousness within minutes after the injection of flumazenil. When a mixture of BZD and other CNS depressants was abused, a range of effects was observed. This varied from no change to a return to full orientation, depending on the contribution of the BZD to the state of unconsciousness. Re-sedation occurred in about 65% of flumazenil treated patients, usually within 0.5-3 h after the first dose, the shorter interval being associated with mixed-drug poisoning. Repeated doses of the antagonist (0.2-2 mg), sometimes followed by continuous infusion (0.1-0.5 mg/h), were effective in maintaining patients fully oriented.(ABSTRACT TRUNCATED AT 250 WORDS)

Midazolam versus propofol for long-term sedation in the ICU: a randomized prospective comparison.

OBJECTIVE: To compare the efficacy, safety, and cost of midazolam and propofol in prolonged sedation of critically ill patients. DESIGN: Randomized, prospective study. SETTING: General intensive care unit (ICU) in a 1100-bed teaching hospital. PATIENTS: 67 critically ill, mechanically ventilated patients. INTERVENTIONS: Patients were invasively monitored and mechanically ventilated. A loading dose [midazolam 0.11 +/- 0.02 (SEM) mg.kg-1, propofol 1.3 +/- 0.2 mg.kg-1] was administered, followed by continuous infusion, titrated to achieve a predetermined sedation score. Sedation was continued as long as clinically indicated. MEASUREMENTS AND RESULTS: Mean duration of sedation was 141 and 99 h (NS) for midazolam and propofol, respectively, at mean hourly doses of 0.070 +/- 0.003 mg.kg-1 midazolam and 1.80 +/- 0.08 mg.kg-1 propofol. Overall, 68% of propofol patients versus 31% of midazolam (p < 0.001) patients had a > 20% decrease in systolic blood pressure after the loading dose, and 26 versus 45% (p < 0.01) showed a 25% decrease in spontaneous minute volume. Propofol required more daily dose adjustments (2.1 +/- 0.1 vs 1.4 +/- 0.1, p < 0.001). Nurse-rated quality of sedation with midazolam was higher (8.2 +/- 0.1 vs 7.3 +/- 0.1 on a 10-cm visual analog scale, p < 0.001). Resumption of spontaneous respiration was equally rapid. Recovery was faster after propofol (p < 0.02), albeit with a higher degree of agitation. Amnesia was evident in all midazolam patients but in only a third of propofol patients. The cost of propofol was 4-5 times higher. CONCLUSIONS: Both drugs afforded reliable, safe, and controllable long-term sedation in ICU patients and rapid weaning from mechanical ventilation. Midazolam depressed respiration, allowed better maintenance of sedation, and yielded complete amnesia at a lower cost, while propofol caused more cardiovascular depression during induction.

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.

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.

Impairment of aortal tone by no flow-reflow conditions and its partial amelioration by mannitol.

BACKGROUND: Although postischemic cardiac or pulmonary dysfunction can relate to the impact of remotely generated oxygen stress mediators on the heart, their direct effect on the vascular bed remains unresolved. Thus, we tested these remote effects in an ex-vivo double organ model. METHODS: After stabilization With Krebs-Henseleit solution, isolated rat livers were either perfused or made ischemic for 2 hours. Aortic rings were stabilized, immersed in postischemic liver perfusates and their functions were tested. Some organs originated from donors fed with tungstate, whereas others had mannitol (0.25 g/kg) in the buffer. RESULTS: Incubation of aortic rings with postischemic hepatic effluent resulted in protracted contraction. Spasm was slightly lesser when the livers were pretreated with tungstate or exposed to mannitol, but worse in pretreated rings. The return to basal tone was abrupt in all ischemia-reperfusion aortae. The response of the rings to phenylephrine under the influence of the ischemia-reperfusion hepatic effluent was deficient. Mannitol prevented most abnormal responses. CONCLUSIONS: Aortal tone impairment can occur by direct influence of the ischemia-reperfusion liver. It cannot be attributed entirely to xanthine oxidase, but also to other hepatic-released factors.

Beta-chemokine secretion patterns in relation to clinical course and outcome in children after cardiopulmonary bypass: continuing the search to abrogate systemic inflammatory response.

BACKGROUND: Surgery involving cardiopulmonary bypass (CPB) is frequently accompanied by a systemic inflammatory response partly triggered by neutrophils and monocyte-macrophages. Certain cytokines that are powerful leukocyte-chemotactic factors have recently been characterized and shown to be important in evoking inflammatory responses: monocyte chemoattractant protein-1 (MCP-1) has monocyte-macrophage chemotactic activity, and regulated-upon-activation normal T-cell expressed and secreted (RANTES) has a potent chemoattractant activity for mononuclear phagocytes. This prospective cohort study investigated possible roles of these chemokines in the inflammatory response to CPB and relationships between the changes in chemokine levels and the clinical course and outcome. METHODS: Systemic blood of 16 children undergoing CPB was collected after induction of anesthesia (base line); at 15 minutes after bypass onset; at CPB cessation; and at 1, 2, 4, 8, 12, and 24 hours afterward to measure MCP-1 and RANTES. RESULTS: The significant changes of plasma beta chemokine levels following CPB were associated with patient characteristics, operative variables, and postoperative course. Cardiopulmonary bypass of more than 2 hours, longer surgical times, inotropic support, and reoperation were associated with higher MCP-1 levels and lower RANTES levels. CONCLUSIONS: Our results suggest a relation between CPB-induced mediators and clinical effects, implying pathogenic roles for chemokines following CPB. These molecules should be considered as possible targets for therapeutic intervention.

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.

Flumazenil potentiation of postoperative morphine analgesia.

OBJECTIVE: The goal of this study was to test the effect of concomitant administration of flumazenil (FL) and morphine (MO) on immediate postoperative analgesia and the MO requirement to control pain in human beings. DESIGN AND INTERVENTIONS: Thirty-six patients undergoing inguinal hernioplasty under lidocaine epidural anesthesia were enrolled in this double-blind, randomized, controlled study. On the first complaint of pain, either MO (2 mg) only or MO (2 mg) plus FL (0.2 mg) was administered. Additional doses of the same medications administered via a patient-controlled analgesia device with a 10-minute lockout period were available thereafter. The study continued for 2 hours after the loading doses of the medications were administered, with an additional 2-hour period of observation. RESULTS: Thirty-two patients completed the study. Both groups reached a similar satisfactory equianalgesic state (2 in a 0-10 visual analogue scale). The MO plus FL group consumed 9.5 +/- 1.1 mg of MO versus 14.1 +/- 1.1 mg of MO (p < 0.001) in the MO only group. The MO plus FL patients were subjectively (visual analogue scale) more comfortable and less sedated than the MO patients. "Fine" coordination (using an electronic maze) and "coarse" coordination (measured by transferring a pen from one hand to another as rapidly as possible with both arms placed inside an 80-cm metal frame) in the MO group were worse than in the MO plus FL group. End-tidal CO2 increased and blood pressure decreased in the MO group. There were few and insignificant side effects in the MO group. None of these patients required an MO antagonist, and recovery was prolonged in none. CONCLUSIONS: Flumazenil afforded lower MO consumption during the immediate postoperative period. Cognitive, hemodynamic, and respiratory functions were better after MO plus FL than after MO alone.

Anaesthesia and critical care considerations in nerve agent warfare trauma casualties.

Nerve agents (NA) (tabun, sarin, suman, VX) have been stocked around the world for some time and still present a major threat to civilian as well as to military populations. Since NA can be delivered through both an aerial spray system and a ballistic system, victims could suffer both NA intoxication and multiple trauma necessitating urgent surgical intervention followed by intensive care. These patients can be expected to be extremely precarious neurologically, respiratorily and haemodynamically. Moreover, their clinical signs can be misleading. Further exacerbating the problem is the fact that interactions of NA with the pharmacological agents used for resuscitation and/or during anaesthesia can aggravate organ instability even more and possibly cause systemic collapse. There are no protocols for perioperative critical care and early assessment or for the administration of anaesthesia for surgical interventions in such combined multiple trauma and intoxicated casualties. We propose a scheme for the administration of critical care and anaesthesia based on the scant anecdotal reports that have emerged after the occurrence of local accidents involving NA intoxication and on the neuropharmacological knowledge of the pesticide organophosphate poisoning database, these compounds being related chemical substances.

Hemodynamic effects of tracheal administration of vasopressin in dogs.

BACKGROUND: Intravenous administration of vasopressin during cardiopulmonary resuscitation (CPR) has been shown to be more effective than optimal doses of epinephrine. Earlier studies had been performed on a porcine model, but pigs produce lysine vasopressin hormone, while humans and dogs do not. This study was designed to compare the effects of tracheal vasopressin with those of NaCl 0.9% (placebo) on haemodynamic variables in a dog model. METHODS: Five dogs were allocated to receive either vasopressin 1.2 U/kg or placebo (10 ml of NaCl 0.9%) via the tracheal route after being anesthetized and ventilated. Haemodynamic variables were determined and arterial blood gases were measured. RESULTS: All animals of the vasopressin group demonstrated a significant increase of the systolic (from 135+/-7 to 165+/-6 mmHg, P<0.05), diastolic (from 85+/-10 to 110+/-10 mmHg, P<0.05) and mean blood pressure (from 98.5+/-3 to 142.2+/-5, P<0.05). Blood pressure rose rapidly and lasted for more than an hour (plateau effect). Heart rate decreased significantly following vasopressin (from 54+/-9 to 40+/-5 beats per min, P<0.05) but not in the placebo group. These changes were not demonstrated with placebo injection. CONCLUSION: Tracheal administration of vasopressin was followed by significantly higher diastolic, systolic and mean blood pressures in the vasopressin group compared with the placebo group. Blood gases remained unchanged in both groups. Vasopressin administered via the trachea may be an acceptable alternative for vasopressor administration during CPR, when intravenous access is delayed or not available, however, further investigation is necessary.