Perioperative care of children with nerve agent intoxication.

Nerve agents (NA) present a major threat to civilian populations. When a ballistic system is used for spreading poison, multiple trauma, as well as toxic trauma could be caused. Children are more susceptible, due to their smaller physiological reserve. Urgent surgical intervention for combined intoxication in the multiple-traumatized child could be a tremendous task in view of the background of physiological instability. Nerve agents affect the autonomic, as well as the central nervous system, leading occasionally to unexpected interactions with agents normally used for resuscitation. This can cause additional instability, and possibly systemic collapse. This review presents and emphasizes points concerning treatment of a child who suffers from combined multiple and toxic traumas. The review is based on scant knowledge of a database of similar cases of pesticide organophosphate poisoning in children since these compounds are alike. We also extrapolated data from reports concerning episodic civilian exposure to NA.

Liver glutathione level influences myocardial reperfusion injury following liver ischemia-reperfusion.

BACKGROUND: N-acetyl-L-cysteine (NAC) both replenishes reduced glutathione (GSH) and mitigates reperfusion injury. We hypothesized that liver content of GSH could affect remote myocardial reperfusion injury following liver ischemia-reperfusion. MATERIAL AND METHODS: Following stabilization (30 min), isolated rat livers (6/group) were perfused with Krebs-Henseleit solution (two control groups) or made globally ischemic (two ischemia groups) for 120 min. Paired livers + paced hearts (Langendorff preparation) were then reperfused for 15 min after which the hearts were recirculated alone for 50 min. NAC was added to Krebs (2 mM) that perfused livers during stabilization and reperfusion phases in one control and one ischemia group. RESULTS: GSH levels in the two control liver groups were identical (30.1 +/- 5.7 [SD] nmol/mg protein), and similar to that of the ischemia + NAC livers (28.6 +/- 2.8) but 2-fold that of the ischemia + 0 livers (15.8 +/- 2.4 nmol/mg protein, p<0.05). While hearts paired with control livers maintained unchanged their myocardial velocity of contraction, the contraction in the ischemia + NAC-paired hearts reduced, but was better than in the ischemia + 0-paired hearts (71 +/- 8% vs. 41 +/- 6% off baseline, p<0.05). Coronary flow also decreased dissimilarly in the two ischemia-associated groups of heart: 72 +/- 9% (ischemia + NAC) vs. 46 +/- 7% (ischemia + 0, p<0.05). Xanthine oxidase in the ischemia + 0 livers was 7.5-folds higher than in the ischemia-treated livers. CONCLUSIONS: NAC treatment of ischemia-reperfused livers, associated with GSH replenishment, prevents remote myocardial reperfusion injury. The role of NAC and GSH in reducing liver-associated oxidative burst propagation is discussed.

External pacing does not potentiate allopurinol protection of the heart from liver ischemia-reperfusion -- a study in an isolated perfused liver-heart rat model.

BACKGROUND: We recently demonstrated that isolated paced hearts perfused with modified Krebs-Henseleit solution containing high dose allopurinol (1 mM) were protected from liver ischemia-reperfusion (IR)-induced reperfusion injury. The objective was to study the effects of low dose allopurinol together with external pacing in attenuating myocardial reperfusion dysfunction following liver IR in the same double organ model. MATERIAL AND METHODS: Isolated rat livers were perfused with modified Krebs-Henseleit solution (groups 1 and 2, n=8/all groups) or underwent global ischemia (groups 3-6) for 120 minutes. Following a 15-minute conjoint reperfusion of earlier separately isolated liver+heart, the hearts were recirculated alone for additional 45 minutes. The organs of three-group donating animals (groups 2, 4, and 6) were treated with allopurinol 18 hours and 1 hour before the experiment (50 mg x kg(-1) intraperitoneally) and it was also added during perfusion (0.1 mM in Krebs). The hearts in groups 5 and 6 were paced (300 x min(-1)). RESULTS: The hearts perfused with IR Krebs (group 3) experienced decreased myocardial left ventricular-developed pressure (LVP), heart rate (in the unpaced hearts) and later coronary flow (by 68%, 21% and 32%, respectively); LVP and coronary flow also decreased correspondingly in the IR-paced hearts (group 4). Xanthine oxidase (XO) was high in groups 3 and 4 compared to group 1. IR allopurinol-treated hearts, both unpaced and paced (groups 5 and 6) had normal, similar myocardial performance, while their circulating XO was as low as in group 2 (allopurinol-treated controls). CONCLUSIONS: External pacing in the double organ, isolated-perfused liver-heart did not ameliorate XO-mediated dysfunction compared to low dose allopurinol. The unexpected delayed coronary insufficiency in myocardial reperfusion injury is discussed.

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.

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.

Bcl-2 overexpression protects photooxidative stress-induced apoptosis of photoreceptor cells via NF-kappaB preservation.

We recently showed that photooxidative stress on cultured photoreceptor cells results in down-modulation of NF-kappaB activity which then leads to apoptosis of cultured 661W photoreceptor cells. In an effort to further delineate the mechanism of photoreceptor cell death, we sought to determine the effects of Bcl-2 overexpression on cell survivability. Wild-type 661W cells were transfected with the plasmid construct pSFFV-neo-Bcl-2 and several clones were isolated. All clones demonstrated increased Bcl-2 mRNA and protein levels, with the B4 clone exhibiting the greatest enhancement. On exposure to visible light the B4 cells were protected from undergoing apoptosis when compared with the mock transfected cells, as ascertained by TUNEL apoptosis assay and formazan based estimation of cell viability. The Bcl-2 overexpressing cells also maintained a higher Bcl-2/Bax ratio, suggesting that this ratio is important in protection from photooxidative stress. Electrophoretic mobility shift assays for NF-kappaB demonstrated higher activity in both nuclear and cytosolic fractions of the B4 photoreceptors compared with the 661W wild-type cells at all light exposure time points. Furthermore, the findings of the gel shift assays were further supported by immunocytochemistry for NF-kappaB which revealed that protein levels of the RelA subunit of NF-kappaB were protected in the nucleus as well as in the cytoplasm of Bcl-2 overexpressing B4 cells exposed to light compared to the 661W cells. These results suggest that Bcl-2 overexpression protects NF-kappaB protein levels and activity in the nucleus, indicating that preservation of NF-kappaB binding activity in the nucleus may be essential for photoreceptor cells to survive photooxidative damage induced apoptosis.

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.

Dextromethorphan attenuation of postoperative pain and primary and secondary thermal hyperalgesia.

PURPOSE: To determine the effect of 90 mg dextromethorphan (DM) p.o. vs placebo 90 min preoperatively, on the immediate and delayed postoperative course. METHODS: Thirty patients undergoing laparoscopic cholecystectomy or inguinal hernioplasty under general anesthesia were studied. Half (DM) received 90 mg dextromethorphan and half received placebo 90 min before anesthesia. Intravenous Patient Controlled Aanalgesia with morphine was available for two hours within a six-hour observation period; 75 mg diclofenac i.m. prn was given later in PACU and on-ward (24 hr). Pain was assessed using the visual analogue scales. Thermal thresholds for cold and hot sensation and for pain (by limit method) were evaluated at the site of skin incision (primary-) and distantly (secondary hyperalgesia). Von Frey filaments were applied testing touch sensation. Sedation level and morphine consumption were also assessed in PACU. RESULTS: Demographic, surgical and perioperative parameters were similar; no untoward effects were encountered. Pain intensity and sedation were lower, and the feeling of well-being was greater, in the DM patients: one vs five (median), two vs five, five vs two, respectively, P <0.01 (90 min time-point). Thermal application revealed absence of primary and secondary hyperalgesia only in the DM patients; von Frey filaments induced similar pain sensation in both groups. Mean morphine/group, morphine/weight and diclofenac injection rates were approximately 55% lower in the DM group: 2.1 +/- 1.2 (SD) vs 4.7 +/- 2.3, 0.03 +/- 0.02 vs 0.07 +/- 0.03, 1.0 +/- 0.3 vs 2.4 +/- 0.2, respectively, P <0.01. CONCLUSIONS: Compared with placebo, DM enabled reduction of postoperative analgesics consumption, improved well-being, and reduced sedation, pain intensity and primary and secondary thermal hyperalgesia.

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.

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.

[FK506 (tacrolimus) does not increase hepatic damage due to hypoperfusion].

Deterioration of hepatic function following liver transplantation is a known complication, sometimes attributed to the use of cyclosporin A. Reaction to tacrolimus (Prograf), a relatively new and effective immunosuppressant drug, is thought to result in a much lower grade of organ dysfunction, especially in the transplanted liver. Using the ex-vivo rat model of isolated perfused liver, we evaluated hepatocellular damage and oxygen extraction when tacrolimus was administered following liver hypoperfusion. Tacrolimus did not worsen hepatic dysfunction caused by the hypoperfusion. Therefore using tacrolimus in the perioperative period might be safer than cyclosporin A, which tends to worsen hepatic damage in the presence of hypoperfusion.

The role of dextromethorphan in pain control.

PURPOSE: To review the clinical benefits of dextromethorphan (DM) in pain management, describe its neuropharmacological properties. SOURCE: A Medline search was made for experimental and clinical data on DM use from 1967 to date using keywords nociception, acute and chronic pain control, N-methyl-D-aspartate, antagonists, dextromethorphan. PRINCIPLE FINDINGS: The 930 DM citations mostly described its antitussive, metabolic and toxicological aspects, animal studies and its possible role in minimizing post-brain ischemia complications in humans. The use of DM in acute pain revealed eight original studies involving 443 patients, as well as two preliminary reports and our own unpublished data on 513 patients. Most of the 956 patients had general anesthesia. Eight studies (154 patients) and one case report dealt with chronic pain management. This N-methyl-D-aspartate (NMDA) receptor antagonist binds to receptor sites in the spinal cord and central nervous system, thereby blocking the generation of central acute and chronic pain sensations arising from peripheral nociceptive stimuli and enabling reduction in the amount of analgesics required for pain control. DM attenuated the sensation of acute pain at doses of 30-90 mg, without major side effects, and reduced the amount of analgesics in 73% of the postoperative DM-treated patients. Studies in secondary pain models in healthy volunteers and in various types of chronic pain showed DM to be associated with unsatisfactory pain relief. CONCLUSION: DM attenuates acute pain sensation with tolerable side effects. Its availability in oral form bestow advantages over other NMDA antagonists.

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.

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.

Multiple organ dysfunction after remote circulatory arrest: common pathway of radical oxygen species?

OBJECTIVES: Cardiovascular, respiratory, and vascular dysfunction can follow trauma-induced no-flow-reflow states: hemorrhage, blunt trauma, or neurogenic shock. Liver ischemia-reperfusion (IR) induces remote lung damage by means of xanthine oxidase (XO) pro-oxidant activity. This damage was not proven in the heart, neither was the independent role of radical oxygen species (ROS) established in such cases. We investigated whether multiple organ dysfunction after a trauma-like IR is XO and ROS related and whether clinically used ROS scavengers could be beneficial. METHODS: A controlled, randomized trial in which isolated rat livers, hearts, lungs, and aortic rings were perfused with Krebs-Henseleit solutions. After stabilization, livers were either perfused or made ischemic (2 hours). Then, pairs of liver plus heart, lung, or ring were reperfused in series (15 minutes), and then the second organ circulated alone for 45 minutes. Remote organ protection against the pro-oxidant hepatic-induced toxicity was evaluated by using allopurinol (1 mmol/L, heart), mannitol (0.25 g/kg, lung), or methylene blue (40 mg/kg, ring). RESULTS: IR liver effluents typically contained high lactate dehydrogenase, XO, and uric acid concentrations compared with control organs. IR was associated with doubled lung peak inspiratory pressure and reduced static compliance. Myocardial velocity of contraction and relaxation decreased by one third of baseline, and rings contracted abnormally and responded inadequately to phenylephrine. Wet-weight to dry-weight ratios in the remote organs increased as well. Most remote reperfusion injuries were attenuated by the drugs. CONCLUSION: Liver no-flow-reflow directly induces myocardial, pulmonary, and vascular dysfunction. These are likely mediated by XO and ROS. The tested drugs protected against these pro-oxidants, even in the presence of circulating XO.

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.

Antinociceptive effect induced by the combined administration of spinal morphine and systemic buprenorphine.

UNLABELLED: We evaluated the antinociceptive effect of combined spinal administration of morphine and systemic administration of buprenorphine. Experiments were performed on male Wistar rats. Nociception was measured using the tail immersion test. Buprenorphine was injected intraperitoneally (IP) and morphine was injected intrathecally (IT) via a catheter implanted in the subarachnoid space. Interaction of drugs was analyzed using a dose addition model. Both IT (1-5 microg) morphine and IP (50-500 microg/kg) buprenorphine increased the latencies of nociceptive responses in a dose-dependent manner. IT morphine (4 microg) and IP buprenorphine (100 microg/kg) produced 62.9+/-6.3 and 48.8+/-6.6 percent of the maximal possible effect (%MPE), respectively. The combined administration of 2 microg of IT morphine and 50 microg/kg IP buprenorphine produced a %MPE of 97.1+/-3.4. The analysis of drug interaction revealed that IT morphine interacted with IP buprenorphine in a supraadditive manner while producing a potent antinociceptive effect. IMPLICATIONS: The concurrent administration of spinal morphine and systemic buprenorphine produces an antinociceptive effect that is greater than what could have been predicted from individual dose-response curves. This mode of interaction allows maintenance at a significant level of analgesia with reduced doses of opioids, which minimizes the incidence of undesirable side effects.

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.