Comparison of ketamine and pentobarbital anesthesia with the conscious state in a porcine model of Pseudomonas aeruginosa septicemia

Live Pseudomonas aeruginosa (2.5.10(9).kg-1.h-1) were administered to awake (Group A, n = 10) and anesthetized piglets, which were given intravenous ketamine (Group K, 10 mg.kg-1.h-1, n = 8) or pentobarbital (Group P, 15 mg.kg-1.h-1, n = 8). The anesthetized animals were mechanically ventilated. In addition, a pentobarbital group (Group CP, n = 6) and a ketamine control group (Group CK, n = 6) were studied. The mean survival time was 10.5 +/- 3.0 h in Group A, 10.6 +/- 2.8 h in Group K, and 1.8 +/- 1.3 h in Group P. In Group P the arterial pressure, the cardiac output and the systemic vascular resistance declined soon after start of the bacterial infusion, whereas the pulmonary artery pressure increased. The animals died of irreversible circulatory failure. In Group K pronounced pulmonary hypertension and lethal pulmonary edema developed. There was no circulatory failure in Group A, but the animals also died of marked pulmonary edema. Groups CP and CK exhibited stable hemodynamics for a period of 8 h. The results of this study suggest a deleterious effect of pentobarbital on hemodynamics and survival time, and a minor suppressive action of ketamine on the circulation in septicemia. Therefore, data obtained from septic shock studies applying pentobarbital have to be evaluated carefully. Investigation of the effects of gram-negative bacteria or endotoxin should be performed in unanesthetized or, if anesthesia is necessary, in ketamine-anesthetized animals.     

Prophylactic and Delayed Treatment with High-Dose Methylprednisolone in a Porcine Model of Early ARDS Induced by Endotoxaemia

The effects of prophylactic and delayed treatment with high-dose methylprednisolone were evaluated in a porcine model of early adult respiratory distress syndrome induced by endotoxaemia. Spontaneously breathing pigs under ketamine anaesthesia were infused i.v. with E. coli endotoxin (10 micrograms . h-1 . kg-1) over 6h. Twenty animals received endotoxin without treatment. Eight animals were pretreated with methylprednisolone i.v., 60 mg . kg-1, followed by an i.v. infusion at a rate of 10 mg . h-1 . kg-1. Ten animals received the same dosage of methylprednisolone beginning 2 h after the start of endotoxin infusion. Pretreatment with methylprednisolone prevented the endotoxin-induced impairment in pulmonary gas exchange and the development of pulmonary oedema. The pulmonary hypertension was counteracted. Cardiac output (Qt) and O2 delivery were improved. Mean arterial blood pressure (MAP) increased and was higher than in the untreated endotoxin group. The profound fall in PMN count was inhibited, while the accumulation of these cells in the lung was still substantial. Survival was improved. Delayed methylprednisolone treatment prevented further deterioration in pulmonary gas exchange and tended to restore it towards baseline. The pulmonary oedema and pulmonary hypertension were reduced. Qt and O2 delivery did not improve. MAP was higher than in the untreated endotoxin group towards the end of the observation period. The decline in PMN count and the pulmonary accumulation of these cells were not significantly influenced. Survival was improved. These results indicate that high-dose methylprednisolone, when given early in the course of sepsis, might be of clinical value in prevention of the devastating pulmonary and circulatory complications of this disease.     

Effects of ibuprofen on a porcine model of acute respiratory failure

Blockade of the arachidonic acid cascade has been shown to improve survival and hemodynamic alterations in animal models of sepsis and acute respiratory failure (ARF). The effects of intravenous ibuprofen, a cyclooxygenase inhibitor, were observed in 20-30 kg pigs with ARF induced by a continuous LD100 infusion of live Pseudomonas aeruginosa (2 X 10(8)/20 kg/min). Cardiopulmonary parameters were monitored in animals intubated, paralyzed, and ventilated at a 250-ml tidal volume and 0.5 FiO2. Pigs were randomly assigned to three groups: Group I received 2 bolus infusions of ibuprofen (12.5 mg/kg) at 20 and 210 min after baseline; Group II had Ps. aeruginosa (2 X 10(8) CFU/20 kg/min) only; Group III received Ps. aeruginosa and 12.5 mg/kg of ibuprofen at 20 and 210 min of ARF. Ibuprofen alone caused no significant changes in cardiorespiratory parameters. With Ps. aeruginosa infusion, significant pulmonary hypertension, hypoxemia, increased intrapulmonary shunt fraction, and systemic hypotension occurred. In the septic animals treated with ibuprofen, oxygenation was improved by a significant decrease in shunt, pulmonary edema, and pulmonary hypertension.     

The neuromuscular response of infants to a continuous infusion of succinylcholine

The response of the adductor of the thumb to ulnar nerve stimulation (0.1 Hz) was evaluated during continuous infusion of succinylcholine (SCh) in 20 infants anesthetized with halothane (1%) and N2O2/O2. Train-of-four stimulation (2 Hz for 2 s) was used to differentiate between phase I and phase II block. Some infants were very resistant to the neuromuscular effects of SCh. These infants (Group 1) were younger in age, 57 +/- 15 days (mean +/- SE) and required 24.6 +/- 3.3 mg X kg-1h-1 SCh to achieve more than 90% depression of the twitch. Older infants (Group 2), 188 +/- 33 days, required significantly less (P less than 0.001) SCh (8.7 +/- 0.5 mg X kg-1h-1) to achieve the same degree of twitch suppression. Group 1 infants recovered from the effects of SCh very rapidly. After 10 mg/kg SCh, the train-of-four ratio in Group 1 infants recovered to 75% in 4.7 +/- 0.6 min, whereas it took 34 +/- 10 min in Group 2 infants (P less than 0.01). Tachyphylaxis developed in infants after 3.6 +/- 0.3 mg/kg (mean +/- SE) and phase II block after 5.3 +/- 0.7 mg/kg (P less than 0.05) SCh. Combining the data of infants with that of children from a previous study conducted in a similar fashion resulted in significant correlation (P less than 0.001) between the log age and SCh requirement. The rate of administration of a continuous infusion of SCh in infants should be based upon the response of infants and not on a fixed dose (mg X kg-1 X h-1).     

The changes in hemodynamics and dose requirements in total intravenous anesthesia using propofol and buprenorphine

A retrospective study was performed to evaluate the changes in hemodynamics and dose requirements in total intravenous anesthesia (TIVA) using propofol and buprenorphine without (Group S: spinal surgery (3-6 h), n = 8, 28-79 Y) or with (Group A: abdominal surgery (5-10 h), n = 15, 36-83 Y) epidural anesthesia. All patients were premedicated with midazolam i.m. (2-5 mg). Anesthesia was maintained with a single dose of buprenorphine (Group S: 1.9 +/- 0.4 micrograms.kg-1, Group A: 2.0 +/- 0.5 micrograms.kg-1), propofol infusion and vecuronium with 40% oxygen in air. Group A was supplemented with continuous epidural anesthesia using 2% mepivacaine. In Group A, mean arterial pressure (MAP) and heart rate remained stable after the start of surgery. However, in Group S, 2 hours after the start of surgery MAP increased (P < 0.05) and remained elevated (P < 0.05) at higher levels than those in Group A. The maintenance dose of propofol in Group A (4.0 +/- 1.1 mg.kg-1.h-1) was significantly smaller than in Group S (6.5 +/- 0.9 mg.kg-1.h-1). In both groups, infusion rates of propofol were unchanged from 1 hour after the start to the end of surgery. Infusion rates of mepivacaine (5.2 +/- 0.9 ml.h-1) were unchanged following the increase 2 hours after the start of surgery. Awakening times were within 25 min (Group S 11.3 +/- 7.2 min vs Group A 14.7 +/- 7.3 min). There was no awareness during anesthesia in either group. The results suggest that additional continuous epidural anesthesia in TIVA would be useful to reduce propofol dose, to stabilize hemodynamic state and to obtain rapid recovery in anesthesia of long duration.     

Role of vitamin C on adrenocortical effects of etomidate]

This study was carried out to assess whether the adrenal inhibition induced by etomidate could be prevented by associating ascorbic acid with etomidate, as a protective effect of ascorbic acid administered three hours after etomidate has been described. Sixteen ASA 1 or 2 patients, less than 65 years old, free of endocrine disease, were included. At induction of anaesthesia, eight of them (group B) were given an infusion of ascorbic acid 1 g, in 500 ml of 5% glucose. Group A patients (n = 8) were given 500 ml of 5% glucose. Anaesthesia was induced with etomidate 0.3 mg.kg-1, fentanyl 0.005 mg.kg-1 and vecuronium 0.1 mg.kg-1. Maintenance was carried out using a continuous infusion of etomidate (0.1 mg.kg-1.h-1 for 10 min, followed by 0.01 to 0.02 mg.kg-1.h-1). Additional boluses of fentanyl or diazepam (10 mg) were administered when arterial blood pressure or heart rate were 20% greater than preanaesthetic values. The number of injections required was the same in both groups. Plasma cortisol concentrations were measured by radioimmunoassay (RIA) before anaesthesia (T0), 4 h (T4) and 24 h (T24) after the end of surgery. Blood ACTH levels were also assessed by RIA at T0 and T4. The adrenal insufficiency at T4 had completely ended at T24. In fact, the relative decrease in cortisol levels was greater in patients treated with ascorbic acid (T4/T0: 47.6 +/- 9% in group A vs 76.5 +/- 33% in group B, p less than 0.05); this was suggestive of a higher degree of adrenal inhibition in patients receiving ascorbic acid.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prophylactic and delayed treatment with indomethacin in a porcine model of early adult respiratory distress syndrome induced by endotoxaemia

The effects of prophylactic and delayed treatment with indomethacin were evaluated in a porcine model of early adult respiratory distress syndrome (ARDS) induced by endotoxaemia. Spontaneously breathing pigs under ketamine anaesthesia were infused i.v. with E. coli endotoxin (10 micrograms . h-1 . kg-1) over 6 h. Twenty animals received endotoxin without treatment. Eight animals were pretreated with indomethacin i.v., 5 mg . kg-1 in 30 min, followed by further infusion at a rate of 2 mg . h-1 . kg-1. Ten animals received the same dosage of indomethacin beginning 2 h after the start of endotoxin infusion. Pretreatment with indomethacin inhibited the endotoxin-induced impairment in pulmonary gas exchange, but did not prevent pulmonary oedema. The pulmonary hypertension was counteracted. Oxygen delivery did not improve, because of a marked reduction in cardiac output (Qt). Systemic vascular resistance (SVR) increased markedly, and mean arterial pressure (MAP) was higher. Survival was improved. Delayed indomethacin treatment prevented a further deterioration in pulmonary gas exchange and restored it towards the baseline level. The pulmonary oedema was not counteracted, while the pulmonary hypertension was reduced. O2 delivery was not restored, owing to the greater decrease in Qt compared with the untreated endotoxin group. SVR increased considerably, and MAP was better maintained. Survival was not improved. These results indicate that cyclo-oxygenase inhibitors might benefit pulmonary gas exchange in human ARDS. Drugs which interfere with arachidonate metabolism will probably be of great importance in the prophylaxis, in particular, and also in the treatment of ARDS.     

Sedation with propofol and fentanyl in patients under intensive care]

This study investigated the efficacy of a constant rate infusion of propofol and fentanyl in thirty patients requiring artificial ventilation for more than 24 h. A loading dose, which differed according to the patient's age, was administered over a 30 min period: 2.5 mg.kg-1 for patients less than 50 (G1) (n = 9), 2 mg.kg-1 for patients between 50 and 60 years old (G2) (n = 9), and 1.5 mg.kg-1 for patients over 60 (G3) (n = 12). This was followed by an infusion of 3 mg.kg-1.h-1 in G1 and G2, and 2 mg.kg-1.h-1 in G3. A 1 microgram.kg-1.h-1 infusion of fentanyl was also given. The degree of sedation was assessed with the Ramsay scale before starting, after induction, and every four hours thereafter. When this proved to be insufficient, the dose of propofol was increased by 0.5 mg.kg-1.h-1 as well as that of fentanyl by 0.5 microgram.kg-1.h-1. Heart rate, mean arterial blood pressure, blood propofol, creatinine, transaminase and lipid levels, and urine output were measured before, during, and after the infusion. The blood propofol level increased during the infusion, being correlated to the doses given (r = 0.64, p less than 0.001). Sedation lasted 91.7 +/- 57.7 h. After stopping the infusion of propofol, mean recovery times were 7.5 +/- 5.9 min (G1), 11.4 +/- 11.4 min, and 14.4 +/- 13.5 min (G3) (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Propofol Anesthesia Compared to Awake Reduces Infarct Size in Rats

Background: Propofol has not been studied directly in animals subject to cerebral ischemia in the conscious state. Strokes are usually induced in animals while they are anesthetized, making it difficult to eliminate anesthetic interactions as a complicating factor. Therefore, to compare the neuroprotective effects of propofol to the unanesthetized state, experiments were performed using a model that induces a stroke in the conscious rat.

Methods: Cerebral ischemia was induced in awake Wistar rats by a local intracerebral injection of the potent vasoconstrictor endothelin. Four days before the strokes were induced, a guide cannula was implanted for the injection of endothelin. On the day of the experiment, endothelin (6.0 pmol in 3 [mu]l) was injected into the striatum. Propofol (25 or 15 mg [middle dot] kg-1 [middle dot] h-1) or intralipid (vehicle) were infused for 4 h starting immediately after the endothelin injection. In another series, the propofol infusion was begun 1 h after the endothelin injection and continued for 4 h. Three days later, the animals were killed, and the brains were sectioned and stained.

Results: The propofol group (25 mg [middle dot] kg-1 [middle dot] h-1) had a significantly reduced infarct size (0.7 +/- 0.21 mm3, first 4 h; 0.27 +/- 0.07 mm3, started 1 h after initiation of infarct) compared with the intralipid controls (3.40 +/- 0.53 mm3). To exclude a direct interaction between propofol and endothelin, in thiobutabarbital anesthetized rats, endothelin-induced cerebral vasoconstriction was examined using videomicroscopy, with or without propofol. Propofol had no effect on the magnitude or time course of the endothelin-induced vasoconstriction.     

Propofol anesthesia compared to awake reduces infarct size in rats

BACKGROUND: Propofol has not been studied directly in animals subject to cerebral ischemia in the conscious state. Strokes are usually induced in animals while they are anesthetized, making it difficult to eliminate anesthetic interactions as a complicating factor. Therefore, to compare the neuroprotective effects of propofol to the unanesthetized state, experiments were performed using a model that induces a stroke in the conscious rat. METHODS: Cerebral ischemia was induced in awake Wistar rats by a local intracerebral injection of the potent vasoconstrictor endothelin. Four days before the strokes were induced, a guide cannula was implanted for the injection of endothelin. On the day of the experiment, endothelin (6.0 pmol in 3 microl) was injected into the striatum. Propofol (25 or 15 mg. kg-1. h-1) or intralipid (vehicle) were infused for 4 h starting immediately after the endothelin injection. In another series, the propofol infusion was begun 1 h after the endothelin injection and continued for 4 h. Three days later, the animals were killed, and the brains were sectioned and stained. RESULTS: The propofol group (25 mg. kg-1. h-1) had a significantly reduced infarct size (0.7 +/- 0.21 mm3, first 4 h; 0.27 +/- 0.07 mm3, started 1 h after initiation of infarct) compared with the intralipid controls (3.40 +/- 0.53 mm3). To exclude a direct interaction between propofol and endothelin, in thiobutabarbital anesthetized rats, endothelin-induced cerebral vasoconstriction was examined using videomicroscopy, with or without propofol. Propofol had no effect on the magnitude or time course of the endothelin-induced vasoconstriction. CONCLUSIONS: The results show that concurrent or delayed administration of propofol is neuroprotective.     

A new sedation technique with propofol during spinal anesthesia

We compared our new sedation technique with propofol during spinal anesthesia (Group B, n = 50) with a previously described method by Mackenzie et al. (Group A, n = 20). In Group A, propofol was started at a rate of 6 mg.kg-1.h-1 for 10 minutes, followed by continuous infusion at a rate of 4 mg.kg-1.h-1 till the end of surgery. In Group B, propofol 0.4 mg.kg-1 was administered by a bolus injection at the beginning. One-hundred and fifty minutes after the first injection, propofol 0.2 mg.kg-1 was added. The third dose of 0.1 mg.kg-1 of propofol was given 150 seconds after the second dose, followed by continuous infusion at a rate of 4 mg.kg-1.h-1 till the end of surgery. When adequate sedation was not obtained in Group B, propofol 0.1 mg.kg-1 was added by bolus fashion occasionally. In Group A, it took 9 min. 29 sec. to complete adequate sedation assessed by Mackenzie and Grant's sedation score. On the other hand, in Group B, it was 7 min. 27 sec. (P < 0.05 compared with Group A). There was neither excitation nor movement during sedation in Group B, while 5 patients experienced such events in Group A. The blood concentrations of propofol in Group B was 0.946 +/- 0.076 microgram.ml-1 and 0.693 +/- 0.136 microgram.ml-1 at 5 minutes and 10 minutes after the beginning of propofol, respectively. These values were significantly lower than those reported by Kugimiya. Our newly developed method for sedation with propofol during spinal anesthesia would be safer and more effective than that previously described by Mackenzie et al.     

Prophylactic treatment with an aerosolized corticosteroid liposome in a porcine model of early ARDS induced by endotoxaemia

The effects of prophylactic treatment with an aerosolized corticosteroid liposome (CSL) in high dose were evaluated in a porcine model of early Adult Respiratory Distress Syndrome (ARDS) induced by endotoxaemia. Intermittent positive pressure ventilated (IPPV) pigs under chlormethiazole anaesthesia were infused with E. coli endotoxin (18 micrograms.kg-1.h-1) over 4 h. Eight animals served as controls and were pretreated with aerosolized placebo liposomes, either 15 min or 2 h, before start of the endotoxin infusion. Eight animals were pretreated with CSL in aerosolized form 15 min before start of endotoxin, and eight animals were pretreated 2 h before start of endotoxin. Pretreatment with CSL, both 15 min and 2 h before endotoxin, modified and partly counteracted the late endotoxin-induced impairment in expiratory resistance (EXPres), dynamic compliance (Cdyn) and mean pulmonary artery pressure (MPAP). The administration of CSL did not seem to have a restrictive influence on the endogenous cortisol production estimated by repeated measurements of serum cortisol levels. These results indicate that CSL, administered prophylactically in an aerosolized form to the lung, might be valuable as a modulator without systemic side effects in regard to some of the endotoxin-induced pulmonary impairments seen in this experimental model of early ARDS.     

Thiopental pharmacokinetics under conditions of long-term infusion

Thiopental was used in long-term infusion (3-4.5 mg . kg-1 . h-1 during 4-8 days) to protect the brain from injury following trauma. Thiopental plasma concentrations were measured during infusion (48 patients) and after infusion (14 patients) to determine the kinetics of the drug in continuous infusion. All mean values were mean +/- SD. Steady state concentrations (Css) were 31.8 +/- 10.7 mg/l for an infusion rate of 3.05 +/- 0.37 mg . kg-1 . h-1 and 48.9 +/- 14.6 mg/l for a rate of 4.2 +/- 0.3 mg . kg-1 . h-1. Corresponding steady state clearance decreased when Css increased, indicating possible saturation of the metabolic enzymatic system. Michaelis-Menten kinetics were confirmed by postinfusion data that give, for higher Css, a nonlinear decay of log C versus time. First-order kinetics were only obtained with Css below 30 mg/l. The maximum rate of elimination (Vm) was 1.76 +/- 1.15 mg . l-1 . h-1 (n = 11), and the Michaelis constant (Km) was 26.7 +/- 22.9 mg/l (n = 11). Hepatic enzyme saturation was between 35 and 85%. The volume of distribution at steady state was 4.35 +/- 1.83 l/kg (n = 11). Apparent half-lives of elimination were between 18 and 36 h at the end of infusion, and predicted terminal half-lives were 10.15 +/- 5.43 h (n = 11). Phases of burst-suppression were observed on electroencephalographic traces for concentrations greater than 40 mg/l. The authors' results suggest that a continuous infusion at a dose of 4 mg . kg-1 . h-1 induces EEG changes consistent with a near-maximum reduction in cerebral metabolism. Because of the thiopental Michaelis-Menten kinetics at doses above 4 mg . kg-1 . h-1, the authors suggest that thiopental plasma concentrations be measured and/or the drug effect be measured with the EEG to prevent excessive thiopental overdosage, causing a prolonged recovery time.     

A comparison of fentanyl and buprenorphine in total intravenous anesthesia using propofol during spinal surgery

A retrospective study was performed to compare the hemodynamic effect and postoperative pain relief of fentanyl (Group F, n = 11) and buprenorphine (Group B, n = 11) in total intravenous anesthesia (TIVA) using propofol during spinal surgery. All patients were premedicated with midazolam (3-5 mg) i.m. Anesthesia was maintained with propofol infusion, and increments of fentanyl or single dose of buprenorphine with 40% oxygen in air. Total doses of fentanyl and buprenorphine were 7.6 +/- 1.0 micrograms.kg-1 and 2.0 +/- 0.4 micrograms.kg-1, respectively. Maintenance doses of propofol (Group F: 5.5 +/- 0.8 mg.kg-1.h-1, Group B: 5.9 +/- 1.1 mg.kg-1.h-1) and vecuronium were not significantly different. Mean arterial pressures from 2 hours after incision to the end of surgery were elevated significantly in Group F than in Group B. Recovery time (Group F 12.5 +/- 6.1 min vs Group B 11.8 +/- 6.1 min) and extubation time (Group F 19.5 +/- 10.3 min vs Group B 15.0 +/- 7.0 min) were not different. At the end of anesthesia, seven patients in Group F and one patient in Group B (P < 0.01) complained of severe pain. All patients in Group F, and only two in Group B (P < 0.02) received analgesics within 20 hours. Neither nausea nor respiratory depression was found in both groups. This study suggests that buprenorphine would provide a more stable hemodynamic state and better postoperative pain relief than fentanyl in TIVA using propofol.     

A comparison of the effect on gastric emptying of propofol or dexmedetomidine in critically ill patients: preliminary study

BACKGROUND: Propofol and dexmedetomidine are widely used for sedation in the intensive care unit yet there are limited data on its effects on gastric motility. In our preliminary study, we examined whether or not any effect of propofol and dexmedetomidine on gastric emptying is preserved in critically ill patients. METHODS: Twenty-four critically ill, enterally fed adult patients each received enteral feeding via a nasogastric tube at 50 mL h-1 throughout the 5-h study period. Either propofol 2 mg kg-1 h-1 (n = 12, Group P) or dexmedetomidine 0.2 microg kg-1 h- (n = 12, Group D) was given intravenously over 5 h. Gastric motility was measured indirectly by analysis of the absorption over time of 1.5 g of paracetamol administered into the stomach at the start of the study period. At the beginning and end of the study, residual gastric volume and pH of residual gastric fluid were measured. RESULTS: Gastric residual volume measured at the end of propofol infusion (19.33 +/- 11.33) was found to be higher when compared with the volume measured before infusion (11.33 +/- 4.84) and after dexmedetomidine infusion (9.17 +/- 4.54). But, there was no difference between groups in gastric emptying time (AUC120 894.53 +/- 499.39 vs. 1113.46 +/- 598.09 propofol and dexmedetomidine groups, respectively). CONCLUSION: In our study, gastric residual volume measured at the end of propofol infusion was found to be higher when compared with the volume measured before infusion and after dexmedetomidine infusion. There was no difference between groups in gastric emptying time.     

A critical comparison of the hematologic, cardiovascular, and pulmonary response to steroids and nonsteroidal anti-inflammatory drugs in a model of sepsis and adult respiratory distress syndrome

Improved survival of patients receiving high-dose steroid therapy in sepsis and adult respiratory distress syndrome (ARDS) has been reported, but such therapy and its benefits remain controversial. Recently research has been directed toward manipulation of the arachidonic acid cascade. Improved survival and hemodynamics with administration of nonsteroidal anti-inflammatory drugs (NSAID) have been reported in animal models of sepsis and ARDS. The purpose of this study was to compare the effects of steroids (methylprednisolone) and NSAID (ibuprofen) in a porcine model of septic ARDS induced by a continuous infusion of live Pseudomonas aeruginosa. Cardiopulmonary parameters were monitored in animals intubated, paralyzed, and ventilated at a 250 ml tidal volume and 0.5 Fio2. Pigs were randomly assigned to one of five groups: groups I and II received respective doses of 12.5 mg/kg ibuprofen and 30 mg/kg methylprednisolone at 20 and 210 minutes after baseline; group III had P. aeruginosa only; groups IV and V received respective doses of ibuprofen and methylprednisolone at 20 and 210 minutes of sepsis. Significant pulmonary edema, increased intrapulmonary shunting, hypoxemia, hemoconcentration, and systemic hypotension occurred with P. aeruginosa infusion. In septic animals treated with ibuprofen normal systemic arterial pressure was maintained, hemoconcentration was decreased, and oxygenation was improved with a significant decrease in shunting and pulmonary edema. Administration of methylprednisolone improved hemoconcentration and cardiac index, but no significant effect on pulmonary edema, intrapulmonary shunting, or oxygenation was observed. The results of this study demonstrated a significant beneficial effect of ibuprofen and we would encourage controlled clinical trials of this drug in the management of sepsis and ARDS. On the other hand, methylprednisolone was found to be relatively ineffective in treatment of circulatory collapse and ARDS associated with sepsis.     

Effects of trimethaphan on arterial blood histamine and systemic hemodynamics in humans

Because of lack of direct evidence of histamine release by trimethaphan, the authors determined serum histamine levels and hemodynamic responses to trimethaphan administration in 19 consecutive patients. Group 1 patients (n = 7) received a single intravenous injection of trimethaphan, 0.5 mg X kg-1, while awake and again during stable halothane-nitrous oxide anesthesia. Group 2 patients (n = 6) were pretreated with intravenous H1 (chlorpheniramine, 0.1 mg X kg-1) and H2 (cimetidine, 4 mg X kg-1) receptor antagonists administered 15 min before trimethaphan, 0.5 mg X kg-1, in the awake and anesthetized states. In Group 3 (n = 6), the effects of infusion of trimethaphan, 3 mg X min-1 for 15 min, were studied during halothane-nitrous oxide anesthesia. In Group 1, bolus doses of trimethaphan were associated with maximal increases in serum histamine from 0.56 +/- 0.14 to 2.56 +/- 0.35 ng X ml-1 (P less than 0.01) and from 0.60 +/- 0.11 to 2.58 +/- 0.33 ng X ml-1 (P less than 0.01) 2 min after drug administration in the awake and anesthetized states, respectively; there were also clinical manifestations of histamine release. Mean arterial pressure decreased maximally after 5 min in the awake (from 92.0 +/- 3.4 to 69.9 +/- 2.2 mmHg; P less than 0.01) and anesthetized (from 82.6 +/- 3.7 to 57.3 +/- 2.5 mmHg; P less than 0.01) states, and was associated with increases in cardiac output and heart rate; stroke volume increased in the awake state only.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of magnesium sulfate administration on cerebral and cardiac toxicity of bupivacaine in dogs

The effect of acutely elevated serum magnesium on the CNS and cardiac toxicity of bupivacaine was studied. Anesthesia was induced in mongrel dogs with thiopental, 25 mg/kg, and ventilation was controlled. Sedation was maintained with fentanyl (25 micrograms/kg bolus and 5 micrograms.kg-1h-1) and pancuronium (0.15 mg/kg bolus and 0.05 mg.kg-1h-1) provided paralysis. Two hours after the thiopental bolus, all animals received an intravenous (iv) infusion of bupivacaine (1 mg.kg-1 min-1). The control group (5 animals) received bupivacaine only. The Mg++ group (5 animals) received MgSO4 140 mg/kg iv and 80 mg.kg-1 h-1 15 min prior to beginning the bupivacaine infusion. Lead II ECG, cardiac hemodynamics, and two-channel EEG were continuously monitored. Serum magnesium concentrations in the Mg++ group rose from 0.67 mM (1.3 mEq/L) to 2.42 mM (4.8 mEq/L). The bupivacaine infusion caused PR and QRS interval prolongation in both groups, but QRS widening was greater in the control group. QT interval corrected for heart rate (QTIc) lengthened only in the control group. A depression of left ventricular stroke work index (LVSWI) occurred to an equal extent in both groups. The seizure dose of bupivacaine was not different between the two groups: 12.9 +/- 2.3 (SEM) mg/kg in the control group and 13.9 +/- 2.5 mg/kg in the Mg++ group.(ABSTRACT TRUNCATED AT 250 WORDS)     

4-Chloro-m-cresol is a Trigger of Malignant Hyperthermia in Susceptible Swine

Background: 4-Chloro-m-cresol (4-CmC) induces marked contractures in skeletal muscle specimens from individuals susceptible to malignant hyperthermia (MHS). In contrast, 4-CmC induces only small contractures in specimens from normal (MHN) patients. 4-CmC is a preservative within a large number of commercially available drug-preparations (e.g., insulin, heparin, succinylcholine), and it has been suggested that 4-CmC might trigger malignant hyperthermia. This study was designed to investigate the effects of 4-CmC in vivo and in vitro in the same animals.

Methods: After approval of the animal care committee, six Pietrain MHS and six control (MHN) swine were anesthetized with azaperone 4 mg/kg intramuscularly and metomidate 10 mg/kg intraperitoneally. After endotracheal intubation, lungs were mechanically ventilated (inspired oxygen fraction 0.3) and anesthesia was maintained with etomidate 2.5 mg [middle dot] kg-1 [middle dot] h-1 and fentanyl 50 [micro sign]g [middle dot] kg-1 [middle dot] h-1. Animals were surgically prepared with arterial and central venous catheters for measurement of hemodynamic parameters and to obtain blood samples. Before exposure to 4-CmC in vivo, muscle specimens were excised for in vitro contracture tests with 4-CmC in concentrations of 75 and 200 [micro sign]M. Subsequently, pigs were exposed to cumulative administration of 3, 6, 12, 24, and 48 mg/kg 4-CmC intravenously. If an unequivocal episode of malignant hyperthermia occurred, as indicated by venous carbon dioxide concentration >or= to 70 mmHg, pH or= to 2 [degree sign]C, the animals were treated with dantrolene, 3.5 mg/kg.

Results: All MHS swine developed malignant hyperthermia after administration of 4-CmC in doses of 12 or 24 mg/kg. Venous carbon dioxide concentration significantly increased and pH significantly decreased. Temperature increased in all MHS animals more than 2 [degree sign]C. Blood lactate concentrations and creatine kinase levels were significantly elevated. All MHS swine were treated successfully with dantrolene. In contrast, no MHN swine developed signs of malignant hyperthermia. After receiving 4-CmC in a concentration of 48 mg/kg, however, all MHN animals died by ventricular fibrillation. The in vitro experiments showed that both concentrations of 4-CmC produced significantly greater contractures in MHS than in MHN specimens.     

Effects of Perfluorohexan Vapor on Gas Exchange, Respiratory Mechanics, and Lung Histology in Pigs with Lung Injury after Endotoxin Infusion

Background: Inhaled perfluorohexan vapor has been shown to improve gas exchange and pulmonary mechanics in oleic acid- and ventilator-induced lung injury. However, in the clinical setting, lung injury frequently occurs in the context of systemic inflammation and consecutive lung injury, which may be induced experimentally by intravenous administration of endotoxin. The authors studied whether vaporized perfluorohexan is efficacious during endotoxin-induced lung injury in domestic pigs.

Methods: Twenty-two pigs (29 [23, 31] kg body weight [first, third interquartile]; tracheostomy) were anesthetized and mechanically ventilated. In the endotoxin (n = 8) and perfluorohexan groups (n = 7), we administered endotoxin of Escherichia coli 111:B4, 1 mg [middle dot] kg-1 [middle dot] h-1 for 1 h and 10 [mu]g [middle dot] kg-1 [middle dot] h-1 for 5 h in consecutive order. In the perfluorohexan group, inhalation of the test drug was started 2 h 30 min after the start of the intravenous endotoxin and terminated after 30 min. In a control group (n = 7), animals were instrumented and observed over time without further intervention. Oxygenation function was assessed from oxygen partial pressures (Po2, blood gases) and calculated shunt fraction. Respiratory compliance was calculated from airway pressure and tidal volume. Measurements were performed before and every hour during endotoxin infusion.

Results: After 6 h of endotoxin, gas exchange and pulmonary compliance were deteriorated in the endotoxin group (Pao2: 184 [114, 289] vs. 638 [615, 658] mmHg, pulmonary shunt fraction: 30 [23, 38] vs. 4 [3, 6]%, respiratory compliance: 12 [11, 14] vs. 22 [19, 23] ml/mbar; P < 0.05, endotoxin vs. control). Inhalation of vaporized perfluorohexan did not improve Pao 2 (107 [60, 221] mmHg), pulmonary shunt fraction (32 [26, 58]%), or respiratory compliance (14 [10, 17] ml/mbar) when compared with intravenous endotoxin (not significant, perfluorohexan vs. endotoxin).