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We conducted the current study to compare the efficacy of partial liquid ventilation (PLV), pulmonary surfactant (PSF), and their combination in ameliorating the acidified infant-formula-induced acute lung injury (ALI). In the Part I study, 42 rabbits receiving volume-controlled ventilation with positive end-expiratory pressure 10 cm H(2)O were randomly divided into 6 groups (groups noninjuryI, gas ventilation [GVi], PLVi, PSFi, PLVi-->PSFi, and PSFi-->PLVi). ALI was induced by intratracheal acidified infant formula (2 mL/kg, pH 1.8). Group GVi received neither PLV nor PSF therapy. Groups PLV and PSF received intratracheal fluorocarbon 15 mL/kg or surfactant 100 mg/kg, respectively, 30 min after acidified infant formula. Groups PLVi-->PSFi and PSFi-->PLVi received both treatments at 30-min intervals. In Part II, 42 rabbits (in 6 groups) undergoing pressure-controlled ventilation received the same drug therapies as in Part I. The lungs were excised to assess biochemical and histological damage 150 min after induction of ALI. In Parts I and II, PSF, fluorocarbon, and their combination attenuated lung leukosequestration and edema and superoxide production of neutrophils, consequently improving oxygenation, lung mechanics, and pathological changes. Independent of ventilation mode, PSF followed by fluorocarbon provided the most beneficial effects and fluorocarbon followed by PSF produced the least efficacy.

Endotoxin causes acute lung injury (ALI) through many mediators of inflammatory and immune responses. Propofol is an antiinflammatory and immunosuppressive drug. We conducted this study to evaluate whether propofol attenuates ALI associated with endotoxemia. Thirty-two anesthetized rabbits were randomly divided into four groups (n = 8 each). ALI was induced by IV endotoxin 5 mg/kg over 30 min in 3 groups. In 2 of the ALI groups, IV administration of propofol (2 or 5 mg/kg as a bolus followed by continuous infusion at 4 or 15 mg x kg(-1) x h(-1)) was started 15 min before endotoxin. The other ALI group received soybean-oil emulsion. The nonlung injury control group received infusion of both vehicles. The lungs were mechanically ventilated with 40% oxygen for 6 h after endotoxin. Hemodynamics did not differ among groups. The large dose of propofol attenuated lung leukosequestration, pulmonary edema (as assessed by lung wet/dry weight ratio), and pulmonary hyperpermeability (as assessed by albumin levels in bronchoalveolar lavage fluid) and resulted in better oxygenation, lung mechanics, and histological change. The small dose of propofol failed to do so. Our findings suggest that a large dose of propofol successfully mitigates physiological, biochemical, and histological deterioration in ALI in endotoxemia.

Unlabelled: Our aim in the current study was to determine whether recombinant surfactant protein-C (rSP-C) surfactant improves acute lung injury (ALI) induced by intratracheal acidified milk products. Twenty-eight rabbits were randomly divided into four groups. ALI was induced with intratracheal acidified infant formula (0.8 mL/kg, pH 1.8) in 3 groups. The control group received intratracheal acidified saline. Therapy groups received 1 of 2 doses of intratracheal rSP-C surfactant (0.5 or 2 SP-C mg/kg) 30 min after the acidified infant formula. The lungs were ventilated with 100% oxygen for 4 h after induction of ALI. Acidified infant formula dramatically reduced oxygenation and lung compliance, and increased resistance. Both doses of rSP-C improved the variables [mean PaO(2) (mm Hg) and compliance (mL/cm H(2)O) at 4 h: 61 and 0.4 for infant formula, 162 and 1.0 for small-dose rSP-C, and 152 and 1.2 for large-dose rSP-C, respectively; P < 0.05]. Pulmonary leukosequestration and edema, and severe morphological changes were attenuated by rSP-C treatment (ALI score: 14, 7, 7 in infant formula, small-dose rSP-C, and large-dose rSP-C; P < 0.05). The efficacy was similar for the two doses of rSP-C. These findings suggest that intratracheal administration of rSP-C ameliorates ALI induced by aspiration of acidified milk products., Implications: Small or large doses of recombinant surfactant protein-C surfactant given 30 min after intratracheal acidified infant formula attenuated physiological, biochemical, and morphological lung damage.

Unlabelled: Overproduction of nitric oxide by inducible nitric oxide synthase (iNOS) expressed in the lung is thought to play a crucial role in the pathogenesis of endotoxin-induced acute lung injury (ALI). In this two-part study, we determined whether ONO-1714, a new selective iNOS inhibitor, attenuates endotoxin-induced ALI in rabbits. For Part I of the study, a control group received IV saline and ALI was induced by IV infusion of endotoxin 5 mg/kg over 30 min in 4 groups. Three groups received either 0.1, 0.03, or 0.01 mg/kg of ONO-1714 10 min before the start of endotoxin and the fourth group received saline. For Part II of the study, ALI was induced by endotoxin infusion in all 6 groups. One group was treated with saline. The other 5 groups received ONO-1714 0.1 mg/kg at various timings (10 min before or 1, 2, 3, or 4 h after ALI induction). The lungs were mechanically ventilated with 40% oxygen for 6 h after induction of ALI. In Part I, pretreatment with 0.1 mg/kg ONO-1714 mitigated endotoxin-induced ALI. In Part II, early posttreatment (within 2 h after the insult) with ONO-1714 was as effective as pretreatment in improving oxygenation, lung mechanics, lung leukosequestration, pulmonary edema, and histological change. However, lung damage was not improved in rabbits receiving the drug 3 or 4 h after endotoxin. These data suggest that the current study is a basis for future clinical trials to elucidate whether ONO-1714 can be a promising therapeutic approach in patients with acute respiratory distress syndrome induced by endotoxin/sepsis., Implications: An excess of nitric oxide is thought to play a crucial role in the pathogenesis of acute organ injury in endotoxemia. Early posttreatment with ONO-1714, a nitric oxide synthase inhibitor, attenuated physiological, biochemical, and pathological changes in endotoxin-induced acute lung injury in rabbits.

Implications: Acid aspiration syndrome remains a potentially critical perioperative complication. We compared lafutidine, ranitidine, and rabeprazole for reduction of preoperative gastric fluid acidity and volume in elective surgery and found that these variables were minimized with a single morning dose of lafutidine 20 mg compared with ranitidine or rabeprazole. Preoperative oral lafutidine may be an alternative to ranitidine as a prophylaxis against aspiration pneumonia.

Unlabelled: Acid aspiration syndrome at the induction of anesthesia is still a potentially life-threatening complication. Its severity is affected by both pH and volume of the gastric juice that is aspirated. We compared the effects of rabeprazole (a new proton pump inhibitor), lansoprazole, and ranitidine on gastric fluid properties in a prospective, randomized, double-blinded fashion in 180 adult patients undergoing elective surgery. Patients were divided into six groups (n = 30 in each) according to their premedication. Patients in each group received placebo-rabeprazole (PLA-RAB), rabeprazole-placebo (RAB-PLA), rabeprazole-rabeprazole (RAB-RAB), lansoprazole-lansoprazole (LAN-LAN), placebo-ranitidine (PLA-RAN), or placebo-placebo (PLA-PLA) for the first-second medication. Each dose of the study drug was 20 mg for rabeprazole, 30 mg for lansoprazole, and 150 mg for ranitidine. The first medication was given orally at 9:00 PM on the day before surgery and the second at 5:30 AM on the day of surgery. Each patient fasted overnight and took the drug with 20 mL of water. After tracheal intubation, gastric fluid was aspirated via an orogastric tube, and the volume and pH of the aspirate was measured. Preoperative gastric fluid acidity and volume were improved by the study drugs in the following order: PLA-RAN (pH 5.3, volume 0.10 mL/kg), RAB-RAB, LAN-LAN, PLA-RAB, and RAB-PLA (pH 3.8, volume 0.22 mL/kg). The proportion of patients at risk of acid aspiration syndrome according to the traditional criteria (pH < 2.5 and volume > 0.4 mL/kg) was minimized in Groups RAB-RAB and PLA-RAN (0%). We concluded that a single morning dose of ranitidine rather than two doses (bedtime and morning) of rabeprazole was the most effective premedicant to control gastric fluid properties and to minimize the risk of aspiration pneumonitis., Implications: Acid aspiration syndrome at the induction of anesthesia is rare but still a potentially life-threatening complication. We compared rabeprazole, lansoprazole, and ranitidine for reduction of preoperative gastric fluid acidity and volume in elective surgery and found that a combination of bedtime and morning doses of rabeprazole, or a morning dose of ranitidine, similarly minimized the variables. In adult patients who are at risk of aspirating gastric contents, improvement of gastric fluid environment by rabeprazole can reasonably be anticipated to provide protection against pneumonitis should regurgitation and aspiration of gastric contents occur.

Unlabelled: We recently showed that verapamil attenuated hemodynamic responses to tracheal extubation. The aim of the current study was to compare the efficacy of a combination of intravenous (I.V.) verapamil (0.1 mg/kg) and I.V. lidocaine (1 mg/kg) with that of each drug alone in suppressing the cardiovascular changes during tracheal extubation and emergence from anesthesia. One hundred adult patients (ASA physical status I) who were to undergo elective minor surgery were randomly assigned to one of four groups (n = 25 each): Group S = saline plus saline (control), Group V = verapamil 0.1 mg/kg I.V. plus saline, Group L = lidocaine 1 mg/kg I.V. plus saline, and Group V-L = verapamil 0.1 mg/kg I.V. plus lidocaine 1 mg/kg I.V. These medications were given 2 min before tracheal extubation. Anesthesia was maintained with 1.0%-2.0% sevoflurane and 60% nitrous oxide (N2O) in oxygen. Muscle relaxation was achieved with vecuronium, and a residual neuromuscular blockade was reversed with neostigmine 0.05 mg/kg (combined with atropine 0.02 mg/kg). Changes in heart rate (HR) and arterial blood pressure (AP) were measured during and after tracheal extubation. In the control group, the HR and systolic and diastolic AP increased significantly during tracheal extubation. Verapamil, lidocaine, and their combination attenuated the increases in these variables. The beneficial effect was the greatest with the combination of verapamil and lidocaine. These findings suggest that verapamil 0.1 mg/kg and lidocaine 1 mg/kg given I.V. concomitantly 2 min before tracheal extubation is a simple and more effective prophylaxis than verapamil or lidocaine alone for attenuating the cardiovascular changes associated with tracheal extubation., Implications: Tachycardia and hypertension associated with tracheal extubation, which may lead to myocardial ischemia, represent a potential risk for patients with coronary arterial disease. To seek effective pharmacological prophylaxis against these complications, we compared the attenuation of hemodynamic changes among verapamil, lidocaine, and a verapamil/lidocaine combination using ASA physical status I patients and found the combination to be effective.

Unlabelled: We previously reported that 20 and 40 microg/kg of granisetron given during anesthesia prevented postoperative emesis with no severe complications. The aim of the current study was to determine the optimal dose of granisetron for the prevention of postoperative nausea and vomiting (PONV) after gynecological surgery. Two hundred female patients (ASA physical status I) were randomly allocated to one of five groups (n = 40 for each): saline (as a control), granisetron 2 microg/kg, granisetron 5 microg/kg, granisetron 10 microg/kg, and granisetron 20 microg/kg. Saline or granisetron was given intravenously immediately after induction of anesthesia. PONV was assessed 24 h after surgery. The percentage of emesis-free patients was significantly greater in the 5- to 20-microg/kg granisetron groups than in the control and 2-microg/kg granisetron groups (18%, 23%, 68%, 78%, and 75% of patients receiving saline or granisetron 2 microg/kg, 5 microg/kg, 10 microg/kg, and 20 microg/kg, respectively). Granisetron doses of 5 microg/kg or larger were also superior to the saline and 2-microg/kg granisetron treatment for the prevention of nausea over the 24-h study period (nausea visual analog scales 24 h after surgery: 49, 41, 18, 16, and 14 mm in the control and granisetron 2 microg/kg, 5 microg/kg, 10 microg/kg, and 20 microg/kg groups, respectively). A smaller proportion of patients received "rescue" antiemetic in the 5-microg/kg or larger granisetron groups than in the control and 2-microg/kg granisetron groups (48%, 40%, 18%, 13%, and 10% of patients in the control and granisetron 2 microg/kg, 5 microg/kg, 10 microg/kg, and 20 microg/kg groups, respectively). The antiemetic effect of granisetron was similar among the groups who received 5-microg/kg or larger doses. In conclusion, we suggest that the optimal dose of granisetron is 5 microg/kg for the prevention of PONV after gynecological surgery., Implications: Nausea and vomiting postoperatively after gynecologic surgery is a significant problem. The authors found that granisetron, a selective antagonist of serotonin, markedly decreases the incidence of postoperative nausea and vomiting at doses of 5 microg/kg or larger.

Endotoxin causes acute lung injury resembling acute respiratory distress syndrome. Elastase, as well as reactive oxygen species released from activated neutrophils, are thought to play pivotal roles in the pathogenesis of this lung injury. This study investigated whether ONO-5046, a specific elastase inhibitor, can attenuate acute lung injury induced by endotoxin in rabbits. Thirty-two male anesthetized rabbits were randomly assigned to receive one of four treatments (n = 8 for each group): infusion of saline without ONO-5046 treatment (Group S-S), infusion of saline with ONO-5046 (Group S-O), infusion of Escherichia coli endotoxin (100 micrograms/kg over 60 min) without ONO-5046 (Group E-S), and infusion of endotoxin with ONO-5046 (Group E-O). Fifteen minutes before the infusion of endotoxin (Groups E-O and E-S) or saline (Groups S-S and S-O), the animals received a bolus injection of ONO-5046 (10 mg/kg) followed by continuous infusion (10 mg.kg-1.h-1: Groups S-O and E-O) or saline (Groups S-S and E-S). The lungs of the rabbits were ventilated with 40% oxygen. Hemodynamics, peripheral leukocyte and platelet counts, and PaO2 were recorded during the ventilation period (6 h). Lung mechanics, cell fraction of the bronchoalveolar lavage fluid (BALF), activated complement, cytokines, and arachidonic acid metabolite concentrations in the BALF were measured at 6 h. The wet- to dry (W/D)-weight ratio of the lung and albumin concentrations in BALF were analyzed as indices of pulmonary edema. Endotoxin decreased lung compliance and PaO2, and increased the W/D weight ratio, neutrophil counts, and albumin concentration in the BALF. Concentrations of activated complement C5a, interleukin-6, interleukin-8, and thromboxane B2 in the BALF were increased by the infusion of endotoxin. ONO-5046 treatment attenuated these changes. Endotoxin caused extensive morphologic lung damage, which was lessened by ONO-5046. In conclusion, intravenous ONO-5046 pretreatment attenuated endotoxin-induced lung injury in rabbits. This beneficial effect of ONO-5046 may be due, in part, to a reduction in the levels of mediators that activate neutrophils, in addition to the direct inhibitory effect on elastase.

Acid aspiration syndrome of induction of anesthesia is a life-threatening complication whose severity is affected by both pH and volume of the aspirated gastric juice. We compared the effects of two proton pump inhibitors (PPIs), lansoprazole and omeprazole, and an H2 blocker, ranitidine, on gastric secretion in a prospective, randomized, double-blind fashion in 200 adult patients of ASA physical status I undergoing elective surgery. The patients were divided into eight groups (n = 25 each) according to their premedication. The patients received lansoprazole-lansoprazole (Group L-L), lansoprazole-placebo (Group L-P), placebo-lansoprazole (Group P-L), omeprazole-omeprazole (Group O-O), omeprazole-placebo (Group O-P), placebo-omeprazole (Group P-O), placebo-ranitidine (Group P-R), or placebo-placebo (Group P-P), as the first and second medications. The dose of the study drug was 30 mg for lansoprazole, 150 mg for ranitidine, and 80 mg for omeprazole. The first medication was administered orally at 9:00 PM on the night before surgery and the second at 5:30 AM in the morning on the day of the surgery. Each patient fasted overnight and took the drug with 20 mL of water. After tracheal intubation, gastric fluid was aspirated via an orogastric tube and the volume and pH of the aspirate were measured. The pH of the aspirated gastric fluid was higher in Groups P-R, L-L, P-L, O-O, and O-P than in Group P-P (P < 0.05). The volume of the gastric contents was similar in Groups P-0 and P-P, and the other groups had smaller gastric volume than Group P-P (P < 0.05). Gastric fluid from patients in Group P-R was the least acidic (pH 6.1 +/- 1.2) and had the least volume (0.09 +/- 0.06 mL/kg). Group L-L was comparable with Group P-R in both pH and volume, whereas Groups P-L and O-O were similar to Group P-R only in volume. The proportion of patients at risk according to the traditional criteria (pH < 2.5 and volume 0.4 mL/kg) was significantly lower in Groups L-L (0%), P-L (4%), O-O (4%), and P-R (0%) than in Group P-P (48%) (P < 0.05). We concluded that two consecutive doses of lansoprazole or a morning dose of ranitidine seemed to be the most effective preanesthetic medication for reducing gastric acidity and volume.

Postoperative nausea and vomiting are common after recovery from anesthesia. We examined the prophylactic effect of granisetron on postoperative nausea and vomiting in 120 female patients (ASA physical status I) undergoing gynecologic surgery. They were randomly allocated to one of three groups (n = 40 for each): saline (as a control), granisetron 20 micrograms/kg, and granisetron 40 micrograms/kg. Saline or granisetron was given intravenously (IV) over 5 min approximately 30 min before the end of anesthesia. Nausea, vomiting, and safety assessments were performed during the 24-h recovery period. For the 24-h period after surgery, the number of emesis-free patients was significantly larger in the granisetron groups than in the control group (83%, 78%, and 20% of patients receiving granisetron 20 micrograms/kg and 40 micrograms/kg, and saline, respectively). Granisetron at both doses also was superior to the control for the prevention of nausea over the 24-h study period (nausea visual analog scales at 24-h postsurgery: 49 mm, 17 mm, and 18 mm in the control, granisetron 20 micrograms/kg, and granisetron 40 micrograms/kg groups, respectively). Fewer patients received "rescue" antiemetics in the granisetron groups than in the control group (10%, 10%, and 43% of patients in granisetron 20 micrograms/kg and 40 micrograms/kg, and the control groups, respectively). The adverse events in the granisetron groups were similar to those in the control group. The administration of granisetron had no significant effect on vital signs or clinical laboratory test profiles. Granisetron given at 20 or 40 micrograms/kg i.v. during anesthesia appears to be a simple, effective, and safe method for preventing postoperative nausea and vomiting.

Clonidine is a useful drug to give preoperatively because it produces anxiolysis, sedation, and hemodynamic stability, and reduces intravenous and volatile anesthetic requirements. Several premedicants, including midazolam and diazepam, have been shown to reduce the induction dose of intravenous anesthetics, such as thiopental, ketamine, or propofol. A randomized, double-blind controlled study was conducted to evaluate the effect of premedication with oral clonidine on thiamylal requirement for the induction of anesthesia and on associated hemodynamic changes in children. Sixty children (ASA grades I-II, 7-12 yr old) were assigned randomly to receive one of three treatments (n = 20, for each group): placebo (control), clonidine 2 micrograms/kg, or clonidine 4 micrograms/kg 105 min before the induction of anesthesia. Thiamylal was injected at a dose of 1 mg/kg every 15 s until loss of the eyelash reflex and the dose was recorded. Blood pressure (BP), heart rate (HR), and arterial oxygen saturation were recorded every minute from the beginning of injection of thiamylal for 5 min. Significant decreases in thiamylal dose were observed in patients receiving clonidine. The induction dose of thiamylal (mean +/- SD) was 5.4 +/- 0.9, 4.5 +/- 1.1, and 3.4 +/- 0.9 mg/kg for patients receiving placebo, clonidine 2 micrograms/kg, and clonidine 4 micrograms/kg, respectively (P < 0.05). Systolic BP decreased by 6.8%, 5.6%, and 6.6% and HR increased by 5.7%, 4.8%, and 4.1% after administration of thiamylal in the control (placebo) group and the clonidine 2 micrograms/kg and clonidine 4 micrograms/kg groups, respectively (P > 0.05). Premedication with oral clonidine reduced the dose of intravenous thiamylal required for the induction of anesthesia in children.

We conducted a randomized, placebo-controlled, and double-blind study to evaluate the efficacy of oral guanabenz, an alpha 2-adrenergic agonist, in attenuating the cardiovascular and catecholamine responses to laryngoscopy and tracheal intubation in 30 normotensive (ASA physical status 1) patients undergoing elective surgery. They were allocated to one of three groups (n = 10 for each): placebo, 4 mg, or 6 mg of guanabenz groups. These tablets were administered 2 h before the induction of anesthesia. Anesthesia was induced with thiopental 5.0 mg/kg intravenously (IV), and tracheal intubation was facilitated by the administration of vecuronium, 0.2 mg/kg IV. During anesthesia, ventilation was assisted or controlled with 1% enflurane and 50% nitrous oxide in oxygen. Laryngoscopy lasting 30 s was attempted 2 min after the administration of thiopental and vecuronium. Patients receiving placebo showed a significant increase in mean arterial blood pressure, heart rate, and plasma catecholamine concentrations in response to tracheal intubation. These changes were significantly smaller in patients receiving either dose of guanabenz (P < 0.05). Oral administration of guanabenz before induction of anesthesia is a simple and effective method for attenuating the pressor and tachycardic responses to laryngoscopy and tracheal intubation with the drug acting at least partly via inhibition of the increases in plasma catecholamines concentrations.