CYP2D6- and CYP3A-dependent enantioselective plasma concentrations of ondansetron in postanesthesia care

An influence of polymorphic cytochromes P450 (CYP) 2D6 genetic variants on antiemetic efficacy of ondansetron has been suggested. However, the role of CYP3A in ondansetron metabolism and efficacy has been unclear. In this study, we evaluated the hypothesis that genotype-dependent CYP2D6 and CYP3A activity selectively influences plasma concentrations of ondansetron enantiomers. Additionally, the effects of doubling the ondansetron dose on genotype-dependent plasma concentrations were investigated.

Ultrasonographic-guided ilioinguinal/iliohypogastric nerve block in pediatric anesthesia: what is the optimal volume?

Recently, our study group demonstrated the usefulness of ultrasonographic guidance in ilioinguinal/iliohypogastric nerve blocks in children. As a consequence, we designed a follow-up study to evaluate the optimal volume of local anesthetic for this regional anesthetic technique. Using a modified step-up-step-down approach, with 10 children in each study group, a starting dose of 0.2 mL/kg of 0.25% levobupivacaine was administered to perform an ilioinguinal/iliohypogastric nerve block under ultrasonographic guidance. After each group of 10 patients, the results were analyzed, and if all blocks were successful, the volume of local anesthetic was decreased by 50%, and a further 10 patients were enrolled into the study. Failure to achieve a 100% success rate within a group subjected patients to an automatic increase of half the previous volume reduction to be used in the subsequent group. Using 0.2 and 0.1 mL/kg of 0.25% levobupivacaine, the success rate was 100%. With a volume of 0.05 mL/kg of 0.25% levobupivacaine, 4 of 10 children received additional analgesia because of an inadequate block. Therefore, according to the protocol, the amount was increased to 0.075 mL/kg of 0.25% levobupivacaine, where the success rate was again 100%. We conclude that ultrasonographic guidance for ilioinguinal/iliohypogastric nerve blocks in children allowed a reduction of the volume of local anesthetic to 0.075 mL/kg.

The effects of dexmedetomidine/remifentanil and midazolam/remifentanil on auditory-evoked potentials and electroencephalogram at light-to-moderate sedation levels in healthy subjects

Avoidance of excessively deep sedation levels is problematic in intensive care patients. Electrophysiologic monitoring may offer an approach to solving this problem. Since electroencephalogram (EEG) responses to different sedation regimens vary, we assessed electrophysiologic responses to two sedative drug regimens in 10 healthy volunteers. Dexmedetomidine/remifentanil (dex/remi group) and midazolam/remifentanil (mida/remi group) were infused 7 days apart. Each combination of medications was given at stepwise intervals to reach Ramsay scores (RS) 2, 3, and 4. Resting EEG, bispectral index (BIS), and the N100 amplitudes of long-latency auditory-evoked potentials (ERP) were recorded at each level of sedation. During dex/remi, resting EEG was characterized by a recurrent high-power low-frequency pattern which became more pronounced at deeper levels of sedation. BIS Index decreased uniformly in only the dex/remi group (from 94 +/- 3 at baseline to 58 +/- 14 at RS 4) compared to the mida/remi group (from 94 +/- 2 to 76 +/- 10; P = 0.029 between groups). The ERP amplitudes decreased from 5.3 +/- 1.3 at baseline to 0.4 +/- 1.1 at RS 4 (P = 0.003) in only the mida/remi group. We conclude that ERPs in volunteers sedated with dex/remi, in contrast to mida/remi, indicate a cortical response to acoustic stimuli, even when sedation reaches deeper levels. Consequently, ERP can monitor sedation with midazolam but not with dexmedetomidine. The reverse is true for BIS.

The implications of arterial Po2 oscillations for conventional arterial blood gas analysis

In a surfactant-depletion model of lung injury, tidal recruitment of atelectasis and changes in shunt fraction lead to large Pao2 oscillations. We investigated the effect of these oscillations on conventional arterial blood gas (ABG) results using different sampling techniques in ventilated rabbits. In each rabbit, 5 different ventilator settings were studied, 2 before saline lavage injury and 3 after lavage injury. Ventilator settings were altered according to 5 different goals for the amplitude and mean value of brachiocephalic Pao2 oscillations, as guided by a fast responding intraarterial probe. ABG collection was timed to obtain the sample at the peak or trough of the Pao2 oscillations, or over several respiratory cycles. Before lung injury, oscillations were small and sample timing did not influence Pao2. After saline lavage, when Po2 fluctuations measured by the indwelling arterial Po2 probe confirmed tidal recruitment, Pao2 by ABG was significantly higher at peak (295 +/- 130 mm Hg) compared with trough (74 +/- 15 mm Hg) or mean (125 +/- 75 mm Hg). In early, mild lung injury after saline lavage, Pao2 can vary markedly during the respiratory cycle. When atelectasis is recruited with each breath, interpretation of changes in shunt fraction, based on conventional ABG analysis, should account for potentially large respiratory variations in arterial Po2.

Supplemental oxygen, but not supplemental crystalloid fluid, increases tissue oxygen tension in healthy and anastomotic colon in pigs

BACKGROUND: Low tissue oxygen tension is an important factor leading to the development of wound dehiscence and anastomotic leakage after colon surgery. We tested whether supplemental fluid and supplemental oxygen can increase tissue oxygen tension in healthy and injured, perianastomotic, and anastomotic colon in an acutely instrumented pig model of anastomosis surgery. METHODS: Sixteen Swiss Landrace pigs were anesthetized (isoflurane 0.8%-1%) and their lungs ventilated. The animals were randomly assigned to low fluid treatment ("low" group, 3 mL x kg(-1) x h(-1) lactated Ringer's solution) or high fluid treatment ("high" group, 10 mL/kg bolus, 18 mL x kg(-1) x h(-1) lactated Ringer's solution) during colon anastomosis surgery and a subsequent measurement period (4 h). Two-and-half hours after surgery, tissue oxygen tension was recorded for 30 min during ventilation with 30% oxygen. Three hours after surgery, the animals' lungs were ventilated with 100% oxygen for 60 min. Tissue oxygen tension was recorded in the last 30 min. Tissue oxygen tension was measured with polarographic Clark-type electrodes, positioned in healthy colonic wall, close (2 cm) to the anastomosis, and in the anastomosis. RESULTS: In every group, tissue oxygen tension during ventilation with 100% oxygen was approximately twice as high as during ventilation with 30% oxygen, a statistically significant result. High or low volume crystalloid fluid treatment had no effect on colon tissue oxygen tension. CONCLUSIONS: Supplemental oxygen, but not supplemental crystalloid fluid, increased tissue oxygen tension in healthy, perianastomotic, and anastomotic colon tissue.

Chronic phantom limb pain: the effects of calcitonin, ketamine, and their combination on pain and sensory thresholds

BACKGROUND: Calcitonin was effective in a study of acute phantom limb pain, but it was not studied in the chronic phase. The overall literature on N-methyl-D-aspartate antagonists is equivocal. We tested the hypothesis that calcitonin, ketamine, and their combination are effective in treating chronic phantom limb pain. Our secondary aim was to improve our understanding of the mechanisms of action of the investigated drugs using quantitative sensory testing. METHODS: Twenty patients received, in a randomized, double-blind, crossover manner, 4 i.v. infusions of: 200 IE calcitonin; ketamine 0.4 mg/kg (only 10 patients); 200 IE of calcitonin combined with ketamine 0.4 mg/kg; placebo, 0.9% saline. Intensity of phantom pain (visual analog scale) was recorded before, during, at the end, and the 48 h after each infusion. Pain thresholds after electrical, thermal, and pressure stimulation were recorded before and during each infusion. RESULTS: Ketamine, but not calcitonin, reduced phantom limb pain. The combination was not superior to ketamine alone. There was no difference in basal pain thresholds between the amputated and contralateral side except for pressure pain. Pain thresholds were unaffected by calcitonin. The analgesic effect of the combination of calcitonin and ketamine was associated with a significant increase in electrical thresholds, but with no change in pressure and heat thresholds. CONCLUSIONS: Our results question the usefulness of calcitonin in chronic phantom limb pain and stress the potential interest of N-methyl-D-aspartate antagonists. Sensory assessments indicated that peripheral mechanisms are unlikely important determinants of phantom limb pain. Ketamine, but not calcitonin, affects central sensitization processes that are probably involved in the pathophysiology of phantom limb pain.

Is the combination of morphine with ketamine better than morphine alone for postoperative intravenous patient-controlled analgesia?

BACKGROUND: The addition of ketamine to morphine for patient-controlled analgesia (PCA) is supported by previous basic and clinical research, but has been challenged by subsequent negative studies. Important limitations of previous studies are the low number of patients analyzed, the use of morphine-ketamine combinations that may not the optimal, and that not all the relevant outcomes have been analyzed. In this study, we compared the combination of morphine and ketamine with morphine alone for postoperative PCA in large patient groups. We used a morphine-ketamine combination identified by an optimization procedure in our previous study. METHODS: After major elective orthopedic surgery, 352 patients received either PCA with morphine bolus 1.5 mg (Group M, n = 176) or a bolus of morphine plus ketamine 1.5 mg each (Group MK, n = 176) in a randomized, double-blind fashion. Unsatisfactory treatment was defined as the occurrence of either inadequate analgesia or unacceptable side effects. In addition, total consumption of PCA drugs, duration of PCA use, direct medical costs, and number of patients with chronic postoperative pain 3 and 6 mo after operation were recorded. RESULTS: The incidence of unsatisfactory treatment was 33.0% in Group M and 36.9% in Group MK (P = 0.50). No significant differences were found between the groups with respect to secondary end points. CONCLUSIONS: Small-dose ketamine combined with morphine for PCA provides no benefit to patients undergoing major orthopedic surgery and cannot be recommended for routine use.

The immediate and sustained effects of volume challenge on regional blood flows in pigs

BACKGROUND: The postoperative assessment of volume status is not straightforward because of concomitant changes in intravascular volume and vascular tone. Hypovolemia and blood flow redistribution may compromise the perfusion of the intraabdominal organs. We investigated the effects of a volume challenge in different intra- and extraabdominal vascular beds. METHODS: Twelve pigs were studied 6 h after major intraabdominal surgery under general anesthesia when clinically normovolemic. Volume challenges consisted of 200 mL rapidly infused 6% hydroxyethyl starch. Systemic (continuous thermodilution) and regional (ultrasound Doppler) flows in carotid, renal, celiac trunk, hepatic, and superior mesenteric arteries and the portal vein were continuously measured. The acute and sustained effects of the challenge were compared with baseline. RESULTS: Volume challenge produced a sustained increase of 22% +/- 15% in cardiac output (P < 0.001). Blood flow increased by 10% +/- 9% in the renal artery, by 22% +/- 15% in the carotid artery, by 26% +/- 15% in the superior mesenteric artery, and by 31% +/- 20% in the portal vein (all P < 0.001). Blood flow increases in the celiac trunk (8% +/- 13%) and the hepatic artery (7% +/- 19%) were not significant. Increases in regional blood flow occurred early and were sustained. Mean arterial and central venous blood pressures increased early and decreased later (all P < 0.05). CONCLUSIONS: A volume challenge in clinically euvolemic postoperative animals was associated with a sustained increase in blood flow to all vascular beds, although the increase in the celiac trunk and the hepatic artery was very modest and did not reach statistical significance. Whether improved postoperative organ perfusion is accompanied by a lower complication rate should be evaluated in further studies.

Resistive polymer versus forced-air warming: comparable heat transfer and core rewarming rates in volunteers

BACKGROUND: Mild perioperative hypothermia increases the risk of several severe complications. Perioperative patient warming to preserve normothermia has thus become routine, with forced-air warming being used most often. In previous studies, various resistive warming systems have shown mixed results in comparison with forced-air. Recently, a polymer-based resistive patient warming system has been developed. We compared the efficacy of a standard forced-air warming system with the resistive polymer system in volunteers. METHODS: Eight healthy volunteers participated, each on two separate study days. Unanesthetized volunteers were cooled to a core temperature (tympanic membrane) of 34 degrees C by application of forced-air at 10 degrees C and a circulating-water mattress at 4 degrees C. Meperidine and buspirone were administered to prevent shivering. In a randomly designated order, volunteers were then rewarmed (until their core temperatures reached 36 degrees C) with one of the following active warming systems: (1) forced-air warming (Bair Hugger warming cover #300, blower #750, Arizant, Eden Prairie, MN); or (2) polymer fiber resistive warming (HotDog whole body blanket, HotDog standard controller, Augustine Biomedical, Eden Prairie, MN). The alternate system was used on the second study day. Metabolic heat production, cutaneous heat loss, and core temperature were measured. RESULTS: Metabolic heat production and cutaneous heat loss were similar with each system. After a 30-min delay, core temperature increased nearly linearly by 0.98 (95% confidence interval 0.91-1.04) degrees C/h with forced-air and by 0.92 (0.85-1.00) degrees C/h with resistive heating (P = 0.4). CONCLUSIONS: Heating efficacy and core rewarming rates were similar with full-body forced-air and full-body resistive polymer heating in healthy volunteers.