Remifentanil-induced Postoperative Hyperalgesia and Its Prevention with Small-dose Ketamine

Background: Remifentanil-induced secondary hyperalgesia has been documented experimentally in both animals and healthy human volunteers, but never clinically. This study tested the hypotheses that increased pain sensitivity assessed by periincisional allodynia and hyperalgesia can occur after relatively large-dose intraoperative remifentanil and that small-dose ketamine prevents this hyperalgesia.

Methods: Seventy-five patients undergoing major abdominal surgery were randomly assigned to receive (1) intraoperative remifentanil at 0.05 [mu]g [middle dot]kg-1 [middle dot]min-1 (small-dose remifentanil); (2) intraoperative remifentanil at 0.40 [mu]g [middle dot]kg-1 [middle dot]min-1 (large-dose remifentanil); or (3) intraoperative remifentanil at 0.40 [mu]g [middle dot]kg-1 [middle dot]min-1 and 0.5 mg/kg ketamine just after the induction, followed by an intraoperative infusion of 5 [mu]g [middle dot] kg-1 [middle dot] min-1 until skin closure and then 2 [mu]g [middle dot]kg-1 [middle dot]min-1 for 48 h (large-dose remifentanil-ketamine). Pain scores and morphine consumption were recorded for 48 postoperative hours. Quantitative sensory tests, peak expiratory flow measures, and cognitive tests were performed at 24 and 48 h.

Results: Hyperalgesia to von Frey hair stimulation adjacent to the surgical wound and morphine requirements were larger (P < 0.05) and allodynia to von Frey hair stimulation was greater (P < 0.01) in the large-dose remifentanil group compared with the other two groups, which were comparable. There were no significant differences in pain, pressure pain detection threshold with an algometer, peak flow, cognitive tests, or side effects.     

High-frequency oscillatory ventilation in premature infants with respiratory failure: a preliminary report

High-frequency ventilation has been used successfully to manage life-threatening complications in premature infants with lung disease. Here we report a preliminary assessment of the efficacy and safety of high-frequency oscillatory ventilation-(HFO-A, A = active expiratory phase) when used as a primary ventilator in 11 infants of 24-34 weeks gestation who required ventilatory support. HFO-A was initiated after no more than 5.5 hr of conventional mechanical ventilation (CMV). HFO-A at 15 Hz was used for 12-203 hr following a protocol designed for rapid reduction of FI02 requirements. CO2 elimination was easily achieved in all infants. Oxygenation was satisfactory, except in one infant with congenital pneumonia. There were four deaths during HFO-A: two pulmonary (one congenital pneumonia; one pulmonary hemorrhage) and two nonpulmonary. The HFO-A protocol utilized lung volume recruitment maneuvers plus mean airway pressures (MAwP) greater than those generally used early in the course of CMV. Therefore, in a subset of infants less than or equal to 29 weeks' gestation with respiratory distress syndrome (RDS), ventilator pressures and gas exchange were compared in infants treated with either HFO-A or CMV. Maximum MAwP levels were reached earlier in six infants on HFO-A (5.2 +/- 2.5 hr; mean +/- SD) than in a comparable group of 9 CMV-treated infants (36 +/- 1 hr). This earlier use of high MAwP lowered the FI02 to less than 0.4 by 18.9 +/- 11 hr with HFO-A as compared with 64 +/- 6 hr using CMV, without any evidence of an increase in pulmonary complications. There were 17 complications in the nine CMV-treated infants; and four in the six HFO-A treated ones. We conclude that HFO-A, instituted early and used with a protocol designed for early reduction in FI02 requirements, demonstrates sufficient efficacy and safety to warrant further clinical trials in the routine management of infant RDS.     

Significance of diffuse cardiac activity on In-111 labeled leucocyte scans

To assess the significance of diffuse cardiac activity (DCA) seen on In-111 labeled leukocyte scans, we reviewed 87 studies performed over the last 4 years. Inflammatory cardiac conditions were seen as frequently in patients with DCA (15%) as those without (7%, P=0.3). There was a higher ratio of RBC:WBC in the final WBC preparation in the false-positive DCA group than the true positive DCA and no DCA groups. False-positive studies showing DCA are most likely due to residual blood pool activity.Presented in part, 70th annual meeting, Radiological Society of North America, Washington D.C., 25 November 1984     

Similarities and differences in mechanisms of cardiotoxins, melittin and other myotoxins

Myonecrosis induced in vivo by cardiotoxin, melittin, and Asp49 and Lys49 phospholipase A₂ (PLA₂) myotoxins involves rapid lysis of the sarcolemma, myofibril clumping, and hypercontraction of sarcomeres. In contrast, skeletal muscle necrosis induced by crotamine and myotoxin a is much slower, consisting of mitochondrial and sarcoplasmic reticulum swelling, myofibril degeneration, and lack of sarcolemma or transverse tubule damage. The mechanisms contributing to the myonecrosis induced by these peptides were evaluated. Two cardiotoxins and two Lys49 PLA₂ myotoxins lysed primary cultures of human skeletal muscle within 24 hr at a concentration of 0.25 μM, while melittin, crotamine, and myotoxin a, and an Asp49 PLA₂ myotoxin were non-cytolytic at concentrations up to 5.0 μM, suggesting that cytolysis is not a good measure of myotoxicity. Crotamine and the Lys49 PLA₂ myotoxin altered Ca²⁺ ion flux in human heavy sarcoplasmic reticulum by opening the ryanodine receptor. Whole-cell patch-clamp studies demonstrated that administrating crotamine intracellularly increased Na⁺ currents. Free fatty acids, liberated by activation of tissue phospholipase C or by the PLA₂ activity of the myotoxins, were monitored for crotamine, myotoxin a and a Lys49 PLA₂ myotoxin in cell cultures in which the lipids had been radiolabeled. Only the Lys49 myotoxin produced significant amounts of fatty acid in cell cultures, supporting a potential role for fatty acid production only in the mechanism of sarcolemma-destroying myotoxins. These findings, coupled with those in the literature, support a hypothesis in which the myotoxins and/or products of lipase activity (e.g. fatty acids) are acting at a site existing on both the Na⁺ channel and a protein involved in Ca²⁺ release and probably serving a modulatory function for ion regulation. Based on the similarities in mechanisms between the toxins and fatty acids, the most likely site would be a fatty acid binding site on the protein (either similar to that on fatty acid binding proteins, or an acylated cysteine residue) or in the membrane.     

Injections of -amphetamine into the ventral pallidum increase locomotor activity and responding for conditioned reward: a comparison with injections into the nucleus accumbens

The nucleus accumbens and ventral pallidum receive dopamine (DA) projections from the mesencephalon. Although DA inputs to the nucleus accumbens are implicated in both locomotion and reward processes, little is known of the behavioural significance of DA in the ventral pallidum. These studies examined the effects of -amphetamine injected into the nucleus accumbens or ventral pallidum on locomotor activity and responding for a conditioned reward (CR). In the nucleus accumbens -amphetamine dose dependently (1, 3 and 10 μg) increased locomotion within 5–10 min of injection. Intra-ventral pallidum microinjections of -amphetamine also increased activity in this dose range, but the effect occurred with a longer latency (5–20 min). The magnitude of the response evoked by ventral pallidum injections was lower than that evoked by nucleus accumbens injections. The GABA_A antagonist picrotoxin (0.1 μg) stimulated activity when injected into the ventral pallidum but not the nucleus accumbens, providing a pharmacological dissociation between the two injection sites. In the CR studies, -amphetamine injected into both sites potentiated responding for a CR previously paired with food delivery, without altering responding on an inactive lever. Picrotoxin injected into the ventral pallidum reduced responding and abolished the selectivity of responding for CR. The results show that DA release in the ventral pallidum enhances locomotion and responding for a CR, providing evidence that DA in the ventral pallidum plays a significant role in the mediation of the effects of -amphetamine. The failure of picrotoxin to elevate responding for CR despite increasing locomotor activity indicates that pharmacologically-induced blockade of GABA_A receptors in the ventral pallidum disrupts goal-directed responding.     

Reinstatement of alcohol-seeking by priming injections of alcohol and exposure to stress in rats

 Previous studies using a reinstatement procedure have found that acute reexposure to the self-administered drug and exposure to footshock stress reinstate heroin and cocaine seeking after prolonged drug-free periods. Here we tested whether these findings generalize to alcohol-taking behavior. Male rats were initially allowed to consume alcohol in a two-bottle choice procedure (water versus alcohol) for 30 min/day for 36 days. Rats were then trained for 60 min/day in operant chambers to press a lever for the drug (0.13 ml of 12% w/v of an alcohol solution) for up to 55 days. After stable drug-taking on a fixed-ratio-3 schedule of reinforcement was obtained, lever pressing for alcohol was extinguished by terminating drug delivery for 4–9 days. Reinstatement of drug seeking was then determined after non-contingent priming injections of alcohol (0.24 and 0.48 g/kg; given IP and orally) or exposure to intermittent footshock stress (5 and 15 min; 0.8 mA). Priming injections of alcohol produced a modest dose-dependent reinstatement of drug seeking, whereas footshock stress potently reinstated extinguished alcohol seeking. In contrast, similar parameters of footshock failed to reinstate extinguished sucrose-taking behavior in rats previously trained to lever press for sucrose pellets. These findings extend previous reports on reinstatement of cocaine and heroin seeking by a footshock stressor and by priming drug injections. It also appears that the reinstatement procedure provides an appropriate methodology to study relapse to alcohol-taking behavior in the drug-free state. Received: 9 April 1997 / Final version: 1 August 1997