Piotr K. Janicki

A randomized, double-blind comparison of the NK1 antagonist, aprepitant, versus ondansetron for the prevention of postoperative nausea and vomiting

BACKGROUND: Antiemetics currently in use are not totally effective. Neurokinin-1 receptor antagonists are a new class of antiemetic that have shown promise for chemotherapy-induced nausea and vomiting. This is the first study evaluating the efficacy and tolerability of the neurokinin-1 receptor antagonist, aprepitant, for the prevention of postoperative nausea and vomiting. METHODS: In this multicenter, double-blind trial, we randomly assigned 805 patients receiving general anesthesia for open abdominal surgery to a preoperative dose of aprepitant 40 mg orally, aprepitant 125 mg orally, or ondansetron 4 mg IV. Vomiting, nausea, and use of rescue therapy were assessed over 48 h after surgery. Treatments were compared using logistic regression. RESULTS: Incidence rates for the primary end point (complete response [no vomiting and no use of rescue] over 0–24 h after surgery, tested for superiority of aprepitant) were not different across groups (45% with aprepitant 40 mg, 43% with aprepitant 125 mg, and 42% with ondansetron). The incidence of no vomiting (0–24 h) was higher with aprepitant 40 mg (90%) and aprepitant 125 mg (95%) versus ondansetron (74%) (P < 0.001 for both comparisons), although between-treatment use of rescue and nausea control was not different. Both aprepitant doses also had higher incidences of no vomiting over 0–48 h (P < 0.001). No statistically significant differences were seen among the side effect profiles of the treatments. CONCLUSIONS: Aprepitant was superior to ondansetron for prevention of vomiting in the first 24 and 48 h, but no significant differences were observed between aprepitant and ondansetron for nausea control, use of rescue, or complete response.

A genetic association study of the functional A118G polymorphism of the human mu-opioid receptor gene in patients with acute and chronic pain.

In this prospective, observational study we explored whether A118G single nucleotide polymorphism in the human &mgr;-opioid receptor (MOR) gene could explain the inter-individual differences in opioid analgesic requirements in patients with acute postoperative pain and chronic pain. The frequency of the wild-type A118 MOR (major) and variant G118 MOR (minor) alleles in the subjects with chronic, noncancer pain (n = 121) and opioid-naïve subjects with acute postoperative pain (n = 101), serving as the control group, were examined. The relationships among the A118G MOR genotype, opioid requirements, and the numerical pain score were analyzed in both groups. The frequency of the minor allele was significantly lower in the subjects with chronic pain when compared with the group with acute postoperative pain (0.079 versus 0.158; P = 0.009 by &khgr;2 test). No statistically significant association was observed between the presence of A118G MOR polymorphism and the average postoperative pain score or the doses of morphine used in the immediate postoperative period. In the high-quartile, opioid utilization, chronic pain patients, the homozygotic carriers of the major allele required significantly higher opioid dose than did the carriers of the minor allele. The results indicate that although the presence of the minor allele does not appear to affect opioid analgesic use in acute postoperative pain, the minor allele is less common in chronic pain patients, especially in those requiring higher doses of opioid analgesics.

Comparison of two different temperature maintenance strategies during open abdominal surgery: upper body forced-air warming versus whole body water garment.

BackgroundA new system has been developed that circulates warm water through a whole body garment worn by the patient during surgery. In this study the authors compared two different strategies for the maintenance of intraoperative normothermia. One strategy used a new water garment warming system that permitted active warming of both the upper and lower extremities and the back. The other strategy used a single (upper body) forced-air warming system. MethodsIn this prospective, randomized study, 53 adult patients were enrolled in one of two intraoperative temperature management groups during open abdominal surgery with general anesthesia. The water-garment group (n = 25) received warming with a body temperature (rectal) set point of 36.8°C. The forced-air–warmer group (n = 28) received routine warming therapy using upper body forced-air warming system (set on high). The ambient temperature in the operating room was maintained constant at approximately 20°C. Rectal, distal esophageal, tympanic, forearm, and fingertip temperatures were recorded perioperatively and during 2 h after surgery. Extubated patients in both groups were assessed postoperatively for shivering, use of additional warming devices, and subjective thermal comfort. ResultsThe mean rectal and esophageal temperatures at incision, 1 h after incision, at skin closure, and immediately postoperatively were significantly higher (0.4–0.6°C) in the group that received water-garment warming when compared with the group that received upper body forced-air warming. The calculated 95% confidence intervals for the above differences in core temperatures were 0.7–0.1, 0.8–0.2, 0.8–0.2, and 0.9–0.1, retrospectively. In addition, 14 and 7% of patients in the control upper body forced-air group remained hypothermic (< 35.5°C) 1 and 2 h after surgery, respectively. No core temperature less than 35.5°C was observed perioperatively in any of the patients from the water-garment group. A similar frequency of the thermal stress events (shivering, use of additional warming devices, subjective thermal discomfort) was observed after extubation in both groups during the 2 h after surgery. ConclusionsThe investigated water warming system, by virtue of its ability to deliver heat to a greater percentage of the body, results in better maintenance of intraoperative normothermia that does forced-air warming applied only to the upper extremities, as is common practice.

Halothane, Isoflurane, Xenon, and Nitrous Oxide Inhibit Calcium ATPase Pump Activity in Rat Brain Synaptic Plasma Membranes

Background Perturbation of neuronal calcium homeostasis may alter neurotransmission in the brain, a phenomenon postulated to characterize the anesthetic state. Because of the central role of plasma membrane Calcium2+ ‐ATPase (PMCA) in maintaining Calcium2+ homeostasis, the authors examined the effect of several inhalational anesthetics on PMCA function in synaptic plasma membranes (SPM) prepared from rat brain. Methods Calcium2+ ‐ATPase pumping activity was assessed by measurement of ATP‐dependent uptake of Calcium2+ by SPM vesicles. ATPase hydrolytic activity was assessed by spectrophotometric measurement of inorganic phosphate (Pi) released from ATP. For studies of anesthetic effects on PMCA activity, Calcium2+ uptake or Pi release was measured in SPM exposed to halothane, isoflurane, xenon, and nitrous oxide at partial pressures ranging from 0 to 1.6 MAC equivalents. Halothane and isoflurane exposures were carried out under a gassing hood. For xenon and nitrous oxide exposures, samples were incubated in a pressure chamber at total pressures sufficient to provide anesthetizing partial pressures for each agent. Results Dose‐related inhibition of Calcium2+ ‐ATPase pumping activity was observed in SPM exposed to increasing concentrations of halothane and isoflurane, confirmed by ANOVA and multiple comparison testing (P < 0.05). Concentrations of halothane and isoflurane equivalent to one minimum effective dose (MED) depressed PMCA pumping approximately 30%. Xenon and nitrous oxide also inhibited Calcium2+ uptake by SPM vesicles. At partial pressures of these two gases equivalent to 1.3 MAC, PMCA was inhibited approximately 20%. Hydrolysis of ATP by SPM fractions was also inhibited in a dose‐related fashion. An additive effect occurred when 1 vol% of halothane was added to xenon or nitrous oxide at partial pressures equivalent to 0–1.6 MAC for the latter two agents. Conclusions Plasma membranes Calcium2+ ‐ATPase is significantly inhibited, in a dose‐related manner, by clinically relevant partial pressures of halothane, isoflurane, xenon, and nitrous oxide. Furthermore, these anesthetics inhibit PMCA activity in accordance with their known potencies, and an additive effect was observed. How inhalational anesthetics inhibit the PMCA pump is not known at this time. It is noteworthy that the only shared characteristic of this group of agents of widely different structure is anesthetic action. The relevance of this dual commonality, anesthetic action and PMCA inhibition, to actual production of the anesthetic state remains to be determined.

Genome-wide Association Study Using Pooled DNA to Identify Candidate Markers Mediating Susceptibility to Postoperative Nausea and Vomiting

Background:A family history has been established as a risk factor for postoperative nausea and vomiting (PONV), but the identities of susceptibility genes remain unknown. The goal of this study was to identify the genetic loci that may contribute to PONV susceptibility in an adult population. Methods:The authors performed a genome-wide association study involving pooling of DNA obtained from 122 patients with severe PONV and 129 matched controls. Each pool was hybridized to a single nucleotide polymorphism (SNP) microarray, and probe intensity was used to predict allele frequency. Differences in allele frequency between SNP in the PONV and control groups were ranked after accounting for the pooling error. The highest ranking SNPs were selected for individual genotyping in the subjects from whom the DNA pool was comprised and in the new verification cohort consisting of 208 subjects (104 PONV patients and 104 controls). Results:The authors identified 41 SNP targets showing substantial difference in allelic frequency between pools. These markers were first genotyped in the individual DNA samples from which the pools were comprised. The authors observed evidence for an association between PONV and 19 different loci in the genome. In the separate verification cohort, the association with PONV was observed for four SNPs. This association remained significant after correcting for multiple testing (P < 0.0023) for one SNP (rs2165870), which is located upstream of the promoter for the muscarinic acetylcholine receptor 3 subtype (CHRM3) gene. Conclusions:The authors performed the genome-wide association study for PONV using pooled DNA samples. Through individual genotyping, they confirmed association of at least one SNP that is predictive of PONV susceptibility.

Intrathecal ketorolac tromethamine produces analgesia after chronic constriction injury of sciatic nerve in rat

PurposeThe study compared analgesic efficacy of intrathecally administered ketorolac tromethamine (K) and morphine hydrochlorïde (M) (in equimolar doses) in the chronic neuropathic pain model, induced by chronic constriction injury (CCI) of the sciatic nerve in rat.MethodsMale Sprague-Dawley rats (n = 30) were anaesthetized with halothane and an intrathecal catheter was inserted to the mid-lumbar level of the spinal cord. On the 5th postoperative day, rats were anaesthetized with halothane and four ligatures were loosely applied around the right sciatic nerve. Seven days later, those animals were randomly divided into three groups and were injected with either saline, M (20 nmoles) or K (20 nmoles). Two pain responses (foot-withdrawal delay and hind paw elevation time) were measured on both sides using the radiant heat method. Further, thermal (“cold”) allodynia was assessed by measuring of the total time of hind paw elevation in animals placed on the cold metal plate.ResultsTwenty nmoles of M and K injected intrathecally produced decrease of differential pain score calculated for both measured responses (hind paw withdrawal and hind paw elevation), compared with saline injected animals (P < 0.05). The reduction in pain response produced by K was less (P < 0.05) than the reduction in pain response observed in the animals receiving intrathecal M. Measurement of cold allodynia revealed that the animals in M and K injected groups demonstrated decreases in the total hind paw elevation lime, when compared with saline-injected animals (P < 0.05).ConclusionM and K produced hypoalgesia after intrathecal administration in rats with CCI, with M being more potent than K at an equimolar dose range. The analgesic effect of K was equal to equimolar doses of M for alleviation of cold allodynia.RésuméObjectifComparer l’efficacité analgésique sous-archnoïdienne de la trométhamine de kétorolac (K) à celle de l’hydrochlorure de morphine (M) (à doses équimolaires) sur un modèle de douleur neuropathique chronique induite par une lésion constrictive chronique (LCC) du nerf sciatique chez le rat.MéthodesTrente rats Sprague-Dawley ont été anesthésiés à l’halothane et un cathéter sous-arachnoïdien inséré au niveau lombaire rachidien moyen. Cinq jours plus tard, quatre ligatures ont été nouées lâchement autour du nerf sciatique droit. Sept jours plus tard, ces animaux ont été répartis aléatoirement entre trois groupes et ont reçu soit du sol. physiologique, soit M (20 nmoles), soit K (20 nmoles). Deux réponses à la douleur (l’intervalle jusqu’au retrait de la patte, et la durée de l’élévation de la patte de derrière) ont été mesurées bilatéralement avec la méthode de la chaleur radiante. En outre, l’allodynie thermique («froide») a été évaluée en mesurant la durée totale de l’élévation de la patte de derrière chez les animaux placés sur la plaque de métal froide.RésultatsL’injection sous-arachnoïdienne de 20 nmoles de M et de K a provoqué une baisse des scores de douleurs différentiels calculés pour les deux réactions mesurées (retrait et élévation de la patte de derrière) comparativement aux animaux qui avaient reçu le sol. physiologique (P < 0,05). La réduction de la réponse douloureuse produite par K était moindre (P < 0,05) que celle produite par M. La mesure de l’allodynie au froid a révélé que les animaux des groupes M et K présentaient des diminutions de la durée totale d’élévatoin de la patte de derrière comparativement aux groupe qui avait reçu du sol. physiologique (P < 0,05).ConclusionChez le rat porteur de LCC, l’administration sous-arachnoïdienne de M et de K a produit de l’hypoalgésie, mais M était plus puissant pour une gamme de doses équimolaires. Pour l’atténuation de l’allodynie au froid, à des doses équimolaires, l’effet analgésique de K était égal à celui de M.

Prevention of postoperative nausea and vomiting with granisetron and dolasetron in relation to CYP2D6 genotype.

We investigated the efficacy of granisetron and dolasetron in preventing postoperative nausea and vomiting. Because the metabolism of the various antiemetic 5-hydroxytryptamine type 3 (5-HT3) antagonists involves different isoforms of the hepatic cytochrome P450 system, we examined the relationship between the clinical efficacy of these drugs and polymorphic cytochrome P450 2D6 (CYP2D6) genotype. This prospective, randomized, double-blind study involved 150 adult patients with a moderate to high risk for postoperative nausea and vomiting. All subjects received dexamethasone at induction of anesthesia followed by either 12.5 mg of dolasetron or 1 mg of granisetron. We analyzed the number of complete responders (no vomiting or rescue medication) during the first 24 hours after surgery. CYP2D6 genotyping was performed using a TaqMan real-time polymerase chain reaction. A complete response was more frequent in the granisetron group (54.7%) compared with the dolasetron group (38.7%, P < 0.05). In subjects receiving dolasetron, carriers of the duplication of the CYP2D6 allele predicting ultrarapid metabolizer status had more frequent vomiting episodes (P < 0.05) than patients in the granisetron group. It is postulated that the difference in the antiemetic efficacy between two investigated 5-HT3 receptor antagonists may be associated with differences in the carrier status for the duplication of the CYP2D6 allele.

Single-Dose Kinetics of Nifedipine in Rat Plasma and Brain

Nifedipine concentrations in plasma and brain tissue of rats were assayed from 5 min to 4 h after an intravenous injection of 6 mg/kg body weight. Samples of rat plasma and homogenized brain tissue were extracted under sodium light with a dichloromethane-pentane mixture. Analyses were done by high-performance liquid chromatography on a reverse-phase C18 column with electrochemical detection. The peak concentration of nifedipine in brain obtained after 10 min was 37 micrograms/g wet weight tissue, the half-life was 75 min. Apparently, nifedipine can easily cross the blood-brain barrier in the rat.

Water warming garment versus forced air warming system in prevention of intraoperative hypothermia during liver transplantation: a randomized controlled trial [ISRCTN32154832].

BackgroundThe authors compared two strategies for the maintenance of intraoperative normothermia during orthotopic liver transplantation (OLT): the routine forced-air warming system and the newly developed, whole body water garment.MethodsIn this prospective, randomized and open-labelled study, 24 adult patients were enrolled in one of two intraoperative temperature management groups during OLT. The water-garment group (N = 12) received warming with a body temperature (esophageal) set point of 36.8°C. The forced air-warmer group (N = 12) received routine warming therapy using upper- and lower-body forced-air warming system. Body core temperature (primary outcome) was recorded intraoperatively and during the two hours after surgery in both groups.ResultsThe mean core temperatures during incision, one hour after incision and during the skin closing were significantly higher (p < 0.05, t test with Bonferroni corrections for the individual tests) in the water warmer group compared to the control group (36.7 ± 0.1, 36.7 ± 0.2, 36.8 ± 0.1 vs 36.1 ± 0.4, 36.1 ± 0.4, 36.07 ± 0.4°C, respectively). Moreover, significantly higher core temperatures were observed in the water warmer group than in the control group during the placement of cold liver allograft (36.75 ± 0.17 vs 36.09 ± 0.38°C, respectively) and during the allograft reperfusion period (36.3 ± 0.26 vs 35.52 ± 0.42°C, respectively). In addition, the core temperatures immediately after admission to the SICU (36.75 ± 0.13 vs 36.22 ± 0.3°C, respectively) and at one hr (36.95 ± 0.13 vs 36.46 ± 0.2°C, respectively) were significantly higher in the water warmer group, compared to the control group, whereas the core temperature did not differ significantly afte two hours in ICU in both groups.ConclusionsThe investigated water warming system results in better maintenance of intraoperative normothermia than routine air forced warming applied to upper- and lower body.

Lidocaine and bupivacaine cardiorespiratory toxicity is additive: a study in rats.

The purpose of this study was to determine whether equipotent solutions of lidocaine, bupivacaine, or a mixture of these compounds infused at a fixed rate in anesthetized rats resulted in equivalent lethal cardiorespiratory toxicity and to establish whether the lethality of the individual drugs was additive. This was assessed by comparing the time to respiratory and circulatory arrest, determining the lethal doses of administered local anesthetic in each group, and ascertaining the concentration of lidocaine or bupivacaine, or both, at the time of circulatory arrest. The times to respiratory and circulatory arrest were similar in rats receiving either lidocaine (2%) or bupivacaine (0.5%) or a mixture of 1% lidocaine and 0.25% bupivacaine. The mean lidocaine-to-bupivacaine cumulative lethal dose ratio (3.36) and concentration ratio (2.33) were determined and used to calculate lidocaine equivalent values for bupivacaine data. Lidocaine equivalent cumulative lethal doses and plasma concentrations were similar in all three groups studied. This work suggests that the lethal cardiorespiratory toxicity of lidocaine and bupivacaine associated with intravenous infusion is additively toxic in rats.