Investigation into spinal anesthetic failure with hyperbaric bupivacaine: the role of cold exposure on bupivacaine degradation.

PURPOSE: Hyperbaric bupivacaine (0.75% in dextrose) is used for spinal obstetric anesthesia. Occasional clusters of anesthetic failures occur in this setting, not readily attributable to clinical factors. We hypothesized that cold temperature exposure is related to bupivacaine instability. METHODS: An electronic survey was distributed to Canadian anesthesiologists to determine consistencies in spinal anesthesia practice, and to invite submission of failed bupivacaine samples for analysis. Another survey for hospital pharmacists focused on bupivacaine logistics. Ultraviolet (UV) spectrometry, differential scanning calorimetry, and high performance liquid chromatography were used to evaluate the effect of temperature on bupivacaine chemical stability. Mass spectrometry (MS) was used to observe bupivacaine and dextrose degradation in laboratory samples of hyperbaric 0.75% bupivacaine in dextrose. Hyperbaric bupivacaine that failed to produce adequate anesthesia in labour and delivery patients was subject to tandem MS/MS analysis on commonly observed ions to look for ion patterns consistent with bupivacaine degradation products and to compare with laboratory samples subjected to cold temperatures. RESULTS: Canadian obstetric anesthesiologists report similar practices and use hyperbaric bupivacaine for spinal anesthesia. Pharmacists surveyed indicated facility storage at room temperature but variable temperatures during shipping. No standard procedure for failure reporting was identified. Analysis of bupivacaine showed a slight decrease in bupivacaine concentration or UV spectral changes after incubation at temperatures ≤ 4°C. Mass spectrometric analysis of hyperbaric bupivacaine from failed spinal anesthesia cases showed complex and inconsistent patterns of ion formation, and different from the ion patterns observed for cooled vs uncooled bupivacaine solutions. Temperature-related changes were noted for dextrose in cooled samples in which dextrose-related ions were formed. CONCLUSIONS: Canadian clinical practice and handling of hyperbaric bupivacaine is consistent. Most respondents indicated an interest in a formal reporting and collection process. Cold exposure did not degrade bupivacaine. A complex and possibly inconsistent reaction involving dextrose was identified that requires further analysis of a larger sample size to elucidate the mechanisms.

RéSUMé: OBJECTIF: La bupivacaïne hyperbare (0,75 % dans du dextrose) est utilisée pour l'anesthésie obstétricale rachidienne. Il arrive parfois que plusieurs anesthésies rapprochées soient inefficaces dans cette situation, et ces échecs ne sont pas nécessairement attribuables à des facteurs cliniques. Nous avons émis l'hypothèse qu'une exposition de la bupivacaïne au froid expliquerait son instabilité. MéTHODE: Un sondage électronique a été distribué aux anesthésiologistes canadiens afin de déterminer les similitudes dans la pratique de la rachianesthésie, et nous avons invité les médecins à nous envoyer des échantillons de bupivacaïne à des fins d'analyse lorsque leur anesthésie était inefficace. Un autre sondage, envoyé aux pharmaciens hospitaliers, mettait l'emphase sur la logistique entourant la manutention de la bupivacaïne. Nous avons utilisé une spectrométrie de rayons ultraviolets (UV), une analyse calorimétrique différentielle et une chromatographie liquide à haute performance afin d'évaluer l'effet de la température sur la stabilité chimique de la bupivacaïne. Une spectrométrie de masse (SM) a été utilisée pour observer la dégradation de la bupivacaïne et du dextrose dans des échantillons de laboratoire de bupivacaïne hyperbare 0,75 % dans le dextrose. La bupivacaïne hyperbare qui n'a pas procuré une anesthésie adéquate chez des patientes en travail ou en accouchement a été sujette à une analyse de SM/SM en tandem sur les ions fréquemment observés afin d'identifier des modèles ioniques correspondant aux produits de dégradation de la bupivacaïne et les comparer à des échantillons de laboratoire soumis au froid. RéSULTATS: Les anesthésiologistes obstétricaux canadiens font état de pratiques semblables et utilisent de la bupivacaïne hyperbare pour réaliser une rachianesthésie. Les pharmaciens interrogés ont indiqué que la bupivacaïne était entreposée à température ambiante au sein de leur établissement mais qu'elle était exposée à des températures variables pendant l'expédition. Aucune procédure standardisée n'a été identifiée pour rapporter les échecs d'anesthésie. L'analyse de la bupivacaïne a montré une légère réduction dans la concentration de bupivacaïne ou des changements spectraux UV après une période d'incubation à des températures ≤ 4°C. L'analyse par spectrométrie de masse des échantillons de bupivacaïne hyperbare utilisés lors d'échecs de la rachianesthésie a révélé des types de formation des ions complexes et incohérents, lesquels différaient des modèles des ions observés dans les solutions de bupivacaïne refroidies vs non refroidies. Les changements liés à la température ont été notés sur le dextrose dans les échantillons refroidis dans lesquels des ions liés au dextrose se sont formés. CONCLUSION: La pratique clinique canadienne et la manutention de la bupivacaïne hyperbare est homogène. La plupart des répondants ont indiqué être intéressés par un processus formel d'enregistrement et de récolte des données. L'exposition au froid n'a pas dégradé la bupivacaïne. Une réaction complexe et possiblement inconstante ayant un rapport avec le dextrose a été identifiée; elle requiert des analyses approfondies sur un échantillonnage plus important afin d'en élucider les mécanismes.

Subcutaneous ketamine for postoperative pain relief in Rwanda: a randomized clinical trial.

PURPOSE: Postoperative pain control is often inadequate in low-income countries such as Rwanda, prompting the search for an inexpensive improvement. A randomized controlled trial was conducted to study the use of subcutaneous ketamine for the management of postoperative pain in patients undergoing major surgery in Kigali, Rwanda. METHODS: Fifty-nine patients undergoing major abdominal, head and neck, plastic, or gynecological surgeries were studied. In addition to standard care, patients received five subcutaneous injections of ketamine 1 mg·kg-1 (ketamine group, n = 30) or normal saline (placebo group, n = 29) during the postoperative period. The first injection was administered in the postanesthesia care unit and then every 12 hr thereafter starting at 20:00 on the day of surgery. Pain was assessed three times per day using an 11-point verbal response scale. Patients were also assessed for side effects, including nausea and vomiting, hallucinations, nightmares, sedation, hypertension, and seizures. RESULTS: The mean (SD) overall postoperative pain scale score was higher in the control group than in the ketamine group [4.8 (1.7) vs 3.7 (1.5), respectively; difference of means, 1.1; 95% confidence interval [CI], 0.3 to 1.9; P = 0.009]. Brief hallucinations (ketamine group, 11 patients; placebo group, 0 patients; risk difference, 0.37; 95% CI, 0.18 to 0.54; P < 0.001) were associated with ketamine administration. CONCLUSIONS: Results of this study in Kigali, Rwanda showed that subcutaneous administration of ketamine 1 mg·kg-1 twice daily, in addition to standard postoperative care, produced a small improvement in postoperative pain but resulted in more minor side effects TRIAL REGISTRATION: www.clinicaltrials.gov (NCT02514122). Registered 31 July 2015.

Epigenetic regulation of glucose transporters in non-small cell lung cancer.

Due to their inherently hypoxic environment, cancer cells often resort to glycolysis, or the anaerobic breakdown of glucose to form ATP to provide for their energy needs, known as the Warburg effect. At the same time, overexpression of the insulin receptor in non-small cell lung cancer (NSCLC) is associated with an increased risk of metastasis and decreased survival. The uptake of glucose into cells is carried out via glucose transporters or GLUTs. Of these, GLUT-4 is essential for insulin-stimulated glucose uptake. Following treatment with the epigenetic targeting agents histone deacetylase inhibitors (HDACi), GLUT-3 and GLUT-4 expression were found to be induced in NSCLC cell lines, with minimal responses in transformed normal human bronchial epithelial cells (HBECs). Similar results for GLUT-4 were observed in cells derived from liver, muscle, kidney and pre-adipocytes. Bioinformatic analysis of the promoter for GLUT-4 indicates that it may also be regulated by several chromatin binding factors or complexes including CTCF, SP1 and SMYD3. Chromatin immunoprecipitation studies demonstrate that the promoter for GLUT-4 is dynamically remodeled in response to HDACi. Overall, these results may have value within the clinical setting as (a) it may be possible to use this to enhance fluorodeoxyglucose (18F) positron emission tomography (FDG-PET) imaging sensitivity; (b) it may be possible to target NSCLC through the use of HDACi and insulin mediated uptake of the metabolic targeting drugs such as 2-deoxyglucose (2-DG); or (c) enhance or sensitize NSCLC to chemotherapy.