Brian Milne

Comparative effects of cyclo-oxygenase and nitric oxide synthase inhibition on the development and reversal of spinal opioid tolerance.

This study examined the effects of the COX inhibitors, ketorolac and ibuprofen, and the NOS inhibitor L‐NAME for their potential to both inhibit the development and reverse tolerance to the antinociceptive action of morphine. Repeated administration of intrathecal morphine (15 μg), once daily, resulted in a progressive decline of antinociceptive effect and an increase in the ED50 value in the tailflick and paw pressure tests. Co‐administration of ketorolac (30 and 45 μg) or S(+) ibuprofen (10 μg) with morphine (15 μg) prevented the decline of antinociceptive effect and increase in ED50 value. Similar treatment with L‐NAME (100 μg) exerted weaker effects. Administration of S(+) but not R(−) ibuprofen (10 mg kg−1) had similar effects on systemic administration of morphine (15 mg kg−1). Intrathecal or systemic administration of the COX or NOS inhibitors did not alter the baseline responses in either tests. Acute keterolac or S(+) ibuprofen also did not potentiate the acute actions of spinal or systemic morphine, but chronic intrathecal administration of these agents increased the potency of acute morphine. In animals already tolerant to intrathecal morphine, subsequent administration of ketorolac (30 μg) with morphine (15 μg) partially restored the antinociceptive effect and ED50 value of acute morphine, reflecting the reversal of tolerance. Intrathecal L‐NAME (100 μg) exerted a weaker effect. These data suggest that spinal COX activity, and to a lesser extent NOS activity, contributes to the development and expression of opioid tolerance. Inhibition of COX may represent a useful approach for the prevention as well as reversal of opioid tolerance.

Cyclooxygenase-2 inhibitors in postoperative pain management: current evidence and future directions.

NONSTEROIDAL antiinflammatory drugs (NSAIDs) have been shown to reduce pain and opioid consumption and often accelerate recovery after surgery. However, perioperative inhibition of prostaglandin synthesis by NSAIDs may cause complications, including renal injury, gastric ulceration, and bleeding. Recent molecular studies distinguishing between constitutive cyclooxygenase-1 (COX-1) and inflammation-inducible cyclooxygenase-2 (COX-2) enzymes have led to the exciting hypothesis that the therapeutic and adverse effects of NSAIDs could be uncoupled. The purpose of this article is to review the mechanistic differences between nonselective NSAIDs and selective COX-2 inhibitors (COX-2Is) and to examine currently available COX-2I clinical trials to consider the role of these drugs in postoperative pain management.

Propofol for electrical storm; a case report of cardioversion and suppression of ventricular tachycardia by propofol.

PurposeTo present a case report where propofol abolished recurrent ventricular tachycardia (VT) and to suggest a mechanism by which this may have occurred.Clinical featuresA 65-yr-old male was admitted to the intensive care unit (ICU) with electrical storm. Recurrent episodes of VT persisted despite maximal anti-arrhythmic therapy and resulted in a prolonged ICU course and the need for intra-aortic balloon pump support. This was complicated by an ischemic limb, necessitating an anesthetic for femoral thrombectomy. On several occasions while in the ICU, episodes of VT had resolved with boluses of propofol prior to planned cardioversion. In the operating room, episodes of non-sustained VT resolved after a bolus of propofol and remained suppressed for the duration of the case with the use of a propofol infusion.ConclusionThe effects of propofol on cardiac conduction and on the autonomic nervous system have been studied but its effects on arrhythmias are not well documented. In this case report, propofol was associated with the resolution and suppression of VT. Recent evidence suggests that sympathetic blockade may be an effective treatment for electrical storm. This may be the mechanism by which propofol can abolish this arrhythmia intraoperatively.RésuméObjectifPrésenter un cas où le propofol a aboli une tachycardie ventriculaire récurrente (TV) et tenter d’expliquer le mécanisme qui a produit cet effet.Éléments cliniquesUn homme de 65 ans a été hospitalisé à l’unité des soins intensifs (USI), victime d’une tempête électrique. Des épisodes récurrents de TV ont persisté malgré un traitement antiarythmique maximal et ont entraîné un traitement prolongé à l’USI et le besoin d’un ballon intra-aortique. La situation s’est compliquée par une ischémie d’un membre, ce qui a nécessité une anesthésie pour thrombectomie fémorale. À quelques reprises, à l’USI, des épisodes de TV ont été traités avec des bolus de propofol avant la cardioversion planifiée. Dans la salle d’opération, des épisodes non soutenus de TV ont été supprimés après un bolus de propofol et sont demeurés ainsi pendant toute la durée de l’intervention avec l’utilisation d’une perfusion de propofol.ConclusionLes effets du propofol sur la conduction cardiaque et sur le système nerveux autonome ont été étudiés, mais ses effets sur les arythmies ne sont pas encore bien connus. Dans le cas présent, le propofol est associé à la résolution et à la suppression de TV. Des observations récentes portent à croire que le blocage sympathique pourrait traiter efficacement la tempête électrique. C’est peut-être le mécanisme par lequel le propofol peut abolir l’arythmie pendant l’opération.

Informed consent for labour epidurals : what labouring women want to know

Purpose: To determine A) what a labouring woman expects to hear about epidural analgesia before consenting, B) if she feels able to understand the risks and thereby assess if we are obtaining informed consent.Methods: Sixty actively labouring women were surveyed immediately after requesting an epidural. Demographic, labour, epidural and consent information were included in the questionnaire. Answers were categorical (yes/no, multiple choice) or scored on a scale from 0 to 10 (visual analogue scale).Results: The majority of parturients wanted all potential epidural complications but not their incidences disclosed in the consent process. However, a discussion of risks would not dissuade women from consenting to an epidural in the majority of cases. Labouring women have a moderate understanding of epidural risks. The ability to understand risks was not affected by labour pain, anxiety, opioid premedication, duration of labour pain, desire for an epidural, previous epidural experience, level of education or age.Conclusion: This prospective survey characterizes what 60 reasonable labouring women wanted to know about labour epidural analgesia. Parturients wanted all risks of epidural analgesia disclosed in the informed consent process. The majority of women did not want the incidences quoted. This study suggests that labouring patients are as able to give informed consent as are other members of our patient population.RésuméObjectif: Déterminer ce qu’une parturiente en travail voudrait connaître de l’analgésie épidurale avant de consentir à la recevoir et vérifier si elle croit en comprendre les risques. De là, évaluer si nous obtenons un consentement éclairé.Méthode: On a interrogé 60 femmes en travail obstétrical actif immédiatement après leur demande d’une analgésie épidurale. Le questionnaire comprenait des données personnelles, des informations sur le travail, l’analgésie épidurale et le consentement. Les résponses étaient catégorielles (oui/non, choix multiples) ou cotées sur une échelle visuelle analogique de 1 à 10.Résultats: La majorité des femmes voulait que toutes les complications possibles de l’analgésie épidurale soient révélées dans la formule de consentement, mais non leur incidence. Une discussion sur les risques ne les a pas empêchées d’accepter cette analgésie dans la majorité des cas. Les femmes en travail ont une connaissance moyenne des risques de l’analgésie épidurale. La capacité de comprendre les risques n’a pas été influencée par les douleurs du travail, l’anxiété, la prémédication avec des opioïdes, la durée des douleurs, le désir d’une analgésie épidurale, l’expérience antérieure de cette analgésie, le niveau d’éducation ou l’âge.Conclusion: Cette enquête prospective a précisé ce que 60 parturientes en travail obstétrical veulent connaître sur l’analgésie épidurale. Elles ont demandé que tous les risques de l’analgésie épidurale soient inscrits à la formule du consentement éclairé, mais la majorité ne voulait pas qu’on y ajoute l’incidence. Cette enquête permet d’affirmer que les patientes en travail peuvent donner leur consentement éclairé aussi bien que tout autre patient.

Epidural analgesia for labour and delivery: informed consent issues

ObjectiveMany anaesthetists believe that informed consent for epidural analgesia during labour is inadequate. Patients are perceived to be poorly informed and unable to cope with the information given during labour for informed consent. We reviewed these two hypotheses: A) to define complications for which patients want information; B) to quantify the influence of pain, anxiety, opioid premedication, and the importance of level of education, on a patient’s level of satisfaction with regard to the consent process; and C) to assess how satisfactory epidural pain relief correlates with satisfaction with the consent process.MethodsSixty patients were surveyed during the first two months after vaginal delivery by two interviewers. Questions related to demographics, seventy of labour pain, level of satisfaction with the epidural anaesthetic, risk of complications and satisfaction with information received were either categorical or scored on a scale from 0 to 10.ResultsAll epidural related complications were considered important to disclose (8,4/10). The level of satisfaction with the consent process was 8.1/10. Patient satisfaction was not affected by opioid premedication, anxiety, pain score, education group or level of pain relief.ConclusionPatients indicated they should be informed of all possible complications associated with epidural analgesia, regardless of severity or risk. In contrast to reports in the literature, non disclosure of serious risks during iabour was not acceptable to parturients.RésuméObjectifPlusieurs anesthéststes croient que la façon d’obtenir un consentement éclairé en vue de I’analgésie épidurale pendant le travail est incorrecte. Les patientes semblent mal informées et incapables d’assimiler, pendant le travail, les renseignements foumis au sujet du consentement éclairé. Nous avons révisé ces deux hypothèses dans le but de: A) decrire les complications pour lesquelles les patientes désirent être informées avec précision; B) quantifier I’influence de la douleur, de l’anxiété, de la préméedication morphinique et l’importance du niveau d’éducation sur le degré de satisfaction exprimé sur te mécanisme de consentement; et C) évaluer le degré de corrélation entre le soulagement par épidurale et la satisfaction avec le mécanisme de consentement.MethodesL’enquête réalisée deux mois après I’accouchement par deux sondeurs visait sur soixante accouchées par voie vacinale. Les questions en rapport avec la démographic l’intensité de la douleur pendant le travail, le degré de satisfaction avec l’anesthésie épidurale, le risque de complications et la satisfaction avec l’information reçue exigeaient des reponses catégoriques ou graduées sur une échelle de 0 à 10.RésultatsIl était considéré comme important de révéler toutes les complications potentielles de l’épidurale (8,4/10). Pour le mécanisme de consentement, le degré de satisfaction se situait à 8,1 /1 0. La prémédication morphinique, l’anxiété, l’évaluation de la douleur, le niveau d’éducation et le degré de soulagement n’affectaient pas la satisfaction des patientes.ConclusionLes patientes ont montré qu’elles désiraient connaître toutes les complications potentielles associées à l’anesthésie épidurale, indépendamment de leur gravité et du risque encouru. Contrairement à certaines publications, la dissimulation des risques sérieux pendant le travail semble inacceptable aux parturientes.

Augmentation of spinal morphine analgesia and inhibition of tolerance by low doses of μ- and δ-opioid receptor antagonists

Ultralow doses of naltrexone, a non‐selective opioid antagonist, have previously been found to augment acute morphine analgesia and block the development of tolerance to this effect. Since morphine tolerance is dependent on the activity of μ and δ receptors, the present study investigated the effects of ultralow doses of antagonists selective for these receptor types on morphine analgesia and tolerance in tests of thermal and mechanical nociception.

Spinal GABAergic transplants attenuate mechanical allodynia in a rat model of neuropathic pain.

Injury to the spinal cord or peripheral nerves can lead to the development of allodynia due to the loss of inhibitory tone involved in spinal sensory function. The potential of intraspinal transplants of GABAergic cells to restore inhibitory tone and thus decrease pain behaviors in a rat model of neuropathic pain was investigated. Allodynia of the left hind paw was induced in rats by unilateral L5– 6 spinal nerve root ligation. Mechanical sensitivity was assessed using von Frey filaments. Postinjury, transgenic fetal green fluorescent protein mouse GABAergic cells or human neural precursor cells (HNPCs) expanded in suspension bioreactors and differentiated into a GABAergic phenotype were transplanted into the spinal cord. Control rats received undifferentiated HNPCs or cell suspension medium only. Animals that received either fetal mouse GABAergic cell or differentiated GABAergic HNPC intraspinal transplants demonstrated a significant increase in paw withdrawal thresholds at 1 week post‐transplantation that was sustained for 6 weeks. Transplanted fetal mouse GABAergic cells demonstrated immunoreactivity for glutamic acid decarboxylase and GABA that colocalized with green fluorescent protein. Intraspinally transplanted differentiated GABAergic HNPCs demonstrated immunoreactivity for GABA and β‐III tubulin. In contrast, intraspinal transplantation of undifferentiated HNPCs, which predominantly differentiated into astrocytes, or cell suspension medium did not affect any behavioral recovery. Intraspinally transplanted GABAergic cells can reduce allodynia in a rat model of neuropathic pain. In addition, HNPCs expanded in a standardized fashion in suspension bioreactors and differentiated into a GABAergic phenotype may be an alternative to fetal cells for cell‐based therapies to treat chronic pain syndromes.

Prophylaxis against the systemic hypotension induced by propofol during rapid-sequence intubation.

The objective of this study was to determine the effectiveness of two prophylactic approaches against the anticipated hypotension induced by propofol during rapid-sequence intubation. Thirty-six male or female nonpremedicated ASA class I-II patients aged 21– 60 yr undergoing elective outpatient surgery were included in the study. Patients were randomly allocated to receive pre-induction ephedrine sulphate (70 μg · kg− 1 iv), preinduction volume loading (12 ml · kg− 1 Ringer’s lactate) or no treatment. Rapid-sequence intubation with cricoid pressure was then performed with propofol (2.5 mg · kg− 1) and succinylcholine (1.5 mg · kg− 1). The lungs were subsequently ventilated with 0.25– 0.5% isoflurane in a 2:1 N2O/O2 mixture. Vecuronium was given once neuromuscular function had recovered from the succinylcholine. Heart rate and systemic arterial blood pressure were measured non-invasively before induction, after propofol administration and every minute for ten minutes after intubation. Pre-induction volume loading prevented the hypotension observed before surgical stimulation in control and ephedrine groups. Moreover, pre-induction volume loading was not associated with increases in heart rate after intubation as was ephedrine administration. The intubating conditions were excellent to satisfactory in most patients and the overall incidence of adverse events during induction was mainly due to pain during injection of propofol. The present study showed that preoperative volume loading is more efficacious than preinduction administration of ephedrine sulphate in maintaining haemodynamic stability during rapid-sequence induction with propofol and succinylcholine. In addition, propofol in combination with succinylcholine provides excellent conditions for rapid-sequence intubation.RésuméCette étude a pour objet de déterminer l’efficacité de deux approches visant à prévenir l’hypotension induite par le propofol pendant l’induction en séquence rapide. Trente-six patients des deux sexes non prémédiqués de classe ASA I et II âgés de 21 à 60 ans programmés en chirurgie ambulatoire font partie de l’étude. Les patients sont répartis au hasard pour recevoir du sulfate d’éphédrine (70 μg · kg− 1 iv) avec une charge liquidienne (12 ml · kg− 1 de lactate de Ringer) ou aucun traitement. L’intubation en séquence rapide avec pression cricoïdienne est exécutée sous propofol (2,5 mg · kg− 1) et succinylcholine (1,5 mg · kg− 1). La ventilation mécanique est ensuite initiée avec de l’isoflurane 0,25 à 0,5% dans une mélange N2O/O2 2:1. Du vécuronium est administré après récupération de la succinylcholine. La fréquence cardiaque et la pression artérielle systémique sont mesurées avant l’induction et à toutes les minutes pendant dix minutes. La charge liquidienne préinduction prévient l’hypotension observée avant la stimulation chirurgicale dans les groupes contrôles et éphédrine. En outre, la charge liquidienne préinduction n’est pas associée à une augmentation de la fréquence cardiaque après l’intubation comme l’est l’éphédrine. Les conditions d’intubation sont excellentes dans la plupart des cas et les complications se limitent presque totalement à de la douleur au moment de l’injection du propofol. La présente étude montre que la charge liquidienne préinduction est plus efficace que l’administration de sulfate d’éphédrine pour maintenir la stabilité hémodynamique pendant l’induction à séquence rapide avec le propofol et la succinylcholine. D’ailleurs, l’association de propofol et de succinylcholine procure d’excellentes conditions pour l’intubation en séquence rapide.

Intrathecal Clonidine: Analgesia and Effect on Opiate Withdrawal in the Rat

Clonidine, an α2, adrenergic agonist, has analgesic properties and recently has been used to suppress opiate withdrawal. These two properties theoretically make it a suitable analgesic substitute in patients tolerant to opioids. The objectives of this study were to see if intrathecal clonidine is analgesic and whether it can modify morphine withdrawal at the spinal level. Rats chronically implanted with catheters in the lumbar subarachnoid space were utilized. In analgesia experiments, intrathecal clonidine produced analgesia with the peak effect in the paw-lick test occurring at 200 nM, and in the tail-flick test analgesia was apparent at 100 nM and peaked at 400 nM (in 10 μL Ringers lactate). In dependency experiments, animals dependent on morphine (300 mg · kg−1) received intrathecal clonidine 25, 50, 200 nM in 10 μ1 Ringers lactate 72 h after morphine. Following this, a naloxone challenge, 3 mg · kg−1 was administered and withdrawal assessed. Clonidine-treated animals showed significant weight loss and decrease in temperature, and those treated with high doses showed marked hypothermia and hind-limb flaccidity. Intrathecal clonidine prevented the hyperalgesia associated with opiate withdrawal but did not affect the occurrence of the majority of behavioral signs (e.g., piloerection, irritability) associated with morphine withdrawal. Intrathecal clonidine prevented the naloxone-induced increase in blood pressure during withdrawal and in animals not treated with morphine-produced hypotension. Thus, intrathecal clonidine is analgesic, and part of the antiwithdrawal action of clonidine may be exerted at the spinal level.

In Canada, anesthesiologists are less likely to respond to an electronic, compared to a paper questionnaire

PurposeA randomized unblinded controlled trial was used to assess the utility of electronic questionnaires in a survey of Canadian anesthesiologists.MethodsPostal or electronic questionnaires were sent between November 2001 and March 2002 to 1,333 anesthesiologists registered with the Canadian Anesthesiologists’ Society. The primary outcome measure was the difference in response rates between electronic and postal questionnaires. Secondary outcome measures included a comparison of demographic characteristics, cost, and knowledge and practice regarding prophylactic perioperative beta blockade.ResultsThe overall response rate was 52%. E-mail participants were half as likely as postal participants to respond to the questionnaire (35% vs 69%, relative risk = 0.51, 95% confidence interval 0.45–0.58). Respondents who provided an e-mail address were younger and more likely to be affiliated with an academic institution. There were no significant differences in responses to knowledge and practice questions. The electronic arm was faster than the postal arm and the cost per reply was one-third the cost of the postal arm (