Michael G. Irwin

A Comparison of Intranasal Dexmedetomidine and Oral Midazolam for Premedication in Pediatric Anesthesia: A Double-Blinded Randomized Controlled Trial

BACKGROUND:Midazolam is the most commonly used premedication in children. It has been shown to be more effective than parental presence or placebo in reducing anxiety and improving compliance at induction of anesthesia. Clonidine, an &agr;2 agonist, has been suggested as an alternative. Dexmedetomidine is a more &agr;2 selective drug with more favorable pharmacokinetic properties than clonidine. We designed this prospective, randomized, double-blind, controlled trial to evaluate whether intranasal dexmedetomidine is as effective as oral midazolam for premedication in children. METHODS:Ninety-six children of ASA physical status I or II scheduled for elective minor surgery were randomly assigned to one of three groups. Group M received midazolam 0.5 mg/kg in acetaminophen syrup and intranasal placebo. Group D0.5 and Group D1 received intranasal dexmedetomidine 0.5 or 1 &mgr;g/kg, respectively, and acetaminophen syrup. Patients’ sedation status, behavior scores, blood pressure, heart rate, and oxygen saturation were recorded by an observer until induction of anesthesia. Recovery characteristics were also recorded. RESULTS:There were no significant differences in parental separation acceptance, behavior score at induction and wake-up behavior score. When compared with group M, patients in group D0.5 and D1 were significantly more sedated when they were separated from their parents (P < 0.001). Patients from group D1 were significantly more sedated at induction of anesthesia when compared with group M (P = 0.016). CONCLUSIONS:Intranasal dexmedetomidine produces more sedation than oral midazolam, but with similar and acceptable cooperation.

A double-blind, crossover assessment of the sedative and analgesic effects of intranasal dexmedetomidine.

BACKGROUND:The alpha2-receptor agonist, dexmedetomidine, provides sedation with facilitated arousal and analgesia with no respiratory depression. These properties render it potentially useful for anesthesia premedication, although parenteral administration is not practical in this setting. We designed this study to evaluate the sedative, anxiolytic, analgesic, and hemodynamic effects of dexmedetomidine administered intranasally in healthy volunteers. METHODS:Kochs design for crossover trials (three-treatment and two-period design) was adopted. The study was double-blind and there were three treatment groups: A (placebo), B (intranasal dexmedetomidine 1 &mgr;g/kg) and C (intranasal dexmedetomidine 1.5 &mgr;g/kg). Each of the 18 subjects participated in two study periods. The study drug was administered intranasally after baseline observations of modified Observer Assessment of Alertness/Sedation Scale, visual analog scale of sedation, bispectral index, visual analog scale of anxiety, pain pressure threshold measured by an electronic algometer, systolic blood pressure (SBP) and diastolic blood pressure, heart rate, respiratory rate, and oxygen saturation. These were repeated during the course of the study. RESULTS:Intranasal dexmedetomidine was well tolerated. Both 1 and 1.5 &mgr;g/kg doses equally produced significant sedation and decreases in bispectral index, SBP, diastolic blood pressure, and heart rate when compared with placebo (P < 0.05). The onset of sedation occurred at 45 min with a peak effect at 90–150 min. The maximum reduction in SBP was 6%, 23%, and 21% for Groups A, B, and C respectively. There was no effect on pain pressure threshold, oxygen saturation or respiratory rate. Anxiolysis could not be evaluated as no subjects were anxious at baseline. CONCLUSION:The intranasal route is effective, well tolerated, and convenient for the administration of dexmedetomidine. Future studies are required to evaluate the possible role of the noninvasive route of administration of dexmedetomidine in various clinical settings, including its role as premedication prior to induction of anesthesia.

Remifentanil Preconditioning Protects against Ischemic Injury in the Intact Rat Heart

Background:Opioid receptors mediate cardiac ischemic preconditioning. Remifentanil is a new, potent ultra-short-acting phenylpiperidine opioid used in high doses for anesthesia. The authors hypothesize that pretreatment with this drug confers cardioprotection. Methods:Male Sprague-Dawley rats were anesthetized and the chest was opened. All animals were subjected to 30 min of occlusion of the left coronary artery and 2 h of reperfusion. Before the 30-min occlusion, rats received either preconditioning by ischemia (ischemic preconditioning, 5-min occlusion, 5-min reperfusion × 3) or pretreatment with remifentanil, performed with the same regime (3 × 5-min infusions) using 0.2, 0.6, 2, 6, or 20 μg·kg−1·min−1 intravenously. The experiment was repeated with naltrindole (a selective Δ-opioid receptor antagonist, 5 mg/kg), nor-binaltorphimine (a selective &kgr;-OR antagonist, 5 mg/kg), or CTOP (a selective μ-opioid receptor antagonist, 1 mg/kg) administered before remifentanil-induced preconditioning or ischemic preconditioning, respectively. Infarct size, as a percentage of the area at risk, was determined by 2,3,5-triphenyltetrazolium staining. Results:There was a dose-related reduction in infarct size/area at risk after treatment with remifentanil that was similar to that seen with ischemic preconditioning. This effect was prevented or significantly attenuated by coadministration of a μ, &kgr;, or Δ-opioid antagonist. The infarct-sparing effect of ischemic preconditioning was abolished by blockade of &kgr;-opioid receptors or Δ-opioid receptors but not by μ-opioid receptors. Conclusion:Remifentanil mimics cardioprotection via all three opioid receptors. This differs from ischemic preconditioning, which confers cardioprotection via &kgr;- and Δ-, but not μ-opioid receptors. Part of the protective effect of remifentanil may be produced by μ-agonist activity outside the heart.

Intraoperative Remifentanil Infusion Does Not Increase Postoperative Opioid Consumption Compared with 70% Nitrous Oxide

Background:Remifentanil is commonly used to replace nitrous oxide in general anesthesia to avoid the side effects of the latter. However, there are reports that intraoperative remifentanil infusion can lead to acute opioid tolerance. In this study, the authors tried to determine the dose of remifentanil comparable in efficacy to 70% nitrous oxide and to evaluate its effect on postoperative pain and morphine consumption after colorectal surgery using isoflurane anesthesia. Methods:Sixty adult patients undergoing open colorectal surgery were randomly assigned to receive either remifentanil or 70% nitrous oxide along with isoflurane anesthesia. After morphine analgesia titration in the postanesthesia care unit, patient-controlled analgesia was commenced. Morphine consumption and pain were scored at rest and during cough or movement for 24 h. Results:The mean remifentanil infusion rate was 0.17 &mgr;g · kg−1 · min−1. The median visual analog pain score on arrival in the postanesthesia care unit was 1 (0–10) in the nitrous oxide group and 3 (0–9) in the remifentanil group (P < 0.05). Otherwise, there was no difference in pain scores at 5, 10, and 15 min and no difference in the total morphine consumption during the stay in the postanesthesia care unit. The two groups had similar total morphine consumption in the first 24 h and pain scores at rest and during movement. The incidence of postoperative nausea and vomiting was 10% in both groups. There was no difference in the sedation scores. Conclusion:The substitution of 70% nitrous oxide with remifentanil at a mean infusion rate of 0.17 &mgr;g · kg−1 · minute−1 for colorectal surgery did not affect postoperative opioid consumption.

Remifentanil Preconditioning Confers Cardioprotection via Cardiac κ- and δ-Opioid Receptors

Background:Remifentanil preconditioning (RPC) reduces the infarct size in anesthetized rat hearts, and this effect seems to be mediated by all three types of opioid receptors (ORs). Because there is evidence of only &kgr;- and &dgr;- but not &mgr;-ORs in the rat heart, the authors investigated whether RPC confers cardioprotection via cardiac &kgr;- and &dgr;-OR as well as via extracardiac &mgr;-OR agonist activity. The authors also investigated the involvement of signaling mechanisms, namely protein kinase C and mitochondrial adenosine triphosphate–sensitive potassium (KATP) channels. Methods:The hearts of male Sprague-Dawley rats weighing 190–210 g were removed, mounted on a Langendorff apparatus, and perfused retrogradely at 100 cm H2O with Krebs-Ringer’s solution. All hearts were subjected to 30 min of ischemia and 2 h of reperfusion. The study consisted of three series of experiments on the effect of ischemic preconditioning or RPC (10, 50, and 100 ng/ml remifentanil) after blockade of OR subtypes (&dgr;-OR antagonist naltrindol, &kgr;-OR antagonist nor-binaltorphimine, and &mgr;-OR antagonist CTOP). The involvement of protein kinase C or the KATP channel in the cardioprotection of RPC was also investigated using specific blockers in each group. RPC was produced by three cycles of 5-min perfusion of remifentanil in Krebs-Ringer’s solution interspersed with a 5-min reperfusion with Krebs solution only. Infarct size, as a percentage of the area at risk, was determined by 2,3,5-triphenyltetrazolium staining. Results:Infarct size as a percentage of the area at risk was significantly reduced after RPC from 51.9 ± 5.0% (control, n = 8) to 36.2 ± 10.0% (100 ng/ml RPC, n = 8, P < 0.01). This effect was stopped by pretreatment with naltrindol (52.3 ± 5.2%) and nor-binaltorphimine (43.5 ± 6.0%) but not CTOP (37.1 ± 6.0%). Chelerythrine and GF109203X, both protein kinase C inhibitors, abolished the effects of RPC or ischemic preconditioning on infarct size as a percentage of area at risk. 5-Hydroxydecanoate (a selective mitochondrial KATP channel blocker) also abolished the cardioprotection of RPC and IPC, but HMR-1098 (a selective inhibitor of the sarcolemmal KATP channel) did not. Conclusion:Cardiac &dgr;- and &kgr;- but not &mgr;-ORs mediate the cardioprotection produced by RPC. Both protein kinase C and the mitochondrial KATP channel were involved in this effect.

Remifentanil reduces the release of biochemical markers of myocardial damage after coronary artery bypass surgery: a randomized trial.

OBJECTIVE Opioids, including remifentanil, have been demonstrated to confer cardiac protection against ischemia reperfusion injury in animals. This study evaluated whether remifentanil preconditioning is protective in first-time elective on-pump coronary artery bypass surgery patients receiving a standardized fentanyl (25 μg/kg in total) and propofol anesthetic. DESIGN A prospective, double blind, randomized, controlled study. SETTING University hospital; single institution. PARTICIPANTS Forty patients scheduled for first-time elective, on-pump coronary artery bypass surgery for at least 3 diseased vessels. INTERVENTIONS Patients randomized to the remifentanil group (n = 20) received a 1 μg/kg bolus followed by a 0.5 μg/kg/min infusion for 30 minutes after induction but before sternotomy, while the control group (n = 20) received normal saline. Serial samples for measurement of creatine kinase (CK-MB), cardiac troponin I (cTnI), ischemia-modified albumin (IMA) and heart-type fatty-acid-binding protein (hFABP) were taken at baseline, prebypass, T = 10 minutes, 2, 6, 12, and 24 hours after cross-clamp release, to assess the degree of myocardial damage. MEASUREMENTS AND MAIN RESULTS Patients in the remifentanil group had lower levels of CK-MB from T = 2 hours to 24 hours, cTnI from T = 10 minutes to T = 12 hours, IMA from T = 10 minutes to T = 2 hours and h-FABP from T = 10 minutes to T = 12 hours (p < 0.05). The time to tracheal extubation was shorter in patients in the remifentanil group. The overall lengths of ICU and hospital stays were not different. CONCLUSIONS The addition of remifentanil to the anesthesia regimen reduced the degree of myocardial damage. This incremental benefit may be attributable either to remifentanil itself or to an overall increased opioid dose, the latter may be necessary to trigger cardiac protection.

Anaesthesia for deep brain stimulation and in patients with implanted neurostimulator devices

Deep brain stimulation has become an increasingly common treatment for Parkinsons disease and other movement disorders. Consequently, it is important to understand the concepts of appropriate patient selection, the implantation process, and the various drugs and techniques that can be used to facilitate this treatment. Currently, none of the anaesthetic techniques for neurostimulator implantation has proven to be superior to others, although awake or sedation techniques are popular as they facilitate intraoperative neurological testing. However, even with meticulous anaesthetic care, perioperative complications such as hypertension and seizures do occasionally occur and close monitoring is required. Anaesthesia in patients with an implanted neurostimulator requires special considerations because of possible interference between neurostimulators and other devices. We have reviewed the current knowledge of anaesthetic techniques and perioperative complications of neurostimulator insertion. Anaesthetic considerations in patients with an implanted neurostimulator are also discussed.

Desmopressin does not decrease blood loss and transfusion requirements in patients undergoing hepatectomy

PurposeTo determine the effects of desmopressin on coagulation and blood loss in patients undergoing elective partial hepatectomy.MethodsA randomized, controlled and double-blind study on 59 patients who received either 0.3 μg·kg−1 of desmopressin or an equal volume of normal saline (control) infused intravenously over 20 min after induction of general anesthesia.ResultsThere was an increase in plasma levels of factors VIII and von Willebrand after the infusion of study drug in both groups (P < 0.001). The activated partial thromboplastin time was shortened in Group D whereas prothrombin time was prolonged in Group C; (P = 0.02). A large range of intraoperative blood loss (400–7128 mL) was observed, with no significant differences between groups. There were no changes in plasma electrolyte levels or osmolality. Transfusion requirements were similar in both groups.ConclusionDesmopressin did not reduce intraoperative blood loss or transfusion requirements during hepatectomy despite raising clotting factor levels and improving tests of hemostasis.RésuméObjectifDéterminer les effets de la desmopressine sur la coagulation et les pertes sanguines pendant une hépatectomie partielle réglée.MéthodeIl s’agit d’une étude randomisée, contrôlée et à double insu auprès de 59 patients qui ont reçu, soit 0,3 μg·kg−1 de desmopressine ou un volume égale de soluté normal (témoin) administré par voie intraveineuse 20 min au moins après l’induction de l’anesthésie générale.RésultatsOn a noté une augmentation des niveaux plasmatiques des facteurs VIII et von Willebrand à la suite de la perfusion du médicament expérimenté chez les patients des deux groupes (P < 0,001). Le temps de céphaline activé a été plus court dans le groupe D tandis que le temps de prothrombine a été plus long dans le groupe T ; (P = t0,02). D’importants écarts ont été observés pour les pertes sanguines peropératoires (400–7128 mL), mais sans différence significative intergroupe. Aucune modification des niveaux plasmatiques d’électrolyte ou d’osmolalité n’a été notée. Les besoins de transfusion ont été comparables dans les deux groupes.ConclusionLa desmopressine ne réduit pas les pertes sanguines ou les besoins de transfusion peropératoires pendant l’hépatectomie, malgré l’élévation des niveaux de facteurs de coagulation et l’amélioration de l’hémostase.

Prevention of hypotension during spinal anaesthesia for Caesarean section : Ephedrine infusion versus fluid preload

We compared the efficacy of prophylactic ephedrine infusion over fluid preloading in prevention of maternal hypotension during spinal anaesthesia for Caesarean section. Forty‐six women undergoing elective Caesarean section at term were allocated randomly to receive either intravenous fluid preloading with Hartmanns solution 20 ml.kg−1 (fluid group) or prophylactic intravenous ephedrine 0.25 mgkg−1 (ephedrine group). Moderate hypotension was defined as ≥ 20% reduction in systolic blood pressure and severe hypotension as ≥ 30% reduction in systolic blood pressure. Maternal uterine circulation was measured using Doppler ultrasound in 11 parturients before and after spinal anaesthesia. There was a lower incidence of severe hypotension in the ephedrine group compared with the fluid group (35% vs. 65%, p = 0.04), although the incidence of moderate hypotension was similar. Mean umbilical venous pH was higher in the ephedrine group than in the fluid group (7.33 vs. 7.29, p = 0.02) and the number of patients shivering was lower in the ephedrine group (2 vs. 9, p = 0.02). No difference was found between pre‐ and postspinal uterine artery pulsatility indices in either group. We conclude that prophylactic ephedrine infusion alone is at least as good as fluid preload alone in combating the hypotension associated with spinal anaesthesia for Caesarean section.

An audit of the safety of an acute pain service

We audited and analysed the adverse effects and safety of postoperative pain management on 2509 consecutive patients under care of the Acute Pain Service at a tertiary referral teaching hospital over a 32‐month period. Our standard respiratory monitoring consisted of continuous pulse oximetry, hourly respiratory rate counting, sedation scoring and intermittent arterial blood gas sampling. This protocol was reliable and detected six episodes of bradypnoea, 13 of hypercapnia and 23 of oxygen desaturation occurring in 39 patients (1.8% of all spontaneously breathing patients). Two patients required naloxone injection and none had long‐term sequelae. Hypotension due to epidural bupivacaine 0.0625% and fentanyl 3.3 μg.ml−1 infusion occurred in four patients (1.2%), all with a sensory block higher than T5. They readily responded to fluid infusion and ephedrine (two patients). Postoperative nausea or vomiting occurred in 723 (28.8%) and 380 (15.1%) patients, respectively. Odds ratio analysis showed that the risk factors for postoperative nausea and vomiting were: female gender, gynaecological operations, nongeriatric patients and systemic analgesia. Postoperative nausea and vomiting decreased analgesic efficacy by discouraging the use of patient‐controlled analgesia and was regarded as equally distressing as pain. Other side‐effects included: pruritus in 182 patients; dizziness in 333 and lower limb weakness in 73 (21.2% of patients receiving epidural local anaesthetics). It is concluded that a standard monitoring and management protocol, an experienced nursing team and reliable Acute Pain Service coverage is mandatory for the safe use of modern analgesic techniques.