Avi A. Weinbroum

A Single Small Dose of Postoperative Ketamine Provides Rapid and Sustained Improvement in Morphine Analgesia in the Presence of Morphine-resistant Pain

It is a common clinical observation that postoperative pain may be resistant to morphine. The analgesic potentials of ketamine have also been well documented. In this study, we evaluated the effects of postoperative coadministration of small doses of ketamine and morphine on pain intensity, Spo2, and subjectively rated variables in surgical patients who underwent standardized general anesthesia and complained of pain (≥6 of 10 on a visual analog scale [VAS]) despite >0.1 mg/kg of IV morphine administration within 30 min. Patients randomly received up to three boluses of 30 &mgr;g/kg of morphine plus saline (MS;n = 114) or 15 &mgr;g/kg of morphine plus 250 &mgr;g/kg of ketamine (MK;n = 131) within 10 min in a double-blinded manner. The MS group’s pain VAS scores were 5.5 ± 1.18 and 3.8 ± 0.9 after 10 and 120 min, respectively, after 2.52 ± 0.56 injections, versus the MK group’s VAS scores of 2.94 ± 1.28 and 1.47 ± 0.65, respectively (P < 0.001), after 1.35 ± 0.56 injections (P < 0.001). The 10-min level of wakefulness (1–10 VAS) in the MS group was significantly (P < 0.001) less (6.1 ± 1.5) than the MK group’s (8.37 ± 1.19). Spo2 decreased by 0.26% in the MS group but increased by 1.71% in the MK patients at the 10-min time point (P < 0.001). Thirty MS versus nine MK patients (P < 0.001) experienced nausea/vomiting; nine MK patients sustained a 2-min light-headed sensation, and one patient had a weird dream after the second drug injection.

Current Knowledge of Buprenorphine and Its Unique Pharmacological Profile

Despite the increasing clinical use of transdermal buprenorphine, questions have persisted about the possibility of a ceiling effect for analgesia, its combination with other μ‐opioid agonists, and the reversibility of side effects. In October 2008, a consensus group of experts met to review recent research into the pharmacology and clinical use of buprenorphine. The objective was to achieve consensus on the conclusions to be drawn from this work. It was agreed that buprenorphine clearly behaves as a full μ‐opioid agonist for analgesia in clinical practice, with no ceiling effect, but that there is a ceiling effect for respiratory depression, reducing the likelihood of this potentially fatal adverse event. This is entirely consistent with receptor theory. In addition, the effects of buprenorphine can be completely reversed by naloxone. No problems are encountered when switching to and from buprenorphine and other opioids, or in combining them. Buprenorphine exhibits a pronounced antihyperalgesic effect that might indicate potential advantages in the treatment of neuropathic pain. Other beneficial properties are the compounds favorable safety profile, particularly in elderly patients and those with renal impairment, and its lack of effect on sex hormones and the immune system. The expert group agreed that these properties, as well as proven efficacy in severe pain and favorable tolerability, mean that buprenorphine can be considered a safe and effective option for treating chronic cancer and noncancer pain.

Midazolam versus propofol for long-term sedation in the ICU: a randomized prospective comparison

Objective: To compare the efficacy, safety, and cost of midazolam and propofol in prolonged sedation of critically ill patients.Design: Randomized, prospective study.Setting: General intensive care unit (ICU) in a 1100-bed teaching hospital.Patients: 67 critically ill, mechanically ventilated patients.Interventions: Patients were invasively monitored and mechanically ventilated. A loading dose [midazolam 0.11 ± 0.02 (SEM) mg · kg−1, propofol 1.3 ± 0.2 mg · kg−1] was administered, followed by continuous infusion, titrated to achieve a predetermined sedation score. Sedation was continued as long as clinically indicated.Measurements and results: Mean duration of sedation was 141 and 99 h (NS) for midazolam and propofol, respectively, at mean hourly doses of 0.070 ± 0.003 mg · kg−1 midazolam and 1.80 ± 0.08 mg · kg−1 propofol. Overall, 68 % of propofol patients versus 31 % of midazolam (p<0.001) patients had a > 20 % decrease in systolic blood pressure after the loading dose, and 26 versus 45 % (p<0.01) showed a 25 % decrease in spontaneous minute volume. Propofol required more daily dose adjustments (2.1 ± 0.1 vs 1.4 ± 0.1, p<0.001). Nurserated quality of sedation with midazolam was higher (8.2 ± 0.1 vs 7.3 ± 0.1 on a 10-cm visual analog scale, p<0.001). Resumption of spontaneous respiration was equally rapid. Recovery was faster after propofol (p<0.02), albeit with a higher degree of agitation. Amnesia was evident in all midazolam patients but in only a third of propofol patients. The cost of propofol was 4–5 times higher.Conclusions: Both drugs afforded reliable, safe, and controllable long-term sedation in ICU patients and rapid weaning from mechanical ventilation. Midazolam depressed respiration, allowed better maintenance of sedation, and yielded complete amnesia at a lower cost, while propofol caused more cardiovascular depression during induction.

The role of dextromethorphan in pain control

Purpose: To review the clinical benefits of dextromethorphan (DM) in pain management, describe its neuropharmacological properties.Source: A Medline search was made for experimental and clinical data on DM use from 1967 to date using keywordsnociception, acute and chronic pain control, N-methyl-D-aspartate, antagonists, dextromethorphan.Principle findings: The 930 DM citations mostly described its antitussive, metabolic and toxicological aspects, animal studies and its possible role in minimizing post-brain ischemia complications in humans. The use of DM inacute pain revealed eight original studies involving 443 patients, as well as two preliminary reports and our own unpublished data on 513 patients. Most of the 956 patients had general anesthesia. Eight studies (154 patients) and one case report dealt withchronic pain management. This N-methyl-D-aspartate (NMDA) receptor antagonist binds to receptor sites in the spinal cord and central nervous system, thereby blocking the generation of central acute and chronic pain sensations arising from peripheral nociceptive stimuli and enabling reduction in the amount of analgesics required for pain control. DM attenuated the sensation ofacute pain at doses of 30–90 mg, without major side effects, and reduced the amount of analgesics in 73% of the postoperative DM-treated patients. Studies in secondary pain models in healthy volunteers and in various types ofchronic pain showed DM to be associated with unsatisfactory pain relief.Conclusion: DM attenuatesacute pain sensation with tolerable side effects. Its availability in oral form bestow advantages over other NMDA antagonists.RésuméObjectif: Passer en revue les bénéfices cliniques du dextrométhorphane (DM) et décrire ses propriétés neuropharmacologiques.Source: Une recherche dans Medline a fourni des données expérimentales et cliniques sur le DM, utilisé de 1967 à aujourd’hui, à l’aide des mots-clésnociception, soulagement de la douleur aiguë et chronique, N-méthyl-D-aspartate, antagonistes, dextrométhorphane.Constations principales: Les 930 références trouvées décrivent surtout les aspects antitussifs, métaboliques et toxicologiques du DM, les études sur des animaux et le rôle possible dans la réduction des complications de l’ischémie cérébrale chez l’humain. Huit études originales auprès de 443 patients, deux rapports préliminaires et nos propres données non publiées sur 513 patients concernent le soulagement de la douleuraiguë. La majorité des 956 patients ont eu une anesthésie générale. Huit études (154 patients) et une observation portent sur le traitement de la douleurchronique. Cet antagoniste des récepteurs N-méthyl-D-aspartate (NMDA) se fixe sur les sites récepteurs dans la moelle épinière et le système nerveux central. Il empêche ainsi la propagation centrale des sensations de douleurs aiguës et chroniques provenant de stimuli nociceptifs périphériques, et contribue à la réduction de la quantité d’analgésiques nécessaires au traitement. Des doses de 30–90 mg de DM atténuent la sensation de douleuraiguë, sans produire d’effets secondaires importants, et permettent de réduire la quantité d’analgésiques chez 73 % des patients traités avec du DM après une intervention chirurgicale. Les études de modèles de douleurs secondaires chez des volontaires sains et de différents types de douleurschroniques, ont révélé que le DM n’apporte pas de soulagement de la douleur satisfaisant.Conclusion: Le DM atténue la sensation de douleuraiguë et présente des effets secondaires acceptables. Son conditionnement sous forme orale lui confère des avantages sur d’autres antagonistes de NMDA.

Practical Guidelines for Acute Care of Victims of Bioterrorism: Conventional Injuries and Concomitant Nerve Agent Intoxication

THE potential use of weapons of mass destruction has recently become a real threat even in regions of the world that are remote from areas of ongoing armed conflicts. Episodes of the use of sarin or VX, both potent acetylcholinesterase (AChE) inhibitors that cause cholinergic crisis, in the terrorist attacks against civilians in Japan in 1994 and 1995 which produced several fatalities and hundreds of casualties, 1,2 and the military use of nerve agents (NA) by Iraq against Iran and the Kurdish population during the 1980s are grim examples of the deadly potential of NA. Victims of a mass casualty event can suffer from physical trauma alone or from trauma in combination with gas intoxication. The exposure of a physically injured patient to a toxic substance, in a scenario of mass injury, has recently gained major attention among planners of future protocols for emergency medical services. 3 Furthermore, when a civilian population becomes the prime target of an NA attack, diversity in age and previous health status are expected to increase the extent of the injuries compared with those of healthy adult soldiers by as much as 10-fold. 4 Because rapid deterioration and multiorgan involvement are to be expected after a physically injured individual is exposed to a toxic substance, proper organization and complex but efficient acute medical and surgical care systems must be organized and deployed to ensure a maximal number of saved lives. The various national rescue forces that have traditionally been tasked with models of rapid evacuation and decontamination of large numbers of poisoned civilians from affected areas appear to be only a fraction of future necessities. 5 The proposed management of mass casualty events needs to be based on triage principles and acute care measures. These should include: rapid identification of the offending agent, swift decontamination by wellprotected emergency medical personnel, and triageguided mass evacuation to a nearby medical facility that should be well equipped and staffed with personnel who have been properly trained to deal with such multifaceted events.

N-acetyl-L-cysteine for preventing lung reperfusion injury after liver ischemia-reperfusion: a possible dual protective mechanism in a dose-response study.

BACKGROUND Acute lung reperfusion injury (ALI) frequently follows an ischemic event in another organ, such as organ transplantation. We recently demonstrated that lung priming with N-acetyl-L-cysteine (NAC) prevented liver ischemia-reperfusion (IR)-induced ALI pending on reduced glutathione (GSH) amount of replenishment. We now assessed the therapeutic effect of NAC-in preventing ALI caused by liver IR-if administered to the lung during liver reperfusion. PROCEDURES Rat isolated livers were stabilized (30 min) and then perfused with modified Krebs-Henseleit solution (control, n=20) or made globally ischemic (IR, n=20) for 2 hr. Rat lungs were isolated separately, ventilated, and stabilized (30 min) with Krebs plus 5% bovine albumin. Pairs of liver and lung were then reperfused together for 15 min, followed by only lung recirculation with the liver effluent for another 45 min. Three more controls (n=20 each) and three ischemic groups (n=20 each) included lungs which were treated with 100, 150 or 225 mg x kg(-1) NAC (0.5, 0.74, or 1.1 mmol, respectively) during the 15-min liver and lung reperfusion period. RESULTS Pulmonary artery and ventilatory pressures and vascular resistance increased by 60-80% of baseline, compliance decreased, and bronchoalveolar lavage volume and content were abnormally high in the IR-nontreated and the IR-100 lungs. Most parameters in IR-150 and IR-225 lungs remained almost similar to controls. Postinsult GSH content in IR-100, -150, and -225 lungs was at 20%, 110%, and 90% above the IR-nontreated lungs, respectively. CONCLUSIONS Lung treatment with NAC during its reperfusion with IR liver effluent prevented ALI. Lung GSH replenishment accounted for lung protection, but its content did not correlate directly with grade of protection; NAC itself seemingly afforded lung protection as well.

Non-opioid IV adjuvants in the perioperative period: Pharmacological and clinical aspects of ketamine and gabapentinoids

Untreated acute postoperative pain can transform into chronic pain that may have major negative effects on the individuals quality of life. It can also prolong recovery, rehabilitation and length of hospital stay, thus affecting societal economic burden. Given the multiplicity of mechanisms involved in postoperative pain, a multimodal analgesia regimen, using a combination of opioids and multiple agents aiming to augment their effects via different routes of administration, is a pharmacologically appropriate approach. This polypharmacological application provides superior pain relief at rest and after movement, reduced opioid consumption associated with reduced analgesic-related adverse effects, and better chances to prevent the induction of later hyperalgesia. The most important adjuncts currently employed are ketamine and gabapentinoids. They have been shown to help in reaching the desired effect when administered at drug-specific modes and at proven effective dosing throughout the perioperative period.

A Risk-Benefit Assessment of Flumazenil in the Management of Benzodiazepine Overdose

SummaryThe worldwide expansion in the use of benzodiazepines has led to their frequent, and often inappropriate, use and to an increase in their involvement in self-induced poisoning and iatrogenic overdosing. Flumazenil is a specific and competitive antagonist at the central benzodiazepine receptor, reversing all effects of benzodiazepine agonists without tranquillising or anticonvulsant actions. Incremental intravenous bolus injections of flumazenil 0.1 to 0.3mg are the most effective and well tolerated in the diagnosis and treatment of pure benzodiazepine overdose; additional boluses or an infusion (0.3 to 0.5 mg/h) can be given to prevent patients from relapsing into coma. Intravenous flumazenil 10 to 20 µg/kg is effective in neonates and small children. Intramuscular, oral (20 to 25mg 3 times daily or as required) and rectal administration may be used as alternatives in long term regimens. Patients with mixed-drug overdose require higher doses (up to 2mg bolus, ≈1 mg/h infusion) to regain consciousness. Children and the elderly, chronically ill patients, and pregnant women and their fetuses all respond satisfactorily to flumazenil, but the usefulness of the drug in patients with hepatic encephalopathy and alcohol overdose is debatable.The use of flumazenil results in complete awakening with restoration of upper airway protective reflexes, thus enabling gastric lavage to be performed and transfer of the patient from the emergency room to another hospital department. Resumption of effective spontaneous respiration allows for expeditious extubation, weaning off mechanical ventilation or the avoidance of endotracheal intubation. While flumazenil is not associated with haemodynamic adverse effects, caution should be exercised when using this agent in patients who have co-ingested chloral hydrate or carbamazepine or whose ECG shows abnormalities typical of those seen after overdose with tricyclic antidepressants (TCAs); the use of flumazenil in the presence of these drugs can sometimes induce treatable cardiac dysrrhythmia.Flumazenil per se does not induce adverse effects. Coma reversal by flumazenil may cause mild, short-lived reactions caused by sudden awakening. Withdrawal symptoms in long term benzodiazepine users and seizures in patients who have taken an overdose of TCA or carbamazepine and a benzodiazepine can occur with flumazenil; these symptoms are avoidable by utilising slow flumazenil dose titration.

Dextromethorphan and dexmedetomidine : New agents for the control of perioperative pain

Most traditional opioids and non-steroidal anti-inflammatory drugs that are used to control perioperative pain have substantial side effects. The number of choices in clinical use was recently increased by two promising groups of drugs: N-methyl-D-aspartate receptor antagonists and central alpha2 agonists. One N-methyl-D-aspartate antagonist, dextromethorphan, blocks the generation of central pain sensation that arise from peripheral nociceptive stimuli by moderating the activity of N-methyl-D-aspartate. It pre-empts the sensation of acute pain at doses of 30-90 mg without serious side effects, while reducing the amount of analgesics required perioperatively by 50%. It is available in oral form and has a confirmed lack of effect on haemodynamics and respiration. Dexmedetomidine is a relatively new, highly selective central alpha2 agonist. Its sedative, pro-anaesthetic and pro-analgesic effects at 0.5-2 microg/kg given intravenously stem mainly from its ability to blunt the central sympathetic response by as yet unknown mechanism(s) of action. It also minimises opioid-induced muscle rigidity, lessens postoperative shivering, causes minimal respiratory depression, and has haemodynamic stabilising effects.

Ketamine spares morphine consumption after transthoracic lung and heart surgery without adverse hemodynamic effects.

BACKGROUND Thoracotomy is associated with severe pain. Large doses of morphine can depress respiratory drive and compromise hemodynamic stability. Ketamine reduces hyperalgesia, prevents opioid tolerance and resistance and lowers morphine consumption. At sub-anesthetic (< or = 500 microg/kg) doses, ketamine rarely produces undesirable hemodynamic alterations. We hypothesized that by combining a sub-anesthetic dose of ketamine with morphine, we could effectively control pain with less morphine and minimize drowsiness, while maintaining safe hemodynamic and respiratory parameters. METHODS Sequential patients undergoing anterolateral thoracotomy for MIDCAB, lung tumor resection, or median sternotomy for OPCAB were randomized to one of the two intravenous patient-controlled analgesia (IV-PCA) protocols. MO-only patients received 1.5 mg MO bolus, and MK patients received 1.0 mg MO+5 mg ketamine/bolus, both with a 7 min lockout time. IV-PCA was initiated when the patient was sufficiently awake (> or = 5/10 VAS) and rated pain > or = 5/10 on a 0-10 VAS. Rescue intramuscular diclofenac 75 mg was available. Follow-up of respiratory, hemodynamic and pain statuses lasted 72 h. RESULTS Fifty-eight patients completed the 6-month study. Heart rate and blood pressures were identically stable in both groups. Respiratory rate and pulse oximetry were higher (P < 0.05) in the MK than in the MO group. MO patients (n = 28) used twice (2.0 +/-2.3 mg/patient/h) the amount of morphine compared to MK patients (n = 30, 1.0 +/- 1.4 mg/patient/h, P < 0.05). Thirty-six hours after starting PCA, 10 MO patients still required IV-PCA compared to 5 MK patients (P < 0.05). Diclofenac was used 70% more in MO than in MK patients. MO patients suffered more postoperative nausea and vomiting. No patients had hallucinations. CONCLUSIONS The concomitant use of sub-anesthetic ketamine plus two-thirds the standard MO dose following thoracotomy, MIDCAB or OPCAB resulted in lower pain scores, reduced MO consumption and shorter postoperative IV-PCA dependence. These advantages were associated with cardiovascular stability and even better respiratory parameters.