Jean-Xavier Mazoit

Successful resuscitation after ropivacaine and lidocaine-induced ventricular arrhythmia following posterior lumbar plexus block in a child.

We report the case of a 13-yr-old girl scheduled for knee surgery under general anesthesia and posterior lumbar plexus block. A ventricular arrhythmia developed 15 min after local anesthetic injection. A 20% lipid emulsion was successful in converting the ventricular arrhythmia to a sinus rhythm. This is consistent with previous reports suggesting that lipid emulsion is an effective emergency treatment of local anesthetic toxicity. We recommend the immediate availability of lipid emulsion along with other emergency therapeutics in operating rooms where local anesthetics are used.

Binding of Long-lasting Local Anesthetics to Lipid Emulsions

Background:Rapid infusion of lipid emulsion has been proposed to treat local anesthetic toxicity. The authors wanted to test the buffering properties of two commercially available emulsions made of long- and of long- and medium-chain triglycerides. Methods:Using the shake-flask method, the authors measured the solubility and binding of racemic bupivacaine, levobupivacaine, and ropivacaine to diluted Intralipid (Fresenius Kabi, Paris, France) and Medialipide (B-Braun, Boulogne, France). Results:The apparent distribution coefficient expressed as the ratio of mole fraction was 823 ± 198 and 320 ± 65 for racemic bupivacaine and levobupivacaine, and ropivacaine, respectively, at 500 mg in the Medialipide/buffer emulsion; and 1,870 ± 92 and 1,240 ± 14 for racemic bupivacaine and levobupivacaine, and ropivacaine, respectively, in the Intralipid/buffer emulsion. Decreasing the pH from 7.40 to 7.00 of the Medialipide/buffer emulsion led to a decrease in ratio of molar concentration from 121 ± 3.8 to 46 ± 2.8 for bupivacaine, and to a lesser extent from 51 ± 4.0 to 31 ± 1.6 for ropivacaine. The capacity of the 1% emulsions was 871 and 2,200 &mgr;m for the 1% Medialipide and Intralipid emulsions, respectively. The dissociation constant was 818 and 2,120 &mgr;m for racemic bupivacaine and levobupivacaine, and ropivacaine, respectively. Increasing the temperature from 20 to 37°C led to a greater increase in affinity for ropivacaine (55%) than for bupivacaine (27%). When the pH of the buffer was decreased from 7.40 to 7.00, the affinity was decreased by a factor of 1.68, similar for both anesthetics. Conclusions:The solubility of long-acting local anesthetics in lipid emulsions and the high capacity of binding of these emulsions most probably explain their clinical efficacy in case of toxicity. The long-chain triglyceride emulsion Intralipid appears to be about 2.5 times more efficacious than the 50/50 medium-chain/long-chain Medialipide emulsion. Also, because of their higher hydrophobicity, racemic bupivacaine and levobupivacaine seem to clear more rapidly than ropivacaine.

Clinical Assessment of the Ultrasonographic Measurement of Antral Area for Estimating Preoperative Gastric Content and Volume

BACKGROUND This prospective observational study aimed to assess the feasibility and performance of the ultrasonographic measurement of antral cross-sectional area (CSA) for the preoperative assessment of gastric contents and volume in adult patients and for the diagnosis of risk stomach (defined by the presence of solid particles and/or gastric fluid volume >0.8 ml/kg). METHODS A preoperative ultrasonographic measurement of the antral CSA was performed for each patient by a physician (L.B.) blinded to the history of the patient. Immediately after tracheal intubation, an 18-French multiorifice Salem tube was inserted and gastric contents were aspirated in five different patient positions; during this time, the patients epigastrium was massaged and the tube was moved backward and forward in the stomach. The relationship between the antral area and the volume of aspirated gastric contents was analyzed, as was the performance of ultrasonographic measurement of antral area for the diagnosis of risk stomach. RESULTS The measurement of antral CSA was performed on 180 of 183 patients. A significant positive relationship between antral CSA and aspirated fluid volume was found. The cutoff value of antral CSA of 340 mm(2) for the diagnosis of risk stomach was associated with a sensitivity of 91% and a specificity of 71%. The area under the receiver operating characteristic curve for the diagnosis of risk stomach was 90%. CONCLUSIONS The ultrasonographic measurement of antral CSA could be an important help for the anesthesiologist in minimizing the risk of pulmonary aspiration of gastric contents due to general anesthesia.

Cortisol response to corticotropin stimulation in trauma patients: influence of hemorrhagic shock.

Background An abnormal adrenocortical function and a vasopressor dependency have been demonstrated during septic shock. Because trauma and hemorrhage are the leading causes of noninfectious inflammatory syndromes, the goal of this study was to assess the adrenal reserve of trauma patients and its relation with clinical course. Methods Cortisol response to an intravenous corticotropin bolus was obtained in 34 young trauma patients (Injury Severity Score =29.1 ± 7.3) at the end of the resuscitative period (“early phase”) and at the end of the first posttraumatic week (“late period”). Cortisol response less than +9 g/dl defined an impaired adrenal function, and the corresponding patient was called a nonresponder. According to the early response, hemorrhagic shock, circulating interleukin-6, need for vasopressor therapy, subsequent organ dysfunction and infection, and outcomes were studied. Results Sixteen patients (47%) were nonresponders at the end of the early phase. Hemorrhagic shock was more frequent (69 vs. 28%;P = 0.037) and interleukin-6 concentrations were higher (728 ± 589 vs. 311 ± 466 pg/ml;P = 0.048) in these patients. The early cortisol responses were negatively correlated with the concomitant interleukin-6 serum concentrations (r2 = 0.298;P = 0.003). Four early nonresponders (and shock patients) remained nonresponders during the late phase (25%). Morbidity and mortality were similar in early nonresponders and responders. The duration of norepinephrine treatment and the total amount of infused drug were significantly higher in early nonresponders. Conclusions A sustained impairment of adrenal reserve is frequently observed in trauma patients. This abnormal cortisol response to corticotropin stimulation is related with the inflammatory consequences of hemorrhagic shock and is followed by a prolonged vasopressor dependency.

A single dose of intrathecal morphine in rats induces long-lasting hyperalgesia: the protective effect of prior administration of ketamine.

An active pronociceptive process involving N-methyl-d-aspartate (NMDA) receptor activation is initiated by opioid administration, leading to opioid-induced pain sensitivity. Experimental observations in rats have reported reduction of baseline nociceptive threshold after prolonged spinal opioid administration. In this study we sought to determine whether a single dose of intrathecal morphine can induce hyperalgesia in uninjured rats and to assess the effects of pretreatment with the NMDA-antagonist ketamine on nociceptive thresholds. Sensitivity to nociceptive stimuli (paw pressure test) was assessed for several days after an acute intrathecal injection of morphine (5 &mgr;g and 10 &mgr;g) in male Sprague-Dawley rats. The effects of subcutaneously administered NMDA-receptor antagonist ketamine (10 mg/kg) before intrathecally administered morphine were also evaluated. A single intrathecal injection of morphine led to a biphasic effect on nociception; early analgesia associated with an increase in the nociceptive threshold lasting 3-5 h was followed by delayed hyperalgesia associated with a decrease in the nociceptive threshold lasting 1-2 days. Subcutaneous ketamine did not significantly modify the early analgesic component but almost completely prevented the delayed decrease in nociceptive threshold after intrathecal administration of morphine. A single intrathecal injection of morphine in rats produces a delayed and sustained hyperalgesia linked to the development of opioid-induced pain sensitivity.

Gabapentin Prevents Delayed and Long-lasting Hyperalgesia Induced by Fentanyl in Rats

Background:Opioid-induced hyperalgesia can develop rapidly after opioid exposure. Neuropathic pain and opioid-induced hyperalgesia share common pathophysiologic mechanisms. Gabapentin is effective for the management of neuropathic pain and may therefore prevent opioid-induced hyperalgesia. This study tested the effectiveness of gabapentin for prevention of long-lasting hyperalgesia induced by acute systemic fentanyl in uninjured rats. Involvement of the &agr;2&dgr; auxiliary subunits of voltage-gated calcium channels in the prevention of opioid-induced hyperalgesia by gabapentin also was assessed. Methods:Hyperalgesia was induced in male Sprague-Dawley rats with subcutaneous fentanyl (four injections, 20, 60, or 100 &mgr;g/kg per injection at 15-min intervals). Intraperitoneal (30, 75, 150, or 300 mg/kg) or intrathecal (300 &mgr;g) gabapentin was administered 30 min before or 300 min after (intraperitoneal 150 mg/kg) the first fentanyl injection. Sensitivity to nociceptive stimuli (paw-pressure test) was assessed on the day of the experiment and for several days after injections. The effects combining gabapentin with intrathecal ruthenium red (20 ng) also were assessed. Results:Fentanyl administration was followed by an early increase (analgesia) and by a later and sustained decrease (hyperalgesia) in nociceptive thresholds. Gabapentin did not significantly modify the early analgesic component but dose-dependently prevented the delayed decrease in nociceptive threshold. Ruthenium red partially, but significantly, opposed the prevention of opioid-induced hyperalgesia by gabapentin. Conclusions:Intraperitoneal and intrathecal gabapentin prevents the development of hyperalgesia induced by acute systemic exposure to opioids. This prevention may result, at least in part, from binding of gabapentin to the &agr;2&dgr; auxiliary subunits of voltage-gated calcium channels.

Median effective dose (ED50) of nefopam and ketoprofen in postoperative patients: a study of interaction using sequential analysis and isobolographic analysis.

Background:The analgesic efficacy of ketoprofen has been shown after moderate- and severe-pain surgery, and the analgesic efficacy of nefopam has been shown after moderate-pain surgery. The aim of this study was to define the median effective analgesic doses of each drug and to determine whether the interaction of nefopam and of ketoprofen is synergistic. Methods:Seventy-two patients scheduled to undergo moderately painful surgery were enrolled in one of three groups. The dose of nefopam and ketoprofen received by a particular patient was determined by the response of the previous patient of the same group, using an up-and-down technique. Initial doses were 18 and 40 mg, with dose adjustment intervals of 2 and 5 mg, in the nefopam and ketoprofen groups, respectively. The initial doses of nefopam and ketoprofen were 8 and 20 mg, respectively, in the nefopam–ketoprofen group, with the same dose adjustment intervals. Analgesic efficacy was defined as a decrease to less than 3 on a 0–10 numeric pain scale, 45 min after the beginning of drug infusion. Results:The median effective analgesic dose (median value and 95% confidence interval) of nefopam and ketoprofen were, respectively, 28 mg (17–39 mg) and 30 mg (14–46 mg). The median effective analgesic dose of the combination was 1.75 mg (0.9–2.3 mg) for nefopam and 4.3 mg (2.2–6.5 mg) for ketoprofen. Conclusion:The isobolographic analysis demonstrated that the combination of the two drugs produces effective analgesia with an important synergistic interaction.

The median effective dose of tramadol and morphine for postoperative patients: a study of interactions.

Tramadol is a centrally-acting analgesic drug. In a search of an effective balanced analgesia technique with a morphine-sparing component, we studied the median effective analgesic doses (ED50) of tramadol, morphine, and their combination to determine the nature of their interaction using an isobolographic analysis. In this double-blind, randomized, two-stage prospective study, 90 postoperative patients were enrolled in one of three groups. The dose of tramadol and morphine received by a particular patient was determined using an up-down allocation technique. Initial doses and increments were, respectively, 100 mg and 10 mg in the tramadol group and 5 mg and 1 mg in the morphine group. In the second part, a 40:3 tramadol:morphine dosing ratio was used. The threshold of effective analgesia was defined as 3 or less on a numerical pain score (0–10). Isobolographic analysis was subsequently applied. The ED50 values (95% confidence interval) of tramadol and morphine were, respectively, 86 mg (57–115 mg) and 5.7 mg (4.2–7.2 mg). The ED50 of the combination was 72 mg (62–82 mg) for tramadol and 5.4 mg (4–6.6.2 mg) for morphine. The combination of tramadol and morphine was infra-additive and thus not recommended for postoperative analgesia.

The μ Opioid Receptor Mediates Morphine-induced Tumor Necrosis Factor and Interleukin-6 Inhibition in Toll-like Receptor 2-stimulated Monocytes

BACKGROUND: Morphine possesses immunomodulatory effects but its intrinsic mechanisms, especially in the toll-like receptor 2 (TLR2) signaling pathway, are only partially understood. In this study, we evaluated the effects of morphine on tumor necrosis factor (TNF), interleukin-6 (IL-6), and interleukin-10 (IL-10) production in TLR2-stimulated human monocytes and identified the involvement of the different opioid receptors, and of the lymphocyte-to-monocyte contact. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from fresh blood by centrifugation on a density gradient. Monocytes were secondarily separated using a high-gradient magnetic cell sorting kit with specific anti-CD14 antibodies. Monocytes or PBMCs were pretreated with opioid receptors antagonists before being cultured with morphine and peptidoglycan (PGN) from Staphylococcus aureus (specific TLR2 agonist). The amount of TNF, IL-6, and IL-10 was measured in the supernatant enzyme-linked immunosorbent assay. RESULTS: Proinflammatory cytokines: Morphine significantly inhibited the production of cytokines in a dose and concentration-dependent manner in PGN-stimulated monocytes. &mgr; Opioid receptor activation specifically mediated this morphine-induced TNF and IL-6 inhibition in monocytes. Morphine significantly inhibited the TNF, but not the IL-6 production, in PGN-stimulated PBMCs. The &mgr; opioid receptor was not involved in this morphine-induced TNF inhibition in PBMCs. Antiinflammatory cytokines: IL-10 was not a factor for the inhibition of TNF and IL-6 production after PGN stimulation in either monocytes or PBMCs cultures. CONCLUSIONS: The &mgr; opioid receptor mediates morphine-induced TNF and IL-6 inhibition in PGN-stimulated monocytes, but not in PBMCs. A direct monocyte-to-lymphocyte contact (PBMCs) alters the inhibitory effects of morphine observed on monocytes alone. IL-10 is not a factor for the inhibition of TNF or for IL-6 production. Interactions between TLR2 and &mgr; opioid intracellular pathways remain to be studied to delineate these morphine immunosuppressive effects.

The Median Effective Dose of Preemptive Gabapentin on Postoperative Morphine Consumption After Posterior Lumbar Spinal Fusion

BACKGROUND:A single dose of preemptive gabapentin reduces postoperative pain and postoperative analgesic consumption. However, the optimal dose of preemptive gabapentin remains to be evaluated. METHODS:In this prospective study, we defined the median effective analgesic dose using an up-and-down sequential allocation technique of preemptive gabapentin in 67 patients undergoing elective posterior lumbar spinal fusion. The efficacy of the study drug was assessed by morphine consumption during the first 24 h postoperatively. RESULTS:The median effective analgesic dose (median value and 95% confidence interval) of gabapentin was 21.7 mg/kg (19.9–23.5 mg/kg). CONCLUSION:Given the large dose of gabapentin needed, further powered studies are warranted to assess side effects.