Michel Y. Dubois

Epidural clonidine analgesia for intractable cancer pain

&NA; Although the vast majority of patients with cancer pain receive effective analgesia from standard therapy, a few patients, particularly those with neuropathic pain, continue to experience severe pain despite large doses of systemic or intraspinal opioids. Animal studies suggest intraspinal &agr;2‐adrenergic agonists may be effective in such cases. Eighty‐five patients with severe cancer pain despite large doses of opioids or with therapy‐limiting side effects from opioids were randomized to receive, in a double‐blind manner, 30 gmg/h epidural clonidine or placebo for 14 days, together with rescue epidural morphine. Pain was assessed by visual analog score (VAS), McGill Pain Questionnaire, and daily epidural morphine use. Success was defined as a decrease in either morphine use or VAS pain, with the alternative variable either decreasing or remaining constant. Blood pressure, heart rate, and degree of nausea and sedation were monitored. Successful analgesia was more common with epidural clonidine (45%) than with placebo (21%). This was particularly prominent in those with neuropathic pain (56% vs. 5%). Pain scores were lower at the end of the treatment period in patients with neuropathic pain treated with clonidine rather than placebo, whereas morphine use was unaffected. Clonidine, but not placebo, decreased blood pressure and heart rate. Hypotension was considered a serious complication in 2 patients receiving clonidine and in 1 patient receiving placebo. This study confirms the findings from previous animal studies which showed the effective, potent analgesic properties of intraspinal &agr;2‐adrenergic agonists and suggests that epidural clonidine may provide effective relief for intractable cancer pain, particular of the neuropathic type.

The pharmacokinetics of propofol in children using three different data analysis approaches.

BackgroundAccurate dosing of propofol in children requires accurate knowledge of propofol pharmacokinetics in this population. Improvement in pharmacokinetic accuracy may depend on the incorporation of individual patient factors into the pharmacokinetic model or the use of population approaches to estimating the pharmacokinetic parameters. We investigated whether incorporating individual subject covariated (e.g., age, weight, and gender) into the pharmacokinetic model improved the accuracy. We also investigated whether the use of a mixed-effects population model (e.g., the computer program NONMEM) improved the accuracy of the pharmacokinetic model beyond the accuracy obtained with models estimated using two simple approaches. MethodsWe studied 53 healthy, unpremedicated children (28 boys and 25 girls) ranging from 3 to 11 yr of age. Twenty children only received an initial loading dose of 3 mg/kg intravenous propofol. In the remaining 33 children, an initial intravenous propofol dose of 3.5 mg/kg was followed by a propofol maintenance infusion. Six hundred fifty-eight venous plasma samples were gathered and assayed for propofol concentrations. Three different regression techniques were used to analyze the pharmacokinetics: the “standard two-stage‘’ approach, the “naive pooled-data‘’ approach, and the nonlinear mixed-effects modeling approach (as implemented in NONMEM). In both the pooled-data and mixed-effects approaches, individual covariates (age, weight, height, body surface area, and gender) were added to the model to examine whether they improved the quality of the fit. Accuracy of the model was measured by the ability of the model to describe the observed concentrations. ResultsThe pharmacokinetics of propofol in children were best described by a three-compartment pharmacokinetic model. There were no appreciable differences among the pharmacokinetics estimated using the two-stage, pooled-data, and mixed-effects approaches. Weight was a significant covariate, and the weight-proportional model was supported by all three regression approaches. The pharmacokinetic parameters of the weight-proportional pharmacokinetic model (pooled-data approach) were: central compartment (V1) = 0.52 1.kg−1 rapid-distribution compartment (V2) = 1.01.kg−1; slow-distribution compartment (V3) = 8.2 1.kg−1; metabolic clearance (Cl1) = 34 ml.kg−1.min−1; rapid-distribution clearance (Cl2) = 58 ml.kg−1.min−1; and slow-distribution clearance (Cl3) = 26 ml.kg−1.min−1. The inclusion of age as an additional covariate of V2 statistically improved the model, but the actual improvement in the fit was small. ConclusionsThe pharmacokinetics of propofol in children are well described by a standard three-compartment pharmacokinetic model. Weight-adjusting the volumes and clearances significantly improved the accuracy of the pharmacokinetics. Adjusting the pharmacokinetics for inclusion of additional patient covariates or using a mixed-effects model did not further improve the ability of the pharmacokinetic parameters to describe the observations.

Mortality Associated with Implantation and Management of Intrathecal Opioid Drug Infusion Systems to Treat Noncancer Pain

Background:In 2006, the authors observed a cluster of three deaths, which circumstances suggested were opioid-related, within 1 day after placement of intrathecal opioid pumps for noncancer pain. Further investigation suggested that mortality among such patients was higher than previously appreciated. The authors performed investigations to quantify that mortality and compare the results to control populations, including spinal cord stimulation and low back surgery. Methods:After analyzing nine index cases–three sentinel cases and six identified by a prospective strategy–the authors used epidemiological methods to investigate whether mortality rates reflected patient- or therapy-related differences. Mortality rates after intrathecal opioid therapy and spinal cord stimulation were derived by correlating Medtronic device registration data with deidentified data from the Social Security Death Master File. Aggregate demographic and comorbidity data were obtained from Medicare and United Healthcare population databases to examine the influence of demographics and comorbidities on mortality. Results:Device registration and Social Security analyses revealed an intrathecal opioid therapy mortality rate of 0.088% at 3 days after implantation, 0.39% at 1 month, and 3.89% at 1 yr–a higher mortality than after spinal cord stimulation implants or after lumbar diskectomy in community hospitals. Demographic, illness profile, and mortality analyses of large databases suggest, despite limitations, that excess mortality was related to intrathecal opioid therapy, and could not be fully explained by other factors. These findings were consistent with the nine index cases that revealed that respiratory arrest caused or contributed to death in all patients. No device malfunctions associated with overinfusion were identified among cases where data were available. Conclusions:Patients with noncancer pain treated with intrathecal opioid therapy experience increased mortality compared to similar patients treated by using other therapies. Respiratory depression as a consequence of intrathecal drug overdosage or mixed intrathecal and systemic drug interactions is one plausible, but hypothetical mechanism. The exact causes for patient deaths and the proportion of those deaths attributable to intrathecal opioid therapy remain to be determined. These findings, although based on incomplete information, suggest that it may be possible to reduce mortality in noncancer intrathecal opioid therapy patients.

Sufentanil and alfentanil pattern of consumption during patient-controlled analgesia: a comparison with morphine.

Pattern of drug consumption and side effects of sufentanil and alfentanil were compared to morphine, using “on-demand” patient-controlled analgesia (PCA). After a non-narcotic general anesthetic, a bolus dose of the narcotic was given intravenously towards the end of surgery. PCA was started in the recovery room. Data were retrieved postoperatively for a total of 24h. Results showed a wide range of pattern of drug consumption and uniform acceptance of therapy by the nurses and the patients in all the groups. The frequency of use of incremental dose was > 2–2.5-fold for the sufentanil and alfentanil groups, respectively, compared with morphine. The bolus dose of the narcotics failed to achieve adequate analgesia for 2h for morphine and sufentanil and for 6h for alfentanil. Overall patients were most sedated with sufentanil. At the time intervals sampled, there was a higher incidence of oxygen desaturation—less < 95% with morphine and alfentanil, compared with sufentanil. There was similar incidence of nausea in all the groups. Further study is needed to determine precisely the best dose regimens for Sufentanil appears to be a promising drug for PCA use.

Pharmacodynamics of rocuronium with and without prior administration of succinylcholine

STUDY OBJECTIVES To compare succinylcholine (S) and rocuronium (R) used for endotracheal intubation, and to assess the possible action of S on subsequently administered R. DESIGN Double-blind, randomized, phase III study. SETTING University Medical Center. PATIENTS 24 ASA physical status I and II patients, ages 28 to 65, undergoing general anesthesia for abdominal procedures. INTERVENTION Double-blind administration of R 600 mcg/kg (Group A) or S 1 mg/kg was achieved with open label R 150 mcg/kg. Standardized general anesthetic technique with sodium thiopental, fentanyl, and nitrous oxide in oxygen was administered. MEASUREMENTS AND MAIN RESULTS Neuromuscular junction was tested by ulnar nerve stimulation and mechanomyograph. Intubation was attempted at 80% first twitch depression of train-of-four. Heart rate and blood pressure were recorded throughout. Onset times were 74 +/- 37 seconds for S and 130 +/- 46 seconds for R. Intubation times were 76 +/- 29 seconds for S and 85 +/- 23 seconds for R (no significant difference). Good to excellent intubation conditions were achieved in both groups. S given prior to R decreased onset time and increased duration of R, when compared with R given alone. No drug related cardiovascular events were noted. CONCLUSION Rapid intubation conditions can be obtained after both S and R. Given its overall safety profile, R can be used when S is contraindicated, or in healthy patients with no apparent difficult airway, when procedures are expected to last more than 25 minutes.

Cerebral blood flow measurements during blood pressure control with intravenous labetalol following craniotomy.

Cerebral blood flow measurements using a thermal diffusion technique were made in conjunction with an extensive cardiovascular evaluation, during and after administration of intravenous labetalol given for blood pressure control in craniotomy patients. Eighteen patients, ages 30-65 years, ASAII and III, scheduled for elective craniotomy, became hypertensive during emergence and recovery from a pentothal/fentanyl/vecuronium/N2O/isoflurane general anesthesia. Labetalol was administered in a stepwise manner every 10 minutes during an average period of 1 h. After this titration period, an 8-h maintenance period followed. During titration and maintenance periods, comprehensive systemic hemodynamic parameters were collected through intra-arterial and flow-directed pulmonary artery catheters. Cerebral cortical blood flow (CBF) was continuously recorded using a thermal diffusion cortical blood flow probe (Saber System). Data were analyzed using variance F tests to evaluate changes from baseline over time. Labetalol controlled postoperative hypertension in all cases with a total dose range of 0.4-6.8 mg/kg. During titration, statistically significant decreases in blood pressure were obtained, accompanied by a small decrease in systemic vascular resistance (SVR) and slight increase in cardiac index (CI). Heart rate decreased in a manner directly proportional to the dose of labetalol administered. In the maintenance period, further decreases in blood pressure and heart rate were observed, with significant decreases in central venous pressure, pulmonary capillary wedge pressure, and SVR and an increase in CI. All values remained within normal ranges and no adverse effects were observed. CBF decreased slightly during the study period, although not significantly (from 67 +/- 8 to 57 +/- 7 ml 100 g min). Blood pressure control achieved with labetalol in postoperative neurosurgical patients seems to be the result of mild alpha-adrenoceptor blocking effects (i.e., reduced SVR) and beta-adrenoceptor blocking effects (i.e., reduced heart rate) at higher doses. The 6-8 h duration of effect of labetalol was enough to control postoperative hypertension in all patients with no additional therapy. Compared with alternative drugs available for blood pressure control in similar clinical conditions, labetalol appears to be reliable, safe, and effective, by providing a lasting effect with no evidence of rebound hypertension, increased CBF, or cardiac dysfunction.

Pharmacodynamic effects of three doses of ORG 9426 used for endotracheal intubation in humans

STUDY OBJECTIVE To determine the pharmacodynamic characteristics of three incremental doses of ORG 9426 used for endotracheal intubation in patients. DESIGN Double-blind, randomized administration of one of three doses of intravenous ORG 9426. SETTING Inpatients requiring surgery at Georgetown University Medical Center. PATIENTS Thirty-six patients, ages 18 to 65, ASA physical status I, II, and III, scheduled for general surgery. INTERVENTIONS After Georgetown University Institutional Review Board approval and patient consent, patients were premedicated with midazolam or droperidol. Anesthesia was induced with thiopental sodium and fentanyl. Anesthesia was maintained with 60% nitrous oxide in oxygen. The ulnar nerve was stimulated supramaximally with a 2 Hz train-of-four (TOF) every 20 seconds. Thumb contractions were measured with a force transducer. When TOF and anesthesia were stable, 2, 2.5, or 3 times the ED95 of ORG 9426 (570 micrograms/kg, 710 micrograms/kg, or 850 micrograms/kg) was administered randomly. Tracheal intubation was attempted at maximal depression of the first TOF response (T1). MEASUREMENTS AND MAIN RESULTS The following parameters were measured: time interval from the injection of ORG 9426 to 90% depression of T1 (T1 90% block), maximal T1 depression (onset time), intubating conditions, clinical duration (time for return of T1 to 25% of control), heart rate (HR), blood pressure (BP), and any adverse clinical experience. ORG 9426 provided adequate intubating conditions in all patients but two, independent of the dose used. Its onset time was rapid, but increasing the dose did not shorten the onset. T1 90% block was achieved rapidly (75 +/- 25 seconds to 78 +/- 18 seconds, means +/- SD). The clinical duration of ORG 9426 was relatively short and lengthened with increasing doses (from 36 +/- 18 minutes at 570 micrograms/kg to 42 +/- 10 minutes at 850 micrograms/kg. Spontaneous twitch recovery from 10% to 25% was similar in all dosage groups (5 +/- 1 minutes to 6 +/- 4 minutes). No clinically significant changes in HR and BP and no adverse clinical experiences were noted in any group. CONCLUSION These findings warrant further clinical evaluation of ORG 9426 for induction and maintenance of muscle relaxation in humans.

Pharmacodynamic effects of vecuronium: A dose response study

Vecuronium was administered to patients in dosages of 0.1, 0.2, 0.3, and 0.4 mg/kg to determine the clinical efficacy of large doses of vecuronium. Onset times shortened with larger doses up to 0.3 mg/kg. With 0.4 mg/kg, however, there was no significant improvement in onset time and the duration of action became unpredictable and often prolonged. Mean onset times were 172, 138, 106, and 100 seconds for the four groups, respectively. Prolonged duration of action (43, 96, 111, and 174 minutes, respectively) was observed with increasing dosages. Recovery rates for the first twitch response of the train-of-four stimulus from 10% to 25% were similar in all groups. There were no adverse hemodynamic effects secondary to large doses of vecuronium.

Alfentanil infusion in neurosurgical patients.

Alfentanil administered by constant rate infusion was evaluated as a main anesthetic in craniotomy patients. Eleven patients (ASA II) received either an induction dose of 200 microg/kg alfentanil followed by a 1 microg/kg/min infusion, or a 150 microg/kg bolus followed by a 1.5 microg/kg/min infusion. The infusion was stopped at least 1 h before the end of surgery. In addition to routine clinical neuroanesthesia monitoring, cardiovascular parameters, extubation conditions, and recovery scores were systematically recorded. Plasma alfentanil levels were determined in all patients during and for 6 h after the infusion. Finally, pharmacokinetic studies were carried out in five patients from both groups. This technique provided a remarkable cardiovascular stability, excellent extubation conditions, a comfortable recovery period, and no signs of prolonged or recurrent narcotization. No difference in clinical signs or alfentanil blood concentrations between the two drug regimens could be found. Pharmacokinetic parameters found were comparable to those obtained after single bolus drug elimination. Despite large individual variations and sometimes very prolonged infusion, there was no evidence of delayed drug administration. All of the above findings warrant the use of alfentanil infusion in neuroanesthesia and confirm the unique pharmacological properties of this drug among existing narcotics.

Evaluation of intravenous esmolol for treatment of postoperative hypertension

The efficacy and safety of intravenous (IV) esmolol to treat postoperative hypertension was studied in 30 adult patients, during emergence and recovery from anesthesia after general surgery. Esmolol was given as an IV infusion when the patient developed systolic blood pressure (SBP) ≥150 mm Hg or diastolic blood pressure (OBP) ≥95 mm Hg and heart rate (HR) ≥70 beats/min in the recovery room. Patients received a dose ranging from 100 to 2,104 mg of esmolol. Mean duration of the infusion was 63.6 ± 28.3 minutes. There were statistically significant differences between the control measurements and the end of esmolol titration for SBP, DBP, and HR. Side effects such as HR less than 60 beats/min or a decrease in SBP greater than 25% were observed in 33% (10/30) of the patient population; however, these effects were temporary and self-limiting. Hypotension (SBP β -adrenergic blocker esmolol was 90% (27/30) efficacious (ie, at least a 10% decrease in SBP or DBP) in controlling postoperative hypertension. As a fastacting, short-lasting antihypertensive drug, it joins the armamentarium of other drugs in the treatment of postoperative hypertension during emergence from anesthesia after general surgery.