Multimodal therapies for postoperative nausea and vomiting, and pain.

Postoperative nausea and vomiting (PONV) and pain are two of the major concerns for patients presenting for surgery. The causes of PONV are multifactorial and can largely be categorized as patient risk factors, anaesthetic technique, and surgical procedure. Antiemetics work on several different receptor sites to prevent or treat PONV. This is probably why numerous studies have now demonstrated that using more than one antiemetic is usually more effective and results in fewer side-effects than simply increasing the dose of a single antiemetic. A multimodal approach to PONV should not be limited to drug therapy alone but should involve a holistic approach starting before operation and continuing intraoperatively with risk reduction strategies to which are added prophylactic antiemetics according to the assessed patient risk for PONV. With the increasing understanding of the pathophysiology of acute pain, especially the occurrence of peripheral and central hypersensitization, it is unlikely that a single drug or intervention is sufficiently broad in its action to be adequately effective, especially with moderate or greater pain. Although morphine and its congeners are usually the foundation of pain management regimens, as their dose increases so does the incidence of side-effects. Thus, the approach for the management of acute postoperative pain is to use multiple drugs or modalities (e.g. regional anaesthesia) to maximize pain relief and reduce side-effects.

Age-associated differences in the inhibition of mitochondrial permeability transition pore opening by cyclosporine A.

BACKGROUND: Inhibiting mitochondrial permeability transition pore (mPTP) opening is a key protection of the myocardium from ischemia/reperfusion (I/R) injury. Here, we investigated age-associated differences in the ability of cyclosporine A (CsA) to protect the heart and to modulate mPTP opening during I/R injury in vivo and its opening induced by reactive oxygen species (ROS) in vitro. METHODS: Fischer 344 male rats were assigned from their respective age groups, young or old groups, to (1) I/R or (2) I/R+CsA. All animals were subjected to 30 min of ischemia following 120 min of reperfusion to determine myocardial infarct size in vivo. To measure mPTP opening in vivo, left ventricular tissues were collected 10 min after reperfusion and nicotinamide adenine dinucleotide (NAD(+)) levels were measured. In parallel experiments, rat ventricular myocytes were prepared from young and old hearts, loaded with tetramethylrhodamine ethylester and then subjected to oxidative stress in the presence or absence of CsA, and the mPTP opening time was measured using laser scanning confocal microscopy. RESULTS: CsA reduced myocardial infarct size in young I/R rats. Whereas CsA failed to significantly affect myocardial infarct size in old I/R rats, NAD(+) levels were better preserved in young CsA-treated rats, but this relative improvement was not observed in old rats. CsA also significantly prolonged the time necessary to induce mPTP opening in young cardiomyocytes, but not in cardiomyocytes isolated from the old rats. CONCLUSIONS: mPTP regulation is dysfunctional in the aged myocardium and this could account for loss of cardioprotection with aging.

The effect of desflurane on rocuronium onset, clinical duration and maintenance requirements.

Volatile anesthetics potentiate the effects of non-depolarizing agents. This study investigated the interaction between the inhalational anesthetic desflurane and rocuronium. Forty ASA I and II patients randomly received desflurane/N2O/fentanyl, or propofol/ N2O/fentanyl anesthesia, and rocuronium 0.6 mg/kg. Neuromuscular block was assessed at the adductor pollicis muscle. Block onset and clinical duration times were measured; a rocuronium infusion was started when the first twitch on train-of-four returned to 10% of control (T10%). Maintenance infusion requirements and recovery profiles (spontaneous and after reversal) were recorded until recovery of twitch to 90% of control (T90%). Rocuronium onset was prolonged by 67% (p = 0.034), clinical duration by 30% (p = NS), and infusion requirements were lower in the desflurane group (4.5 vs. 7.1 mg/kg/min, p = 0.003). Recovery times were not statistically different. Desflurane significantly delays the onset of neuromuscular block, potentiates rocuronium during maintenance infusion, but does not affect clinical duration or recovery.

Propofol regulation of calcium entry pathways in cultured A10 and rat aortic smooth muscle cells.

1. We have investigated the effect of propofol, an intravenous anaesthetic, on the intracellular calcium concentration ([Ca2+]i), Ca2+ entry pathways and on inositol phosphate formation in vascular smooth muscle cells. [Ca2+]i and Ca2+ flux were monitored with the Ca(2+)-sensitive fluorescent dye, fura-2, and by 45Ca2+ uptake. Production of labelled inositol phosphates was analysed by anion-exchange chromatography. 2. Treatment of the cells with endothelin-1 (ET-1) increased formation of inositol phosphates and elevated [Ca2+]i due to both release of Ca2+ from intracellular pools and prolonged entry of Ca2+ from outside the cell. Propofol reduced production of inositol phosphates mediated by ET-1 and arginine vasopressin which activate phospholipase C. 3. The sustained Ca2+ entry stimulated by ET-1 was found to occur through the activation of L-type Ca channels. This was inhibited by propofol in a dose-dependent manner. 4. Activation of protein kinase C (PKC) by phorbol esters activated a pharmacologically-similar channel and produced a similar change in [Ca2+]i due to Ca2+ entry. The entry was blocked by an L-type channel antagonist, nicardipine and by the anaesthetic drug, propofol. 5. Treatment of the cells with thapsigargin, a selective inhibitor of the sarcoplasmic reticulum Ca(2+)-ATPase, also elevated [Ca2+]i by inducing the release of intracellular Ca2+ and the continued entry of extracellular Ca2+ through a nicardipine-insensitive Ca channel. Neither release nor entry induced by thapsigargin was affected by propofol. 6. These findings suggest that propofol selectively inhibits Ca2+ entry through the L-type channel induced by ET-1 and phorbol esters but has no effects on Ca2+ entry via the nicardipine-insensitive channel and on Ca2+ release from intracellular pools initiated by thapsigargin. This may represent one of the mechanisms responsible for propofol-induced vasodilatation.

Quantitative analysis of regional wall thickening by transesophageal echocardiography.

To develop a method for quantitative analysis of regional left ventricular function from transesophageal two-dimensional echocardiograms, we conducted studies 10 and 20 minutes after induction of anesthesia in 16 patients with normal hearts who were undergoing minor orthopedic operations. Wall thickening was measured with the centerwall method along 100 chords drawn perpendicular to a line constructed around the center of the ventricular wall, midway between the endocardial and epicardial contours. Thickening, either normalized by the length of the end-diastolic perimeter or expressed as a percentage of the end-diastolic wall thickness at each chord, was compared with measurements of endocardial motion. Wall motion was relatively diminished in the anteroseptal region and enhanced on the contralateral wall, but wall thickening was homogeneous throughout the contour. Normalized wall thickening was significantly less variable (standard deviation/mean, 0.47 +/- 0.13) in the normal population than were either percent wall thickening (0.53 +/- 0.012) or wall motion (0.51 +/- 0.09) (p less than 0.005 for both comparisons). There was no significant change in regional or global function between 10 minutes and 20 minutes after the induction of anesthesia. In summary, normalized wall thickening as a parameter of regional left ventricular function is more homogeneous and less variable in subjects with normal hearts than is endocardial motion because wall thickening measurements are not subject to cardiac translocation artifacts. This low variability suggests that normalized wall thickening measured by the centerwall method may prove particularly useful for intraoperative and postoperative monitoring of regional left ventricular function by transesophageal echocardiography in patients undergoing both cardiac and noncardiac surgical procedures.

Remifentanil: a new opioid.

Remifentanil appears to have pharmacodynamic properties similar to other potent mu opioid agonists. It does, however, have unique pharmacokinetic properties, with a rapid onset and rapid offset of effect, irrespective of the duration of its administration. With this property, remifentanil appears to be a very titratable opioid that will make it suitable for administration for either very brief periods, in which analgesia is required, or over prolonged periods, without the concern for prolonged recovery.

A comparison of vecuronium by continuous infusion with either isoflurane or fentanyl-nitrous oxide anesthesia.

The average infusion rate and efficacy of vecuronium bromide continuous infusions for surgical relaxation in human subjects was evaluated. Nineteen adult patients requiring more than 120 min of neuromuscular blockade for surgery were randomized to receive either fentanyl-nitrous oxide (Group 1) or isoflurane-fentanyl-nitrous oxide (Group 2). Neuromuscular function was monitored using train-of-four evoked electromyography (EMG). Following an intubating dose of 0.08 mg/kg of vecuronium bromide, the first twitch was allowed to return to 10% of its control value. An infusion of vecuronium at an initial rate of 60.0 micrograms/kg/h was then started and adjusted to maintain the first twitch at 10% of control. The average infusion rate (total infusion dose divided by the duration of the infusion) was 57.2 +/- 14 micrograms/kg/h in Group 1 (n = 10) and 42.4 +/- 12 micrograms/kg/h (n = 9) in Group 2, approximately 25% less (p = 0.02). There was a significant decrease in the infusion rate with time in Group 1 (p = 0.02), but this decrease was not observed in Group 2.

Drug interactions: volatile anesthetics and opioids.

Multiple drugs are used to provide anesthesia. Volatile anesthetics are commonly combined with opioids. Several studies have demonstrated that small doses of opioid (i.e., within the analgesic range) result in a marked reduction in minimum alveolar concentration (MAC) of the volatile anesthetic that will prevent purposeful movement in 50% of patients at skin incision). Further increases in opioid dose provide only a further small reduction in MAC. Thus, a ceiling effect of the opioid is observed at a MAC value of the volatile anesthetic equal to its MAC awake. Recovery from anesthesia when an opioid is combined with a volatile anesthetic is dependent on the rate of decrease of both drugs to their respective concentrations that are associated with adequate spontaneous ventilation and awakening. Through an understanding of the pharmacodynamic interaction of volatile anesthetics with opioids and the pharmacokinetic processes responsible for the recovery from drug effect, optimal dosing schemes can thus be developed. A review of these pharmacodynamic and pharmacokinetic principles that will allow clinicians to administer drugs to provide a more optimal anesthetic is provided.

The use of propofol for its antiemetic effect: a survey of clinical practice in the United States.

STUDY OBJECTIVES: To investigate the use of propofol by anesthesiologists for its antiemetic effect and to compare our findings with published evidence. DESIGN: Anonymous survey of U.S. anesthesiologists. SETTING: American Society of Anesthesiologists' annual meeting. MEASUREMENTS AND MAIN RESULTS: One hundred fifty anesthesiologists were surveyed on how they use propofol to achieve an antiemetic effect. A large majority (84%) of the anesthesiologists surveyed stated they used propofol for its antiemetic effect: 63% of those used propofol for induction only for cases lasting <1 h to achieve an antiemetic effect. In addition 37% used a "sandwich" technique, using propofol at the beginning and end of a case for a similar purpose. There is evidence that the antiemetic effect of propofol is associated with a defined plasma concentration range; mean, 343 ng/mL (10-90% confidence intervals [CI] 200-600 ng/mL). Simulation data demonstrated that after propofol 2 mg/kg, its concentration will drop below 350 ng/mL at 32 min. After 2 mg/kg and 20 mg within 10 min of the end of surgery, its concentration will drop below 350 ng/mL by 7 min after the 20 mg bolus dose. This finding suggests that the plasma concentrations of propofol, when used in these cases, will be below the effective range of antiemetic effect. CONCLUSIONS: Many anesthesiologists used propofol for its antiemetic effect. There is strong evidence for its antiemetic efficacy after anesthesia maintained by a propofol infusion and also for its use in the postanesthesia care unit (PACU). However, there is little evidence to support its use purely at induction of anesthesia or as part of a "sandwich" technique in an attempt to reduce postoperative nausea and vomiting. This is especially true in cases lasting longer than a few minutes.

A comparison of mivacurium dosage requirements during isoflurane and desflurane anesthesia.

STUDY OBJECTIVE: To evaluate the dose requirement and recovery characteristics of mivacurium infusions during anesthesia with equipotent concentrations of either desflurane or isoflurane. DESIGN: Randomized, open-study comparing the effects of desflurane and isoflurane on mivacurium-induced neuromuscular blockade. SETTING: Operating suite of a university-affiliated medical center. PATIENTS: 41 ASA status I, II, and III adult patients, requiring more than 45 minutes of neuromuscular blockade for surgery. INTERVENTIONS: Following a standardized induction sequence and established steady desflurane-nitrous oxide (DES group) or isoflurane-nitrous oxide (ISO group) anesthesia at 1 minimum alveolar concentration (MAC), an intubating dose of 0.2 mg/kg of mivacurium chloride was administered. Ventilation was maintained with a face mask until the first twitch (T1) of the evoked train-of-four (TOF) reached 10% or less of control when tracheal intubation was performed. T1 was allowed to return to 10% of its control value. An infusion of mivacurium at the initial rate of 5 micrograms/kg/min was then started and adjusted to maintain T1 at 10% +/- 2% of control. Within 20 minutes of completion of surgery, the mivacurium infusion was stopped, and the time for the evoked electromyograph (EMG) to return to 25% and 75% of the original baseline was noted. MEASUREMENTS AND MAIN RESULTS: Neuromuscular function was monitored continuously by an evoked EMG. The average infusion rate was 5.7 +/- 2.4 micrograms/kg/min (mean +/- SD) for DES group (n = 20) and 6.6 +/- 2.7 micrograms/kg/min for ISO group (n = 21) (p = NS). There was no change in the infusion rate of mivacurium over time for both groups. However, there was an inverse relationship in both groups between the time to recovery following a bolus dose and the subsequent mean infusion rate of mivacurium (correlation coefficient = -5.0; p < 0.005). The spontaneous recovery index (T25-75) for the two groups was identical, 11.5 +/- 4.9 min (mean +/- SD) for DES group and 11.5 +/- 7.9 min for ISO group (p = NS). CONCLUSION: There were no differences in the dose requirement and recovery indices of mivacurium during either desflurane or isoflurane-based anesthesia. Patients who took longer to recover from the bolus dose in both groups showed a subsequent reduction in dose requirements of mivacurium.

Duration and recovery profile of cisatracurium after succinylcholine during propofol or isoflurane anesthesia.

STUDY OBJECTIVE: To determine the duration and recovery profile of maintenance doses of cisatracurium besylate following succinylcholine, and during propofol or isoflurane anesthesia. DESIGN: Randomized, open-label study. SETTING: Operating suite of a university-affiliated medical center. PATIENTS: Forty ASA physical status I and II adult patients having elective surgery with general anesthesia lasting longer than 90 minutes. INTERVENTIONS: Following a standardized induction sequence, a baseline electromyogram (EMG) was obtained. An intubating dose of intravenous (i.v.) succinylcholine 1.0 mg/kg was administered. Ventilation was maintained with a face mask until the first twitch (T1) of the evoked train-of-four (TOF) reached 10% of control when tracheal intubation was performed. Spontaneous recovery from neuromuscular blockade was allowed to occur until the first twitch returned to 25% of control. Patients then were randomized to receive cisatracurium as follows. Group 1: 0.025 mg/kg [0.5 x 95% effective dose (ED95)]; Group 2: 0.05 mg/kg (ED95); Group 3: 0.05 mg/kg (ED95); and Group 4: 0.1 mg/kg (2 x ED95). Anesthesia for Groups 1 and 2 were maintained with isoflurane 1% to 2%, 66% nitrous oxide (N2O) in oxygen (O2), and in Groups 3 and 4, anesthesia was maintained with propofol 80 to 160 micrograms/kg/min, 66% N2O in O2. The TOF-evoked EMG was recorded at 10-second intervals. The time for the evoked EMG to spontaneously return to 25%, 50%, and 75% of the original baseline was recorded. MEASUREMENTS AND MAIN RESULTS: There were 10 patients in each of the four groups. The duration of action of cisatracurium 0.05 mg/kg (ED95) after an intubating dose of succinylcholine is 24.5 +/- 10 minutes and 21.3 +/- 9 minutes during anesthesia maintained with isoflurance and propofol, respectively. Doubling the dose of cisatracurium resulted in approximately twice the duration of action (40.2 +/- 7 min) during propofol anesthesia. Following a dose of cisatracurium 0.025 mg/kg (0.5 x ED95), the T1 of the EMG-evoked response did not decrease below 25% in 7 of 10 patients. CONCLUSION: Following succinylcholine, the duration of action of a single dose of cisatracurium 0.05 mg/kg is 20 to 25 minutes during anesthesia maintained with propofol or isoflurane. The duration and recovery profile of cisatracurium is dose dependent during propofol and isoflurane anesthetics. Cisatracurium 0.025 mg/kg is an inadequate maintenance dose following recovery from succinylcholine and it fails to provide adequate surgical relaxation.

Does functional ability in the postoperative period differ between remifentanil- and fentanyl-based anesthesia?

STUDY OBJECTIVES: To compare patients' functional ability in the 24-hour postoperative period following a remifentanil compared to a hypnotic-fentanyl-treated anesthesia regimen using a 24-Hour Functional Ability Questionnaire. DESIGN: Prospective, 1:1 single-blind, randomized, controlled effectiveness study. SETTING: Multicenter study including 156 hospitals and ambulatory surgery facilities. PATIENTS: 2438 patients (1496 outpatients and 942 inpatients) 18 years of age or older, scheduled for elective surgeries under general endotracheal anesthesia, with an expected duration of unconsciousness of > or =30 minutes. INTERVENTIONS: Patients were randomized to receive either intravenous remifentanil (0.5 microg/kg/min for induction and intubation; with the infusion rate decreased to 0.25 microg/kg/min after intubation) or fentanyl (administered according to anesthesiologists' usual practice) as the opioid during surgery. Concomitant hypnotic drugs were propofol and/or isoflurane (with or without nitrous oxide) titrated according to protocol. Transition analgesia with either morphine or fentanyl was given in the remifentanil patients and at the discretion of the anesthesiologists in the fentanyl patients. MEASUREMENTS: A validated set of measurements of functional ability, rather than more traditional clinical psychological methods, to compare the recovery of patients from remifentanil- and fentanyl-treated anesthetic regimens up to 24 hours after surgery. MAIN RESULTS: Remifentanil was statistically superior to fentanyl for the four functional assessments evaluated: walking without dizziness, thinking clearly, concentration, and communicating effectively. These differences reflect events occurring within the first 24 hours after anesthesia and surgery. CONCLUSIONS: A remifentanil-treated anesthetic demonstrated earlier return to some functions than a fentanyl-treated technique. Although functional assessment is a field that is still in its infancy, a questionnaire to assess functional ability during the 24 hours after anesthesia may provide more practical information about anesthetic recovery than previously used, traditional psychomotor evaluations.

[The art of reasonable combining drugs in anesthesia]. / L'art des associations raisonnées en anesthésie.

As yet no single intravenous anaesthetic drug can effectively and safely provide hypnosis, analgesia and amnesia. Thus intelligent combinations of hypnotics and opioids are necessary, especially for total intravenous anaesthesia (TIVA). Inescapable interactions occur, most of which are synergistic and should be evaluated for the optimal care of the patient. This synergism varies considerably according to the different drugs, the different endpoints of anaesthesia and the differently combined dosage of both agents. Because of their complex pharmacological properties, a valuable approach to evaluating interactions consists in administering both drugs to known plasma concentrations with the help of pharmacokinetic model-driven drug delivery systems (computer assisted continuous infusion). The Cp50 concept (plasma concentration that will prevent a pre-defined response to a given stimulus in 50% of the patients) is of prime interest. Recent (and current) studies have tried to define Cp50s of various hypnotics (such as propofol) and opioids (fentanyl, alfentanil, sufentanil). The best IV delivery technique appears to be infusing an opioid drug at analgesic concentrations (1-3 ng.ml-1 for fentanyl) and the hypnotic drug at modulated (but always hypnotic, no less than 3.0 micrograms.ml-1 for propofol) concentrations according to the different surgical stimuli and the patient's responses. The opposite approach (fixed hypnotic concentration, varying analgesic concentration) would be much less satisfactory. In addition, preoperative medications should be taken into account. Thus a better knowledge of the type and degree of interactions, as in a well-administered inhalational anaesthesia supplemented by opioids, will very likely contribute to develop TIVA liability and popularity.

Anesthetic implications of prolonged QT interval syndromes.

The prolonged QT interval syndromes consist of two forms, one congenital and one acquired. The congenital form is probably due to an imbalance in the sympathetic nervous system supply to the heart. It is a preventable cause of sudden death both at an early age and during anesthesia. Recognition of congenital forms of prolonged QT interval and treatment with beta-adrenergic blockers have reduced the mortality. Special care in the perioperative period is necessary to prevent anesthetic-related deaths. The acquired form has many causes. These may be present preoperatively or they may occur intraoperatively. It is important that patients with ALQTS are recognized early and the underlying cause treated.

Comparison of potency and duration of action of nalmefene and naloxone.

Nalmefene, a pure opiate antagonist structurally similar to naloxone, possesses a longer duration of action than naloxone at the same dose. However, the relative potency of these two antagonists is not known. This study was, therefore, designed to establish their potency ratio and duration of action at equipotent doses. Sixteen healthy, adult volunteers were allocated to one of four groups of four subjects each. A continuous fentanyl infusion was started to obtain a target plasma concentration of 1.5 ng/mL. The extent of respiratory depression was evaluated at 20 min (first depression) by recording end-tidal CO2 (ETCO2), respiratory rate (RR), arterial oxygen saturation (SpO2), arterial blood gases, and ventilatory response to a hypercapnic challenge. Consecutive groups then received 1, 2, 4, and 8 micrograms/kg of naloxone and nalmefene, in a double-blind, cross-over fashion, on separate occasions. Fentanyl infusion was continued and ETCO2, SpO2, and RR were recorded every 5 min until the values obtained at the first depression were reestablished (second depression). Multiple blood samples for plasma levels of the test drug and fentanyl were taken. Ventilatory function was assessed at baseline, first depression, 5 min after test drug administration, and at second depression. The ventilatory variables were compared using analysis of variance (ANOVA). There was a significant improvement in the slope and intercept of the CO2 response curve produced by the increasing doses (P < 0.05). There was no difference in recovery of these variables between the two drugs at the same dose, implying that the doses were equipotent.(ABSTRACT TRUNCATED AT 250 WORDS)

Context-sensitive half-time in multicompartment pharmacokinetic models for intravenous anesthetic drugs.

Elimination half-life is the pharmacokinetic parameter used most commonly to describe duration of pharmacologic action, including that expected of intravenous anesthetic drugs administered by continuous infusion. Little consideration has been given, however, to the relevance of elimination half-life in describing plasma (central compartment) drug concentrations in the context of relevant infusion durations. Therefore, simulations were performed with multicompartment pharmacokinetic models for six intravenous anesthetic drugs. These models had elimination half-lives ranging from 111 to 577 min. The input in each simulation was an infusion regimen designed to maintain a constant plasma drug concentration for durations ranging from 1 min to 8 h and until steady state. The time required for the plasma drug concentration to decline by 50% after terminating each infusion in each of the models was determined and was designated the "context-sensitive half-time," where "context" refers to infusion duration. The context-sensitive half-times were markedly different from their respective elimination half-lives and ranged from 1 to 306 min. The half-times were explained by posing each pharmacokinetic model in the form of a hydraulic model. These simulations demonstrate that elimination half-life is of no value in characterizing disposition of intravenous anesthetic drugs during dosing periods relevant to anesthesia. We propose that context-sensitive half-times are a useful descriptor of postinfusion central compartment kinetics.

Arm pain as an unusual presentation of postdural puncture intracranial hypotension.

IMPLICATIONS: We report a case of a patient experiencing severe arm pain after dural puncture. This complication has not been reported previously. The patient was successfully treated with an epidural patch.

Evaluation of pentamorphone in humans: a new potent opiate.

We evaluated the analgesic properties of 14-beta-n-pentylaminomorphinone (pentamorphone), a new morphinan derivative, in 23 male volunteers divided into 6 groups who were given either placebo (1 per group) or 0.015, 0.03, 0.06, 0.12, 0.24, 0.48 microgram.kg-1 pentamorphone intravenously. Analgesia was evaluated by the maximal tolerance to a spring-loaded rod on the tibia and manubrium. Analgesic assessments and arterial blood samples were taken prior to and at set time intervals following drug administration. Pentamorphone produced a linear increase in pain tolerance with increasing dose as well as a dose-dependent depression of ventilation. Pentamorphone had no effect on blood pressure or heart rate in the doses used. Plasma histamine levels at 5 minutes were not elevated with any of the dosages. Pentamorphone appears to be an analgesic with clinically tolerable side effects in the range 0.12 to 0.24 microgram.kg-1 that merits further evaluation under clinical conditions.