John F. Butterworth

Molecular mechanisms of local anesthesia: a review

Impulse block by LA occurs through the inhibition of voltage-gated Na+ channels. Both protonated and neutral LAs can inhibit Na+ channels though interference with the conformational changes that underly the activation process (the sequence of events that occurs as channels progress from the closed resting state to the open conducting state). The occlusion of open channels contributes little to the overall inhibition. Local anesthetic inhibition of Na+ currents increases with repetitive depolarizations in a process called phasic block. Phasic block represents increased LA binding, either because more channels become accessible during depolarization or because the channel conformations favored by depolarization bind LA with higher affinity. The details of phasic block are dependent on LA chemistry: certain LAs bind and dissociate quite rapidly, others act more slowly; some LAs interact effectively with closed states that occur intermediately between resting and open states, others favor the open channel, and still others have a higher affinity for inactivated states. Channel activation accelerates LA binding, and LAs may bind more tightly to activated and inactivated than to resting channels. In this regard, both the modulated receptor and the guarded receptor hypotheses are valid. In binding to activated and inactivated channels, LAs prevent the conformational changes of activation and antagonize the binding of activator agents that poise channels in activated, open states. These reciprocal actions are one aspect of the concerted conformational rearrangements that occur throughout Na+ channels during gating. The LA binding site may exist in the channels pore, at the membrane-protein interface, or within the protein subunits of the channel. Judging from its susceptibility to intracellular proteases and its accessibility to LAs with limited membrane permeability (i.e., quaternary LAs in the cytoplasm), the site lies nearer to the cytoplasmic than the external surface of the membrane. Nevertheless, protons in the external medium influence the dissociation of LA from the closed channel. Binding of LAs at the inhibitory site is weak and loose. If one accounts for the membrane-concentrating effects of LA hydrophobicity that are expressed as membrane: buffer partition coefficients equal to 10(2)-10(4), then the apparent LA affinities are low. The equilibrium dissociation constants calculated on the basis of free drug in the membrane are 1-10 mM, with a correspondingly weak binding to the inhibitory LA site. The stereospecificity of LA action is also relatively nonselective, suggesting a loose fit between ligand and binding site.(ABSTRACT TRUNCATED AT 400 WORDS)

Cardiac resuscitation after incremental overdosage with lidocaine, bupivacaine, levobupivacaine, and ropivacaine in anesthetized dogs

There is no information comparing the ability to reverse the cardiotoxic effects associated with incremental overdosage of bupivacaine (BUP) to levobupivacaine (LBUP), ropivacaine (ROP), or lidocaine (LIDO). Open-chest dogs were randomized to receive incremental escalating infusions of BUP, LBUP, ROP, and LIDO to the point of cardiovascular collapse (mean arterial pressure [MAP] ≤45 mm Hg). Hypotension and arrhythmias were treated with epinephrine, open-chest massage, and advanced cardiac life support protocols, respectively. Outcomes were defined as the following: successful (stable rhythm and MAP ≥55 mm Hg for 20 min), successful with continued therapy (stable rhythm and MAP <55 mm Hg after 20 min), or death. Continued therapy was required in 86% of LIDO dogs compared with only 10%–30% of the other dogs (P < 0.002). Mortality from BUP, LBUP, ROP, and LIDO was 50%, 30%, 10%, and 0%, respectively. Myocardial depression was primarily responsible for the profound hypotension, as the occurrence of lethal arrhythmias preceding resuscitation was not different among local anesthetics. Epinephrine-induced ventricular fibrillation occurred more frequently in BUP-intoxicated dogs than in dogs given LIDO or ROP (P < 0.05). The unbound plasma concentrations at collapse were larger for ROP, 19.8 &mgr;g/mL (10–39 &mgr;g/mL), compared with BUP, 5.7 &mgr;g/mL (3–11 &mgr;g/mL); whereas the concentrations of LBUP, 9.4 &mgr;g/mL (5–18 &mgr;g/mL) and BUP were not significantly different from each other. IMPLICATIONS There were consistent differences among the local anesthetics, the sum of which suggests that larger doses and blood concentrations of ropivacaine (ROP) and lidocaine will be tolerated as compared with bupivacaine (BUP) and levobupivacaine (LBUP). Lidocaine intoxication results in myocardial depression from which resuscitation is consistently successful but will require continuing drug support. After BUP, LBUP, or ROP, resuscitation is not always successful, and the administration of epinephrine may lead to severe arrhythmias. The unbound plasma concentrations at collapse were larger for ROP compared with BUP, whereas the concentrations of LBUP and BUP were not significantly different from each other. Furthermore, larger plasma concentrations of ROP than BUP are present after resuscitation, suggesting a wider margin of safety when large volumes and large concentrations are used to establish upper or lower extremity nerve blocks for surgical anesthesia and during long-term infusions for pain management.

Sodium Nitroprusside: Twenty Years and Counting

SNP remains an effective, reliable, and commonly used drug for the rapid reduction of significant arterial hypertension regardless of the etiology, for afterload reduction in the face of low CO when blood volume is normal or increased, and for intraoperative induced hypotension. After establishing indwelling arterial monitoring, an initial infusion rate of 0.3-0.5 micrograms.kg-1.min-1 is begun with titration as needed up to 2.0 micrograms.kg-1.min-1. Higher rates for brief periods of time (10 min) are acceptable. The use of alternative drugs to reduce the dose or shorten the duration of infusion should be considered when the 2.0 micrograms.kg-1.min-1 range is exceeded (Table 1). SNP should not be used by individuals unfamiliar with its potency and metabolic pathways, as the many reports of adverse reactions testify. Careful attention to infusion rates, particularly in patients at risk for depleted thiosulfate stores, is mandatory, and the use of other drugs in conjunction with or instead of SNP should always be considered. As with many therapeutic interventions, SNP requires careful administration to appropriately selected patients by a clinician who knows its inherent hazards. Despite its toxicity, SNP is popular because it is often the most (in some cases, the only) effective drug in some difficult clinical circumstances.

Pharmacokinetics of tranexamic acid during cardiopulmonary bypass.

Background Tranexamic acid (TA) reduces blood loss and blood transfusion during heart surgery with cardiopulmonary bypass (CPB). TA dosing has been empiric because only limited pharmacokinetic studies have been reported, and CPB effects have not been characterized. We hypothesized that many of the published TA dosing techniques would prove, with pharmacokinetic modeling and simulation, to yield unstable TA concentrations. Methods Thirty adult patients undergoing elective coronary artery bypass grafting, valve surgery, or repair of atrial septal defect received after induction of anesthesia: TA 50 mg/kg (n = 11), TA 100 mg/kg (n = 10), or TA 10 mg/kg (n = 10) over 15 min, with 1 mg · kg−1· hr−1 maintenance infusion for 10 h. TA was measured in plasma using high performance liquid chromatography. Pharmacokinetic modeling was accomplished using a mixed effects technique. Models of increasing complexity were compared using Schwarz-Bayesian Criterion (SBC). Results Tranexamic acid concentrations rapidly fell in all three groups. Data were well fit to a 2-compartment model, and adjustments for CPB were supported by SBC. Assuming a body weight of 80 kg, our model estimates V1 = 10.3 l before CPB and 11.9 l during and after CPB; V2 = 8.5 l before CPB and 9.8 l during and after CPB; Cl1 = 0.15 l/s before CPB, 0.11 l/s during CPB, and 0.17 l/s after CPB; and Cl2 = 0.18 l/s before CPB and 0.21 l/s during and after CPB. Based on simulation of previous studies of TA efficacy, we estimate that a 30-min loading dose of 12.5 mg/kg with a maintenance infusion of 6.5 mg · kg−1· hr−1 and 1 mg/kg added to the pump prime will maintain TA concentration greater than 334 &mgr;m, and a higher dose based on 30 mg/kg loading dose plus 16 mg·kg−1 ·h−1 continuous infusion and 2 mg/kg added to the pump prime would maintain TA concentrations greater than 800 &mgr;m. Conclusions Tranexamic acid pharmacokinetics are influenced by CPB. Our TA pharmacokinetic model does not provide support for the wide range of TA dosing techniques that have been reported. Variation in TA efficacy from study to study and confusion about the optimal duration of TA treatment may be the result of dosing techniques that do not maintain stable, therapeutic TA concentrations.

Dexmedetomidine-Induced Sedation in Volunteers Decreases Regional and Global Cerebral Blood Flow

Dexmedetomidine is a selective &agr;2-agonist approved for sedation of critically ill patients. There is little information on the effects of dexmedetomidine on cerebral blood flow (CBF) or intracranial hemodynamics, despite considerable other pharmacodynamic data. We hypothesized that therapeutic doses of dexmedetomidine would decrease CBF. Therefore, nine supine volunteers, aged 24–48 yr, were infused with a 1 &mgr;g/kg IV loading dose of dexmedetomidine, followed by an infusion of 0.2 &mgr;g · kg−1 · h−1 (LOW DEX) and 0.6 &mgr;g · kg−1 · h−1 (HIGH DEX). Hemodynamic and CBF (via positron emission tomography) measurements were determined at each experimental time point. Dexmedetomidine decreased both cardiac output and heart rate during and 30 min after drug administration. Blood pressure decreased from 12% to 16% during and after the dexmedetomidine administration. Global CBF was decreased significantly from baseline (91 mL · 100 g−1 · min−1 [95% confidence interval, 72–114] to 64 mL · 100 g−1 · min−1 [51–81] LOW DEX and 61 mL · 100 g−1 · min−1 [48–76] HIGH DEX). This decrease in CBF remained constant for at least 30 min after the dexmedetomidine infusion was discontinued, despite the plasma dexmedetomidine concentration decreasing 40% during this same time period (628 pg/mL [524–732] to 380 pg/mL [253–507]).

Pharmacokinetics of dopamine in healthy male subjects.

Background Dopamine is an agonist of &agr;, &bgr;, and dopaminergic receptors with varying hemodynamic effects depending on the dose of drug being administered. The purpose of this study was to measure plasma concentrations of dopamine in a homogeneous group of healthy male subjects to develop a pharmacokinetic model for the drug. Our hypothesis was that dopamine concentrations can be predicted from the infusion dose using a population-based pharmacokinetic model. Methods Nine healthy male volunteers aged 23 to 45 yr were studied in a clinical research facility within our academic medical center. After placement of venous and arterial catheters, dopamine was infused at 10 &mgr;g · kg−1 · min−1 for 10 min, followed by a 30-min washout period. Subsequently, dopamine was infused at 3 &mgr;g · kg−1 · min−1 for 90 min, followed by another 30-min washout period. Timed arterial blood samples were centrifuged, and the plasma was analyzed by high-performance liquid chromatography. Mixed-effects pharmacokinetic models using NONMEM software (NONMEM Project Group, University of California, San Francisco, CA) were used to determine the optimal compartmental pharmacokinetic model for dopamine. Results Plasma concentrations of dopamine varied from 12,300 to 201,500 ng/l after 10 min of dopamine infusion at 10 &mgr;g · kg−1 · min−1. Similarly, steady-state dopamine concentrations varied from 1,880 to 18,300 ng/l in these same subjects receiving 3-&mgr;g · kg−1 · min−1 infusions for 90 min. A two-compartment model adjusted for body weight was the best model based on the Schwartz-Bayesian criterion. Conclusions Despite a homogeneous population of healthy male subjects and weight-based dosing, there was 10- to 75-fold intersubject variability in plasma dopamine concentrations, making standard pharmacokinetic modeling of less utility than for other drugs. The data suggest marked intraindividual and interindividual variability in dopamine distribution and/or metabolism. Thus, plasma dopamine concentrations in patients receiving dopamine infusion at identical rates may vary profoundly. Our data suggest that dosing dopamine based on body weight does not yield predictable blood concentrations.

Preoperative and intraoperative predictors of inotropic support and long-term outcome in patients having coronary artery bypass grafting.

The prognostic value of preoperative symptoms, preoperative left ventricular function, and intraoperative factors as related to postoperative outcome in coronary artery bypass grafting is unclear. This study was performed to identify risk factors that could be used as markers to predict immediate and long-term outcome, knowledge of which might allow physicians to modify these factors to decrease the likelihood of an adverse outcome. We retrospectively evaluated preoperative factors (including age, sex, New York Heart Association [NYHA] classification of symptoms, ejection fraction [EF], wall motion abnormalities, baseline left ventricular end-diastolic pressure [LVEDP], postradiographic contrast infection LVEDP, change in LVEDP with contrast injection, cardiac enlargement, and collateral vessels) and intraoperative factors (duration of bypass and aortic cross-clamp time) in 128 patients. The need for inotropic drug support was used as a marker of immediate outcome. A 36-mo follow-up used death and the postoperative NYHA classification of symptoms as markers of long-term outcome. The various factors associated with the use of inotropes and immediate outcome were analyzed by logistic regression. The factors related to inotrope use (and presumed adverse short-term outcome) in order of decreasing significance were lower EF, older age, cardiac enlargement, female sex, and higher baseline and postcontrast LVEDP. Patients with EF s 55%, but also having wall motion abnormalities and LVEDP change ≥ 10 mm Hg, and all patients with EF ≥ 55% were more likely to require inotropic drug stimulation after cardiopulmonary bypass. Neither the change in LVEDP nor the presence of wall motion abnormalities independently predicted the need for postoperative inotropic support. Analysis of long-term outcome in 113 patients revealed an improvement in mean NYHA score from 2.8 ± 0.9 (mean ± SD) preoperatively to 1.6 ± 0.7 postoperatively. Those factors that predicted a worse long-term outcome (defined as higher postoperative NYHA scores or death) were higher preoperative NYHA scores, older age, female sex, and prolonged duration of cardiopulmonary bypass. Only 5 of 113 patients had died at the 36-mo follow-up, precluding statistical analysis of mortality. In contrast to randomized trials of oral inotropic agents in chronic congestive heart failure, in this study the perioperative use of inotropes (our marker of immediate outcome) was only marginally predictive of a less favorable long-term outcome.

Pregnancy Increases Median Nerve Susceptibility to Lidocaine

To determine whether pregnancy renders women more sensitive to local anesthetics, nine nonpregnant and nine pregnant (third trimester) women underwent median nerve block at the wrist using 1% lidocaine HCl. Inhibition of median nerve A alpha sensory and motor fibers was assessed using measurements of sensory nerve action potential (SNAP) amplitude and compound motor action potential (CMAP) amplitude, respectively. Inhibition of median nerve C fibers was assessed by the increase in skin temperature and by the decrease in median (relative to ulnar) galvanic skin potential (GSP) amplitude. Lidocaine inhibited SNAP to a greater extent in pregnant than nonpregnant women at all time points (P = 0.019). CMAP declined differently in the pregnant and nonpregnant groups (P = 0.01): the pregnant subjects achieved steady state inhibition before the nonpregnant subjects. The two groups developed comparable steady state inhibition. Skin temperature was higher in pregnant women at all time points (P less than 0.0001); moreover, the increased skin temperature of pregnant women differed from that of the nonpregnant women (P = 0.037), reflecting a more rapid temperature increase in the pregnant women. GSP amplitude declined to 50% of control more rapidly in pregnant (mean = 4 min) than nonpregnant women (mean = 11.5 min), but these differences did not achieve statistical significance. It is concluded that pregnancy increases median nerve susceptibility to lidocaine.

A Pharmacokinetic and Pharmacodynamic Evaluation of Milrinone in Adults Undergoing Cardiac Surgery

Milrinone can reverse acute postischemic myocardial dysfunction after cardiopulmonary bypass, although neither the appropriate bolus dose nor its pharmacokinetics has been established for cardiac surgical patients.Consenting patients undergoing cardiac surgery received milrinone (25, 50, or 75 micro gram/kg) in an openlabel, dose-escalating study if their cardiac index was <3 L centered dot min-1 centered dot m-2 after separation from bypass. Heart rate, mean arterial blood pressure, pulmonary capillary wedge pressure, and cardiac index were determined before and after the administration of milrinone. Timed blood samples were obtained for measurement of milrinone plasma concentrations and pharmacokinetic analysis. Twenty-nine of 60 consenting patients had cardiac indices <3 L centered dot min-1 centered dot m-2 after separation from bypass, received milrinone, and completed the protocol. All three bolus doses of milrinone significantly increased cardiac index. The 50- and 75-micro gram/kg doses produced significantly larger increases in cardiac index than the 25-micro gram/kg dose; however, the 75-micro gram/kg dose did not produce a significantly larger increase in cardiac index than did the 50-micro gram/kg dose. Two of 10 patients receiving milrinone 25 micro gram/kg, but no patient receiving either 50 or 75 micro gram/kg, required early epinephrine rescue when the cardiac index failed to increase by >15%. The 75-micro gram/kg dose was associated with a case of ventricular tachycardia. The three-compartment model better described milrinone drug disposition than the two-compartment model by both visual inspection and Schwartz-Bayesian criterion. There was only limited evidence of dose-dependence, so data from all three doses are reported together (and normalized to the 50-micro gram/kg dose). Data from one patient was discarded (samples mislabeled). Using mixed-effects nonlinear regression (for n = 28), the following volumes were determined for the three compartments: V (1) = 11.1 L, V2 = 16.9 L, and V3 = 363 L. Similarly, the following clearances were estimated for the three compartments: Cl1 = 0.067 L/min, Cl2 = 1.05 L/min, and Cl3 = 0.31 L/min. The 50-micro gram/kg loading dose appeared more potent than the 25-micro gram/kg dose, and, as potent, but with possibly fewer side-effects than the 75-micro gram/kg dose. The short context-sensitive half-times of 6.7 or 10.2 min after 1- or 10-min bolus infusions underscore the need for prompt institution of a maintenance infusion when milrinone concentrations must be maintained. Simulations based on our best drug disposition using this studys variables predict a context-sensitive half-time of 4.9 h for plasma milrinone concentrations after a 50-micro gram/kg bolus 1-min infusion with an immediate 24-h maintenance infusion of 0.5 micro gram centered dot min-1 centered dot kg-1. (Anesth Analg 1995;81:783-92)

Local Anesthetic-Induced Cardiac Toxicity: A Survey of Contemporary Practice Strategies Among Academic Anesthesiology Departments

Though new local anesthetics (LA), effective test-dosing, and new regional anesthetic techniques may have improved the safety of regional anesthesia, the optimal management plan for LA-induced cardiac toxicity remains uncertain. Accordingly, we evaluated current approaches to LA cardiotoxicity among academic anesthesiology departments in the United States. A 19-question survey regarding regional anesthesia practices and approaches to LA cardiac toxicity was sent to the 135 academic anesthesiology departments listed by the Society of Academic Anesthesiology Chairs-Association of Anesthesiology Program Directors. Ninety-one anonymously completed questionnaires were returned, at a response rate of 67%. The respondents were categorized into groups according to the number of peripheral nerve blocks (PNBs) performed each month: >70 PNBs (38%), 51–70 PNBs (13%), 31–50 PNBs (20%), 11–30 PNBs (23%), and <10 PNBs (6%). Anesthesia practices administering >70 PNBs were 1.7-times more likely to use ropivacaine (NS), 3.9-times more likely to consider lipid emulsion infusions for resuscitation (P = 0.008), and equally as likely to have an established plan for use of invasive mechanical cardiopulmonary support in the event of LA cardiotoxicity (NS) than low-PNB volume centers. We conclude that there are differences in the management and preparedness for treatment of LA toxicity among institutions, but the safety implications of these differences are undetermined.