Monitoring neuromuscular transmission.

Persistent neuromuscular blockade is not uncommon in the recovery room and contributes to postoperative morbidity and possibly mortality. The use of neuromuscular monitoring and intermediate rather than long-acting neuromuscular blocking drugs have been shown to reduce its incidence. Clinically available methods of detecting and quantitating neuromuscular blockade are reviewed. The writer concludes that such monitoring should be routine when neuromuscular blocking drugs are used.

A comparison of 0.5% ropivacaine and 0.5% bupivacaine for axillary brachial plexus anaesthesia.

The purpose of this study was to compare the use of 0.5% ropivacaine with 0.5% bupivacaine for axillary brachial plexus anaesthesia. Sixty-six patients undergoing upper limb surgery were enrolled in a double-blind, randomized, multicentre trial. Five patients were subsequently excluded for various reasons. Of the remaining patients, 30 received 40 ml of 0.5% ropivacaine and 31 received 40 ml of 0.5% bupivacaine. Brachial plexus block was performed by the axillary approach using a standardized technique with a peripheral nerve stimulator. Parameters investigated included the frequency, onset and duration of sensory and motor block, the quality of anaesthesia and the occurrence of any adverse events. The six principal nerves of the brachial plexus were studied individually. The frequency for achieving anaesthesia per nerve ranged from 70 to 90% in the ropivacaine group and 81 to 87% in the bupivacaine group. The median onset time for anaesthesia was 10 to 20 minutes with ropivacaine and 10 to 30 minutes with bupivacaine, and the median duration was 5.3 to 8.7h with ropivacaine and 6.9 to 20.3h with bupivacaine. Motor block was evaluated at the elbow, wrist and hand, and was completely achieved at a rate of 60 to 73% in the ropivacaine group and 55 to 71% in the bupivacaine group. The median duration of motor block was 6.5 to 7.5h with ropivacaine and 6.0 to 9.0h with bupivacaine. These parameters were not statistically different. The duration of partial motor block at the wrist (6.8 v 16.4h) and hand (6.7 v 12.3h) was significantly longer with bupivacaine. Ropivacaine 0.5% and bupivacaine 0.5% appeared equally efficacious as long-acting local anaesthetics for axillary brachial plexus block.

Pharmacokinetic analysis of the effect of vecuronium in surgical patients: pharmacokinetic and pharmacodynamic modeling without plasma concentrations.

BACKGROUND: Methods of the kinetic analysis of vecuronium based on effect only were developed but have been limited by the short time period of the studies. Using a multicompartment model and sequential dosing, the authors studied the ability of tests to determine most pharmacokinetic and pharmacodynamic parameters of vecuronium without measuring plasma concentrations. METHODS: The time course of neuromuscular blockade by successive bolus doses of vecuronium was recorded using electromyography. Inhibition of neuromuscular transmission by vecuronium was modeled by a biexponential decline in the concentrations in the central compartment and first-order transfer between the central and the effect compartments responsible for the inhibition of the first (T1) and fourth (T4) responses to train-of-four stimulation. RESULTS: The time course of the effect of vecuronium was described well by the model. The mean half-lives of equilibration between plasma and the effect compartments to inhibit T1 and T4 were 2.5 and 3.2 min, respectively. The mean half-lives of distribution and elimination from the central compartment were 7.7 and 7.8 min, respectively. From the kinetic and dynamic parameters calculated after two and three doses, the time taken to recover to 50% of the maximal block of T1 was predicted for the succeeding dose. The mean prediction errors (100 x [absolute difference between actual and predicted times]/actual) were 13.6% (range, 0-40%) and 15% (range, 0-25%) after three and four doses, respectively. CONCLUSIONS: After sequential doses, measurement of the time course of the effect of vecuronium yields pharmacokinetic and pharmacodynamic parameters with clinically acceptable accuracy in individual patients.

Comparison of 0.5% ropivacaine and 0.5% bupivacaine in lumbar epidural anaesthesia for lower limb orthopaedic surgery.

The purpose of this study was to compare the epidural use of 0.5% ropivacaine and 0.5% bupivacaine in patients undergoing lower limb orthopaedic surgery. In a double-blind, randomized, multi-centre study involving 67 patients, thirty-two patients received 20 ml of 0.5% ropivacaine and 35 patients received 20 ml of 0.5% bupivacaine at the L2,3 or L3,4 interspace. Parameters measured were the onset time, duration and spread of sensory block, the onset time, duration and degree of motor block, the quality of anaesthesia and the heart rate and blood pressure profile during block onset. Four patients (3 ropivacaine, 1 bupivacaine) were excluded from the study due to technical failure of the block. The onset and duration of analgesia at the T10 dermatome (median, interquartile range) was 10 (5-15) minutes and 3.5 (2.7-4.3) hours respectively for ropivacaine, and was 10 (6-15) minutes and 3.4 (2.5-3.8) hours respectively for bupivacaine. Maximum block height (median, range) was T6 (T2-T12) for ropivacaine and T6 (C7-T10) for bupivacaine. Nine patients receiving ropivacaine and eight patients receiving bupivacaine developed no apparent motor block. The incidence of complete motor block (Bromage grade 3) was low in both groups, being 4/27 for ropivacaine and 6/34 for bupivacaine. In the ropivacaine group, motor and sensory block were judged to be satisfactory in 78% of patients. In the bupivacaine group, motor and sensory block were judged to be satisfactory in 71% and 62% of patients respectively. Cardiovascular changes were similar in both groups. No statistical differences were found between the two groups regarding any of the study parameters.

Pharmacokinetics and pharmacodynamics of suxamethonium.

A study was undertaken to determine the time constants of elimination and effect compartment equilibration of suxamethonium and for the slope exponent of the Hill equation. Twelve patients were anaesthetized with thiopentone, fentanyl, and isoflurane in nitrous oxide and oxygen. After allowing conditions to become stable, they were administered three small doses of suxamethonium by rapid intravenous injection. The responses to supramaximal stimulation of the ulnar nerve were recorded by EMG in one and by accelerometry in eleven subjects. Because of failure to recover to control conditions, one subject was deleted from analysis. The recorded drug effect was used in a non-linear curve fitting technique to derive estimates of the pharmacokinetic and pharmacodynamic parameters. The plasma concentration of suxamethonium was adequately represented by a single compartment model. The mean half-life of elimination was 47 s with a 95% confidence interval of 24 to 70 s; that of effect compartment equilibration, 211 s with a 95% confidence range of 139 to 282 s. The average slope exponent was 6.4 and its 95% confidence range was 4.6 to 8.2. The data from the first two doses were used to predict the time taken for the third dose to recover 50%. The predictions showed a mean bias of < 1% (NS) and a mean error of 21%, with a confidence interval of 5 to 37%. In only two out of eleven subjects was the prediction error greater than 30%.

Assessment of the agreement between cardiac output measured by bolus thermodilution and continuous methods, with particular reference to the effect of heart rhythm.

Cardiac output (CO) is a fundamentally important haemodynamic parameter and its continuous measurement has the potential to enable early recognition of haemodynamic trends and earlier therapeutic response. A method of continuous cardiac output (CCO) monitoring is now available for clinical use. The accuracy and reliability of this method has been confirmed in clinical trials but not, to our knowledge, in the presence of abnormal heart rhythms. A comparison was made between CCO and bolus thermodilution methods, to determine if there is a greater difference between their respective determinations of CO when heart rhythm is abnormal. A convenience sample of 38 intensive care patients was used to obtain 410 comparisons of CCO and bolus CO determinations. Heart rhythm associated with each comparison was determined. The comparison produced a measurement bias of -0.07 l/min and limits of agreement of -1.77 to 1.63 l/min. The bias of the two measurements was -0.35 l/min for sinus rhythm, -0.19 l/min for sinus tachycardia and -0.12 l/min for atrial flutter/fibrillation. Increased temperature and heart rate did not affect measurement agreement. In conclusion, the agreement between the bolus and continuous methods is clinically acceptable and is unaffected by the heart rhythms of sinus rhythm, sinus tachycardia and atrial flutter/fibrillation.

Paracetamol administration is associated with hypotension in the critically ill.

An association between the administration of paracetamol and relative hypotension in critically ill intensive care patients has been reported anecdotally by nursing staff working in the Intensive Care Unit (ICU) of Prince Henry Hospital. An observational study was therefore undertaken, to determine whether there is a temporal association between the administration of paracetamol and changes in blood pressure. A dose of 1 gram of paracetamol was administered orally or by feeding tube. Blood pressure was recorded 30 minutes prior to paracetamol administration, at the time of administration and then at 15-minute intervals for the first hour and at half-hour intervals for the second hour after administration. Analysis of data from 37 individuals using a repeated measures ANOVA showed that systolic arterial pressure (SAP) and mean arterial pressure (MAP) were reduced significantly over the observation period (p < 0.0001 for both). SAP and MAP fell by an average of approximately 10 and 7 per cent respectively, with maximum falls of 36 and 34 per cent respectively. Paracetamol administration may be indicated for the control of fever in critically ill patients, thereby reducing oxygen demand. However, this must be balanced against the possibility of causing a significant fall in blood pressure.

Comparative clearance performance of two dialyser units used in the CVVHD mode.

Continuous renal replacement therapies are now commonly used modes of support in acute renal failure (ARF). This study compared the clearance performance and it's degradation over time of two dialysers, one of flat plate configuration, and one of hollow fibre configuration (Asahi PAN 06 hollow fibre dialyser, Domedica, Sydney, and Hospal AN69HF flat plate dialyser, Gambro, Sydney) used in the CVVHD mode. Data were obtained from seven patients. Urea clearance was determined at commencement of dialysis and then at 12 hour intervals up to 48 hours post commencement. At each study time, urea clearance was determined at dialysis fluid (DF) flows of 500, 1000, 1500 and 2000 ml/hr. The procedure was repeated for each patient using the alternate dialyser. Comparisons of the two dialyser's urea clearance did not demonstrate any significant difference at any of the time periods studied. Overall, clearance was dependent upon (DF) flow with the diffusive clearance initially equal to DF flow but falling to 0.7 and 0.85 times increase in DF flow at 48 hours.

Pharmacokinetic analysis of the time course of effect of atracurium.

OBJECTIVE: To examine the ability to determine clinically important pharmacokinetic and pharmacodynamic parameters of atracurium by the analysis of the time course of effect without the use of plasma concentration data. DESIGN: Neuromuscular transmission was monitored with train-of-four stimulation and electromyographic quantitation of the first (T1) and fourth (T4) responses in eight anesthetized patients undergoing elective surgery. The time course of onset and recovery of neuromuscular blockade by three successive bolus doses of atracurium was recorded. Equations describing the theoretic time course of concentrations in the effect compartment and the dose-response relationship were fitted simultaneously to these data; the parameters of these equations derived from the fit of two doses were used to predict the response to a third dose. Fitting the equations to all three doses was also performed to assess the accuracy of predictions for atracurium. RESULTS: From the depression of the first twitch after three consecutive doses in eight patients, the half-lives of uptake into and elimination from the effect compartment were 2.1 +/- 0.2 minutes (mean +/- SEM) and 25.8 +/- 2.3 minutes (n = 8). The doses producing 50% and 95% depression of the first twitch (ED50 and ED95) were 168 +/- 15 and 280 +/- 25 micrograms/kg, respectively, with a Hill coefficient of 6.1 +/- 0.5. The half-life of elimination estimated from the fourth twitch was similar to that from the first twitch. CONCLUSIONS: The analysis of high-resolution effect data is capable of giving pharmacokinetic and pharmacodynamic parameters with clinically acceptable accuracy within a short sampling time, without resorting to laboratory analysis. This method is specific for active drug and would be of value for individualization of administration for short-term treatment.

Comparison of extradural fentanyl, bupivacaine and two fentanyl-bupivacaine mixtures of pain relief after abdominal surgery.

Fentanyl 50 micrograms, bupivacaine 50 mg and two mixtures containing fentanyl 50 micrograms and bupivacaine 25 mg or 12.5 mg (0.25 and 0.125%), respectively, in a volume of 10 ml were administered via thoracic extradural catheters to 24 patients after major abdominal surgery. All patients received all four treatments, in a randomized order, so that each patient received one of the 24 possible combinations of the four treatments. Pain relief was assessed by a linear analogue pain scale and the Prince Henry Hospital pain score. The duration of pain relief, effects on ventilatory frequency, heart rate, arterial pressure and central venous pressure were also recorded. Mean reductions in the analogue pain scale for fentanyl, bupivacaine, and fentanyl in 0.25% and 0.125% bupivacaine were 80 (SEM 5) %, 87 (4) %, 86 (5) % and 77 (5) %, respectively (ns). Pain scores decreased by 62 (6) %, 83 (5) %, 77 (6) % and 72 (6) %, respectively (ns). Mean arterial pressure decreased to 90 (2) %, 70 (2) %, 81 (2) % and 82 (3) %, respectively, of pretreatment values. In this respect, bupivacaine alone was significantly different from the three other treatments (P < 0.001). Hypotension (reduction in arterial pressure greater than 25% of pretreatment mean arterial pressure) was also more frequent after bupivacaine alone (P < 0.01). Effects on ventilation, heart rate and central venous pressure did not differ between the four treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

The kinetics of effect of neuromuscular blocking drugs.

In attempts to derive pharmacokinetic constants from effect data three methods were explored, using non-depolarizing neuromuscular blocking drugs as the paradigm for obtaining effect data. The first method, based on the simple assumption that following two doses, the drug concentrations at times of equal effect during recovery, were equal. Provided that recovery took place in the log-linear drug elimination phase, the elimination rate constant (beta) could be calculated. This method proved rather inaccurate, a second method, again dependent on recovery in the log-linear phase yielded a constant which was the product of beta and the exponent of the Hill equation (s). This method yielded results within 20% of values calculated from plasma drug assays, and it was demonstrated that the time-effect curve could be described from knowledge of this constant. The third method, using non-linear curve fitting technique, derived values for the rate constants of plasma redistribution (alpha) and elimination (beta) as well as for the rate constant of elimination from an effect compartment (keo). If the values were derived from the effect of two doses of a drug, the intensity and duration of effect of a third dose could be predicted with reasonable accuracy. The dose dependent constants of the usual compartmental equations for the plasma concentration of a drug (A and B) could be derived in terms of the EC50. The method can be applied to any drug whose effect can be measured and whose maximal effect can be defined. We believe that the method may be useful in rapidly and inexpensively estimating population kinetic parameters, and in screening drugs.

Tests of six continuous flow CPAP devices.

Six continuous flow CPAP devices were tested for pressure fluctuation and stability of inhaled oxygen concentration under conditions of simulated respiration. Four of the systems, the Ambu, Auspap, Downs'-Vital Signs and the Dräger are commercially available and two, the Prince Henry (PHH) and the Prince of Wales (POW) systems were assembled from Bird respirator parts, which were available in the respective Intensive Care Units. All appeared to be clinically effective. The Ambu offers convenience and economy of gases, the Dräger showed the least pressure fluctuations. Three of the four commercial systems lacked certain safety features which could more easily be added to the two non-commercial devices.

Neuromuscular sensitivity to atracurium in humans.

The relation between plasma concentration and the effects of atracurium was studied in seven patients anaesthetised with thiopentone, fentanyl and nitrous oxide-oxygen. The response to train-of-four stimulation at ten-second intervals with tetanic stimuli applied every five minutes were recorded. The first sign of transmission returning after complete blockade was usually the post-tetanic facilitated twitch, which was noted when the mean atracurium concentration was 1.15 mg 1(-1) (SD 0.77). The most sensitive parameter was the train-of-four ratio, which recovered to 0.5 when the concentration was 0.217 mg 1(-1) (SD 0.56), compared with a concentration of 0.271 (SD 0.85) at 50% recovery for twitch height, 0.221 (SD 0.029) for tetanic peak and 0.231 (SD 0.079) for tetanic fade. The value for the train-of-four ratio differed significantly (P less than 0.05) from that for the twitch height, but other differences were not significant. Once recovery commenced, these four parameters recovered at similar rates, with recovery indices (25 to 75% responses) of 14.8 (SD 1.7), 14.0 (SD 1.0), 14.3 (SD 1.8) and 13.7 (SD 2.1) minutes respectively. Post-tetanic facilitation was most marked during severe but incomplete blockade and tetanic stimulation temporarily reversed the atracurium-induced decrease in train-of-four ratio. Clinically, the use of tetanic stimulation did not improve the sensitivity of neuromuscular monitoring, but post-tetanic count may be useful where monitoring of profound relaxation is required.

A simplified approach to the effect kinetics of atracurium.

The combination of the Hill equation, which describes the concentration-effect relation, with the monoexponential function for the terminal decline of plasma concentration, yields a compound time constant, T beta s1/2. This constant is a combination of the terminal elimination half-life (T beta 1/2) and the exponent (s) of the Hill equation and may be used to describe the time course of recovery from neuromuscular block. The constant may be estimated by non-linear curve fitting to f, the effect expressed as fraction of maximal effect, or by linear regression of the logit function of f. The methods were validated using plasma concentration and effect data from seven patients administered atracurium. The two methods utilizing effect data alone yielded values of 4.2 (0.7) min and 4.3 (0.5) min (mean (SEM)), respectively, for T beta s1/2 compared with 4.1 (0.6) min when the constant was calculated using plasma concentration data for T beta 1/2 and curve fitting to the concentration-effect data to determine s. These methods offer an objective measure of the rate of recovery and a means of testing if redistribution or elimination is the primary process in the termination of drug effect.

An electrode montage for electrocardiographic monitoring.

An electrocardiographic electrode montage is described using electrodes mounted on the manubrium sterni (RA), xiphisternum (LA) and V5 position (LL). The lead II setting on the monitor, equivalent to CM5, offers optimal ischaemia detection, while lead I, now a vertical lead, manubrium to xiphisternum, results in maximal P wave amplitude. The montage has been evaluated in sixty-two intensive care patients with electrocardiographic abnormalities and has been used extensively in intensive care, the operating theatres and in shock wave lithotripsy. The 'Prince Henry' montage offers advantages over the standard bipolar leads in P wave amplitude, arrhythmia diagnosis and artefact rejection.