Malachy O. Columb

Determination of the Minimum Local Analgesic Concentrations of Epidural Bupivacaine and Lidocaine in Labor

The aim of this study was to devise a clinical model to determine the effective concentrations in 50% of patients (EC50) for bupivacaine and lidocaine in the first stage of labor and define EC50 as the minimum local analgesic concentration (MLAC).This should allow the determination of relative analgesic potency and, subsequently, the local anesthetic sparing efficacy of other epidural analgesics. Parturients not exceeding 5 cm cervical dilation who requested epidural analgesia were enrolled. The two studies involved 81 women (bupivacaine n = 41, lidocaine n = 40). After a lumbar epidural catheter was placed, 20 mL of the concentration of local anesthetic being tested was given. The concentration was determined by the response of the previous patient to a higher or lower concentration using doubleblinded, up-down sequential allocation. Efficacy was assessed using 100-mm visual analog pain scores with less than 10 mm within 1 h defined as effective. MLAC was determined using the formula of Dixon and Massey. Results show MLAC bupivacaine 0.065% (95% confidence interval [CI] 0.045-0.085), MLAC lidocaine 0.37% (95% CI 0.32-0.42), equivalent to 2 and 14 mmol solutions, respectively. Thus bupivacaine was 5.7 times more potent than lidocaine in weighted and 7 times more potent in molar ratios at analgesic EC50, in the volume of local anesthetic studied. (Anesth Analg 1995;81:833-7)

The Dose-Dependent Effects of Phenylephrine for Elective Cesarean Delivery Under Spinal Anesthesia

BACKGROUND: Hypotension is the most common serious side effect of spinal anesthesia for cesarean delivery. There has been a move recently toward the use of phenylephrine as a vasopressor infusion to improve maternal cardiovascular stability and fetal outcome. Although it seems safe in the elective setting, there have been concerns about its propensity for causing an increase in afterload and a baroreceptor-mediated bradycardia in the mother, with a consequent reduction in maternal cardiac output (CO). Using a noninvasive measure of CO, our aim was to investigate whether there were any dose-dependent effects of phenylephrine on maternal cardiovascular stability and, if so, any impact on fetal outcome. METHODS: In this randomized, double-blind study, 75 women scheduled for elective cesarean delivery were allocated to receive a phenylephrine infusion at 25 &mgr;g/min, 50 &mgr;g/min, or 100 &mgr;g/min. This infusion was titrated to maintain maternal baseline systolic blood pressure (SBP), from induction of spinal anesthesia until delivery. The maternal cardiovascular variables recorded included heart rate (HR) and SBP. A suprasternal Doppler monitor measured CO and stroke volume, as well as measures of venous return (corrected flow time) and contractility, at baseline, and then every 5 minutes for 20 minutes after initiation of spinal anesthesia. Apgar scores and umbilical cord blood gases were recorded. RESULTS: SBP control was satisfactory in all groups; however, the group receiving phenylephrine 100 &mgr;g/min required significantly higher doses to achieve arterial blood pressure control compared with the lower infusion rates. There were no significant differences in the number of times SBP decreased below 80% of baseline, or the numbers of boluses of ephedrine or phenylephrine required to maintain SBP above 80% of baseline. There were significant time and dose-dependent reductions in HR and CO with phenylephrine, such that HR and CO were seen to decrease with time in each group, and also with increasing concentrations of phenylephrine. Stroke volume remained stable throughout. Apgar scores and umbilical cord blood gases were similar among groups. CONCLUSION: By infusing a higher concentration (100 &mgr;g/min), we subject the mother and fetus to a much higher dose of phenylephrine, with significant effects on maternal HR and CO (up to a 20% reduction). Future investigation is required to determine whether this reduction in maternal CO has detrimental effects when providing anesthesia for an emergency cesarean delivery for a compromised fetus.

Minimum local analgesic doses of ropivacaine, levobupivacaine, and bupivacaine for intrathecal labor analgesia.

Background:Doses for intrathecal opioid–local anesthetic mixtures have been arbitrarily chosen. The aim of this study was to compare the analgesic efficacies of intrathecal ropivacaine, levobupivacaine, and bupivacaine for labor analgesia and to determine the analgesic potency ratios for these three drugs. For this purpose, the authors used the up–down sequential allocation model, which estimates the minimum local analgesic dose for intrathecal local anesthetic. Methods:Ninety-seven nulliparous term parturients in spontaneous labor, requesting combined spinal–epidural analgesia, were randomly allocated to one of three groups to receive 0.25% spinal ropivacaine, levobupivacaine, or bupivacaine. The initial dose of the local anesthetic drug was chosen to be 2.5 mg, and the testing interval was set at 0.25 mg. The subsequent doses were determined by the response of the previous parturient. Efficacy was accepted if the visual analog pain score decreased to 10 mm or less on a 100-mm scale within 30 min. The minimum local analgesic dose was calculated using the method of Dixon and Massey. Results:The intrathecal minimum local analgesic dose was 3.64 mg (95% confidence interval, 3.33–3.96 mg) for ropivacaine, 2.94 (2.73–3.16) mg for levobupivacaine, and 2.37 (2.17–2.58) mg for bupivacaine. The relative analgesic potency ratios were 0.65 (0.56–0.76) for ropivacaine:bupivacaine, 0.80 (0.70–0.92) for ropivacaine:levobupivacaine, and 0.81 (0.69–0.94) for levobupivacaine:bupivacaine. There were significant trends (P ≤ 0.021) for greater motor block with bupivacaine and levobupivacaine. Conclusions:This study suggests a potency hierarchy of spinal bupivacaine > levobupivacaine > ropivacaine.

The Relative Potencies for Motor Block After Intrathecal Ropivacaine, Levobupivacaine, and Bupivacaine

BACKGROUND:In this study, we sought to determine the median effective dose (ED50) for motor block of intrathecal ropivacaine, levobupivacaine, and bupivacaine and to define their motor-blocking potency ratios. METHODS:We enrolled 104 parturients undergoing elective cesarean delivery with combined spinal-epidural anesthesia and randomized them to one of three groups to receive intrathecal 0.5% (wt/vol) ropivacaine, levobupivacaine, or bupivacaine. The initial dose was 4 mg, and the testing interval was set at 1 mg. Efficacy was determined by the occurrence of any motor block in either lower limb (modified Bromage and hip motor function scale) within 5 min after the spinal injection. RESULTS:As assessed using up-down analysis, intrathecal ED50 for motor block was 5.79 mg for ropivacaine (95% CI 4.62–6.96), 4.83 mg for levobupivacaine (95% CI 4.35–5.32) and 3.44 mg for bupivacaine (95% CI 2.55–4.34) (P < 0.0007). The relative motor blocking potency ratios were ropivacaine/bupivacaine 0.59 (95% CI, 0.42–0.82), ropivacaine/levobupivacaine 0.83 (95% CI 0.64–1.09), and levobupivacaine/bupivacaine 0.71 (95% CI 0.51–0.98). CONCLUSIONS:There is a clinical profile of potency for motor block for the pipecolylxylidines when administered spinally: low, intermediate, and high for ropivacaine, levobupivacaine, and bupivacaine, respectively.

Minimum local analgesic dose of intrathecal bupivacaine in labor and the effect of intrathecal fentanyl

BackgroundCombining bupivacaine with fentanyl for intrathecal analgesia in labor is well recognized, but dosages commonly used are arbitrarily chosen and may be excessive. This study aimed to determine the median effective dose (ED50) of intrathecal bupivacaine, defined as the minimum local analgesic dose (MLAD), and then use this to assess the effect of different doses of fentanyl. MethodsIn this double-blind, randomized, prospective study, 124 parturients receiving combined spinal epidural analgesia at 2–6-cm cervical dilatation were allocated to one of four groups to receive bupivacaine alone or with 5, 15, or 25 &mgr;g fentanyl, using the technique of up–down sequential allocation. Analgesic effectiveness was assessed using 100-mm visual analog pain scores, with less than or equal to 10 mm within 15 min defined as effective. MLAD was calculated using the formula of Dixon and Massey. Pruritus and duration of spinal analgesia were also recorded. ResultsMinimum local analgesic dose of intrathecal bupivacaine was 1.99 mg (95% confidence interval, 1.71, 2.27). There were similar significant reductions in MLAD (P < 0.001) for all bupivacaine–fentanyl groups compared with bupivacaine control. There was a dose-dependent increase in both pruritus and duration of spinal analgesia with increasing fentanyl (P < 0.0001). ConclusionUnder the conditions of this study, the addition of intrathecal fentanyl 5 &mgr;g offers a similar significant bupivacaine dose-sparing effect as 15 and 25 &mgr;g. Analgesia in the first stage of labor can be achieved using lower doses of fentanyl, resulting in less pruritus but with a shortening of duration of action.

The effect of posture and baricity on the spread of intrathecal bupivacaine for elective cesarean delivery.

Posture and baricity during induction of spinal anesthesia with intrathecal drugs are believed to be important in determining spread within the cerebrospinal fluid. In this double-blind prospective study, 150 patients undergoing elective cesarean delivery were randomized to receive a hyperbaric, isobaric, or hypobaric intrathecal solution of 10 mg bupivacaine during spinal anesthesia induced in either the sitting or right lateral position. After an intrathecal injection using a combined-spinal technique patients were placed in the supine wedged position. We determined the densities of the three intrathecal solutions from a previously validated formula and measured using a DMA-450 density meter. Data collection included sensory level, motor block, episodes of hypotension, and ephedrine use. Statistical analysis included analysis of variance and Cuzick’s trend. In the lateral position, baricity had no effect on the spread of sensory levels for bupivacaine compared to the sitting position, where there was a statistically significant difference in spread with the hypobaric solution producing higher levels of analgesia than the hyperbaric solution (P = 0.002). However, the overall differences in maximal spread only differed by one dermatome, with the hyperbaric solution achieving a median maximum sensory level to T3 compared with T2 for the isobaric and hypobaric solutions. Motor block was significantly (P = 0.029) reduced with increasing baricity and this trend was significant (P = 0.033) for the lateral position only. Hypotension incidence and ephedrine use increased with decreasing baricity (P = 0.003 and 0.004 respectively), with the hypobaric sitting group having the most frequent incidence of hypotension (76%) as well as cervical blocks (24%; P = 0.032).

The relative motor blocking potencies of epidural bupivacaine and ropivacaine in labor.

Minimal local analgesic concentrations (MLAC) have been used to determine the epidural analgesic potencies of bupivacaine and ropivacaine. There are no reports of the motor blocking potencies of these drugs. We sought to determine the motor block MLAC of both drugs and their relative potency ratio. Sixty ASA physical status I and II parturients were randomized to one of two groups, during the first stage of labor. Each received a 20-mL bolus of epidural bupivacaine or ropivacaine. The first woman in each group received 0.35%. Up-down sequential allocation was used to determine subsequent concentrations at a testing interval of 0.025%. Effective motor block was defined as a Bromage score <4 within 30 min. The up-down sequences were analyzed by using the Dixon and Massey method and probit regression to quantify the motor block minimal local analgesic concentration. Two-sided P < 0.05 defined significance. The motor block minimal local analgesic concentration for bupivacaine was 0.326% (95% confidence interval [CI], 0.285–0.367) and for ropivacaine was 0.497% (95% CI, 0.431–0.563) (P = 0.0008). The ropivacaine/bupivacaine potency ratio was 0.66 (95% CI, 0.52–0.82). This is the first MLAC study to estimate the motor blocking potencies of bupivacaine and ropivacaine. Ropivacaine was significantly less potent for motor block, at 66% that of bupivacaine.

Assessment of coagulation in the obstetric population using ROTEM® thromboelastometry

BACKGROUND Assessment of maternal coagulation to determine suitability for neuraxial anaesthesia and management of obstetric haemorrhage remains a challenge. Thromboelastography provides point of care patient assessment of the viscoelastic properties of whole blood clotting and can assist the clinician in haemostatic decision-making. The study aim was to determine the ROTEM® thromboelastometer 95% reference limits for third trimester parturients and to compare these with non-pregnant female controls. METHODS Following ethics committee approval and informed consent, citrated blood was sampled from 120 age-matched healthy pregnant and non-pregnant women. Thromboelastometry, using a ROTEM® point of care monitor, was performed with specific activators to measure the coagulation time (CT), clot formation time (CFT) and the maximal clot firmness (MCF) in order to evaluate the extrinsic (EXTEM® test) and intrinsic (INTEM® test) coagulation systems, as well as the fibrinogen contribution to coagulation (FIBTEM® test). RESULTS After exclusions, data from 54 subjects in each group were analysed. Parturients had significantly lower haemoglobin values and platelet counts (P<0.01). Despite this, thromboelastometry exhibited significantly lower INTEM® CT (7.3%), INTEM® CFT (11.1%) and EXTEM® CFT (18.0%) in the pregnant group (P<0.001). MCF values were significantly higher (INTEM® (10.9%), EXTEM® (10.6%) and FIBTEM® (47.1%)) in the pregnant group compared to the non-pregnant group (P<0.0001). CONCLUSIONS ROTEM® thromboelastometry clearly demonstrates the hypercoagulability of pregnancy. Formal reference ranges for ROTEM® that may be potentially useful in the haemostatic management of the parturient are presented.

Levobupivacaine for epidural analgesia in labor : The sparing effect of epidural fentanyl

Evidence suggests that levobupivacaine has similar pharmacodynamic properties to racemic bupivacaine. We sought to investigate whether this similarity extends to opioid sparing when levobupivacaine is used for epidural analgesia in laboring women by quantifying the effect of fentanyl on the minimum local analgesic concentration (MLAC) of levobupivacaine. One-hundred-six women requesting epidural analgesia for labor pain were recruited in this randomized, double-blinded, up-down sequential allocation study. Each received 20 mL of one of three test solutions: levobupivacaine control, levobupivacaine and fentanyl 2 &mgr;g/mL, or levobupivacaine and fentanyl 3 &mgr;g/mL. The initial levobupivacaine concentration was 0.07% wt/vol in each group, with subsequent concentrations of levobupivacaine being determined by the response of the previous patient (testing interval 0.01% wt/vol). Efficacy was accepted if the visual analog score decreased to 10 mm or less on a 100-mm scale within 30 min. The MLAC of levobupivacaine in the control group was 0.091% wt/vol (95% CI, 0.052–0.130). Fentanyl at concentrations of 2 &mgr;g/mL and 3 &mgr;g/mL significantly reduced the MLAC of levobupivacaine to 0.047% wt/vol (95% CI, 0.023–0.072) and 0.050% wt/vol (95% CI, 0.035–0.065), respectively (P < 0.001). A dose-dependent effect was not demonstrated. We conclude that fentanyl significantly reduces levobupivacaine requirements for epidural analgesia in labor. Implications Determination of minimum local analgesic concentrations by the technique of sequential allocation allows the interaction between epidural opioids and local anesthetics to be quantified. This study demonstrates that the addition of fentanyl significantly reduces levobupivacaine requirements for epidural analgesia.

Up-Down Determination of the 90% Effective Dose of Phenylephrine for the Treatment of Spinal Anesthesia-Induced Hypotension in Parturients Undergoing Cesarean Delivery

INTRODUCTION: Hypotension frequently complicates spinal anesthesia for cesarean delivery, and vasopressors are the mainstay for treatment. The most effective dose of phenylephrine for the treatment of spinal anesthesia-induced hypotension has not been estimated. METHODS: Healthy nonlaboring women undergoing a cesarean delivery were recruited. All women received spinal anesthesia using hyperbaric bupivacaine 12 mg with fentanyl and morphine. Each subject received an IV crystalloid fluid bolus before and at the time of initiation of spinal anesthesia (preload and coload). An up-down sequential allocation method using the biased-coin design was used to estimate the 90% effective dose (ED90) of phenylephrine. The assigned phenylephrine dose was based on the response of the preceding subject. If the systolic blood pressure (SBP) decreased >20% of baseline (i.e., SBP 20%) or to an SBP <90 mm Hg, the assigned dose of phenylephrine was administered. If the SBP returned to within 20% of baseline or ≥90 mm Hg within 1 min, this was considered a success, otherwise it was a failure. The initial dose of phenylephrine was 100 μg. The ED90 with 95% confidence intervals (CIs) was calculated using the maximum likelihood estimation and Firth logistic regression. RESULTS: Sixty-nine subjects were screened to participate, of whom 66 subjects consented. Forty-five of the enrolled subjects experienced spinal anesthesia-induced hypotension and received a blinded dose of phenylephrine. Those subjects who developed hypotension received doses of phenylephrine between 80 and 180 μg. No subjects experienced hypertension. Determined with the maximum likelihood estimation method, the ED90 of phenylephrine was 147 μg (95% CI, 98–222 μg). With Firth regression, the probability of a successful response at 150 μg is 90.5% (95% CI, 66.0%–99.0%). CONCLUSION: In this study, we estimated that the ED90 of phenylephrine required to treat spinal anesthesia-induced hypotension in cesarean delivery is approximately 150 μg.