Anesth Analg 2000;90:1208-1212
© 2000 International Anesthesia Research Society
GENERAL ARTICLES
Intravenous Chloroprocaine Attenuates Hemodynamic Changes Associated with Direct Laryngoscopy and Tracheal Intubation
Mehmood Durrani, MD,
John A. Barwise, MD,
Raymond F. Johnson, BS,
Jay R. Kambam, MD, and
Piotr K. Janicki, MD, PhD
Departments of Anesthesiology, Vanderbilt University Medical Center and Veteran Administration Medical Center, Nashville, Tennessee
Address correspondence and reprint to Piotr K Janicki, MD, PhD, Department of Anesthesiology, Vanderbilt University Hospital, 504 Oxford House, 1313 21st Ave. S., Nashville, TN 37232-4125. Address e-mail to piotr.janicki{at}mcmail.vanderbilt.edu
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Abstract
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We compared the effects of an IV administration of chloroprocaine and lidocaine on circulatory responses associated with endotracheal intubation. Thirty patients were randomly allocated to receive normal saline (placebo), lidocaine (1.5 mg/kg), or preservative-free chloroprocaine (4.5 mg/kg) 45 s before endotracheal intubation. Blood pressures and heart rate and rhythm were recorded before laryngoscopy and at 0.5, 1, 1.5, 2, 3, and 5 min after intubation. Blood samples were analyzed for catecholamine and chloroprocaine concentrations. Chloroprocaine reduced increases in blood pressure in response to intubation when compared with patients receiving normal saline and lidocaine. Systolic blood pressures at 0.5 and 1 min after intubation were significantly lower in the chloroprocaine group when compared with both the control and lidocaine groups (P < 0.05). Diastolic and mean blood pressures were significantly lower in the chloroprocaine group at all time points until 5 min after intubation (P < 0.05). Chloroprocaine and, to a lesser degree, lidocaine, produced marked attenuation of intubation-induced increases in plasma concentration of epinephrine and norepinephrine. Plasma concentrations of norepinephrine were significantly smaller in the chloroprocaine group at 0.5, 1, and 1.5 min, and plasma concentrations of epinephrine were significantly smaller at 0.5 after intubation when compared with control and lidocaine groups (P < 0.05). Measurable concentrations of chloroprocaine were recorded in plasma samples for 2 min after its administration. No adverse chloroprocaine effects (i.e., circulatory disturbances, venous irritation) were detected. The IV administration of chloroprocaine effectively blunted cardiovascular response produced by laryngoscopy and endotracheal intubation, and this effect was more pronounced when compared with IV lidocaine.
Implications: The IV administration of chloroprocaine effectively blunted cardiovascular response produced by laryngoscopy and endotracheal intubation, and this effect was more pronounced when compared with IV lidocaine.
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Introduction
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The IV administration of local anesthetics is used to blunt sympathetic response during manipulation of airways. There have been sporadic reports of IV chloroprocaine used for treatment of neuropathic pain (1–3) and IV regional anesthesia (4–6). However, use of IV chloroprocaine in humans has not been as systematically studied as lidocaine administration.
Effects of chloroprocaine in preventing adverse hemodynamic effects associated with laryngoscopy and tracheal intubation have not been investigated. Therefore, we compared the effects of a preintubation IV administration of chloroprocaine and lidocaine with those of saline (placebo) on hemodynamic changes and catecholamine levels associated with direct laryngoscopy and tracheal intubation. In addition, we measured plasma levels of chloroprocaine after its IV bolus administration. Patients were also monitored for adverse cardiovascular side effects.
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Methods
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With approval of our institutional review board, 30 patients, ASA physical status I and II, undergoing general anesthesia for various noncardiac operative procedures were included in this study. Patients with a history of cardiovascular disease, hypertension, cerebrovascular disease, renal disease, liver disease, diabetes mellitus, and allergic reactions to local anesthetics were excluded. After giving informed consent, patients were randomly allocated into three experimental groups (n = 10 in each) to receive normal saline (placebo), lidocaine, or chloroprocaine as part of the induction treatment. All patients were premedicated with fentanyl 1 µg/kg and midazolam 30 µg/kg, both IV. A 20-gauge cannula was placed in the radial artery (for continuous blood pressure monitoring and blood sampling), and patients were taken to the operating room. General anesthesia was induced with 5 mg/kg of sodium thiopental and 0.1 mg/kg vecuronium IV; ventilation was controlled with 1% isoflurane (end-tidal) in oxygen for 5 min. Then, patients received a bolus dose of either preservative-free chloroprocaine 4.5 mg/kg, lidocaine 1.5 mg/kg, or normal saline as preintubation treatment. After 45 s, laryngoscopy and tracheal intubation were performed. Systolic, diastolic, and mean blood pressures, plus heart rate and rhythm were recorded from the arterial line and electrocardiogram (ECG) tracings at 30 s before laryngoscopy, and at 0.5, 1, 1.5, 2, 3, and 5 min after intubation.
All blood samples were collected from the arterial line. Before (0 min) and at 1, 2, and 3 min after the drug injection, blood samples for catecholamine analysis were collected in tubes containing EDTA. Tubes were kept on ice, centrifuged, and then, the separated plasma was stored at -20°C. Blood samples for estimating plasma cholinesterase (PCHE) activity were collected into plain glass tubes before the drug administration. Additional plasma samples for determination of concentrations of chloroprocaine were collected into tubes containing sodium fluoride at 0, 0.5, 1, 1.5, 2, 3, and 5 min after the drug administration.
Plasma catecholamine levels (norepinephrine and epinephrine) were analyzed by using the high-performance liquid chromatography method with electrochemical detection (7). The between-assays coefficient of variation for 300 pg/mL of norepinephrine and epinephrine assays was 9.2% and 8.7%, respectively; and for the coefficient of variation for comparison within-assay it was 8.9% and 8.2%, respectively. The plasma level of chloroprocaine was determined by high performance liquid chromatography with ultraviolet (210 nm) detection, with a sensitivity limit of 0.1 µg/mL (8,9). The coefficient of variation for within-assay comparison was 5.9% at a chloroprocaine concentration of 1 µg/mL and 2.1% at a concentration of 10 µg/mL. The between-assays coefficient of variation was 6.1% for the chloroprocaine concentration of 1 µg/mL and 3.6% for the concentration of 10 µg/mL. The dibucaine number and PCHE activity were determined colometrically by using butyrylthiocholine as the substrate (10,11). The coefficient of variation for PCHE activity assay was 12.9% for within-assay comparison and 14.1% for between-assays comparison. The coefficient of variation for dibucaine number assay was 9.6% for within-assay comparison and 10.1% for between-assays comparison. Pharmacokinetic data, including the area under the plasma chloroprocaine concentration curve, half-life, clearance, and volume of distribution were calculated by using a noncompartmental pharmacokinetic model (12). The data in experimental groups were compared by using an analysis of variance (ANOVA) test, followed by a least-significant difference test for between-group comparison. The results were presented as mean ± SD. A P < 0.05 was considered significant.
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Results
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The chloroprocaine, lidocaine, and normal saline (control) groups were comparable for sex, age, weight, and ASA physical status (Table 1). Direct laryngoscopy and endotracheal intubation produced an increase in heart rate, arterial blood pressure, and plasma catecholamines in all groups of patients (Figs. 1 and 2). No statistically significant differences in heart rate were observed among the three experimental groups of patients at any time after intubation (Fig. 1A). The administration of chloroprocaine (4.5 mg/kg) produced significantly diminished increases in blood pressure in response to intubation when compared with patients who received normal saline and lidocaine. In particular, systolic blood pressures at 0.5 and 1 min after intubation were significantly lower in the chloroprocaine group when compared with both control and lidocaine groups (P < 0.05, ANOVA), diastolic blood pressure was significantly lower in the chloroprocaine group at 0.5, 1, 1.5, 2, 3, and 5 min after intubation (P < 0.05, ANOVA), and mean arterial blood pressure was significantly lower in the chloroprocaine group at 0.5, 1, 1.5, 3, and 5 min after intubation when compared with both the control and lidocaine groups (P < 0.05, ANOVA) (Fig. 1B).
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Figure 1. Effects of pretreatment with chloroprocaine, lidocaine, and saline on the cardiovascular response (A, heart rate, B, mean arterial pressure) associated with direct intubation and endotracheal intubation. Values are mean ± SD. *Significantly different among the groups. #Significantly different from the saline group.
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Figure 2. Effects of pretreatment with chloroprocaine, lidocaine, and saline on the plasma catecholamine (A, norepinephrine, B, epinephrine, in pg/mL) associated with direct intubation and endotracheal intubation. Values are mean ± SD. *Significantly different among the groups. #Significantly different from the saline group.
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Endotracheal intubation caused an increase in plasma concentrations of epinephrine and norepinephrine in the control group. The administration of chloroprocaine and to a lesser degree, lidocaine, produced marked attenuation of this response. The plasma concentration of norepinephrine was significantly smaller in the chloroprocaine group at 0.5, 1, and 1.5 min after endotracheal intubation (Fig. 2A) and the plasma concentration of epinephrine was significantly smaller at 0.5 after endotracheal intubation when compared with the control and lidocaine groups (P < 0.05, ANOVA) (Fig. 2B).
We were able to measure chloroprocaine concentrations in all plasma samples for 2 min after its IV administration. In 4 of 10 patients, minute amounts of chloroprocaine were detected for up to 5 min after the administration. The pharmacokinetic analysis by using a noncompartmental pharmacokinetic model produced the mean value of half-life of chloroprocaine of 0.46 ± 0.17 min and the area under the curve of 74.65 ± 39.8 µg · min-1 · mL-1. The other pharmacokinetic derivatives obtained from this analysis by using the noncompartmental pharmacokinetic model are presented in the Table 2. Analysis of PCHE (by both dibucaine number and total PCHE activity) revealed no statistically significant differences between the saline, chloroprocaine, and lidocaine groups (Table 3). No rhythm abnormalities were documented in the continuous strip ECG recordings at any time after the chloroprocaine administration. In addition, in the recovery room and 24 h after anesthesia, no subjective complaints related to the site of injection were noted in patients obtaining chloroprocaine, lidocaine, and saline.
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Table 3. Plasma Cholinesterase (PCHE) Activity and Dibucaine Number in Control, Chloroprocaine and Lidocaine Groups
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Discussion
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Results of our current study indicate that the IV administration of a bolus dose of chloroprocaine effectively blunted the cardiovascular response produced by direct laryngoscopy and endotracheal intubation, and that this effect was stronger when compared with IV lidocaine. It is important to mention that both drugs were not administered in equipotent doses. Relative anesthetic potency of chloroprocaine to lidocaine is approximately 1:2. The finding, therefore, that chloroprocaine was relatively more effective than lidocaine in suppressing the pressor response to tracheal intubation may be related to the fact that a relatively larger dose of chloroprocaine was used than of lidocaine. Because local anesthetics were administered 45 seconds before direct laryngoscopy, it is also possible that this short time period is sufficient for the anesthetic effect of chloroprocaine but too short for lidocaine after the IV administration. Another limitation of the study was lack of blinding the doses of local anesthetics, so measurements of cardiovascular outcome (heart rate and blood pressure) could be influenced by the subjective bias of the investigator toward one of the drugs. Nevertheless, effects of chloroprocaine were clearly superior to the placebo control and indicate its usefulness for rapid, short-term inhibition of a sympathetic response. The postulated mechanism of IV local anesthetics in inhibiting sympathetic response associated with intubation appears to result from an increased threshold for airway stimulation, central inhibition of sympathetic transmission, and direct depression of cardiovascular response.
We conclude from this study that the IV administration of relatively large doses (4.5 mg/kg) of chloroprocaine, which attenuates pressor response to intubation, produced no adverse cardiovascular or neurotoxic side effects in the investigated group of patients. In previously published reports, relatively small doses of chloroprocaine (1–1.5 mg/kg) in laboring parturient and healthy volunteers produced no adverse effects (i.e., auditory changes, taste changes, dizziness/lightheadedness, and tingling in extremities) when compared with an IV bolus of lidocaine (13–15). Accidental IV injection of larger doses of chloroprocaine (more than 30 mg/kg) was, however, associated with transient psychotic reactions (16–18). It was reported that relative neurotoxicity attributed to chloroprocaine was generally less than other amide- or ester-type local anesthetics. Doses producing seizure activity on electroencephalogram in lightly anesthetized rats (70 mg/kg on average for chloroprocaine) are much larger than those used in clinical practice (usually <10 mg/kg) (19). Chloroprocaine has also less intense neurotoxicity compared with other local anesthetics in the isolated sciatic nerve model in rat (20).
Chloroprocaine itself does not have marked arrhythmogenic properties (19), and we demonstrated that it is a superior antidysrhythmic drug when compared with lidocaine and other amide-type local anesthetics in rats and dogs (21,22). Results of the current study also indicate that the IV bolus administration of chloroprocaine at 4.5 mg/kg in humans does not produce any adverse effects on the cardiovascular system (as judged by continuous ECG and blood pressure recordings). Adverse effects of IV chloroprocaine on venous endothelium were reported in a rabbit model (6). Signs of irritation, venous and antecubital in the test arm, were also described in patients after the administration of chloroprocaine for IV regional anesthesia (4,5). However, other investigators (including those in this study) did not observe local irritation of the vein after the IV administration of chloroprocaine into the free-flowing IV catheter. Symptoms of endothelial irritation are associated with venous stasis caused by tourniquet inflation and do not occur after chloroprocaine into the free-flowing system. It is also possible, that incidence of reporting subjective signs of venous irritation could be diminished by general anesthesia, analgesia, and sedation postoperatively.
Unlike previous reports (23), we were able to detect plasma concentrations and estimate preliminary pharmacokinetic data for chloroprocaine after its IV bolus administration. Plasma half-time of chloroprocaine (27 seconds) obtained in this study is in agreement with previously reported half-life of chloroprocaine obtained by in vitro studies (23). Analysis of pharmacodynamic properties of chloroprocaine administered before intubation indicates that its effects on hemodynamic response and catecholamine levels were observed for several minutes after its IV administration. Despite similar PCHE activity observed in the investigated group of patients, marked variations in the plasma concentration of chloroprocaine were observed after its IV bolus administration. These differences might be associated with relatively short, technically difficult-to-achieve intervals of blood sampling, and sodium fluoride preservative for collected blood samples. Although sodium fluoride is optimal for in vitro inhibition of PCHE and preservation of chloroprocaine in blood samples from various species (24), its usefulness for blood sampling was recently found to be suboptimal for human blood samples (J. Vloka, unpublished results, 1998).
In summary, our results indicate the usefulness of IV chloroprocaine for rapid, short-term inhibition of the sympathetic response. We postulate that IV chloroprocaine would be an excellent alternative to lidocaine, an amide-type local anesthetic for blunting sympathetic response, especially in patients with a history of allergy to amide-type local anesthetics.
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Accepted for publication January 14, 2000.
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Abstract
Introduction
