Inclusion of lignocaine base into a polar lipid formulation--in vitro release, duration of peripheral nerve block and arterial blood concentrations in the rat.

BACKGROUND: Slow-release formulations of local anaesthetics may produce nerve blocks of long duration. The present study aimed at investigating the in vitro and in vivo properties of a polar lipid formulation for slow release of lignocaine and the effects on nerve block duration by inclusion of dexamethasone into the system. METHODS: In vitro release of lignocaine from the lipid formulation was studied in a US Pharmacopoeia rotating apparatus. Sciatic nerve blocks were induced in rats by 0.1 ml of test formulations containing lignocaine HCl 20 mg. ml-1 in aqueous solution, lignocaine base 20, 100 or 200 mg. ml-1 in lipid formulation or the last formulation with dexamethasone 0.05, 0.5 or 5 mg. ml-1. The durations of sensory and motor block and the arterial blood concentrations of lignocaine were investigated. RESULTS: In vitro there was a sustained release of lignocaine from the lipid formulation, with 50% release at around 48 h. In vivo lignocaine base 20 mg. ml-1 in lipid formulation produced sciatic nerve blocks of significantly shorter duration than lignocaine HCl 20 mg. ml-1 in aqueous solution, while lignocaine base 100 and 200 mg. ml-1 in lipid formulation produced blocks lasting two and three times longer, respectively, than the lignocaine HCl solution. Addition of dexamethasone did not affect the duration of nerve block. Following administration of lignocaine base 200 mg. ml-1 in lipid formulation, as compared to lignocaine HCl 20 mg. ml-1 in aqueous solution, the maximal blood concentration of lignocaine was only three times higher in spite of the ten-fold difference in dose, and the mean terminal half-life was three times longer, reflecting the slow release from the formulation. CONCLUSIONS: Our findings indicate that lignocaine base in polar lipids acts as a slow-release preparation of local anaesthetic both in vitro and in vivo.

The duration of action of bupivacaine, levobupivacaine, ropivacaine and pethidine in peripheral nerve block in the rat.

BACKGROUND: There is a current interest in local anaesthetic drugs/formulations exhibiting long durations of sensory block and minor motor-blocking effects. OBJECTIVES: To compare the duration of sensory and motor blockade in peripheral nerve blocks induced by the new agents ropivacaine and levobupivacaine, with that of racemic bupivacaine and pethidine. METHODS: Groups of 8 male Sprague-Dawley rats were subjected to infraorbital (IONB) or sciatic nerve block (SNB) employing 0.2 ml of differently concentrated solutions of bupivacaine, levobupivacaine, ropivacaine or pethidine. The sensory blocking effect in IONB is expressed as (i) the time to elicitation of an abdominal jerk by electrical stimulation at arbitrarily chosen (threshold) intensities (IONB degree 3, 5, 8 and 10), and as (ii) the area under the curve (AUC, threshold intensities vs time). The duration of motor block in SNB is given as the time from injection to regained ability to walk and grip normally with the toes. Comparisons of the dose-effect relationships for the investigated agents were made by analysis of covariance. RESULTS: In IONB the log (dose)-log (effect) lines for bupivacaine, levobupivacaine and ropivacaine did not deviate from parallelism. The duration of sensory block induced by equimolar doses of these agents was similar, although bupivacaine exerted more pronounced effects than levobupivacaine (AUC by 25%, P=0.001; IONB degree 3 by 14%, P=0.03). In SNB only the log (dose)-log (duration) lines for bupivacaine vs levobupivacaine were found not to deviate from parallelism, both agents exerting similar durations of action. The motor-blocking effects of ropivacaine showed an inverse dose-duration relationship (P=0.019). CONCLUSIONS: Equimolar doses of the investigated local anaesthetics exerted similar durations of sensory blockade in a peripheral nerve block model in the rat.

Metabolic, ventilatory and circulatory effects of doxapram in anaesthetized pigs during normoxia and hypoxia.

BACKGROUND: In a previous clinical study doxapram was found to improve ventilatory efficacy postoperatively, presumably via effects on hypoxic pulmonary vasoconstriction (HPV). The present study was designed to see whether doxapram induced any changes of arterial oxygenation and pulmonary vascular resistance during normoxia or hypoxia and whether the changes were influenced by the anaesthetic agents. METHODS: Seventeen piglets were anaesthetized by combinations of either midazolam + fentanyl + pancuronium + pentobarbital (TIVA, n = 9), or by midazolam + fentanyl + pancuronium + halothane, 0.5% in end-tidal gas (Hal, n = 8). Analyses of expired gas and mixed venous and arterial blood in combination with determinations of central blood flow and pressures allowed for calculations of standard metabolic, ventilatory and circulatory data. Values were obtained at normoventilation using normoxic (FIO2 = 0.3) and hypoxic (FIO2 = 0.08) gas mixtures at calculated doxapram plasma concentrations of 1, 2 and 4 micrograms.ml-1. RESULTS: With few exceptions doxapram administration affected the investigated variables only moderately during normoxia. In group Hal, PVR and SVR showed a biphasic raise (P < 0.05), CO fell (P < 0.05-P > or = 0.05) and C (a-v)O2 rose (P < 0.05). In group TIVA, PaO2 fell (P < 0.01-0.05) despite unchanged PVR, CO and VD/VT. Hypoxia affected a moderate increase in PVR in group TIVA (P < 0.05), which was slightly lower at the lowest and highest plasma levels of doxapram (P < 0.05). In group Hal, the induction of hypoxia induced a more pronounced rise in PVR (P < 0.05) which showed a biphasic response to increasing dose levels of doxapram, the lowest dose affecting a further rise (P < 0.05) and the highest a reduction to values below hypoxia control levels (P < 0.05). Pronounced differences between the two groups with respect to values for metabolic and circulatory variables make the interpretation of data difficult. CONCLUSIONS: Doxapram administration to anaesthetized animals did not induce any effects indicative of augmentation of the HPV response.

Effects of pH and buffer capacity modulation on the analgesic efficacy of lignocaine and pethidine solutions.

BACKGROUND: Objectives were to study the effects of variations in the pH and the buffer capacity of solutions of lignocaine or pethidine on their analgesic efficacy in peripheral nerve block. METHODS: Infraorbital nerve blocks (IONB) were induced in rats during light pentobarbitone anaesthesia employing 0.2 ml of test solutions containing 10 mg center dot ml-1 of lignocaine or pethidine dissolved in normal saline, 50 mmol and 150 mmol tris-hydroxymethylaminomethane (THAM) hydrochloride (THAM center dot HCl) of pH 4.8 and 4.5, respectively, or 100 mmol THAM + THAM center dot HCl of pH 7.4. The pH of solutions in saline was varied from 3.0 to 9.3 by adding HCl or NaHCO3. The analgesic efficacy is expressed as the interval from injection to elicitation of a minimal response to electric stimulation at various intensities (threshold intensities) within the blocked area (IONB 3 to 10), and in terms of the area under the curve (AUC, threshold intensities vs. time). RESULTS: When dissolved in saline, pH 7.4, pethidine exerted more pronounced effects than lignocaine [AUC by 3.5 times (P<0.001), IONB 3 to 10 by 2.7 (P<0.05) to 3.6 (P<0.001) times]. Variations of the pH of solutions did not affect their analgesic efficacy. Lignocaine exerted more pronounced local analgesic effects when mixed with 150 mmol THAM center dot HCl than when mixed with saline (pH 7.4), but manifested even more pronounced effects when dissolved in THAM + THAM center dot HCl [AUC by 3.7 times (P<0.001), IONB 3 to 10 by 2.7 (P<0.01) to 3.8 (P<0.001) times]. When dissolved in THAM + THAM center dot HCl, the analgesic efficacy of pethidine increased by 2.0 to 2.8 times (P<0.001), as compared to a solution in saline at the same pH. CONCLUSIONS: It is concluded that variations in the pH of solutions of lignocaine or pethidine in saline does not affect the analgesic efficacy of the drugs, presumably due to the low buffer capacity of the medium, whereas when dissolved in THAM + THAM center dot HCl, their effect is enhanced.

Assessment of sensory block in epidural anaesthesia by electric stimulation.

The onset of sensory block in lumbar epidural anesthesia was investigated in 26 patients, aged 18 to 84 years, employing the loss of discrimination to cold and pinprick, as well as by determining threshold electric stimulation (threshold intensities). A standard dose of 2% mepivacaine with adrenaline, 5 micrograms.ml-1, (0.1 ml per cm body height) was given and the patients' ability to discriminate stimuli within dermatomes T8, T10, T12, L2, L4 and S1 was investigated at five min intervals for 30 min after injection. From the results of the study it is concluded that i) The interval to peak analgesic efficacy of the anaesthetic solution used is < 30 min when assessments are based on the patients' ability to discriminate cold or pinprick but > 30 min when determinations of threshold intensities are employed. ii) Cold discrimination is lost earlier than discrimination to pinprick and at lower threshold intensities. iii) Threshold intensities describe the time course of onset of sensory block more precisely than results of testing by cold or pinprick. iv) The onset of sensory block was found to be positively correlated to the age of patients in the following respects: a) Threshold intensities during early onset in all investigated dermatomes except L2. b) Intensity of block in T8, T10, and S1 at the end of the study period. c) Time to loss of discrimination to cold and pinprick in T12, L2 and S1, and d) Threshold intensities at loss of discrimination to cold and pinprick. We propose that determinations of threshold intensities offer distinct advantages over conventional testing by cold and pinprick discrimination, especially when detailed analyses of the sensory blocking effects of local anaesthetic drugs are being investigated.

On the relative potency of amino-amide local anaesthetics in vivo.

With the aim of comparing the analgesic effectiveness of lidocaine, prilocaine, bupivacaine and etidocaine in vivo, a study of the relationships between dose and duration of infraorbital nerve block (IONB) of various intensities (IONB degrees 3-10) was performed in the rat. With increasing doses longer durations of action were obtained. Further analyses were performed using multiple regression analysis. The log (dose)-duration lines for bupivacaine and etidocaine were found to be linear, whereas those for lidocaine in degree 3 and degree 10 IONB and for prilocaine in degree 10 IONB were so only after omission of some data. The only comparisons yielding no deviation from parallelism of log (dose)-duration lines were etidocaine vs. lidocaine at IONB degree 10 and lidocaine vs. prilocaine and bupivacaine vs. etidocaine at IONB degree 3. The difference between these agents with respect to their duration of action at all dose levels amounted to 11 +/- 3 minutes (M +/- s.e.m.) for etidocaine vs. lidocaine (IONB degree 10), 27 +/- 4 min for prilocaine vs. lidocaine and 54 +/- 5 min for bupivacaine vs. etidocaine (IONB degree 3). For all other comparisons the log (dose)-duration lines deviated from parallelism, i.e. differences between agents with respect to their duration of action were found to be dose-dependent. The slopes of the log (dose)-duration lines were found to correlate closely to the log (partition coefficient) and log (protein binding) of the investigated agents.

Doxapram improves pulmonary function after upper abdominal surgery.

The effects of doxapram on postoperative pulmonary function were studied in 40 ASA I and II patients randomly allocated to receive either doxapram 1.8 mg.kg-1.h-1 or placebo for 2 h immediately after elective cholecystectomy. The two groups displayed similar reductions of carbon dioxide production at 2 h and 6 h postoperatively, whereas oxygen consumption remained at preoperative levels for 24 h. Minute ventilation was similarly reduced in the two groups at 2 h and 6 h postoperatively, with corresponding increases in PaCO2. PaO2 was similarly and significantly decreased in both groups postoperatively, whereas P(A-a)O2 remained unchanged at 2 h and 6 h in doxapram-treated patients. FRC was reduced postoperatively in both groups, significantly more so in the control group at 6 h. Various indices of intrapulmonary gas distribution, including the functional (nitrogen) dead space, underwent similar changes in the two groups. By contrast, the physiological dead space was reduced in doxapram-treated patients at 2 h, 6 h and 24 h postoperatively, whereas no significant changes were seen in the control group. The ventilatory equivalent for CO2 was significantly lower in the doxapram-treated group, implying higher ventilatory efficiency. Our findings indicate that infusion of doxapram postoperatively attenuates the impairment of pulmonary function postoperatively, chiefly via effects on V'A/Q' ratios. No side effects of doxapram were observed.

Duration of experimental nerve block by combinations of local anesthetic agents.

The effects of bupivacaine-prilocaine and meperidine-lidocaine combinations (as compared with those of the agents used alone) on the duration of peripheral sensory nerve block were studied with the infraorbital nerve block model (IONB) in the rat, and those on motor block with spinal anesthesia (SA) in the mouse. The duration of bupivacaine-induced IONB was invariably prolonged when prilocaine was included in the solution. When included in 0.125% bupivacaine, 1.0% prilocaine had a slightly less pronounced enhancing effect than 0.5% prilocaine (24-57% vs. 74%-104%, respectively). The duration of IONB with 1.0% prilocaine was significantly reduced (14-37%) by inclusion of 0.125% bupivacaine. In SA, inclusion in 0.125% bupivacaine of prilocaine (0.5% or 1.0%) prolonged motor block by 128% and 192%, respectively. When included in 0.25% bupivacaine, both 0.5% and 1.0% prilocaine significantly reduced the duration of SA, by 42% and 37%, respectively. With one exception, the duration of IONB by meperidine was significantly shortened (< 44%) when lidocaine was included in the solution. In SA, inclusion of 2% lidocaine with 2% meperidine did not affect the duration of meperidine-induced motor block. The duration of SA obtained with the combination of 4% lidocaine and 4% meperidine was 45% shorter than that induced by 4% meperidine alone. The reasons for these variable effects are not clear, but may be due to interaction or antagonism at any of multiple sites.

Epinephrine as an adjuvant to amino-amide local anesthetics does not prolong their duration of action in infraorbital nerve block in the rat.

The effects of epinephrine as an adjuvant to local anesthetics were studied in the rat infraorbital nerve block (IONB) model, using solutions of 0.5% prilocaine, 0.5% mepivacaine, 0.125% bupivacaine or 0.125% ropivacaine in 50 mmol/l tris-hydroxymethylaminomethane (THAM) tested both without and with epinephrine (EPI) added at 2, 4, 8 or 16 micrograms/ml. Solutions of THAM and EPI in normal saline did not induce IONB. THAM-buffered solutions of bupivacaine induced IONB of longer duration than bicarbonate-buffered solutions. Intensity of block during onset was increased only when EPI at 2 and 16 micrograms/ml was included in bupivacaine solutions. The duration of block induced by prilocaine, bupivacaine and ropivacaine was not significantly prolonged by addition of EPI at any of the concentrations tested. Only at a concentration of 16 micrograms/ml did EPI significantly prolong the duration of mepivacaine-induced block (+48%). Low concentrations of EPI in solutions of bupivacaine and ropivacaine significantly reduced their duration of action by up to 22% and 57%, respectively. It is concluded that the duration of action of local anesthetics in buffered solutions is only moderately affected by the inclusion of EPI, the effects differing only slightly from one to another. The efficacy of EPI as an adjuvant would seem to be governed by factors affecting the local disposition of the main drugs, such as non-specific binding, buffering of solutions and tissue pH.

Hemodynamic and catecholamine responses to laryngoscopy with vs. without endotracheal intubation.

To study the relationship between the intensity of the stimulus exerted against the base of the tongue during direct laryngoscopy and the magnitude of associated hemodynamic and catecholamine responses, a study was conducted in 40 ASA I or II patients. Laryngoscopy lasting 40 s was performed with a size 3 Macintosh blade connected to a force-displacement transducer. The intensity of the stimulus exerted during laryngoscopy is expressed by the product of its average force (N) and duration (s) and given as impulse in Ns. Highly significant relationships were found between the impulse during laryngoscopy and the maximal hemodynamic and catecholamine responses. Also, when laryngoscopy was followed by orotracheal intubation, significant relationships were found with steeper slopes of the regression lines for systolic blood pressure, heart rate and plasma epinephrine concentrations. A more rapid regression of hemodynamic data was seen in intubated patients, whereas their plasma catecholamine concentrations regressed more slowly. The mechanisms of the responses to laryngoscopy and orotracheal intubation are proposed to be by somato-visceral reflexes. Stimulation of proprioceptors at the base of the tongue during laryngoscopy induces impulse-dependent increases of systemic blood pressure, heart rate and plasma catecholamine concentrations. Subsequent orotracheal intubation recruits additional receptors that elicit augmented hemodynamic and epinephrine responses as well as some vagal inhibition of the heart.

Antinociceptive effects of localized administration of opioids compared with lidocaine.

To study possible antinociceptive effects of perineurally administered opioids, the rat infraorbital nerve block (IONB) model was employed for investigations of opioids (morphine, meperidine, buprenorphine, ethylketocyclazocine, and fentanyl) of differing receptor selectivity and physicochemical properties such as lipid solubility. Only meperidine in doses greater than 1 mg/kg produced localized analgesia, the duration of which increased dose-dependently. Naloxone failed to counteract the analgesic effects of meperidine. It is concluded that meperidine exerted its effect by a local anesthetic action and not by the activation of opioid receptors in the peripheral nerve. The local anesthetic potency of meperidine was compared with that of lidocaine in peripheral nerve blocks (IONB in rats and sciatic nerve block in guinea pigs), in central nerve blocks (epidural anesthesia in guinea pigs and spinal anesthesia in mice), and in infiltration anesthesia in guinea pigs. Time to onset of block was generally longer for meperidine. Equal amounts of the drugs produced motor blocks of similar durations except in epidural anesthesia where meperidine was clearly shorter. Sensory blocks were longer with meperidine than with lidocaine when applied in equal amounts to the infraorbital nerve and subarachnoidally. The two agents caused a similar duration of sensory block in infiltration anesthesia. Meperidine was shorter than lidocaine in epidural anesthesia. The characteristics of blocks induced by the two agents may be explained by structural differences and associated differences in physicochemical properties such as lipid solubility and pKa.

Hapten inhibition and dextran anaphylaxis.

Hapten inhibition with dextran 1 has been used in Sweden since 1982 to prevent severe anaphylactic reactions to dextran. This has led to a reduction in the reports of severe reactions to dextran from 22 per 100,000 units of dextran used between 1975 and 1979, to 1.2 per 100,000 units between 1983 and 1985. The number of fatal reactions decreased from 23 to one. More than 600,000 units of dextran were used during each period.

Effects of macromolecular adjuvants on the duration of prilocaine. Experimental studies on the effect of variations of viscosity and sodium content and of inclusion of adrenaline.

Sodium hyaluronate (HA) and dextran (Dx) of different molecular weights and concentrations were used as adjuvants to prilocaine for studies of the duration of infraorbital nerve block in the rat (IONB) and spinal anaesthesia in the mouse (SA). A positive relation was found between duration of block on the one hand and the concentration as well as the molecular weight of the adjuvant on the other. A direct relation was found between the duration of block and the viscosity of the anaesthetic solution. Low-sodium-content solutions of plain prilocaine caused a markedly prolonged duration of the most profound degrees of IONB as compared to medium- or high-sodium-content solutions, while no differences between the solutions were found for the weakest intensity of IONB studied or for SA. Solutions of low-sodium-content containing prilocaine and HA were associated with significant prolongations of IONB and SA as compared to corresponding solutions of medium- or high-sodium content. Inclusion of adrenaline, 5 micrograms/ml, in solutions containing prilocaine and Dx significantly prolonged the duration of the most profound degrees of IONB and of SA. By contrast, the inclusion of adrenaline in solutions containing prilocaine and HA did not prolong the duration of IONB or SA. It is concluded that modulations of the viscosity of local anaesthetic solutions by the addition of macromolecular compounds strongly affect the duration of peripheral and central nerve blocks in experimental animals. A further prolongation is accomplished by reducing the sodium content of the solutions and, in the case of Dx-containing solutions, by inclusion of adrenaline in the anaesthetic solution. The possible mechanisms of these actions are discussed.

Metabolic acidosis in dextran-induced anaphylactic reactions.

Results of arterial blood gas and acid-base balance analyses were analyzed in 50 patients suffering from dextran-induced anaphylactic reactions. Metabolic acidosis was always present in severe cases, leading to cardiac arrest, and also frequently found in those with less severe reactions with only slightly impaired circulation. Bronchospastic respiratory signs were frequently encountered but acidosis was noted to develop even without these symptoms. The severity of the acidosis was generally underestimated during treatment. Arterial PO2 and PCO2 were not significantly affected during these reactions.

Effects of adjuvants to local anaesthetics on their duration. IV. Effect of hyaluronic acid added to bupivacaine or prilocaine on the duration of nerve blockade in man.

A randomized study of the duration of ulnar nerve blockade induced with 2% prilocaine or 0.5% bupivacaine with and without 0.4% hyaluronic acid was performed in volunteers. In contrast to results in experimental animals, the addition of hyaluronic acid to the local anaesthetic solution did not affect the duration of sensory nerve block.

Multiple intercostal blocks by a single injection? A clinical and radiological investigation.

Three different techniques for producing multiple intercostal nerve blocks using bupivacaine were compared in volunteers. The techniques used were multiple injections at intercostal nerves 7-11, or a single injection employing a needle or a catheter inserted in the 9th intercostal space. The injections were made at the costal angle. The anatomical spread of a mixture of a local anaesthetic and a radio-opaque fluid following the single injection technique at the ninth intercostal space or at the subcostal space was evaluated by computerized x-ray tomography (CT). The distribution of cutaneous analgesia/hypalgesia following all techniques was evaluated by pin prick. No spread of the local anaesthetic to adjacent intercostal spaces or to the paravertebral space could be shown by CT. The distribution of cutaneous analgesia was limited to three segments or less following a single injection. No difference in blood levels of bupivacaine could be found. It is concluded that the single injection technique of producing multiple intercostal nerve blocks is inferior to the multiple injection technique.