The effect of age on systemic absorption and systemic disposition of bupivacaine after subarachnoid administration

In order to evaluate the role of the pharmacokinetics of the age-related changes in the clinical profile of spinal anesthesia with bupivacaine, we studied the influence of age on the systemic absorption and systemic disposition of bupivacaine after subarachnoid administration in 20 male patients (22-81 yr), ASA Physical Status 1 or 2, by a stable isotope method. After subarachnoid administration of 3 ml 0.5% bupivacaine in 8% glucose, a deuterium-labeled analog (13.4 mg) was administered intravenously. Blood samples were collected for 24 h. Plasma concentrations of unlabeled and deuterium-labeled bupivacaine were determined with a combination of gas chromatography and mass fragmentography. Biexponential functions were fitted to the plasma concentration-time data of the deuterium-labeled bupivacaine. The systemic absorption was evaluated by means of deconvolution. Mono- and biexponential functions were fitted to the data of fraction absorbed versus time. The maximal height of analgesia and the duration of analgesia at T12 increased with age (r = 0.715, P less than 0.001; r = 0.640, P less than 0.01, respectively). In 18 patients the systemic absorption of bupivacaine was best described by a biexponential equation. The half-life of the slow systemic absorption process (r = -0.478; P less than 0.05) and the mean absorption time (r = -0.551; P less than 0.02) decreased with age. The total plasma clearance decreased with age (r = -0.650, P less than 0.002), whereas the mean residence time and terminal half-life increased with age (r = 0.597, P less than 0.01; r = 0.503, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Venous levels of lignocaine and bupivacaine after peribulbar block

Twenty-five patients undergoing elective cataract day surgery were studied after receiving a dual-injection peribulbar block with a mixture consisting of equal volumes of 2% lignocaine and 0.75% bupivacaine with hyaluronidase. A maximum of 10ml of solution was used for the initial block; supplementary injections of up to 10 ml were given to five patients. Venous blood was taken prior to the block and then 1, 10, 20, 30, 60 and 90 min after the block. The peak mean concentrations of lignocaine (0.722 μg. ml⁻¹) and bupivacaine (0.353 μg. ml⁻¹)were found at 10–20 min after injection when no top-up was given and at 10 min after the top-up injection when required. All measured serum concentrations of lignocaine and bupivacaine were below the accepted toxic levels of the two drugs. However, the highest individual toxicity score after a top-up was 0.915 which was very close to the toxicity threshold (= 1) when a scoring system was used to assess the combined levels.     

Plasma concentrations of bupivacaine after brachial plexus administration of liposome-associated and plain solutions to rabbits

Bupivacaine has been associated to multilamellar liposomes with the aim of altering circulating plasma concentrations after injection into the rabbit brachial plexus. Plasma concentrations of bupivacaine have been compared after administration of free drug (BP) or bupivacaine associated to multilamellar liposomes (BP-MLV) made of phosphatidylcholine and cholesterol (molar ratio 4:3). Under light general anaesthesia, one group of six rabbits received an axillary injection of 2.5 mg BP (1 ml, 0.25%), and a second received the same dose of BP-MLV. In both groups³H bupivacaine was used as a marker. The brachial plexus was located using a nerve stimulator. Injection of the anaesthetic solutions invariably prevented the motor response of the paw. The arterial plasma concentrations of bupivacaine were determined after 5 to 240 min and after 24 hr by beta counting. In the MLV population, additional measurements were performed after 48 and 72 hr. The two plasma curves showed a plateau (0.2 μg · ml^?1) which was reached after five minutes in the BP group and after 90 min using BP-MLV In the BP-MLV group, the plasma concentrations of bupivacaine were lower during the first ten minutes (P < 0.05), and higher after 24 hr (P < 0.05). Radioactivity decreased between 4 and 24 hr in the BP group and between one and two days in the BP-MLV population. It is concluded that elevated plasma drug concentrations were maintained for longer with BP-MLV than with BP This could prolong the action of the local anaesthetic through a slow release.     

Removal of subarachnoid blood clots after subarachnoid hemorrhage

The difficulty in removing subarachnoid blood clots was evaluated in terms of the interval after subarachnoid hemorrhage. Subarachnoid blood clots were removed from a total of 30 cisterns with a Hounsfield unit of more than 70. In 20 cisterns, removal was performed within 24 hours, and in 10 between 24 and 72 hours after subarachnoid hemorrhage. In 16 of the 20 cisterns (80%) and in 4 of the 10 cisterns (40%), the density was reduced to a Hounsfield unit of less than 60 after removal of subarachnoid blood clots. Two typical cases are presented.     

Plasma bupivacaine concentrations after axillary block in children

Venous plasma concentrations of bupivacaine were measured in children following axillary brachial plexus block with either 2 mg/kg (n = 21) or 3 mg/kg (n = 20) of bupivacaine. Absorption was very rapid with a mean time to peak concentrations of 0.37 hours for both doses. Mean peak plasma concentration was 1.35 mg/l after the 2 mg/kg dose and 1.84 mg/kg after the 3 mg/kg dose. Even after a 30% allowance for anticipated higher arterial concentrations, the plasma levels found in the present study were well below those at which toxicity is considered likely (greater than 4 mg/l).     

Plasma endothelin concentrations after aneurysmal subarachnoid hemorrhage

OBJECT: The pathogenesis of cerebral vasospasm and delayed ischemia after subarachnoid hemorrhage (SAH) seems to be complex. An important mediator of chronic vasospasm may be endothelin (ET), with its powerful and long-lasting vasoconstricting activity. In this study the author investigated the correlation between serial plasma concentrations of ET and ischemic symptoms, angiographically demonstrated evidence of vasospasm, and computerized tomography (CT) findings after aneurysmal SAH. METHODS: Endothelin-1 immunoreactivity in plasma was studied in 70 patients with aneurysmal SAH and in 25 healthy volunteers by using a double-antibody sandwich-enzyme immunoassay (immunometric) technique. On the whole, mean plasma ET concentrations in patients with SAH (mean +/- standard error of mean, 2.1 +/- 0.1 pg/ml) did not differ from those of healthy volunteers (1.9 +/- 0.2 pg/ml). Endothelin concentrations were significantly higher (p < 0.05) in patients who experienced delayed cerebral ischemia with fixed neurological deficits compared with those in other patients (post-SAH Days 0-5, 3.1 +/- 0.8 pg/ml compared with 2.1 +/- 0.2 pg/ml; post-SAH Days 6-14, 2.5 +/- 0.4 pg/ml compared with 1.9 +/- 0.2 pg/ml). Patients with angiographic evidence of severe vasospasm also had significantly (p < 0.05) elevated ET concentrations (post-SAH Days 0-5, 3.2 +/- 0.8 pg/ml; post-SAH Days 6-14, 2.7 +/- 0.5 pg/ml) as did those with a cerebral infarction larger than a lacuna on the follow-up CT scan (post-SAH Days 0-5, 3.1 +/- 0.8 pg/ml; post-SAH Days 6-14, 2.5 +/- 0.4 pg/ml) compared with other patients. Patients in whom angiography revealed diffuse moderate-to-severe vasospasm had significantly (p < 0.05) higher ET levels than other patients within 24 hours before or after angiography (2.6 +/- 0.3 compared with 1.9 +/- 0.2 pg/ml). In addition, patients with a history of hypertension or cigarette smoking experienced cerebral infarctions significantly more often than other patients, although angiography did not demonstrate severe or diffuse vasospasm more often in these patients than in others. CONCLUSIONS: Endothelin concentrations seem to correlate with delayed cerebral ischemia and vasospasm after SAH. The highest levels of ET are predictive of the symptoms of cerebral ischemia and vasospasm, and ET may also worsen ischemia in patients with a history of hypertension. Thus, ET may be an important causal or contributing factor to vasospasm, but its significance in the pathogenesis of vasospasm remains unknown.     

Biodistribution of liposome-associated bupivacaine after extradural administration to rabbits

After one extradural injection of 0.25% bupivacaine 0.3 ml and 3H- bupivacaine 0.005 mCi in multilamellar liposomes, no systemic radioactivity (plasma, liver, heart muscle) was obtained for 1 h, and the labelling was less than that of systemic distribution of plain bupivacaine for the following 3 h. In contrast, radioactivity in the lumbar spinal nerves peaked in the first hour and remained higher than that of plain bupivacaine for 4 h. No radioactivity was measured in cerebrospinal fluid. Small unilamellar vesicles incorporating 3H- cholesterol did not significantly label spinal nerves and central nervous structures indicating that the mode of action of liposomal bupivacaine did not involve uptake by nerve structures. Rapid uptake of radioactivity by spinal nerves suggested exchange of bupivacaine between liposomes and nerve sheaths.      

Excessively high plasma bupivacaine concentrations after tonsillar bed and adenoidal injection of 0.25% bupivacaine

The injection of local anaesthetics into the tonsillar bed has gained acceptance in the United States as a method for providing postoperative pain relief. A clinical trial was devised in which the tonsillar bed was injected at the upper and lower poles subsequent to the removal of each tonsil. In addition, a small amount of local anaesthetic was sprayed topically by the nares onto the adenoidal beds subsequent to adenoidectomy to alleviate pain from this area. Bupivacaine was used as the local anaesthetic because of its long duration of action. Despite extreme care in the performance of this study, one patient developed ventricular tachycardia subsequent to the injection of bupivacaine. Plasma bupivacaine levels were obtained after tonsillar bed infiltration and nasal instillation post tonsillectomy and adenoidectomy in each of the patients, and though most levels were below toxic ranges, one patient had high serum levels. This high serum level coincided with the development of ventricular tachycardia. On the basis of this finding, we have abandoned this technique for postoperative pain management after tonsillectomy.     

Anesthetic quality during cesarean section following subarachnoid or epidural administration of bupivacaine with or without fentanyl

Background: It is often assumed that subarachnoid administration of local anesthetics produces a more profound blockade than epidural anesthesia. Furthermore, the addition of fentanyl has been reported to increase preferentially intraoperative analgesia. In the present study we set out to study these two issues in a randomized and controlled study with respect to perceived pain and discomfort during surgery and postoperative pain. Methods: In the present study, 100 parturients subjected to elective cesarean section, 34 nullipara and 66 multipara, received one out of four combinations of the local anesthetic bupivacaine and the opioid fentanyl; group A - bupivacaine 12.5 mg+10 μg fentanyl subarachnoidally, group B - bupivacaine 12.5 mg+saline subarachnoidally, group C - bupivacaine 100 mg+100 μg fentanyl epidurally, group D - bupivacaine 100 mg+saline epidurally; N=25 in each group. Pain intensity and discomfort during surgery was assessed with a visual analogue scale (VAS). Postoperative pain intensity and need for analgesics postoperatively, ketobemidone, was registered for 24 h following surgery. Results: Intraoperative pain intensity and discomfort did not differ significantly between parturients in any of the four groups. Postoperative pain was significantly more intense in parturients receiving local anesthetics subarachnoidally as compared to the epidural groups during the first 6-h period. This difference was also reflected in a significantly increased consumption of analgesics during this period. No significant differences between the groups were observed with regard to hemo-dynamics (blood pressure), respiration (oxygen saturation) or other effects such as nausea or itching. All neonates had normal Apgar and neonatal adaptive capacity scores (NACS). Conclusion: We conclude that subarachnoidal (12.5 mg) and epidural (100 mg) injections with bupivacaine both produced adequate anesthetic quality in women undergoing elective cesarean section. The addition of fentanyl (10 μg subarachnoidally or 100 μg epidurally) did not significantly improve the quality of these already profound blockades.     

Smaller children have greater bupivacaine plasma concentrations after ilioinguinal block

We have measured plasma concentrations of bupivacaine after ilioinguinal block in children of different sizes. We studied 14 children with weights 10-15 kg and 17 children with weights 15-30 kg. Each child received 0.5% bupivacaine 0.25 ml kg-1 (1.25 mg kg-1) (Carbostesin, Astra, Germany). Venous blood was obtained before the block (control) and at 5, 10, 15, 20, 30 and 60 min after block. Mean maximal concentration in the 10-15-kg group (1.5 (SD 0.9) mg litre-1, range 0.43-4.0 mg litre-1, at 18 (5) min) was significantly higher (P < 0.05) than that in the 15-30-kg group (0.9 (0.3) mg litre-1 range 0.35- 1.34 mg litre-1, at 16 (5) min). In the 10-15-kg group, unexpectedly high (up to 4 mg litre-1) bupivacaine concentrations were observed and often concentrations remained high (> 2 mg litre-1) at 60 min. We conclude that smaller children appear to differ in the pharmacokinetic handling of bupivacaine. The maximum safe plasma concentration of bupivacaine in small children, although not clearly established, is likely to be approximately 4 mg litre-1. We recommend, therefore, that a dose of bupivacaine 1.25 mg kg-1 should not be exceeded in the perioperative period when performing ilioinguinal block in children < 15 kg in weight.