Ephedrine shows synergistic motor blockade when combined with bupivacaine or lidocaine for spinal anesthesia in a rat model.

BACKGROUND: Ephedrine is a direct/indirect vasoactive drug. In addition, it also possesses intrinsic local anesthetic properties, mainly due to its sodium-channel blockage. We investigated whether ephedrine demonstrates a synergistic effect with bupivacaine and lidocaine when injected via a spinal catheter into the spinal space of rats. METHODS: Spinal catheters were surgically placed in 47 rats (n = 8 per group; 7 rats were excluded.) Bupivacaine, lidocaine, and ephedrine in various concentrations and constant volumes (60 µL) were injected into the spinal catheters to determine the equipotency of each drug. Ephedrine in combination with either bupivacaine or lidocaine was then injected into the spinal catheters. RESULTS: Ephedrine demonstrated statistically significant synergistic effects with bupivacaine as well as with lidocaine in fixed combinations. The combination index reflecting a synergistic effect was 0.792 (95% confidence interval: 0.665-0.919) for ephedrine + bupivacaine and 0.663 (95% confidence interval: 0.532-0.794) for ephedrine + lidocaine. CONCLUSION: Ephedrine combined with either bupivacaine or lidocaine acted synergistically to block motor function and has the potential to reduce the amount of local anesthetic needed for spinal block. The synergistic effect of ephedrine in combination with local anesthetics is an interesting pharmacological phenomenon that warrants further clinical evaluation.

An absorbable local anesthetic matrix provides several days of functional sciatic nerve blockade.

BACKGROUND: Functional blockade of peripheral nerves is the primary objective of local anesthesia, and it is often desirable to have a persistent blockade, sustained throughout and beyond a surgical procedure. Current local anesthetics give effective analgesia for <8-12 h after a single bolus injection. We report on an implantable, controlled-release drug delivery system intended for use in bone and consisting of a Food and Drug Administration-approved matrix containing lidocaine that is capable of local delivery for several days. METHODS: Xybrex, an absorbable, controlled-release delivery system containing 16% (w/w) lidocaine, was implanted next to the sciatic nerve of male rats (300-350 gm), at lidocaine doses of 5.3, 10.6, 16, and 32 mg lidocaine per rat. For comparison, a lidocaine HCl solution (0.2 mL, 2% = 4 mg) was injected in close proximity to the sciatic nerve. Rats were assessed behaviorally for analgesia by a forceps pinch of the lateral digits, and for motor block by quantifying the extensor postural thrust. Potential neurotoxicity of sciatic nerves was evaluated histologically at 24 h, 4 days, and 4 wk after implantation. The kinetics of lidocaine's release from the matrix was measured in vitro by ultraviolet detection of lidocaine in samples collected at 2.5, 6.5, 20, and 24.25 h. RESULTS: Xybrex at the highest doses (300 and 600 mg/kg, containing 16 and 32 mg of lidocaine free base, respectively) provided complete analgesia to an intense pinch for 7.0 +/- 2.0 h, 6.9 +/- 1.7 h and partial analgesia for 60.0 +/- 5.4 h, 58.8 +/- 4.2 h, respectively, compared to 0.61 +/- 0.03 h of complete analgesia and 0.96 +/- 0.03 h of partial analgesia by sciatic block from the 2% lidocaine solution (containing 4 mg lidocaine). These same high doses of Xybrex produced complete motor block for 17.0 +/- 3.3 h, 17.6 +/- 3.3 h with full recovery in 352.0 +/- 55.7 h (14.7 +/- 2.3 days), 579.0 +/- 36.1 h (24.1 +/- 1.5 days) respectively. Data are reported as mean +/- SE. P < 0.001 for all Xybrex groups compared to the 2% lidocaine group. Minor local tissue inflammation/pathology, primarily in the connective tissue and muscle 0.1 mm adjacent to the nerve, was observed equally in animals treated with Xybrex and 2% lidocaine solution. There were no behavioral signs of systemic toxicity. The in vitro release followed exponential kinetics and its comparison to the time-course of functional nociceptive deficit implied that the duration of nociception represented the local, immediate interaction of lidocaine between the nerve and the matrix and not a cumulative effect of previously released drug. CONCLUSIONS: Xybrex is an absorbable, controlled-release drug delivery system that provides several days of analgesia for rat peripheral nerves without apparent significant local neurotoxicity or systemic toxicity.

Report of a patient with severe transfusion-related acute lung injury after multiple transfusions, resuscitated with albumin.

OBJECTIVE: To report a patient with a large gastrointestinal stromal tumor (GIST) who received multiple blood transfusions intraoperatively and developed a transfusion-related acute lung injury (TRALI). DESIGN: Case report. SETTING: Intensive care unit of a tertiary care hospital. PATIENT AND HISTORY: A 58-year-old man with GIST metastatic to the right lobe of the liver, treated with tyrosine kinase inhibitors, underwent a right hepatectomy requiring multiple transfusions. Prior to abdominal closure, he developed copious pulmonary secretions, hypoxemia, and hypotension. Chest radiograph revealed diffuse bilateral infiltrates. INTERVENTION: Volume resuscitation, vasopressors, high PEEP mechanical ventilation, paralysis, nitric oxide, steroids, rapid albumin infusion. MEASUREMENTS AND MAIN RESULTS: Extensive noncardiogenic pulmonary edema. After unsuccessful fluid resuscitation with crystalloid fluid, the patient's condition improved rapidly with human albumin boluses. No neurological deficit was detected despite prolonged hypoxemia. Acute renal failure required dialysis but with subsequent recovery. Patient was discharged home on postoperative day 19. CONCLUSION: Rapid infusion of albumin might be a rescue option in cases of severe TRALI with extensive pulmonary capillary leak during the acute phase.

Differential block of N-propyl derivatives of amitriptyline and doxepin for sciatic nerve block in rats.

BACKGROUND AND OBJECTIVES: The propyl group of ropivacaine ( N -propyl-2',6'-pipecoloxylidide hydrochloride) could be responsible for conferring some sensory selectivity to this drug. Thus, adding a propyl group to experimental local anesthetics (LAs) (e.g., the tricyclic antidepressants amitriptyline and doxepin) to increase sensory selectivity may be useful. We, therefore, synthesized N -propyl amitriptyline and N -propyl doxepin and investigated a potential predominance of sensory/nociceptive block over motor block (differential block) in a rat sciatic nerve block model. In addition, tetrodotoxin (TTX), a naturally occuring Na + channel blocker, was coinjected to investigate whether it increased block duration. METHODS: A 0.2-mL test dose of N -propyl amitriptyline and N -propyl doxepin, at a concentration of 1, 2.5, 5, and 10 mM, (alone or in combination with TTX at a concentration of 20 microM) was injected by the subfascial sciatic nerve approach. Motor function and sensory function (nociception) were evaluated by the force a rat's hind limb produced when pushing against a balance and the reaction to pinch, respectively. RESULTS: N -propyl amitriptyline and N -propyl doxepin demonstrated prolonged block duration, with N -propyl amitriptyline displaying significant differential block at higher concentrations (5 and 10 mM). The combination of either of these drugs with TTX increased the potency as well as the efficacy. Neurotoxicity commenced at concentrations of 5 to 10 mM. CONCLUSIONS: Detailed histopathologic nerve toxicity evaluations are justified to determine whether N -propyl amitriptyline has potential as a more sensory-selective local anesthetic at lower concentrations or as a predominantly sensory-selective neurolytic agent at higher concentrations.