Abstract ID: A03

Abstract Title: Ephedrine Versus Bupivacaine in Rat Sciatic Nerve Blockade

Poster Type: Discussion


ABSTRACT BODY

Introduction: Ephedrine is an adrenergic agonist used to raise blood pressure and heart rate, particularly for maternal hypotension associated with spinal anesthesia. It is currently FDA-approved for the treatment of nasal congestion, asthma, and hypotension arising from spinal blockade. In general, ephedrine is thought to be an indirect but also a direct sympathomimetic drug.
A review of literature revealed that, due to its vasoconstrictive properties, ephedrine was co-injected with local anesthetics (LAs) in order to decrease the resorption of LAs and thereby prolong their duration. To our surprise, we found that ephedrine was used extensively as a local anesthetic agent more than half a century ago. Hence, our objective is three-fold: (1) to confirm that ephedrine provides dose-dependent reversible rat sciatic nerve blockade without major histopathology, (2) to test for synergistic action with bupivacaine, and (3) to elucidate ephedrine’s mechanism of nerve blockade by determining its Na+ channel blocking capabilities in cultured neuronal cells expressing Na+ channels.
Methods: The animal protocol was approved by the Harvard Medical Area Standing Committee on Animals. For subfascial sciatic nerve blockade, rats were anesthetized by inhalation of 1-2% Sevoflurane, the sciatic nerves were exposed by lateral incision of the thighs and division of the superficial fascia and muscle. 0.2 mL of various concentrations of bupivacaine or ephedrine was injected directly beneath the clear fascia surrounding the nerve but outside the perineurium (n = 8). The superficial muscle layer was sutured with 4-0 silk, and the wound was closed with metal clips as described before. We evaluated nociception by the withdrawal reflex or vocalization to pinch of a skin fold over the lateral metatarsus (cutaneous pain) and of the distal phalanx of the fifth toe (deep pain). Grading was performed on a scale of 0-3 where 0 indicates no block or baseline 1 (minimal block), 2 (moderate block), and 3 (full block). The whole cell configuration of the patch clamp technique was used to record Na+ currents from HEK cells stably transfected with Nav1.4 Na+ channels. Pathological Evaluation: As a pilot study, 6 rats from the 1% ephedrine group were killed 7 days after receiving the test dose.
Results: Fig. 1 shows the Na+ current inhibition by ephedrine. The 50% inhibitory concentrations (IC50s) of ephedrine at –150 mV and –60 mV are ~1043+/- 70 μM and 473 +/-13 μM, respectively. Time course of nociceptive sciatic nerve blockade by ephedrine and bupivacaine are shown in fig. 2A and 2B. Isobolographic analysis (fig. 2C) indicated synergism between bupivacaine and ephedrine (p<0.05, ED50 calculated by linear regression analysis, difference between the theoretical additive point and the experimentally derived value by t-test). Histologically, rat sciatic nerve treated with 1% ephedrine (n = 8) showed normal nerves except occasional activated Schwann cells. There is no endoneurial edema and the endothelial cells are normal. The epineurium is slightly thickened (Fig. 3). Rats treated with 0.125% Bupivacaine (Control, n = 4, not shown) showed similar peripheral nerve histology.
Discussion: We report that ephedrine (1) provides dose-dependent reversible rat sciatic nerve blockade without major histopathology at 1%, (2) demonstrates synergistic action with bupivacaine, and (3) blocks Na+ channels, thereby resulting in a synergistic interaction.

ATTACHED FILES

A03_Figure 1 ASRA.doc

A03_Figure 2A-C ASRA.doc

A03_Figure 3 ASRA.doc

Reg Anesth Pain Med 2004; 29(2):A03