Potentiation of Narcosis After Intravenous Lidocaine in a Patient Given Spinal Opioids

Intrathecal opioids are in clinical use in multiple sites of anesthetic delivery for cardiothoracic surgery. The interactions between the opioids and other drugs, such as local anesthetics, have received much attention when both of these drugs are administered, either into the epidural or the intrathecal space (1). With the possible exception of the α2-adrenergic agonists, little attention has been paid to the systemic administration of adjuvant drugs combined with intraspinal opioids. We present a case of apparent synergistic interaction of intrathecal fentanyl and morphine with systemically administered lidocaine, resulting in potentiation of opioid effects. Case Report A 74-yr-old, 75-kg man was scheduled for elective coronary artery bypass grafting. His medical history was significant for hypertension, type 2 diabetes mellitus, and chronic obstructive pulmonary disease. His coronary artery disease was complicated with two myocardial infarctions. He experienced two episodes of ventricular dysrhythmia, and he is a candidate for automated implantable cardiac defibrillator placement. Medications included amiodarone, furosemide, vancomycin, amlodipine, enteric-coated aspirin, fosinopril, beclomethasone, ipratroprium, lansoprazole, attapulgite (Kaopectate), and lorazepam. Angiography indicated a 50% lesion in the left main coronary and 100% occlusion in the first diagonal and left anterior descending. Left ventricular ejection fraction was 33% by radioisotope studies. Thallium scintigraphy demonstrated a reversible defect in the anterior wall, with a fixed loss inferiorly. Anesthetic induction consisted of intrathecal fentanyl 100 μg and morphine 0.5 mg, followed by IV etomidate 40 mg, midazolam 2 mg, fentanyl 150 μg, and succinylcholine 140 mg. This induction sequence marked the last opioid given. Maintenance of anesthesia was obtained with appropriately titrated sevoflurane/propofol and cisatracurium. At the conclusion, muscle relaxation was reversed. Adequate spontaneous ventilation maintaining tidal volume >5 mL/kg at a respiratory rate >12 breaths/min, with an SpO2 of 98%, resumed 15 min before tracheal extubation, which took place in the operating room at the conclusion of surgery. The patient was alert and stable, and he was transferred to the surgical intensive care unit (SICU), breathing spontaneously with a face mask in place, maintaining an SpO2 of 99%. Four hours after the last opioid was given, the patient experienced an episode of ventricular tachycardia in the SICU, and he was given lidocaine 200 mg IV bolus, followed by a continuous infusion at the rate of 2 mg/min. During the next 5 min, ventilatory rate progressively slowed, requiring reintubation of the trachea. The pupils were miotic bilaterally, and consciousness was lost. Naloxone 0.2 mg was administered by the SICU nursing staff during this time, resulting in complete return of spontaneous ventilation and mental alertness within 1–2 min. However, the patient was allowed to renarcotize and recover spontaneously because the commencement of a naloxone drip could compromise his pain management and unstable cardiac status. The trachea was reextubated 3 h after this event and remained so until his discharge from an otherwise uneventful SICU stay. Discussion Antinociceptive synergy between the coadministration of opioids and local anesthetics into either the intrathecal or epidural spaces has been well established (2). Research in the last decade, however, suggests that this synergistic phenomenon is not simply a combination of the well accepted receptor-mediated actions of these respective drugs (1,3,4). Local anesthetics exert numerous effects in the central nervous system (CNS). Ca2+ currents and absolute intracellular levels are reduced (5), substance P binding is limited (4), and cAMP levels are reduced, in addition to the accepted reduction in sodium conductance and impulse propagation (3). The precise mechanisms involved in the antinociceptive synergy between these two classes of drugs are just beginning to be elucidated, and it seems that these alternative actions of the local anesthetics play an important role. Tsai et al. (6) defined the kinetics and absolute levels of lidocaine in the cerebrospinal fluid (CSF) after IV bolus administration. Their data show a steady increase for 15 minutes and a plateau that persisted for >60 minutes in CSF lidocaine levels after single IV bolus administration. Isobolographic analysis of intrathecal morphine with intrathecal lidocaine was performed, and it defines CSF levels of lidocaine required to produce synergistic antinociceptive effects in rats (7). These studies required lidocaine levels approximately 10-fold greater than those achieved by a 2 mg/kg IV bolus, which this patient received (6). However, the absolute levels of drug required supraspinally to elicit side effect synergy is unknown. Research addressing the synergistic interactions with respect to side effects of local anesthetics and opioids in the CNS is sparse. The opioids, particularly the μ-specific drugs, reduce intracellular Ca2+ in a dose/potency dependent fashion. This mechanism is seen in both spinal and supraspinal sites, and it is considered to be the sine qua non of the opioid effect. Antagonism of Ca2+ influx with diltiazem enhances morphine effects on multiple pain states, whereas intracerebroventricular Ca2+ administration antagonizes opioid analgesia (5). Lidocaine depresses voltage-gated and nociceptive-tachykinin-mediated Ca2+ flow in a dose-dependent manner (4). Lidocaine and the opioids are CNS depressants that could have acted in a generalized, additive fashion to obtund this patient and produce respiratory failure. However, the presence of new onset, profound miosis-marked respiratory depression, and complete reversal with an opioid antagonist suggest a more specific interaction between the lidocaine and the opioids. A simple additive effect causing such a degree of depression is unlikely, considering the small doses of opioids given and the time between the last administration and the events described. Displacement of residual opioid from protein bound sites is an unlikely mechanism, considering the relatively small doses of opioid given and the low CSF concentrations of local anesthetic achieved in CSF after IV bolus. We propose a plausible, mechanistically supported explanation for supraspinal side effect synergy between a systemically administered local anesthetic and spinal opioids focusing on reduced Ca2+ levels in opioid sensitive CNS sites.