Clonidine hydrochloride is used for treating hypertension and narcotic withdrawal. In its injectable form, clonidine is used to treat cancer pain and to prolong regional anesthesia and analgesia [1]. We describe a patient who manifested a prolonged state of unconsciousness after the intravascular injection of a local anesthetic mixed with clonidine that was apparently reversed by the administration of naloxone. Case Report A 52-yr-old woman, ASA physical status II, weight 65 kg, presented for distal radius osteotomy with placement of an iliac crest bone graft for malunion of an old right radius fracture. Significant medical history included a closed head injury in 1978, tobacco abuse, and a "nervous stomach" without reflux. The patient was alert and oriented but emotionally labile. Medications included dicyclomine and conjugated estrogens. The patient agreed to an axillary regional block for perioperative pain control and a general anesthetic with a laryngeal mask airway. Usual monitoring was used. Midazolam 2 mg was given IV for anxiolysis; no narcotic was administered. Room air oxygen saturation (SpO2) was 91%, which improved to 94% with the addition of 2 L of oxygen via a nasal cannula. Arterial blood pressure was 108/65 mm Hg, and heart rate was 72 bpm. A transarterial axillary block was performed using a 25-gauge, 5/8-in. A-bevel needle. After careful aspiration, 20 mL of 1% ropivacaine with 70 [micro sign]g of clonidine, followed by 15 mL of 1% mepivacaine with 1:400,000 epinephrine, was injected with aspiration after every 3-5 mL injected. Generalized tonic clonic seizure activity developed. The injection was immediately abandoned, and the patient was oxygenated via a bag-mask apparatus. Midazolam 2 mg and thiopental 50 mg were administered, and the seizure immediately terminated. After the seizure, arterial blood pressure was 71/48 mm Hg, heart rate was 88 bpm, and SpO2 was 90%. The patient was comatose and apneic, and positive pressure ventilation was initiated. Oxygen saturation rapidly improved to 100%. Because a mask airway was easily maintained, the trachea was not intubated and muscle relaxants were not administered. However, arterial blood pressure decreased to 53/40 mm Hg; ephedrine 10 mg was given IV. Arterial blood pressure increased to 90/60 mm Hg with a heart rate of 88 bpm within 1 min of ephedrine administration. Over the next 10 min, the patient received two additional doses of ephedrine 10 mg to maintain systolic blood pressure >90 mm Hg. The patient had been comatose and apneic for 32 min before she initiated spontaneous respiration at a rate of 12 breaths/min. Oxyhemoglobin saturation remained at 94%-100% throughout this period; blood glucose level was 110 mg/dL. Ninety minutes after the injection, the patient remained comatose with corneal reflexes intact, midsize pupils with conjugate eye movement, a weak gag reflex, and no Babinski reflex. Naloxone 80 [micro sign]g was given IV, and within 1 min, the patient regained consciousness and complained of being hungry. Hemodynamics remained stable with baseline mental/neurologic status. The patient had no apparent sensory or motor block in her arm. She was discharged from the facility with her family. Her subsequent recovery was uneventful, and she had no recollection of the event. Discussion Toxicity from an intravascular injection of a local anesthetic classically presents with symptoms of central nervous system (CNS) excitation leading to seizure activity. At higher local anesthetic levels, symptoms escalate into CNS depression with coma and respiratory arrest. Despite incremental dosing and aspiration, our patient clearly exhibited symptoms of toxic plasma levels of local anesthetic. Her time course and resuscitation were similar to those described in a previous report of an intravascular injection of ropivacaine [2], in which the patient recovered from the postictal state much faster than our patient after a similar dose of IV ropivacaine. There are several other factors that may have confounded our patient's recovery from the toxic local anesthetic levels, including the addition of clonidine to the local anesthetic solution, the patient's use of dicyclomine, and the previous head injury she had suffered. However, reversal of unconsciousness from these factors would not be expected with naloxone administration. Dicyclomine is a centrally acting muscarinic agonist used to treat irritable bowel syndrome. Adults, particularly elderly patients, taking dicyclomine may experience drowsiness, fatigue, or CNS excitement. Our patient was inconsistent in her use of this drug and could not recall her use during the event described. She had been taking the drug for many years without any associated side effects. The use of dicyclomine in infants has been linked to sudden infant death syndrome [3]. It is possible that the use of this centrally acting drug contributed to the prolonged unconsciousness that this patient experienced. Clonidine is a useful adjuvant for regional anesthesia. It prolongs anesthesia and analgesia from 50% to 100% when added to mepivacaine for brachial plexus blockade in a dose of 30-100 [micro sign]g [4]. Although the dose of clonidine our patient received has not been reported to cause unconsciousness, sedation has occurred with a 30-[micro sign]g dose after brachial plexus block [5]. IV clonidine is routinely used in Europe in doses of 1.5 [micro sign]g/kg to prevent postoperative shivering without delaying emergence from anesthesia [6]. Clonidine overdose usually leads to hypotension and bradycardia. Although our patient did not have bradycardia, her response to an intravascular injection of an epinephrine-containing solution and to ephedrine administration was blunted, her heart rate never increasing to >90 bpm. Other manifestations of clonidine toxicity include apnea, drowsiness, miosis, hypothermia, coma, and seizure [7]. Naloxone has been used with variable results to treat oral clonidine overdose in children [7-9]. When it has been successful in reversing clonidine overdose, unconsciousness has been reversed dramatically, as in our patient [8,9]. Naloxone reverses the antihypertensive effect of clonidine in subsets of hypertensive patients [10], and in these "hyperadrenergic" patients, clonidine is thought to promote the release of endogenous opioids that inhibit sympathetic tone. If the intravascular clonidine our patient received promoted the release of endogenous opioids, it may explain the acute reversal of unconsciousness by naloxone that we observed. Increased circulating levels of endogenous opioids may have been the result of the local anestheticinduced seizure itself, not the clonidine in the local anesthetic solution. In rats, electroconvulsive shock produces naloxone-sensitive postictal depression [11]. However, naloxone reversal of postictal depression has not been reported in humans after electroconvulsive therapy or idiopathic seizures. Complications associated with an intravascular injection of a clonidine-containing local anesthetic solution have not been reported. The prolonged period of unconsciousness exhibited by our patient may have been related to the large amount of local anesthetic that she received and may have been confounded by her previous closed head injury [12,13]. However, the dramatic reversal of unconsciousness after naloxone administration may implicate clonidine as the drug responsible for the maintenance of her unconscious state. In sorting out toxic reactions after local anesthetic administration, one should consider not only the total dose of local anesthetic used, but also the adjuvants.