Anesth Analg 2003;97:1251-1253
© 2003 International Anesthesia Research Society
CARDIOVASCULAR ANESTHESIA
Intrathecal Clonidine and Severe Hypotension After Cardiopulmonary Bypass
Ferenc Puskas, MD PhD,
Enrico M. Camporesi, MD,
Colleen E. O’Leary, MD,
Michael Hauser, MD, and
Fadi V. Nasrallah, MD
From the Department of Anesthesiology, SUNY Upstate Medical University, Syracuse, New York
Address correspondence and reprint requests to Ferenc Puskas, MD, PhD, Department of Anesthesiology, SUNY Upstate Medical University, 750 E. Adams Street, Room 2146, Syracuse, New York. Address email to fpuskas{at}twcny.rr.com
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Abstract
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The use of intrathecal clonidine as an adjunct for the management of chronic pain, intra- and postoperative analgesia is gaining an increase in popularity. However, antinociceptive doses of intrathecal clonidine may produce pronounced hemodynamic side effects, including hypotension and bradycardia. In this report, we present a case of severe hypotension after cardiopulmonary bypass in a patient with intrathecal clonidine infusion. We postulate that the intrathecally administered alpha 2-agonist clonidine reduced our patient’s ability to tolerate the hemodynamic lability that is present during the separation from cardiopulmonary bypass by potentially inhibiting sympathetic nervous system activity, renin-angiotensin system, or vasopressin release.
The authors report a case of severe hypotension after cardiopulmonary bypass in a patient receiving intrathecal clonidine infusion for chronic neuropathic pain.
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Introduction
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Clonidine is an  2-adrenergic agonist that has long been used as an adjunct for neuropathic pain and for reducing symptoms in sedative, drug, or alcohol withdrawal. Alpha 2-agonists also produce diverse responses including analgesia, anxiolysis, sedation, and sympatholysis, each of which occurs in the treatment of surgical and chronic pain patients (1–6). Intrathecal clonidine can also diminish sympathetic nervous system activity and decrease renin-angiotensin levels and vasopressin release, thereby reducing the tolerance to hemodynamic changes (7). We present a case of severe hypotension after cardiopulmonary bypass in a patient with an intrathecal clonidine infusion pump used for neuropathic pain control.
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Case Reports
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A 60-yr-old, 172.5 cm, 95-kg man presented with a 4-day history of atypical chest pain. A dobutamine stress test showed lateral wall hypokinesis with a drop in ST segments in the inferior and lateral leads, suggesting inferolateral ischemia. Myocardial infarction was excluded, although creatine kinase did increase without a creatine kinase-MB or troponin increase. The electrocardiogram (ECG) showed normal sinus rhythm with no ischemic changes. Subsequent cardiac catheterization revealed extensive 3-vessel coronary artery disease with mild left ventricular dysfunction (ejection fraction 50%). He was admitted to our hospital for coronary artery revascularization. His medical history was significant for hypertension, anxiety, gastroesophageal reflux, hypercholesterolemia, right upper lobectomy for carcinoid tumor 4 yr previously (currently tumor free), and chronic left leg pain secondary to peripheral vascular angiopathy. In December 1998 he had an intrathecal infusion pump placed for chronic left leg pain with the catheter tip at the T12 level. The pump was replaced in March 2002. On admission he was receiving 370 µg clonidine and 3.7 mg bupivacaine each day as a continuous infusion via the intrathecal infusion system. Admission laboratory values were normal except for slightly increased transaminases (alanine aminotransferase, 75 U/L; aspartate aminotransferase, 57 U/L). Pulmonary function tests revealed a forced expiratory volume in one second of 2.62 L/s (80% of predicted), forced vital capacity of 3.78 (93% of predicted), and a mid segment forced expiratory flow (FEF25–75) of 1.97 L/s (59% of predicted). Other preoperative medications were diltiazem 250 mg per os qd, buspirone 15 mg per os bid, hydrochlorothiazide 12.5 mg per os qd, omeprazole 20 mg per os qd, atorvastatin 10 mg per os qd, tramadol 50 mg per os q4h PRN, salicylate 750 mg q12h bid PRN, gabapentin 600 mg per os tid, celecoxib 200 mg per os bid, nortriptyline 100 mg per os qhs, and oxycodone 5–10 mg q4h prn. After coronary angiography, a nitroglycerine infusion at 1.13 µg · kg-1 · min-1 was begun.
In the surgical holding area immediately before transport to the operating room, the intrathecal clonidine infusion pump was discontinued; a right femoral arterial catheter and a right internal jugular central venous catheter were placed. An oximetric pulmonary artery catheter was placed at 42 cm. General anesthesia was induced with midazolam 5 mg IV and fentanyl 500 µg IV, and muscle relaxation was attained with pancuronium 10 mg IV. Nitroglycerin infusion was decreased to 0.2 µg · kg-1 · min-1. Because of relatively low prebypass systemic vascular resistance index (SVRI) (Table 1) a total of 2600 mL of crystalloid, 500 mL of 5% albumin, and 639 µg/h of phenylephrine IV in divided boluses were administered before institution of cardiopulmonary bypass (CPB) to maintain a mean arterial blood pressure (MAP) of approximately 70 mm Hg (baseline MAP, 90 mm Hg ± 20%) over 3 h and 36 min. Coronary artery bypass grafting of 5 vessels was performed using the right radial artery, bilateral internal mammary arteries and saphenous vein grafts. CPB lasted 4 h and 21 min, with 4 h 6 min aortic cross-clamp time. As a result of the long bypass time and the low pre-CPB SVRI, a need for aggressive vasoactive therapy was anticipated. Nitroglycerin 0.2 µg · kg-1 · min-1, phenylephrine 2 µg · kg-1 · min-1, epinephrine 0.04 µg · kg-1 · min-1, and dopamine 5 µg · kg-1 · min-1 were initiated to support the circulation during separation from CPB. The hemoglobin at CPB separation was 10.4 g/dL. At approximately 15 min post-CPB arterial blood pressure (ABP) decreased to 80/40 mm Hg requiring the titration of phenylephrine infusion up to 2 µg · kg-1 · min-1 (Table 1). Nitroglycerin was discontinued. Despite these measures the SVRI remained low (1208 dyne · s-1 · cm-5/m2). The heart rate suddenly decreased to 40 bpm, and an ECG tracing showed 3rd degree atrio-ventricular block. The surgeon placed pacing wires, and ventricular pacing was initiated at 110 bpm. ABP continued to be labile. Calcium chloride was administered without sustained effect. A norepinephrine infusion at 0.06 µg · kg-1 · min-1 was added to increase SVRI. Subsequently SVRI increased to 1750.7 ± 25.3 dyne · s-1 · cm-5/m2 and the ABP stabilized. Phenylephrine infusion was weaned off. At the end of the surgery the pacemaker was turned off because of the recovery of sinus rhythm. The patient was transported to the cardiac intensive care unit in stable condition. During the operation (over 9 h 53 min) 2600 µg of fentanyl (27.4 µg/kg) and 15 mg of midazolam were used. Two hours postoperatively, the patient was taken back to the operating room, where mediastinal bleeding was controlled. He was transfused with 3 U of packed red blood cells and remained on epinephrine 0.04 µg · kg-1 · min-1, norepinephrine 0.06 µg · kg-1 · min-1, nitroglycerine 0.2 µg · kg-1 · min-1, and dopamine 2 µg · kg-1 · min-1. On postoperative day 2 he was hemodynamically stable, with an SVRI of approximately 2500 dyne · s-1 · cm-5/m2, and the cardiac surgeon and pain specialist elected to restart the intrathecal clonidine/bupivacaine infusion system. Two hours after the pump was restarted his ABP suddenly decreased to 60/40 mm Hg; SVRI decreased from 2420 to around 1830 dyne · s-1 · cm-5/m2. Norepinephrine was increased temporarily to 0.09 µg · kg-1 · min-1, and fluid boluses were given with recovery and stabilization of ABP. On postoperative day 3 vasopressors and inotropes were weaned off maintaining an SVRI of 1942 ± 175 dyne · s-1 · cm-5/m2. On the next day the trachea was extubated and the patient was transferred to the stepdown floor. The patient’s postoperative course was complicated by persistent pleural effusion and he was discharged on postoperative day 17.
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Discussion
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This case highlights that intrathecal clonidine may diminish the ability to maintain blood pressure during periods of hemodynamic lability. In our case this detrimental interaction became apparent after separation from CPB. The observed hypotension, characterized by low SVRI, responded to therapy with volume expansion and additional vasoconstrictors.
Clonidine is a selective 2-agonist, a lipophilic drug with rapid onset and short duration of action, produces analgesia in humans and animals without clinical neurotoxicity (5,6). A plethora of studies have shown that 2-agonists either alone or in combination with local anesthetics or opiate narcotics are highly effective in the treatment of intraoperative, labor, postoperative, and chronic pain (1–4). Clonidine is more potent with neuraxial than systemic administration, suggesting a spinal site of action. Continuous infusion of intrathecal drugs by fully implanted pumps is becoming widely recognized as an effective treatment for patients with chronic nonmalignant pain resistant to oral or parenteral analgesics. Though intrathecal clonidine has been used in dose ranges from 25 to 900 µg/day, usually doses <500 µg/day are recommended for nonmalignant pain (3,4). Elimination half-life often correlates with duration of pharmacologic effect. Clonidine elimination from cerebrospinal fluid is 1.1–1.3 hours; from plasma it is 11.8–18.9 hours. Addition of bupivacaine improves analgesia; side effects are not observed with doses <15 mg/day.
Separation from CPB can be marked by hemodynamic instability, as sudden changes can occur in preload, contractility, and afterload. The potential causes of hypotension after CPB are varied and include hypovolemia, ventricular failure/dysfunction, air emboli in the venous graft, kinked or clotted grafts, excessive cardioplegia, focal/global areas of myocardial ischemia or infarction, bradycardia/arrhythmias, hypothermia, hypocalcemia, inadequate ventilation, and changes in SVRI (8). In our patient, after excluding other possible causes, low SVRI appeared to be responsible for the encountered hypotensive episode after the discontinuation of CPB.
Hemodynamic instability activates a complex array of interacting neural and hormonal reflexes, typified by two distinct phases (9). MAP is maintained in the first phase by a progressive increase in systemic vascular resistance and heart rate, primarily resulting from activation of the sympathetic nervous system and the renin-angiotensin system. Clonidine can diminish sympathetic nervous system activity at three sites: by inhibition of firing of the locus ceruleus, the pivotal noradrenergic relay nucleus in the brainstem (5); by direct inhibition of spinal preganglionic sympathetic neurons (10); and by the peripheral inhibition of norepinephrine release at the neuroeffector junction (11). The second reflexive phase is accompanied by a withdrawal of sympathetic tone and the importance of renin, angiotensin, and vasopressin in protecting against further reductions in MAP (9). Clonidine decreases vasopressin release, plasma renin activity, and angiotensin levels (12,13). Most likely the action of clonidine on these hormones occurs from systemic absorption and central redistribution.
In this case, we postulate that the intrathecally administered 2-agonist clonidine reduced the patient’s ability to tolerate the hemodynamic lability that is present during the separation of CPB by inhibiting the sympathetic nervous system activity, the renin-angiotensin system, and vasopressin release. Similarly, restarting the clonidine infusion pump on postoperative day 2 resulted in the decrease of systemic vascular tone, manifested by transient hypotension and decreased SVRI, which required volume and increased vasopressor infusions.
In conclusion, this case demonstrates a potential risk of intraoperative hypotension in patients with intrathecal clonidine infusion undergoing CPB. In elective cases, when hemodynamic instability can be expected, if other pain control modalities are feasible, we recommend that the clonidine infusions be discontinued 5 days before surgery (6 times elimination half-life). In urgent/emergent cases, the infusion pump should be turned off before the procedure, with the anticipation of hypotension, requiring the use of vasopressors to maintain blood pressure. Although in our case vasopressin was not used, the impact of clonidine on vasopressin release suggests its use in refractory cases should also be considered.
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Acknowledgments
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The authors wish to thank Michele Hayes for her excellent assistance in the preparation of the manuscript.
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References
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Accepted for publication June 11, 2003.
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Abstract
Introduction
