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Clonidine and sleep apnea syndrome interaction: antagonism with yohimbine
The Journal of Emergency Medicine, Vol. 16, No. 5, pp 727–730, 1998 Copyright © 1998 Elsevier Science Inc. Printed in the USA. All rights reserved 0736-4679/98 $19.00 1 .00
PII S0736-4679(98)00086-9
Selected Topics: Toxicology
CLONIDINE AND SLEEP APNEA SYNDROME INTERACTION: ANTAGONISM WITH YOHIMBINE Raymond J. Roberge,
MD, FAAEM, ACMT,*
E. Ted Kimball, MD,† Joseph Rossi, Jonathan Warren, FCCM, FCCP‡
MD, FCCM, FCCP,‡
and
*Department of Emergency Medicine and the ‡Division of Critical Care Medicine, Western Pennsylvania Hospital and the †Affiliated Residency in Emergency Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Reprint Address: Raymond J. Roberge, MD, Department of Emergency Medicine, Western Pennsylvania Hospital, 4800 Friendship Avenue, Pittsburgh, PA 15224
e Abstract—A patient with sleep apnea syndrome, concurrently taking clonidine as an antihypertensive, presented with severe respiratory acidosis, hypotension, and associated central nervous system depression. Acidosis was improved by mechanical ventilation, and central nervous system (CNS) depression and hypotension were reversed with yohimbine. Clonidine may have an additive CNS depressive effect in sleep apnea syndrome and should be used with caution in such patients. Yohimbine’s sympathetic-enhancing effects may be useful in clonidine toxic states. © 1998 Elsevier Science Inc.
tated with mechanical ventilation and yohimbine, a central, pre-synaptic alpha-2-adrenergic antagonist. The role of yohimbine in the management of clonidine-associated toxicity is discussed. CASE REPORT Visiting family members found a 62-year-old man naked and confused in his bathroom with unidentified medication pills strewn about the floor. The patient had recently been in his baseline medical state but had called his family several hours prior and stated that he felt somewhat weak and tired. His prior medical history was significant for moderate obesity, chronic obstructive pulmonary disease, cor pulmonale, hypertension, and stroke. Current prescribed medications included clonidine, terfenadine, iodine, theophylline, potassium supplements, and doxycycline, but compliance was unknown. Paramedics noted confusion with easy arousability, pinpoint pupils, systolic blood pressure of 100 mmHg by palpation, regular heart rate of 80 beats per minute, depressed respirations, and fingerstick glucose determination of 80 –120 mg/dL. The man received 2 mg of intravenous (i.v.) naloxone, without apparent effect, and one liter of crystalloid while being rapidly transported to our emergency department (ED). On arrival at the ED, he was noted to be extremely somnolent, con-
e Keywords—sleep apnea syndrome; clonidine; interaction; antagonist; yohimbine
INTRODUCTION Sleep Apnea Syndrome (SAS) is a disorder of multiple etiologies characterized by cyclical abnormalities of respiratory function leading to disturbed sleep patterns, daytime hypersomnolence, and personality changes. Secondary complications of SAS include pulmonary hypertension and cardiovascular complications, including dysrhythmias and conduction disturbances, which occasionally can be life threatening (1). We present a case of respiratory acidosis, narcosis, and cardiovascular depression in a patient with SAS taking clonidine as an antihypertensive. The patient was successfully resusci-
RECEIVED: 30 June 1997; FINAL SUBMISSION RECEIVED: 14 November 1997; ACCEPTED: 25 November 1997 727
728
fused, and hypoventilating with an oxygen saturation of 78% despite supplemental oxygen (FIO2 5 1.0) by face mask. The patient could be awakened with vigorous physical stimulation but remained confused and would rapidly become obtunded again. The physical examination was remarkable for his altered mental status, 2 mm sluggishly reactive pupils, and diffuse pulmonary rhonchi and rales. Systolic blood pressure dropped to 86 mmHg despite administration of an additional liter of i.v. crystalloid in the ED, and heart rate initially fluctuated between 70 and 98 beats per min, eventually decreasing to 56 – 66 beats per min. A junctional rhythm and deeply inverted T-waves in lead V1– 4 were noted on the initial cardiogram. Chest radiography showed mild congestive heart failure and bibasilar atelectasis. Complete blood count was: white blood cells 12,300/mm3, hemoglobin 13 g, hematocrit 41.6%, and platelets 123,000 mm3. Serum chemistries were: sodium 140 mEq/L, potassium 4.1 mEq/L, chloride 98 mEq/L, CO2 35 mEq/L, blood urea nitrogen 8.5 mmol/L, creatinine 91 umol/L, and glucose 142 mg/dL (7.8 mmol/L). Serial cardiac isoenzymes were normal, and the arterial blood gas analysis on supplemental oxygen (10 liters/min non-rebreather face mask) was: pH 7.05, pCO2 126 mmHg, pO2 78 mmHg (12 min after ED arrival). The patient received i.v. naloxone (boluses of 2 mg and 10 mg) without apparent response and was then endotracheally intubated and mechanically ventilated 40 min after ED arrival (ventilator settings: FIO2 5 .70, tidal volume 900 cc, assist/control respiratory rate of 14). Hypotension, CNS depression, and cardiographic abnormalities persisted despite improvement in arterial blood gas parameters 45 min post-intubation (pH 7.31, pCO2 47, pO2 91). Based upon clinical findings and history of clonidine use, clonidine toxicity was suspected, and the patient was administered a slurry of yohimbine (5.4 mg) via nasogastric tube. Approximately 15 min later, without other therapy except for maintenance i.v. fluids, the patient’s blood pressure rose to 130/70 mmHg, and the heart rate normalized to a regular sinus rhythm of 80 beats per min, although the T-wave inversions persisted throughout his hospitalization and were subsequently noted on prior admission cardiograms. Within 45 min of yohimbine administration, the patient was completely awake, recognized family members, was able to respond appropriately to questioning, and did not re-sedate. A comprehensive drug screen, utilizing gas chromatography/mass spectroscopy, was subsequently reported as positive for theophylline [1.7 ug/mL (therapeutic 5 10 –20 ug/mL)] and clonidine [0.5 ng/mL (therapeutic 0.2–1.3 ng/mL)]. The patient remained alert with normal vital signs and was admitted to the intensive care unit. An echocardiogram demonstrated biatrial enlargement, mild concentric left ventricular hypertrophy with ejec-
R. J. Roberge et al.
tion fraction of 50%, diffuse hypokinesis of the right ventricle, pulmonary hypertension, and mild tricuspid regurgitation. Multiple attempts at weaning from ventilatory support were frustrated by nighttime CO2 retention (.80 mmHg on multiple occasions) with concomitant 02 desaturations and daytime hypersomnolence. The patient responded well to a graduated introduction of biphasic positive airway pressure (biPAP). He denied any drug overdose or suicidal ideation and was subsequently discharged to a rehabilitation center with a diagnosis of central sleep apnea.
DISCUSSION Sleep Apnea Syndrome can be of obstructive, central, or mixed variety. It is associated with absent or impaired respiratory effort, which can then lead to hypoxia and hypercarbia as well as CNS alterations (e.g., hypersomnolence, coma) and cardiovascular abnormalities (e.g., dysrhythmias, conduction blocks; Reference 2). The expected adrenergic response to acute respiratory acidosis (e.g., tachycardia, increased cardiac output, bounding pulses; References 3,4) was not noted in this patient and may have been blunted by the depressive effects of the acidosis, the sympatholytic effects of clonidine, or both. Clonidine, first developed as a nasal decongestant before its antihypertensive effects were noted, exerts its antihypertensive effects through agonism of CNS pre-synaptic alpha-2-adrenergic receptors, which decrease discharge in sympathetic preganglionic fibers with resultant diminished CNS adrenergic output (5). Recent data demonstrating decreased CNS adrenergic output from the locus coeruleus as one etiologic factor in narcolepsy (a disorder with features similar to SAS) suggest a possible SAS/clonidine additive CNS sympatholysis in our patient (6). Despite near-normalization of post-intubation arterial blood gas parameters, the patient’s mental state and cardiovascular status remained abnormal and could have been related to recognized secondary CNS alterations associated with pulmonary failure and the aforementioned decreased CNS adrenergic output (7). The salutary effect temporally related to administration of yohimbine, a central sympathetic-enhancing agent, suggests decreased sympathetic output as contributory to the clinical picture (8). In view of the therapeutic serum clonidine level noted in our patient, this case may represent an adverse reaction to clonidine in a susceptible individual (i.e., one with SAS) rather than clonidine toxicity per se. The CNS sympatholytic effect and other peripheral effects have resulted in increased use of clonidine in numerous disorders (Table 1; References 9 –16). Clonidine is being increasingly prescribed in the pediatric population be-
Yohimbine Treatment of Sleep Apnea Table 1. Some Clonidine Therapeutic Applications Antihypertensive Withdrawal states (i.e., alcohol, opiates, nicotine) Tics (i.e., Tourette’s syndrome) Attention Deficit Hyperactivity Disorder Hot flashes (drug-induced, hormonally induced) Gastrointestinal hypermotility disorders Glaucoma (miotic agent–not approved in U.S.) Analgesia adjunct
cause of perceived benefits in select disorders [e.g., Tourette’s syndrome (11), Attention Deficit Hyperactivity Disorder (ADHD; Reference 12)]. This augmented use, coupled with expanding indications in adults, some of whom may be somewhat unreliable caretakers (e.g., alcoholics, opiate addicts), may result in increased incidences of accidental childhood clonidine toxicity. Additionally, improper disposal of transdermal clonidine preparations is being recognized as a cause of clonidine poisoning in children (17,18). Children are especially susceptible to even small amounts of clonidine, and deaths have been reported outside the U.S., though poorly documented (19,20). Of rising concern is the recent reporting of several unexplained sudden deaths in children who were taking, or had recently taken, clonidine (usually combined with methylphenidate for ADHD; Reference 21). Again, direct causality has not been demonstrated, but the incidents have, rightly, prompted more-intense surveillance and issuance of advisories (22). Clonidine toxicity often resembles opiate overdose (i.e., miosis, hypothermia, coma, respiratory depression, hypotension, bradycardia; Reference 23). Our suspicion of clonidine overdose in this patient prompted us to administer yohimbine because it has CNS actions directly opposite those of clonidine, namely, CNS presynaptic alpha2-adrenergic antagonism with resultant increase in central sympathetic output and decreased parasympathetic activity (8). Yohimbine is used for treatment of organic impotence, and, of note, one recent study demonstrated usefulness in amelioration of narcoleptic symptoms (24,25). Although clinical effects of yohimbine peak within 1 to 2 h of oral administration, we noted a more-rapid response following administration as a slurry (a parenteral preparation is not generally available), which probably enhanced absorption (26,27). Yohimbine has a short serum half-life (0.4 to 18 min following i.v. administration) and elimination half-life (0.5 to 2.5 h) but may possess a secondary elimination phase of 13 h, which is essentially equivalent to clonidine’s half-life (28). We used a yohimbine dose (one standard 5.4 mg tablet) that was the same dose that had been given empirically to successfully reverse clonidine toxicity associated with bradycardia, hypotension, and coma in a
729
previous report (23). Yohimbine can cause a hyperadrenergic state with anxiety, hypertension, and tachycardia, but overdose with this agent is generally well-tolerated, though delayed atrial fibrillation has been documented in one case (24,29,30). Caution is warranted if administering yohimbine for clonidine overdose when paradoxical hypertension is noted (usually early in overdose; Reference 23). Clonidine and related antihypertensives (e.g., guanfascine, guanabenz) may have additive CNS sympatholytic effects with SAS and could be relatively contraindicated for patients with this disorder. With expanding use of clonidine, reports of adverse and toxic effects may increase. Yohimbine’s CNS actions are antagonistic to clonidine’s and may be of use in counteracting toxic symptoms of clonidine use or abuse. Hopefully, further study will shed additional light on the role of yohimbine in clonidine toxic states.
REFERENCES 1. Weinberg SE. Principles of pulmonary medicine, 2nd ed. Philadelphia: WB Saunders Co.; 1992:218 –21. 2. West JB. Disorders of ventilation. In: Braunwald E, Isselbacher KJ, Petersdorf RG, Wilson JD, Martin JB, Fauci AS, eds. Harrison’s principles of internal medicine, 11th ed. New York: McGraw-Hill; 1987:1129 –32. 3. Swensen ER. Approach to the patient with respiratory acid-base disturbance. In: Kelley WN, DeVita VT, DuPont HL, et al., eds. Textbook of internal medicine. Philadelphia: JB Lippincott Co.; 1989:2073. 4. Effros RM, Widell JL. Acid-base balance. In: Murray JF, Nadel JA, eds. Textbook of respiratory medicine. Philadelphia: WB Saunders Co.; 1994:175– 6. 5. Hoffman BB, Lefkowitz RJ. Cathecholamines, sympathomimetic drugs, and adrenergic receptor antagonists. In: Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Gilman A, eds. Goodman Gilman’s The pharmacological basis of therapeutics, 9th ed. New York: McGraw-Hill; 199 –248. 6. Aldrich MS, Ockert K, Albin RL. Adrenergic receptor autoradiography of human narcoleptic brainstem (abstract). Sleep Research. 1993;22:163. 7. Dulfano MJ, Ishikawa S. Hypercapnia: Mental changes and extrapulmonary complications. An expanded concept of the “CO2 intoxication” syndrome. Ann Intern Med. 1965;63:829 – 41. 8. Goldberg MR, Robertson D. Yohimbine: A pharmacological probe for study of the alpha-2 adrenoreceptor. Pharmacol Rev. 1983; 35:143– 80. 9. Gourlay S, Forbes A, Marriner T, et al. A placebo-controlled study of three clonidine doses for smoking cessation. Clin Pharmacol & Therapeut. 1994;55:64 –9. 10. Lohr RH. Treatment of alcohol withdrawal in hospitalized patients. Mayo Clin Proc. 1995;70:777– 82. 11. Kurlan R. Treatment of tics. Neurol Clin North Am. 1997;15:403– 409. 12. Anonymous. Clonidine for treatment of attention-deficit/hyperactivity disorder. Med Lett. 1996;38:109 –10. 13. Goldberg RM, Loprinzi CL, O’Fallon JR, et al. Transdermal clonidine for ameliorating tamoxifen-induced hot flashes. J Clin Oncol. 1994;12:155– 8. 14. Thollander M, Hellstrom PM, Svensson TH. Suppression of castor oil-induced diarrhea by alpha-2 adrenoreceptor agonists. Ailment Pharmacol Ther. 1991;5:255– 62.
730 15. Sihota R, Agarwal HC, Rajashekar YL. A comparative evaluation of pilocarpine 1% and clonidine 0.125% vs. timolol 0.5%. Ind J Ophthalmol. 1996;44:87–9. 16. Mikawa K, Nishina K, Maekawa N, et al. Oral clonidine premedication reduces postoperative pain in children. Anesth & Analges. 1996;82:225–30. 17. Henretig F, Wiley J, Brown L. Clonidine patch toxicity: the proof’s in the poop (abstract)! J Toxicol Clin Toxicol. 1995;33:520 –1. 18. Carvati EM, Bennett DL. Clonidine transdermal patch poisoning. Ann Emerg Med. 1988;17:175– 6. 19. Sanklecha M, Jog A, Raghavan K. Clonidine casualty. Int J Pediatr. 1993;60:611–2. 20. Buklan AI. Smertel’noe otravlenie revenka klofelinom (Fatal poisoning of a child with clofeline). Sudebno-Meditsinskaia Ekspertiza. 1989;32:54 –5. 21. Maloney MJ, Schwam JS. Clonidine and sudden death (letter). Pediatrics. 1995;96:1176 –7. 22. Blackman JA, Samson-Fang L, Gutgesell H. Clonidine and electrocardiograms (letter). Pediatrics. 1996;98:1223– 4.
R. J. Roberge et al. 23. Roberge RJ, McGuire SP, Krenzelok EP. Yohimbine as an antidote for clonidine overdose. Am J Emerg Med. 1996;14:678 – 80. 24. Linden CH, Vellman WP, Remake B. Yohimbine: a new street drug. Ann Emerg Med. 1985;14:1002– 4. 25. Wooten V. Effectiveness of yohimbine in treating narcolepsy. So Med J. 1994;87:1065– 6. 26. Charney DS, Heninger CR, Sternberg DE. Assessment of alpha-2 adrenergic autoreceptor function in humans: Effects of oral yohimbine. Life Sci. 1982;30:2033– 41. 27. Sue Y-J, Shannon M. Pharmacokinetics of drugs in overdose. Clin Pharmacokinet. 1992;23:93–105. 28. Hedner T, Edgar B, Edvinsson L, et al. Yohimbine pharmacokinetics and interaction with the sympathetic nervous system in normal volunteers. Eur J Clin Pharmacol. 1992;43:651– 6. 29. Friesen K, Palatnick W, Tennenbein M. Benign course after massive ingestion of yohimbine. J Emerg Med. 1993; 1:287– 8. 30. Varkey S. Overdose of yohimbine (letter). Br Med J. 1992;304: 548.
PII S0736-4679(98)00086-9
Selected Topics: Toxicology
CLONIDINE AND SLEEP APNEA SYNDROME INTERACTION: ANTAGONISM WITH YOHIMBINE Raymond J. Roberge,
MD, FAAEM, ACMT,*
E. Ted Kimball, MD,† Joseph Rossi, Jonathan Warren, FCCM, FCCP‡
MD, FCCM, FCCP,‡
and
*Department of Emergency Medicine and the ‡Division of Critical Care Medicine, Western Pennsylvania Hospital and the †Affiliated Residency in Emergency Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Reprint Address: Raymond J. Roberge, MD, Department of Emergency Medicine, Western Pennsylvania Hospital, 4800 Friendship Avenue, Pittsburgh, PA 15224
e Abstract—A patient with sleep apnea syndrome, concurrently taking clonidine as an antihypertensive, presented with severe respiratory acidosis, hypotension, and associated central nervous system depression. Acidosis was improved by mechanical ventilation, and central nervous system (CNS) depression and hypotension were reversed with yohimbine. Clonidine may have an additive CNS depressive effect in sleep apnea syndrome and should be used with caution in such patients. Yohimbine’s sympathetic-enhancing effects may be useful in clonidine toxic states. © 1998 Elsevier Science Inc.
tated with mechanical ventilation and yohimbine, a central, pre-synaptic alpha-2-adrenergic antagonist. The role of yohimbine in the management of clonidine-associated toxicity is discussed. CASE REPORT Visiting family members found a 62-year-old man naked and confused in his bathroom with unidentified medication pills strewn about the floor. The patient had recently been in his baseline medical state but had called his family several hours prior and stated that he felt somewhat weak and tired. His prior medical history was significant for moderate obesity, chronic obstructive pulmonary disease, cor pulmonale, hypertension, and stroke. Current prescribed medications included clonidine, terfenadine, iodine, theophylline, potassium supplements, and doxycycline, but compliance was unknown. Paramedics noted confusion with easy arousability, pinpoint pupils, systolic blood pressure of 100 mmHg by palpation, regular heart rate of 80 beats per minute, depressed respirations, and fingerstick glucose determination of 80 –120 mg/dL. The man received 2 mg of intravenous (i.v.) naloxone, without apparent effect, and one liter of crystalloid while being rapidly transported to our emergency department (ED). On arrival at the ED, he was noted to be extremely somnolent, con-
e Keywords—sleep apnea syndrome; clonidine; interaction; antagonist; yohimbine
INTRODUCTION Sleep Apnea Syndrome (SAS) is a disorder of multiple etiologies characterized by cyclical abnormalities of respiratory function leading to disturbed sleep patterns, daytime hypersomnolence, and personality changes. Secondary complications of SAS include pulmonary hypertension and cardiovascular complications, including dysrhythmias and conduction disturbances, which occasionally can be life threatening (1). We present a case of respiratory acidosis, narcosis, and cardiovascular depression in a patient with SAS taking clonidine as an antihypertensive. The patient was successfully resusci-
RECEIVED: 30 June 1997; FINAL SUBMISSION RECEIVED: 14 November 1997; ACCEPTED: 25 November 1997 727
728
fused, and hypoventilating with an oxygen saturation of 78% despite supplemental oxygen (FIO2 5 1.0) by face mask. The patient could be awakened with vigorous physical stimulation but remained confused and would rapidly become obtunded again. The physical examination was remarkable for his altered mental status, 2 mm sluggishly reactive pupils, and diffuse pulmonary rhonchi and rales. Systolic blood pressure dropped to 86 mmHg despite administration of an additional liter of i.v. crystalloid in the ED, and heart rate initially fluctuated between 70 and 98 beats per min, eventually decreasing to 56 – 66 beats per min. A junctional rhythm and deeply inverted T-waves in lead V1– 4 were noted on the initial cardiogram. Chest radiography showed mild congestive heart failure and bibasilar atelectasis. Complete blood count was: white blood cells 12,300/mm3, hemoglobin 13 g, hematocrit 41.6%, and platelets 123,000 mm3. Serum chemistries were: sodium 140 mEq/L, potassium 4.1 mEq/L, chloride 98 mEq/L, CO2 35 mEq/L, blood urea nitrogen 8.5 mmol/L, creatinine 91 umol/L, and glucose 142 mg/dL (7.8 mmol/L). Serial cardiac isoenzymes were normal, and the arterial blood gas analysis on supplemental oxygen (10 liters/min non-rebreather face mask) was: pH 7.05, pCO2 126 mmHg, pO2 78 mmHg (12 min after ED arrival). The patient received i.v. naloxone (boluses of 2 mg and 10 mg) without apparent response and was then endotracheally intubated and mechanically ventilated 40 min after ED arrival (ventilator settings: FIO2 5 .70, tidal volume 900 cc, assist/control respiratory rate of 14). Hypotension, CNS depression, and cardiographic abnormalities persisted despite improvement in arterial blood gas parameters 45 min post-intubation (pH 7.31, pCO2 47, pO2 91). Based upon clinical findings and history of clonidine use, clonidine toxicity was suspected, and the patient was administered a slurry of yohimbine (5.4 mg) via nasogastric tube. Approximately 15 min later, without other therapy except for maintenance i.v. fluids, the patient’s blood pressure rose to 130/70 mmHg, and the heart rate normalized to a regular sinus rhythm of 80 beats per min, although the T-wave inversions persisted throughout his hospitalization and were subsequently noted on prior admission cardiograms. Within 45 min of yohimbine administration, the patient was completely awake, recognized family members, was able to respond appropriately to questioning, and did not re-sedate. A comprehensive drug screen, utilizing gas chromatography/mass spectroscopy, was subsequently reported as positive for theophylline [1.7 ug/mL (therapeutic 5 10 –20 ug/mL)] and clonidine [0.5 ng/mL (therapeutic 0.2–1.3 ng/mL)]. The patient remained alert with normal vital signs and was admitted to the intensive care unit. An echocardiogram demonstrated biatrial enlargement, mild concentric left ventricular hypertrophy with ejec-
R. J. Roberge et al.
tion fraction of 50%, diffuse hypokinesis of the right ventricle, pulmonary hypertension, and mild tricuspid regurgitation. Multiple attempts at weaning from ventilatory support were frustrated by nighttime CO2 retention (.80 mmHg on multiple occasions) with concomitant 02 desaturations and daytime hypersomnolence. The patient responded well to a graduated introduction of biphasic positive airway pressure (biPAP). He denied any drug overdose or suicidal ideation and was subsequently discharged to a rehabilitation center with a diagnosis of central sleep apnea.
DISCUSSION Sleep Apnea Syndrome can be of obstructive, central, or mixed variety. It is associated with absent or impaired respiratory effort, which can then lead to hypoxia and hypercarbia as well as CNS alterations (e.g., hypersomnolence, coma) and cardiovascular abnormalities (e.g., dysrhythmias, conduction blocks; Reference 2). The expected adrenergic response to acute respiratory acidosis (e.g., tachycardia, increased cardiac output, bounding pulses; References 3,4) was not noted in this patient and may have been blunted by the depressive effects of the acidosis, the sympatholytic effects of clonidine, or both. Clonidine, first developed as a nasal decongestant before its antihypertensive effects were noted, exerts its antihypertensive effects through agonism of CNS pre-synaptic alpha-2-adrenergic receptors, which decrease discharge in sympathetic preganglionic fibers with resultant diminished CNS adrenergic output (5). Recent data demonstrating decreased CNS adrenergic output from the locus coeruleus as one etiologic factor in narcolepsy (a disorder with features similar to SAS) suggest a possible SAS/clonidine additive CNS sympatholysis in our patient (6). Despite near-normalization of post-intubation arterial blood gas parameters, the patient’s mental state and cardiovascular status remained abnormal and could have been related to recognized secondary CNS alterations associated with pulmonary failure and the aforementioned decreased CNS adrenergic output (7). The salutary effect temporally related to administration of yohimbine, a central sympathetic-enhancing agent, suggests decreased sympathetic output as contributory to the clinical picture (8). In view of the therapeutic serum clonidine level noted in our patient, this case may represent an adverse reaction to clonidine in a susceptible individual (i.e., one with SAS) rather than clonidine toxicity per se. The CNS sympatholytic effect and other peripheral effects have resulted in increased use of clonidine in numerous disorders (Table 1; References 9 –16). Clonidine is being increasingly prescribed in the pediatric population be-
Yohimbine Treatment of Sleep Apnea Table 1. Some Clonidine Therapeutic Applications Antihypertensive Withdrawal states (i.e., alcohol, opiates, nicotine) Tics (i.e., Tourette’s syndrome) Attention Deficit Hyperactivity Disorder Hot flashes (drug-induced, hormonally induced) Gastrointestinal hypermotility disorders Glaucoma (miotic agent–not approved in U.S.) Analgesia adjunct
cause of perceived benefits in select disorders [e.g., Tourette’s syndrome (11), Attention Deficit Hyperactivity Disorder (ADHD; Reference 12)]. This augmented use, coupled with expanding indications in adults, some of whom may be somewhat unreliable caretakers (e.g., alcoholics, opiate addicts), may result in increased incidences of accidental childhood clonidine toxicity. Additionally, improper disposal of transdermal clonidine preparations is being recognized as a cause of clonidine poisoning in children (17,18). Children are especially susceptible to even small amounts of clonidine, and deaths have been reported outside the U.S., though poorly documented (19,20). Of rising concern is the recent reporting of several unexplained sudden deaths in children who were taking, or had recently taken, clonidine (usually combined with methylphenidate for ADHD; Reference 21). Again, direct causality has not been demonstrated, but the incidents have, rightly, prompted more-intense surveillance and issuance of advisories (22). Clonidine toxicity often resembles opiate overdose (i.e., miosis, hypothermia, coma, respiratory depression, hypotension, bradycardia; Reference 23). Our suspicion of clonidine overdose in this patient prompted us to administer yohimbine because it has CNS actions directly opposite those of clonidine, namely, CNS presynaptic alpha2-adrenergic antagonism with resultant increase in central sympathetic output and decreased parasympathetic activity (8). Yohimbine is used for treatment of organic impotence, and, of note, one recent study demonstrated usefulness in amelioration of narcoleptic symptoms (24,25). Although clinical effects of yohimbine peak within 1 to 2 h of oral administration, we noted a more-rapid response following administration as a slurry (a parenteral preparation is not generally available), which probably enhanced absorption (26,27). Yohimbine has a short serum half-life (0.4 to 18 min following i.v. administration) and elimination half-life (0.5 to 2.5 h) but may possess a secondary elimination phase of 13 h, which is essentially equivalent to clonidine’s half-life (28). We used a yohimbine dose (one standard 5.4 mg tablet) that was the same dose that had been given empirically to successfully reverse clonidine toxicity associated with bradycardia, hypotension, and coma in a
729
previous report (23). Yohimbine can cause a hyperadrenergic state with anxiety, hypertension, and tachycardia, but overdose with this agent is generally well-tolerated, though delayed atrial fibrillation has been documented in one case (24,29,30). Caution is warranted if administering yohimbine for clonidine overdose when paradoxical hypertension is noted (usually early in overdose; Reference 23). Clonidine and related antihypertensives (e.g., guanfascine, guanabenz) may have additive CNS sympatholytic effects with SAS and could be relatively contraindicated for patients with this disorder. With expanding use of clonidine, reports of adverse and toxic effects may increase. Yohimbine’s CNS actions are antagonistic to clonidine’s and may be of use in counteracting toxic symptoms of clonidine use or abuse. Hopefully, further study will shed additional light on the role of yohimbine in clonidine toxic states.
REFERENCES 1. Weinberg SE. Principles of pulmonary medicine, 2nd ed. Philadelphia: WB Saunders Co.; 1992:218 –21. 2. West JB. Disorders of ventilation. In: Braunwald E, Isselbacher KJ, Petersdorf RG, Wilson JD, Martin JB, Fauci AS, eds. Harrison’s principles of internal medicine, 11th ed. New York: McGraw-Hill; 1987:1129 –32. 3. Swensen ER. Approach to the patient with respiratory acid-base disturbance. In: Kelley WN, DeVita VT, DuPont HL, et al., eds. Textbook of internal medicine. Philadelphia: JB Lippincott Co.; 1989:2073. 4. Effros RM, Widell JL. Acid-base balance. In: Murray JF, Nadel JA, eds. Textbook of respiratory medicine. Philadelphia: WB Saunders Co.; 1994:175– 6. 5. Hoffman BB, Lefkowitz RJ. Cathecholamines, sympathomimetic drugs, and adrenergic receptor antagonists. In: Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Gilman A, eds. Goodman Gilman’s The pharmacological basis of therapeutics, 9th ed. New York: McGraw-Hill; 199 –248. 6. Aldrich MS, Ockert K, Albin RL. Adrenergic receptor autoradiography of human narcoleptic brainstem (abstract). Sleep Research. 1993;22:163. 7. Dulfano MJ, Ishikawa S. Hypercapnia: Mental changes and extrapulmonary complications. An expanded concept of the “CO2 intoxication” syndrome. Ann Intern Med. 1965;63:829 – 41. 8. Goldberg MR, Robertson D. Yohimbine: A pharmacological probe for study of the alpha-2 adrenoreceptor. Pharmacol Rev. 1983; 35:143– 80. 9. Gourlay S, Forbes A, Marriner T, et al. A placebo-controlled study of three clonidine doses for smoking cessation. Clin Pharmacol & Therapeut. 1994;55:64 –9. 10. Lohr RH. Treatment of alcohol withdrawal in hospitalized patients. Mayo Clin Proc. 1995;70:777– 82. 11. Kurlan R. Treatment of tics. Neurol Clin North Am. 1997;15:403– 409. 12. Anonymous. Clonidine for treatment of attention-deficit/hyperactivity disorder. Med Lett. 1996;38:109 –10. 13. Goldberg RM, Loprinzi CL, O’Fallon JR, et al. Transdermal clonidine for ameliorating tamoxifen-induced hot flashes. J Clin Oncol. 1994;12:155– 8. 14. Thollander M, Hellstrom PM, Svensson TH. Suppression of castor oil-induced diarrhea by alpha-2 adrenoreceptor agonists. Ailment Pharmacol Ther. 1991;5:255– 62.
730 15. Sihota R, Agarwal HC, Rajashekar YL. A comparative evaluation of pilocarpine 1% and clonidine 0.125% vs. timolol 0.5%. Ind J Ophthalmol. 1996;44:87–9. 16. Mikawa K, Nishina K, Maekawa N, et al. Oral clonidine premedication reduces postoperative pain in children. Anesth & Analges. 1996;82:225–30. 17. Henretig F, Wiley J, Brown L. Clonidine patch toxicity: the proof’s in the poop (abstract)! J Toxicol Clin Toxicol. 1995;33:520 –1. 18. Carvati EM, Bennett DL. Clonidine transdermal patch poisoning. Ann Emerg Med. 1988;17:175– 6. 19. Sanklecha M, Jog A, Raghavan K. Clonidine casualty. Int J Pediatr. 1993;60:611–2. 20. Buklan AI. Smertel’noe otravlenie revenka klofelinom (Fatal poisoning of a child with clofeline). Sudebno-Meditsinskaia Ekspertiza. 1989;32:54 –5. 21. Maloney MJ, Schwam JS. Clonidine and sudden death (letter). Pediatrics. 1995;96:1176 –7. 22. Blackman JA, Samson-Fang L, Gutgesell H. Clonidine and electrocardiograms (letter). Pediatrics. 1996;98:1223– 4.
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