Stroke Associated With Sympathomimetics Contained in Over-the-Counter Cough and Cold Drugs Carlos Cantu, MD, MSc; Antonio Arauz, MD, MSc; Luis M. Murillo-Bonilla, MD; Mario López, MD; Fernando Barinagarrementeria, MD Background and Purpose—Phenylpropanolamine (PPA) and pseudoephedrine are sympathomimetics contained in over-the-counter cold preparations. A case-control study linked PPA use with hemorrhagic stroke in women. Twenty-two patients with stroke associated with use of these drugs are described. Methods—In a consecutive stroke registry since 1988, 22 patients had stroke associated with over-the-counter sympathomimetics. Sympathomimetic dosage and type, time interval until stroke onset, and neuroimaging findings are described. Results—Ten male and 12 female patients were included. Intracerebral hemorrhage occurred in 17 patients, subarachnoid hemorrhage in 4, and ischemic stroke in 1. Stroke was associated with PPA use in 16 patients (dose 75 to 675 mg), with pseudoephedrine in 4 (dose 60 to 300 mg), and with others administered by the nasal route in 2 (oxymetazoline and phenylephrine). Stroke occurred after a single dose in 17 patients and after daily use during several days in 5. The interval between drug exposure and clinical onset varied from 30 minutes to 24 hours. Stroke occurred after recommended doses of PPA (50 to 75 mg) in 32% and pseudoephedrine (60 mg) in 50% of patients. Eight patients had acute hypertension at stroke onset. Cerebral angiography was normal in 8 cases and showed diffuse vasospasm or beading in 10 patients. Conclusions—Stroke related to over-the-counter sympathomimetics was associated with acute hypertension and/or vasospasm or angiitis mechanisms, most related to the use of PPA; however, stroke also occurred with the use of other sympathomimetics, particularly pseudoephedrine. Although stroke complications occurred when doses were used that were higher than recommended doses, apparently there is also a stroke risk when these agents are taken properly. (Stroke. 2003;34:1667-1673.) Key Words: phenylpropanolamine 䡲 stroke 䡲 sympathomimetics
P
henylpropranolamine (PPA) and ephedrine are sympathomimetic amines structurally similar to amphetamines.1 PPA and pseudoephedrine are contained in many over-the-counter cough and cold preparations. Pseudoephedrine is also a bronchodilator and nasal vasoconstrictor, and it is generally harmless when used in recommended doses. Since 1979, many case reports have described the occurrence of intracranial hemorrhage after the ingestion of PPA or other synthetic sympathomimetics.2–20 In a controlled trial, Kernan et al21 found that PPA contained in appetite suppressants, and perhaps in cough and cold preparations, represents an independent risk factor for hemorrhagic stroke. The first 2 cases of PPA-related hemorrhagic stroke in our hospital were described ⬎10 years ago.6 Since then, information on the intake of sympathomimetic agents is systematically obtained in all patients with stroke. The objective of this study was to describe the clinical, neuroimaging, and prognostic findings in 22 patients with stroke associated with the use of over-thecounter sympathomimetics.
See Editorial Comment, page 1673
Subjects and Methods Since 1988, stroke patients have been evaluated prospectively in a tertiary care neurological center. The information from each patient is coded in a computerized database, including demographic data, vascular risk factors, results of diagnostic tests, description of stroke causes and mechanisms, and clinical outcome. There were 2500 patients (mean age, 50.2⫾19.1 years) in the register, with diagnoses of ischemic stroke in 1586, intracerebral hemorrhage in 678, cerebral venous thrombosis in 187, and nonaneurysmal subarachnoid hemorrhage (SAH) in 49. Management of patients with SAH is performed by the Neurosurgical Department and is only referred to our Neurological Department when aneurysms or arteriovenous malformations are excluded. Among the 2500 patients, 22 (0.9%) were diagnosed with stroke associated with over-the-counter cough and cold sympathomimetic agents. All patients were evaluated with the use of a CT scan (n⫽18), MRI (n⫽16), or both. Cerebral digital subtraction angiography (DSA) was performed in 18 patients; in the other 4 patients, DSA was not performed because of death (n⫽2) or
Received November 19, 2002; final revision received January 16, 2003; accepted January 28, 2003. From the Stroke Clinic, National Institute of Neurology and Neurosurgery, Tlalpan, Mexico. Correspondence to Carlos Cantu, MD, Stroke Clinic, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, Mexico City, DF Mexico PC 14269. E-mail
[email protected] © 2003 American Heart Association, Inc. Stroke is available at http://www.strokeaha.org
DOI: 10.1161/01.STR.0000075293.45936.FA
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because it was not considered necessary by the primary care neurologist (n⫽2). The information regarding doses and type of sympathomimetic agent was obtained prospectively. In each patient, the interval between exposure and stroke onset was determined. Exposure to an over-the-counter cough and cold preparation was considered when the patient had used the product within 24 hours before the stroke onset. Information regarding blood pressure (BP) on admission was obtained retrospectively from the medical records. In addition, the neuroradiological findings, particularly angiographic findings, were evaluated. The outcome was assessed at discharge and classified according to the modified Rankin Scale.22 Stroke was considered to be related to over-the-counter cough and cold sympathomimetic agents when 2 conditions were fulfilled: (1) a close relationship existed between drug ingestion and stroke development, as described above; and (2) other known causes of stroke were excluded by appropriate diagnostic tests, as previously reported in our stroke clinic in young patients with stroke.23,24
Results Of the 22 patients, 21 had a hemorrhagic stroke (95%), and only 1 had an ischemic stroke (5%). Sixteen of the 21 hemorrhagic strokes were intracerebral (76%), 4 were subarachnoid (19%), and 1 included both types of hemorrhage. Table 1 shows the details of each patient. Figures 1 to 3 illustrate the neuroimaging findings of representative cases. Ten patients were male (mean age, 33.5 years; range, 17 to 57 years), and 12 were female (mean age, 43.7 years; range, 19 to 78 years). Seventeen patients (77%) were aged ⬍50 years. Traditional vascular risk factors were uncommon (alcohol use in 4 cases, tobacco use in 2, and systemic hypertension in 2). One cerebrovascular event occurred from a suicide attempt. Only 1 had a prior history of substance abuse (sniffing of glue and other solvents). Structural brain lesions associated with hemorrhagic stroke (arteriovenous malformation, tumor, or aneurysm) were excluded in these 22 patients.
Dosage of Sympathomimetics and Interval Until Stroke Sixteen patients received PPA, 4 pseudoephedrine, 1 phenylephrine, and 1 oxymetazoline. The last 2 agents were used by the nasal route. Doses of PPA fluctuated between 50 and 675 mg. Three patients were given a single recommended dose of PPA (50 to 75 mg), 6 received a single double dose (150 to 185 mg), and 4 were given a single excessive dose of PPA (450 to 675 mg). Three other patients received PPA daily during several days before stroke: 2 in recommended doses (75 mg BID) and 1 in double doses (150 mg BID). PPA contained in the cough/cold preparations was usually combined with 1 or more additional drugs, ordinarily an antihistamine: chlorpheniramine in 7 patients, brompheniramine in 6, and dextromethorphan plus guaifenesin in 2. The doses of pseudoephedrine fluctuated between 60 and 300 mg. One patient was given a single regular dose, 2 received a single but excessive dose, and 1 took recommended doses of pseudoephedrine daily during 1 week. In regard to sympathomimetics used by the nasal route, 1 patient received regular doses of oxymetazoline using a nasal spray during 1 week, and 1 had a prior history of systemic hypertension and had been using nasal phenylephrine TID during 4 months.
The interval between the exposure to the sympathomimetic and stroke onset was 30 minutes to 3 hours in 8 patients, 3 to 6 hours in 5 patients, and 6 to 24 hours in 9 patients.
Stroke Features and Clinical Outcome The most common location for intracerebral hemorrhage was lobar in 8 patients, usually involving the frontal lobe. Additional locations included putaminal/capsular in 5 patients, thalamic in 2, and caudate in 2. Intraventricular extension occurred in 7 patients. The only ischemic stroke involved the vertebrobasilar distribution; initially the patient developed “top of basilar artery” symptoms, and subsequently right occipital and thalamic infarctions were documented. High BP was common during admission (90% of patients). Persistent and uncontrolled hypertension (systolic BP ⬎180 mm Hg and/or diastolic BP ⬎110 mm Hg) was documented in 8 cases, including 3 patients using a single low dose of the sympathomimetic drug. Both patients with hypertension history took antihypertensive treatment regularly. They developed a severe hypertensive crisis (BP ⱖ220/ 110 mm Hg): one of them took regular daily doses of pseudoephedrine during the previous week, and the other received daily nasal phenylephrine as a decongestant during 4 months. No information about whether the 6 other patients who developed acute hypertension had previously documented labile hypertension was available. However, a pheochromocytoma was diagnosed in 1 patient 2 years later. Cerebral angiography was normal in 8 patients and showed “vasculitis-like” abnormalities in 10 patients (45%). These features included widespread segmental narrowing and beading, usually in both the carotid and vertebrobasilar territories. Cerebral vascular abnormalities were observed at the main stem of the basal arteries, major branches, or small arteries (Figures 1 to 3). There was no clinical or laboratory evidence of other disorders that explained the “vasculitic” changes seen on cerebral arteriography. These patients usually had spontaneous clinical improvement without using immunosuppressive agents. Moreover, in 4 patients with follow-up DSA, complete resolution of the arterial abnormalities was documented. At discharge, the clinical outcome was total recovery in 11 patients, mild disability in 7, moderate disability in 2, and death in 2 patients.
Discussion This study found that 22 of 2500 consecutive stroke patients in a neurological reference center had a stroke after using an over-the-counter cough and cold sympathomimetic drug. These were implicated in 2.5% of the patients with intracerebral hemorrhage and in 8.1% of the cases with nonaneurysmal SAH in our stroke registry. Although most were related to PPA, stroke can also occur with the use of other sympathomimetics, particularly pseudoephedrine. We found 39 cases reported in the literature: 31 associated with the use of PPA2–10,19 –21,25– 40; 4 with pseudoephedrine, ephedrine, and ephedra alkaloid derivatives16,41– 43; 2 with phentermine44,45; and 2 with sympathomimetics used by the nasal route (oxymetazoline and fenoxazoline).46,47 PPA use is associated largely with the occurrence of intracranial hemorrhage21,26,27 and only occasionally with
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Cantu et al TABLE 1.
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Clinical Findings, Neuroimaging Results, and Outcome
Case
Sex/Age (y)
Drugs/ Dosage
Interval to Stroke*
BP†
CT/MRI Findings
Angiographic Findings
Outcome
1
M/36
PPA, 450 mg, single dose
⬍3 h
140/90
Right putamino-capsular and caudate hemorrhage
Normal
Total recovery
2
M/27
PPA, 600 mg, single dose
6h
150/100
Right putamino-capsular; IV rupture
Diffuse segmental narrowing with beading of MCAs, BA, and PCAs
Total recovery
3
F/78
PPA, 150 mg/day, previous 3 days
6–24 h
160/100
Extensive left hemisphere hemorrhage
Not done
Death
4
M/30
PPA, 50 mg, single dose
24 h
140/100
Left putaminal hemorrhage; IV rupture
Segmental narrowing and occlusions of left MCA small arteries
Total recovery
5
M/39
Pseudoephedrine 10 mL (60 mg), single dose
6h
150/90
Left thalamic hemorrhage; IV rupture
Normal
Mild disability
6
F/34
PPA, 150 mg/day, previous 6 days
⬍6 h
130/80
Mild SAH and small fronto-orbital hemorrhage
Diffuse segmental narrowing branches of ACAs and MCAs
Total recovery
7
F/49
PPA, 150 mg, single dose
2h
140/100
Left putaminal and caudate hemorrhage; IV rupture
Diffuse segmental narrowing in ACAs, MCAs, BA, and PCAs
Total recovery
8
F/57
PPA, 50 mg, single dose
30 min
190/120
Right caudate hemorrhage; IV rupture
Normal
Mild disability
9
F/19
PPA, 675 mg,‡ single dose
⬍1 h
180/110
Right frontal hemorrhage; IV rupture
Diffuse segmental narrowing, mainly in right MCA
Moderate disability
10
M/30
PPA, 150 mg, single dose
3–6 h
140/100
SAH
Normal
Total recovery
11
F/31
PPA, half a bottle (75 mL⫽187.5 mg); single dose
⬍1 h
140/100
Extensive left frontal hemorrhage
Diffuse segmental narrowing
Moderate disability
12
M/38
PPA, 150 mg, single dose
6–24 h
180/110
Small left parietal hemorrhage
Not done
Total recovery
13
F/60
PPA, 75 mg, single dose
6–24 h
190/100
Right occipital hemorrhage
Beading in both PCAs
Total recovery
14
F/48
Pseudoephedrine 1 tab (60 mg)/day during 1 week
24 h
220/115
Extensive left frontal hemorrhage
Severe diffuse narrowing
Death
15
M/57
Phenylephrine, daily nasal spray (TID) during 4 months
1–3 h
240/110
SAH, left temporal hemorrhage, right occipital infarct
Not done
Mild disability
16
M/40
Oxymetazoline, daily nasal spray during 1 week
6–24 h
160/110
SAH
Normal
Total recovery
17
F/36
Pseudoephedrine 300 mg, single dose
6–24 h
140/100
Right thalamic hemorrhage
Normal
Moderate disability
18
F/28
PPA, 150 mg/day, during the previous week
4h
140/90
Right occipital and thalamic infarctions
Beading along BA and both PCAs
Moderate disability
19
F/44
PPA, 450 mg, single dose
1h
100/60
Right caudate; IV rupture
Beading along A1 segment of right ACA
Total recovery
20
M/55
PPA, half bottle (60 mL⫽150 mg) single dose
⬍1 h
180/110
Right putaminal hemorrhage
Not done
Moderate to severe disability
21
M/17
PPA, 150 mg, single dose
6–24 h
160/100
SAH
Normal
Total recovery
22
F/40
Pseudoephedrine 180 mg, single dose
12 h
130/85
Left putaminal hemorrhage; IV rupture
Normal
Moderate disability
SAH indicates subarachnoid hemorrhage; MCA, middle cerebral artery; ACA, anterior cerebral artery; PCA, posterior cerebral artery; BA, basilar artery; PPA, phenylpropanolamine. *Interval between drug exposure and stroke onset. †BP⫽Blood pressure on admission. ‡Suicide attempt.
development of an ischemic stroke.7,25 Only 1 of the 16 patients in our series had an ischemic stroke, and only 2 cases are described in 31 previous reports.7,25 Table 2 compares several features of the PPA-related cases in this series with other previously described patients and with the cases de-
scribed by Kernan et al.21 The latter authors showed that the use of appetite suppressants containing PPA by young women was associated with an increased risk of hemorrhagic stroke. Because no male subject reported the use of appetite suppressants containing PPA, the authors could not determine
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Figure 2. Case 6. CT scan (left top) shows a small hemorrhage in fronto-orbital region. Cerebral angiography reveals widespread segmental narrowing and beading in carotid territories (black arrows). Right top, lateral view of left carotid angiogram; left bottom, left oblique view of right carotid angiogram; right bottom, left oblique view of left carotid angiogram.
Figure 1. Case 4. MRI, coronal view, depicts a left putaminal hemorrhage with mild intraventricular hemorrhage (top). Cerebral angiography, lateral view of left carotid artery, shows segmental narrowing and occlusion of small arteries (arrows) of the left middle cerebral artery.
whether men were at increased risk for hemorrhage under such condition. The study of Kernan et al did not establish cold remedies as risk factors for hemorrhagic stroke. However, this study suggests that an additional association exists between this disorder and the first application of PPA contained in cough or cold preparations only among female patients. Although the stroke risk is more obvious when PPA is used as a chronic appetite suppressor, 15 of 16 cases in our series were related to PPA used as a cold remedy. Additionally, the fact that ⬎40% of the cases included in the present series were men suggests that they are also susceptible to vascular damage secondary to PPA use. Men probably require higher doses of PPA to develop adverse cerebrovascular effects. Male patients in our series (n⫽7) and in previous series (n⫽9) revealed that 14 (87.5%) used a dose ⱖ150 mg. In fact, Kernan et al21 reported that the risk of hemorrhage is greater when a dose ⬎75 mg is used. Approximately 50% of the cases previously reported had daily doses ⱖ150 mg (Table 2). In our study 81% of the patients also had daily doses ⱖ150 mg, usually as an attempt to improve cold symptoms faster. Moreover, some patients have taken an overdose as a deliberate suicide attempt.8,26 Conversely, it should be noted that some cerebrovascular events are asso-
ciated with a single low dose of PPA, probably in an idiosyncratic manner.3,8,9,31,33–37,39 The interval between the use of the sympathomimetic and stroke onset was variable, in most cases ⱕ6 hours (60% to 70%), but in 25% to 35% the interval lasted ⬍1 hour. This finding emphasizes the apparent relationship between drug ingestion and stroke development. Cerebral hemorrhages were largely parenchymal in the present series (80%) and in the reported cases (60%). Kernan et al21 primarily found cases of SAH (61%). Perhaps this is because of the study design used by these last authors, in which the use of PPA was prospectively and carefully investigated in every case of cerebral hemorrhage, either intracerebral or subarachnoid.
Figure 3. Case 7. CT scan (left bottom) shows left caudate hemorrhage with intraventricular rupture. Cerebral angiography on admission (top) shows narrowing (arrows) of main trunks of right middle cerebral artery and anterior cerebral artery (left top), left middle cerebral artery and anterior cerebral artery (middle top), and basilar artery and posterior cerebral arteries (right top). A complete resolution of the arterial abnormalities was documented in a follow-up cerebral angiography (bottom).
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TABLE 2. Comparison of the Clinical and Neuroimaging Features of PhenylpropanolamineRelated Cerebrovascular Complications Current Cases Case Reports n⫽16 n⫽31 Sex, M/F Age, mean⫾SD (y)
Kernan et al Trial n⫽27
7/9
9/22
6/21
39.5⫾16.4
31.4⫾13.7
37.2⫾8.4
Doses, %
(n⫽29)*
12–75 mg
3 (18.7)
12 (41.4)
20 (74.1)
76–149 mg
0 (0)
3 (10.3)
1 (3.7)
150–300 mg
8 (50.0)
6 (20.4)
5 (18.5)
⬎300 mg
5 (31.3)
8 (27.6)
1 (3.7)
Reason for using PPA, % Appetite suppressant Cough/cold remedy Suicide attempt and psychostimulant
(n⫽30)* 0 (0)
15 (50.0)
15 (93.7) 1 (6.3)†
Interval between drug intake and stroke onset, %
21 (77.8)
10 (33.3)
6 (22.2)
5 (16.7)‡ (n⫽30)*
30 min–1 h
5 (31.2)
11 (36.7)
1–3 h
2 (12.5)
10 (33.3)
3–6 h
4 (25.0)
1 (3.3)
6–24 h
5 (31.2)
8 (26.7)
0 (0) The stroke occurred the same day the drug was consumed
Stroke type, % ICH
11 (68.7)
21 (67.7)
9 (33.3)
SAH
3 (18.7)
5 (16.1)
18 (66.7)
ICH⫹SAH
1 (6.2)
3 (9.7)
䡠䡠䡠
Cerebral infarction
1 (6.2)
2 (6.4)
䡠䡠䡠
Cerebral angiography
(n⫽13)
(n⫽18)
Normal
4 (30.8)
8 (37.5)
Vasculitis like-abnormalities
9 (69.2)
10 (62.5)
NA
*Feature not determinated in the remaining cases. †Suicide attempt. ‡Suicide attempt (n⫽2); psychostimulant (n⫽3). ICH indicates intracerebral hemorrhage; SAH, subarachnoid hemorrhage; NA, not available.
Several mechanisms by which PPA causes cerebrovascular complications have been proposed: the development of hypertensive crisis,5,36 as occurred in 31% of our cases and as a consequence of a direct vasoconstrictive action of the drugs, or the development of angiitis,2,19 as documented in 55% of the patients who underwent angiography in our study. In the only case assigned to a histopathological examination, Glick et al37 described a young woman with angiographic and biopsy findings of necrotizing vasculitis of small arteries and veins caused by the PPA contained in her diet pills. Four months later, DSA showed resolution of the vascular lesions. In the present series, in 4 patients with follow-up DSA, complete resolution of the arterial abnormalities was also documented. In several countries the use of PPA has been reduced almost completely, but information on the use of other common sympathomimetics, administered by both oral and nasal routes, is limited. Pseudoephedrine has seldom caused adverse effects because it is a very weak sympathomimetic amine. However, the relationship between pseudoephedrine and stroke was evident in 4 patients in our series, including 2 cases caused by the ingestion of recommended doses. There
are only 2 other cases described in the literature: one after the ingestion of a single regular dose and another after an excessive dose in a suicide attempt.33,42 This last patient and 1 patient included in our series showed angiographic changes similar to those observed with PPA. Recently, Dowd et al48 described 4 cases of ischemic colitis ascribed to pseudoephedrine use. Now that pseudoephedrine is preferred to PPA in cold preparations, one must be aware of the potential cerebrovascular damage that this sympathomimetic can cause. Finally, some anecdotal case reports on the cerebrovascular complications of chronic nasal sprays have been published, including 2 patients with brain infarction, apparently secondary to chronic use of the nasal decongestants oxymetazoline and fenoxazoline, and another case of retinal artery occlusion associated with the excessive use of nasal spray containing oxymetazoline.46,47 The vascular damage in these cases was ascribed to arterial occlusions, in contrast to oral sympathomimetic-related complications, which are predominantly hemorrhages. We describe 2 patients with cerebrovascular complications associated with the application of nasal decongestants. One patient had a SAH after several daily applications
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of oxymetazoline, and the other developed a combination of SAH, temporo-occipital hemorrhage, and contralateral occipital infarction. This patient was hypertensive and was receiving daily applications of phenylephrine during several months because of an allergic rhinitis. Although the stroke may have been caused by the high BP, the distribution of the vascular lesions suggests that the nasal sympathomimetic played a role in the cerebrovascular episode. In conclusion, over-the-counter sympathomimetic-related stroke was associated with hypertensive crisis and/or vasculitis-like mechanisms. Most cases were related to PPA use; however, stroke can also occur with the use of other sympathomimetics, particularly pseudoephedrine. Although stroke complications occurred when doses higher than recommended doses were used, stroke also occurred even when the agents were taken properly.
20.
21.
22.
23.
24. 25. 26.
27.
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panolamine: case report and review of literature. Pediatrics. 1989;83: 737–741. Chung Y-T, Hung D-Z, Hsu C-P, Yang D-Y, Wu T-C. Intracerebral hemorrhage in a young woman with arteriovenous malformation after taking diet control pills containing phenylpropanolamine: a case report. Chung Hua I Hsueh Tsa Chih (Taipei). 1998;61:432– 435. Kernan W, Viscoli C, Brass L, Broderick J, Brott T, Feldmann E, Morgenstern L. Phenylpropanolamine and the risk of hemorrhagic stroke. N Engl J Med. 2000;343:1826 –1832. van Swieten JC, Koudastaal PJ, Viseer MC, Schouten HJ, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1988;19:604 – 607. Barinagarrementeria F, Figuero T, Huebe J, Cantú C. Cerebral Infarction in people under 40 years: etiologic analysis of 300 cases. Cerebrovasc Dis. 1996;6:75–79. Ruiz-Sandoval JL, Cantú C, Barinagarrementeria F. Cerebral hemorrhage in young people: analysis of 200 cases. Stroke. 1999;30:537–541. Harrison WM, McGrath PJ, Steward JW, Quitkin F. MAOIs and hypertensive crises: the role of OTC drugs. J Clin Psychiatry. 1989;50:64 – 65. Maertens P, Lum G, Williams JP, White J. Intracranial hemorrhage and cerebral angiopathic changes in a suicidal phenylpropanolamine poisoning. South Med J. 1987;80:1584 –1586. Kizer KW. Intracranial hemorrhage associated with overdose of decongestant containing phenylpropanolamine. Am J Emerg Med. 1984;2:180–181. Rumack BH, Anderson RJ, Wolfe R, Fletcher EC, Vestal BK. Ornade and anticholinergic toxicity: hypertension, hallucinations, and arrhythmias. Clin Toxicol. 1974;7:573–581. Rumbaugh CL, Fang HC, Higgins RE, Bergeron RT, Segall HD, Teal JS. Cerebral microvascular injury in experimental drug abuse. Invest Radiol. 1976;11:282–294. Mesnard B, Ginn DR. Excessive phenylpropanolamine ingestion followed by subarachnoid hemorrhage. South Med J. 1984;77:939. Deocampo PD. Convulsive seizures due to phenylpropanolamine. J Med Soc N J. 1979;76:591–592. Edwars M, Russo L, Harwood-Nuss A. Cerebral infarction with a single oral dose of phenylpropanolamine. Am J Emerg Med. 1987;5:163–164. Sloan MA, Kittner SJ, Rigamonti D, Price TR. Occurrence of stroke associated with use/abuse of drugs. Neurology. 1991;41:1358 –1364. Hamilton RS, Sharieff G. Phenylpropanolamine-associated intracranial hemorrhage in an infant. Am J Emerg Med. 2000;18:343–345. Tapia J. Cerebral hemorrhage associated with the use of phenylpropanolamine: clinical cases. Rev Med Chi. 1996;124:1499 –1503. Kase CS, Foster TE, Reed JE. Intracerebral hemorrhage and phenylpropanolamine use. Neurology. 1987;37:399 – 402. Glick R, Hoying J, Cerullo L. Phenylpropanolamine: an over-the-counter drug causing central nervous system vasculitis and intracerebral hemorrhage: case report and review. Neurosurgery. 1987;20:969 –972. Mueller SM. Phenylpropanolamine: a non-prescription drug with fatal side effects. N Engl J Med. 1983;308:653. Letter. Bernstein E, Diskant BM. Phenylpropanolamine: a potentially hazardous drug. Ann Emerg Med. 1982;11:311–313. Jick H, Aselton P, Hunter JR. Phenylpropanolamine and cerebral haemorrhage. Lancet. 1984;1071:345–348. Haller CA, Benowitz NL. Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. N Engl J Med. 2000;343:1833–1838. Loizou LA, Hamilton JG, Tsementzis SA. Intracranial hemorrhage in association with pseudoephedrine overdose. J Neurol Neurosurg Psychiatry. 1982;45:471– 475. Mourand I, Ducrocq X, Lacour JC, Taillandier L, Anxionnat R, Weber M. Acute reversible cerebral arteritis associated with parenteral ephedrine use. Cerebrovasc Dis. 1999;9:355–357. Wen PY, Feske SK, Teoh SK, Steig PE. Cerebral hemorrhage in a patient taking fenfluramine and phentermine for obesity. Neurology. 1997;49:632–633. Kokkinos J, Levine SR. Possible association of ischemic stroke with phentermine. Stroke. 1993;24:310 –313. Montalban J, Ibáñez L, Rodríguez C, Lopez M, Sumalla J, Codina A. Cerebral infarction after excessive use of nasal decongestants. J Neurol Neurosurg Psychiatry. 1989;52:541–543. Magargal LE, Sanborn GE, Donoso LA, Gonder JR. Branch retinal artery occlusion after excessive use of nasal spray. Ann Ophthalmol. 1985;17:500–501. Dowd J, Bailey D, Moussa K, Nair S, Doyle R, Culpepper-Morgan JA. Ischemic colitis associated with pseudoephedrine: four cases. Am J Gastroenterol. 1999;94:2430 –2434.
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Cantu et al
Stroke Associated With Symapthomimetic Drugs
1673
Editorial Comment Over-the-Counter Cold Remedies and Stroke For decades a number of sympathomimetic drugs have been marketed as over-the-counter diet pills, decongestants, or both. During the 1980s and 1990s one of these, phenylpropanolamine (PPA), accounted for an estimated 5 billion doses annually in the United States. In humans PPA produces arousal; unlike amphetamine it does not produce euphoria. It is a recognized street drug, however, sometimes misrepresented as amphetamine (“look-alike pills”), and by mail order it has been available as a “legal stimulant.”1 Complications of PPA include acute hypertension, psychosis, seizures, and stroke, especially hemorrhagic. More than 30 case reports describe intracerebral or subarachnoid hemorrhage following either recommended or excessive dosage. Proposed mechanisms include surges of hypertension, cerebral vasospasm (sometimes evident at angiography), and vasculitis (in one case evident at leptomeningeal biopsy).2 In 2000 Kernan and coworkers reported results of a multicenter case-control study addressing the association of PPA use and intracerebral or subarachnoid hemorrhage.3 Patients (n⫽702) and controls (n⫽1375) were 18 to 49 years of age. This study confirmed PPA as an independent risk factor for hemorrhagic stroke. The odds ratio was 16.58 (P⫽0.02) for women using appetite suppressants containing PPA and 3.13 (P⫽0.08) for women using cough or cold remedies containing PPA. For men there was no increased risk of hemorrhagic stroke in association with cough or cold remedies; no men reported use of appetite suppressants. The greater risk of appetite suppressants was attributed to higher dose, but strokes followed recommended as well as excessive doses, and with cough and cold remedies they were associated with first use. It was concluded on the basis of this study that PPA causes between 200 and 400 strokes annually in the United States.4 Later that year the FDA ordered products containing PPA to be withdrawn from the market.5 Ephedrine and pseudoephedrine, present in over-the-counter decongestants and bronchodilators, also have low abuse potential, yet dependence does occur.6 Complications include hypertensive crisis and psychosis. Ischemic and hemorrhagic strokes have occurred in ephedrine users, and intracranial hemorrhage has followed pseudoephedrine use.7,8 Ischemic and hemorrhagic strokes are also described in recreational users of “dietary supplements” containing ephedra alkaloids (“ma huang”).9 Case reports describe cerebral infarction and retinal artery branch occlusion in chronic intranasal abusers of sprays and drops containing phenoxazoline or oxymetazoline.10,11 Evidence that ephedrine, pseudoephedrine, or topical intranasal agents are stroke risk factors is thus anecdotal. Moreover, in contrast to its ban on PPA-containing diet remedies, the FDA’s ban on cough or cold remedies containing PPA was based on a trend that fell short of conventional statistical significance. More convincing data on the association of stroke and cough and cold remedies would thus be welcome. In this issue of Stroke, Cantu and coworkers describe 22 patients with stroke temporally associated with use of these products.12 Patients were culled from a consecutive stroke registry of 2500. Ten were men aged 17 to 57 years; 12 were women aged 17 to 78 years. Twelve were younger than 40
years old. Twenty-one strokes were hemorrhagic (17 intracerebral, 4 subarachnoid). Sixteen patients used PPA, 4 pseudoephedrine, and, by nasal route, 1 phenylephrine and 1 oxymetazoline. With PPA and pseudoephedrine, strokes followed both recommended and excessive doses and either single or daily use. Acute hypertension was present in 8 of the 22 patients. Cerebral angiography was normal in 8 and showed vasospasm or beading in 10. These patients do suggest an association between sympathomimetic cold remedies and stroke. In fact, the number of drugassociated strokes was very likely underestimated by excluding patients with aneurysmal subarachnoid hemorrhage or vascular malformation. (Among patients with cocaine-associated intracranial hemorrhage, saccular aneurysms or vascular malformations were found in nearly half who were studied angiographically.13) The report by Cantu et al is anecdotal, however, for controls are conspicuously lacking. On the basis of what was at stake, the FDA justifiably banned cough and cold remedies containing PPA despite a probability value of only 0.08. Unfortunately, the ban makes it impossible, at least in the United States, to conduct a study that would definitively confirm the FDA’s wisdom. It is not too late, however, to conduct a study assessing the risk of cold remedies containing other sympathomimetic agents. The report presented by Cantu et al suggests that such an endeavor might be fruitful. John C.M. Brust, MD, Guest Editor Department of Neurology Harlem Hospital Center and Columbia University College of Physicians & Surgeons New York, New York
References 1. Brust JCM. Neurological Aspects of Substance Abuse. Boston, Mass: Butterworth-Heinemann; 1993. 2. Fallis RJ, Fisher M. Cerebral vasculitis and hemorrhage associated with phenylpropanolamine. Neurology. 1985;35:405–407. 3. Kernan WN, Viscoli CM, Brass LM, et al. Phenylpropanolamine and the risk of hemorrhagic stroke. N Engl J Med. 2000;343:1826–1832. 4. Fleming GA. The FDA, regulation, and the risk of stroke. N Engl J Med. 2000;343:1886–1887. 5. Mersfelder TL. Phenylpropanolamine and stroke: the study, the FDA ruling, the implications. Cleveland Clin J Med. 2001;68:213–219. 6. Pugh CR, Howie SM. Dependence on pseudoephedrine. Br J Psychiatry. 1986; 149:789. Letter. 7. Wooten MR, Khagure MS, Murphy MJ. Intracerebral hemorrhage and vasculitis related to ephedrine abuse. Ann Neurol. 1983;13:337–340. 8. Loizou LA, Hamilton JG, Tsementzis SA. Intracranial haemorrhage in association with pseudoephedrine overdose. J Neurol Neurosurg Psychiatry. 1982; 45:471–472. 9. Haller CA, Benowitz NL. Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. N Engl J Med. 2000;343:1833–1838. 10. Margaral LE, Sandborn GE, Donoso LA, et al. Branch retinal artery occlusion after excessive use of nasal spray. Ann Ophthalmol. 1985;17:500–501. 11. Montalban J, Ibanez L, Rodriguez C, et al. Cerebral infarction after excessive use of nasal decongestants. J Neurol Neurosurg Psychiatry. 1989;52:541–543. 12. Cantu C, Arauz A, Murillo-Bonilla LM, et al. Stroke associated with sympathomimetics contained in over-the-counter cough and cold drugs. Stroke. 2003;34: 1667–1673. 13. Brust JCM. Stroke and substance abuse. In: Barnett HJM, Mohr JP, Stein BM, Yatsu FM, eds. Stroke: Pathophysiology, Diagnosis, and Management. New York, NY: Churchill Livingstone; 1998:979–1000.
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Stroke Associated With Sympathomimetics Contained in Over-the-Counter Cough and Cold Drugs Carlos Cantu, Antonio Arauz, Luis M. Murillo-Bonilla, Mario López and Fernando Barinagarrementeria Stroke. 2003;34:1667-1672; originally published online June 5, 2003; doi: 10.1161/01.STR.0000075293.45936.FA Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2003 American Heart Association, Inc. All rights reserved. Print ISSN: 0039-2499. Online ISSN: 1524-4628
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