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Echinacea for the Common Cold

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COMMENTS AND RESPONSES
Echinacea for the Common Cold
TO THE EDITOR: Barrett and colleagues (1) are to be lauded for their
efforts to scientifically examine the commonly used phytomedicinal
agent echinacea. However, while they have successfully debunked the
advisability of use of oral unrefined echinacea, it is highly likely that
the preparation used in their study was inadequate and the route of
administration was suboptimal to appropriately test the efficacy of
the herb in the treatment of upper respiratory tract infections. Al-
though echinacea is a native American plant, the best research on it
has been done in Germany, where in 1992 Commission E (the
equivalent of an herbal Food and Drug Administration) approved
the use only of alcoholic root extracts of Echinacea pallida (narrow
leaf coneflower) or juice pressed from E. purpurea (common purple
coneflower) (2). Because all Echinacea species are endangered, the
latter preparation from cultivated sources is preferred. (Individuals
who are concerned about conservation are urged to visit United
Plant Savers at http://plantsavers.org/.)
Many prominent herbal references (3–5) emphasize an impor-
tant point about echinacea administration: Because echinacea may
act locally on oropharyngeal lymphoid tissue, best results accrue
when a tincture is held in the mouth or gargled before swallowing.
Although anecdotal, the experience of roughly 100 of my patients
supports the finding that oral capsular echinacea preparations yield
no useful results, while the gargling technique yields noticeable pro-
phylaxis and attenuation of upper respiratory tract infections and
influenza, as well as rapid healing of aphthous ulcers. Although the
unique taste and mild local anesthetic effects of echinacea tinctures
make true blinding procedures more difficult, it is likely that another
trial employing this technique with a tincture of pressed E. purpurea
aerial parts (for example, EchinaGuard Liquid Extract, Nature’s
Way, Springville, Utah) will have much more encouraging results.
Ethan B. Russo, MD
Montana Neurobehavioral Specialists
Missoula, MT 59802
References
1. Barrett BP, Brown RL, Locken K, Maberry R, Bobula JA, D’Alessio D. Treatment
of the common cold with unrefined echinacea. A randomized, double-blind, placebo-
controlled trial. Ann Intern Med. 2002;137:939-46. [PMID: 12484708]
2. Blumenthal M, Busse WR, Goldberg A, Gruenwald J, Hall T, Riggins CW, et al.
The Complete German Commission E Monographs: Therapeutic Guide to Herbal
Medicines. Klein S, tr. Austin, TX: American Botanical Council; 1998.
3. Foster S, Tyler VE. Tyler’s Honest Herbal: A Sensible Guide to the Use of Herbs
and Related Remedies. 4th ed. New York: Haworth Herbal Pr; 1998.
4. Hobbs H. The Echinacea Handbook. Portland, OR: Eclectic Medical Publications;
1989.
5. Schulz V, Rudolf H, Tyler VE. Rational Phytotherapy: A Physicians’ Guide to
Herbal Medicine. 3rd ed. New York: Springer; 1998.
TO THE EDITOR: Influenza would have been a better subject for
Barrett and colleagues to examine (1). Unfortunately, many manu-
facturers market echinacea as a preventive agent (2), but this has not
been my experience. I have found echinacea drops to be the most
effective preparation, but this method of use is unusual and not
familiar to many practitioners of traditional medicine. The prepara-
tion I use is marketed in Israel as ProtecPlus (Altman Natural Chem-
ist Ltd, Cholon, Israel) and contains additional ingredients besides
echinacea. According to instructions, the patient should mix 30
drops with a little water and use it as a mouthwash for at least 30
seconds, then swallow. The patient should ingest no food or drink
for 5 minutes before or 10 minutes after the treatment and should
repeat the treatment every 4 hours. When improvement is noted, the
patient should reduce the dose to 20 drops 3 times per day until he
or she is better. The medicine is absorbed by the mucous membranes
of the mouth and bypasses the liver.
Echinacea works by acting as a decoy. The influenza virus se-
cretes a protein enzyme called hyaluronidase, which breaks down
hyaluronic acid, a major component of the intracellular cement that
holds body cells together. Hyaluronidase allows the influenza virus to
enter a cell by opening and immediately closing a “trapdoor.” Once
inside, the virus replicates, causing the person to get sick. Echinacea
interferes with secretion of this enzyme, stops it from entering the
cell and the immune system, and kills the virus before it can do any
harm (Jacobs A. Personal communication). Echinacea, therefore, at-
tracts the virus to attack it, allowing the body to heal itself naturally.
It’s always worked for me.
Seth G. Abrahams, BCom LLB (Natal), HDip Ed
Israel
References
1. Barrett BP, Brown RL, Locken K, Maberry R, Bobula JA, D’Alessio D. Treatment
of the common cold with unrefined echinacea. A randomized, double-blind, placebo-
controlled trial. Ann Intern Med. 2002;137:939-46. [PMID: 12484708]
2. Vogel A. Swiss Nature Doctor. Teufen, Switzerland: A Vogel; 1952, 1980:335-7.
TO THE EDITOR: Barrett and colleagues’ study (1) of an unrefined
echinacea product, while elegant, was limited by poorly chosen and
inadequately characterized source material. Clinical trials should be-
gin with botanically identified raw material, with sources and pro-
cessing described and representative voucher specimens of the whole
plant or samples of the raw material preserved in a publicly accessible
herbarium, unless a defined commercial product is to be studied.
Shaklee Technica (Pleasanton, California) distributes an echinacea-
containing product through multilevel marketing, but it is not the
formulation provided to Barrett and colleagues.
The product used by Barrett and colleagues was chemically an-
alyzed only after unblinding, when moderate levels of echinacea-
specific compounds provided the first evidence that the capsules con-
tained some Echinacea species. Contrary to Turner’s suggestion in
the accompanying editorial (2), this does not qualify as “standard-
iz[ation] by measuring specific components,” which would have con-
firmed minimum levels of those components before the study began.
The choice to include 2 species is also strange, since it is not the
rule in commerce. If 1 species was more potent, or if the differing
active metabolites of the 2 species did not combine in an additive
manner, neither would be adequately tested by this method.
Finally, as Barrett and colleagues recognized, the dosage form
limits the applicability of their results. The most popular products,
and those used in virtually all positive studies, are hydroalcoholic
extracts or fresh expressed juice preparations; improved bioavailabil-
ity, preservation of active compounds, and contact with lymphatic
tissue could contribute to their benefits. If Barrett and colleagues
Letters
© 2003 American College of Physicians 599
selected capsules solely for their lack of sensory qualities, then pla-
cebos and blinding have become no longer means, but ends. They
are valuable research tools but are difcult to apply rigorously to
therapies that do not come in pill form, whether open-heart surgery
or chicken soup. If such therapies are to be evaluated fairly, a more
broadly applicable method must evolve.
Wendy L. Applequist, PhD
Missouri Botanical Garden
St. Louis, MO 63166-0299
References
1. Barrett BP, Brown RL, Locken K, Maberry R, Bobula JA, DAlessio D. Treatment
of the common cold with unrened echinacea. A randomized, double-blind, placebo-
controlled trial. Ann Intern Med. 2002;137:939-46. [PMID: 12484708]
2. Turner RB. Echinacea for the common cold: can alternative medicine be evidence-
based medicine? [Editorial] Ann Intern Med. 2002;137:1001-2. [PMID: 12484717]
TO THE EDITOR: The article on echinacea by Barrett and colleagues
(1) has several overt weaknesses. First, alfalfa is not an inactive herb
and cannot be used as a placebo. Alfalfa has proven phytoestrogenic
actions, is an alterative, detoxies the blood, is very nutritive, and is
antipyretic, any of which may explain why echinacea and alfalfa
performed similarly. Were any herbalists on the study team? Just as
physicians would not believe an herbalists claims about cancer re-
search, practitioners of alternative health will not trust this research.
It would also have helped to have studied a pharmaceutical drug for
a more thorough understanding of cold treatment.
Second, the study was seemingly biased. My daughter looked
into participating and was told that the placebo was going to be
alfalfa. Why were the researchers telling potential participants this? A
person involved in the study also told her that the researchers did not
expect positive results for echinacea. By the way, Barrett and col-
leagues inadvertently identied not 1 but 2 remarkable cold treat-
ments, considering that participants colds lasted only 6 days after
treatment with echinacea and alfalfa and colds normally last 10 days
or more.
Third, Barrett and colleagues found that levels of tumor necro-
sis factor increased with the use of echinacea, but why was this not
promoted as a positive result? It is too late to start taking echinacea
after one gets a cold. The researchers should have measured the
length of time between (or the number of) cold infections in persons
taking echinacea or a true placebo for a whole cold season. Immune
enhancement was measured to some degree but inadequately. A good
study would have measured (in vivo if possible) T-cell activation,
macrophage activation, viral receptor blockage, inhibition of hyal-
uronidase, and release of interferon. Echinacea works best for com-
promised immune systems, but the study did not evaluate this. In
addition, students are a very biased sample.
I am keenly interested in good research, but I do not accept the
ndings of studies that are not performed by a qualied cross-disci-
plinary team. This study is just another step backward.
Steve Shober, MS, MH, ND
Biblical Health Ministries
Waunakee, WI 53597
Reference
1. Barrett BP, Brown RL, Locken K, Maberry R, Bobula JA, DAlessio D. Treatment
of the common cold with unrened echinacea. A randomized, double-blind, placebo-
controlled trial. Ann Intern Med. 2002;137:939-46. [PMID: 12484708]
TO THE EDITOR: Barrett and colleagues did not perform a placebo-
controlled trial (1). The study used alfalfa (Medicago sativa) for the
placebo; however, alfalfa has known biological activity. In 1990, we
published a randomized, controlled trial showing the efcacy of Ur-
tica dioica compared with placebo lactose in treating symptoms of
allergic rhinitis (2). During this study, we also observed that alfalfa is
as effective as U. dioica in the treatment of allergic rhinitis (Unpub-
lished data).
Alfalfa contains bioactive phytochemicals, including 15% to
22% crude protein, minerals (phosphorus, calcium, potassium, so-
dium, sulfur, magnesium, copper, manganese, iron, cobalt, boron,
molybdenum), vitamins (A, D, E, K, C, B
1
,B
2
,B
6
,B
12
, niacin,
pantothenic acid, inositole, biotin, folic acid), amino acids (immu-
nomodulatory canavanine, arginine, asparagine), phytoestrogenic
coumarins (coumestrol) and isoavones (genistein, daidzein, biocha-
nin A, formononetin), avones, and antifungal and hypocholester-
olemic saponins (35). In addition, alfalfa has historically been used
to treat upper respiratory tract conditions.
A placebo is a substance that is pharmacodynamically inert,
making it possible to compare an active treatment with one that is
inactive. Placebo must have no impact on the responses being stud-
ied, and certainly no broad effect on systemic nutrition or immune
activity. Since alfalfa is a substance with numerous bioactive phyto-
chemicals and an equally rich herbal medicine tradition, it cannot be
considered an appropriate placebo. Alfalfa is a particularly improper
placebo for outcome studies in upper respiratory tract conditions, for
example, the common cold.
The study by Barrett and colleagues would have been more
reliable if a proper placebo were selected and if the authors had also
compared the echinacea group with a nontreatment group, which
may have demonstrated more clearly the value of echinacea. Barrett
and colleagues study is a comparative study, not a placebo-
controlled trial.
Paul Mittman, ND
Debra Wollner, PhD
Southwest College of Naturopathic Medicine & Health Sciences
Tempe, AZ 85282
Linda Kim, ND
Southwest College Research Institute
Tempe, AZ 85282
References
1. Barrett BP, Brown RL, Locken K, Maberry R, Bobula JA, DAlessio D. Treatment
of the common cold with unrened echinacea. A randomized, double-blind, placebo-
controlled trial. Ann Intern Med. 2002;137:939-46. [PMID: 12484708]
2. Mittman P. Randomized, double-blind study of freeze-dried Urtica dioica in the
treatment of allergic rhinitis. Planta Med. 1990;56:44-7. [PMID: 2192379]
3. Boon H. Alfalfa. In: Chandler F, ed. Herbs: Everyday Reference for Health Profes-
sionals. Ontario, Canada: Canadian Pharmacists Association and Canadian Medical
Association; 2000.
4. Hanson AA, Barnes DK, Hill RR. Alfalfa and Alfalfa Improvement. Monograph 29.
Madison, WI: American Soc of Agronomy; 1988.
Letters
600 7 October 2003 Annals of Internal Medicine Volume 139 Number 7 www.annals.org
5. Alcocer-Varela J, Iglesias A, Llorente L, Alarcon-Segovia D. Effects of L-canavanine
on T cells may explain the induction of systemic lupus erythematosus by alfalfa. Ar-
thritis Rheum. 1985;28:52-7. [PMID: 3155617]
TO THE EDITOR: Barrett and colleagues (1) reported a placebo-
controlled trial of echinacea for the common cold. The Food and
Drug Administration denes a placebo control as an identical-
appearing treatment that does not contain the test drug . . . the
placebo control design, by allowing blinding and randomization and
including a group that receives an inert treatment, controls for all
potential inuences on the actual or apparent course of the disease
other than those arising from the pharmacologic action of the test
drug (2). Alfalfa does not meet these requirements because it is a
potential inuence on the course of the disease and therefore must be
considered an active control.
Alfalfa is biochemically complex, containing large amounts of
vitamins, minerals, phytoestrogens, and saponins. The saponin con-
stituents alone (molecules with a triterpene or steroid moiety) have
shown a wide range of biological activity. Alfalfa saponins are fungi-
cidal, bactericidal, and insecticidal and have cholesterol-lowering
properties (3). Alfalfa has also been found to contain an abundance
of thyrotropin-releasing hormonelike material (4), which may be
the basis of its traditional use in thyroid disease (5). Alfalfa tablets,
seeds, and sprouts have also been associated with rare instances of the
reactivation of systemic lupus erythematosus and the onset of other
autoimmune disorders. As with echinacea, alfalfa is part of the herbal
pharmacopoeia and has signicant known and no doubt unknown
biological effects.
Barrett and colleagues study informed us of the equivalent ef-
fect of alfalfa and echinacea on the outcomes measured. However,
the results cannot be interpreted because neither herb is considered a
standard treatment for the common cold.
Paul J. Millea, MD, MA
Medical College of Wisconsin
Milwaukee, WI 53226
References
1. Barrett BP, Brown RL, Locken K, Maberry R, Bobula JA, DAlessio D. Treatment
of the common cold with unrened echinacea. A randomized, double-blind, placebo-
controlled trial. Ann Intern Med. 2002;137:939-46. [PMID: 12484708]
2. Guidance for Industry. E10: Choice of Control Group and Related Issues in Clinical
Trials. U.S. Department of Health and Human Services, U.S. Food and Drug Admin-
istration, Center for Drug Evaluation and Research, Center for Biologics Evaluation
and Research. May 2001. Accessed at www.fda.gov/cder/guidance/4155fnl.htm on 26
August 2003.
3. Oleszek W. Alfalfa saponins: structure, biological activity and chemotaxonomy. In:
Waller GR, Yamasaki K, eds. Saponins Used in Food and Agriculture. Advances in
Experimental Medicine and Biology. v 405. New York: Plenum Pr; 1996:155-70.
4. Jackson IM. Abundance of immunoreactive thyrotropin-releasing hormone-like ma-
terial in the alfalfa plant. Endocrinology. 1981;108:344-6. [PMID: 6780314]
5. Medicago sativa. In: PDR for Herbal Medicines. Montvale, NJ: Medical Economics;
1998:963-4.
IN RESPONSE: Randomized, controlled trials are designed to test
specic hypotheses. While bias can be reduced, generalizability and
interpretation are limited. In our trial, a specic echinacea prepara-
tion was tested against a specic control as a treatment for the com-
mon cold. The choice of echinacea was inuenced by the literature
and by popular practice. Several trials of Echinacea purpurea and E.
angustifolia preparations had been positively reported (1, 2). Prod-
ucts containing either or both species were in wide use. We chose a
capsulized whole plant preparation for its simplicity and ease of man-
ufacture. We avoided a liquid preparation because the taste and tin-
gling sensation of echinacea are notoriously difcult to disguise. We
were intent on demonstrating intact blinding, since this had not
previously been accomplished. This guided our choice of placebo.
Because we used clear gelatin capsules containing the whole plant
product, and because some of the herbal taste could leak from the
capsules (and was available to participants who opened them), we
needed a plant-based product that would be indistinguishable to
participants and to research personnel. We settled on whole dried
alfalfa because the color and consistency mimicked the echinacea
product and no research had reported any effects of alfalfa on the
severity or duration of the common cold. However, taste was still
distinguishable, so technicians at Shaklee Technica experimented
with adding various avoring agents, eventually nding that a very
small amount of thyme and peppermint successfully disguised echi-
naceas avor.
We agree that these choices could affect results. Although a bit
far-fetched, it is possible that tiny amounts of peppermint or thyme
could block a positive effect of echinacea. It is also possible, although
unlikely, that a few grams of alfalfa could be an effective treatment
for the common cold. If so, the multimillion-dollar cold remedy
industry should shudder, as a few grams of alfalfa costs only a few
pennies. Perhaps an alfalfa trial will be carried out, and perhaps some
benet will be found. In the meantime, we stand by the results of our
trial: The echinacea preparation we used provided no measurable
benet to college students experiencing cold symptoms. Perhaps it
would have worked in an older sample. Perhaps a rened extract or
liquid preparation would have worked. Perhaps dosing should occur
within 12 hours rather than 36 hours of rst symptoms. Our results
cannot address these important questions, nor can our trial by itself
negate the results of the several positively reported trials. More and
better research is warranted.
Bruce Barrett, MD, PhD
University of WisconsinMadison
Madison, WI 53713
References
1. Barrett B. Medicinal properties of Echinacea: a critical review. Phytomedicine. 2003;
10:66-86. [PMID: 12622467]
2. Melchart D, Linde K, Fischer P, Kaesmayr J. Echinacea for preventing and treating
the common cold. Cochrane Database Syst Rev. 2000:CD000530. [PMID: 10796553]
Alcohol, Postmenopausal Hormones, and Breast Cancer
TO THE EDITOR: In the Nurses Health Study cohort, Chen and
colleagues (1) found an approximately 2-fold excess risk for breast
cancer in women who currently used postmenopausal hormones and
drank alcohol. However, the researchers were unable to consider
high alcohol consumption. To address this issue, we analyzed data
from 2 Italian case control studies. The rst was conducted between
1983 and 1991 in greater Milan (2), and the second was conducted
between 1991 and 1994 in 6 centers in various regions of Italy (3).
The studies involved 3573 postmenopausal women (median age, 61
years [range, 31 to 74 years]) with a histologically conrmed diag-
Letters
www.annals.org 7 October 2003 Annals of Internal Medicine Volume 139 Number 7 601
nosis of incident breast cancer. Controls were 3572 postmenopausal
women (median age, 61 years [range, 34 to 74 years]) admitted to
the same network of hospitals for acute, non-neoplastic, non
hormone-related conditions. The participation rate exceeded 95%
for both case-patients and controls. Information collected on alcohol
drinking included the number of days per week that each type of
alcoholic beverage (wine, beer, and spirits) was consumed, the aver-
age numbers of drinks per day, and the duration of the habit in years.
Each drink included approximately 12 g of ethanol.
In comparison with women who did not drink, the multivariate
odds ratio (OR) was 1.62 for women who had never used postmeno-
pausal hormones who consumed at least 3 drinks per day. Compared
with never-users of postmenopausal hormones, the OR was 1.48 for
ever-users who abstained from alcohol. Women exposed to both
factors had an OR of 2.25. Among the 2879 case-patients and 2752
controls who reported natural menopause, the OR for women who
were exposed to both factors was 2.95 (Table).
Moderate alcohol drinking is socially acceptable among Italian
women (4), and the information on alcohol consumption was satis-
factorily valid and reproducible (5). Our ndings, based on a
uniquely large data set and comparatively high levels of alcohol
drinking, provide further evidence of a substantial excess risk for
breast cancer in women who drink alcohol and have ever used post-
menopausal hormones.
Silvano Gallus, ScD
Istituto di Ricerche Farmacologiche Mario Negri
20157 Milan, Italy
Silvia Franceschi, MD
International Agency for Research on Cancer
69372 Lyon Cedex, France
Carlo La Vecchia, MD
Istituto di Statistica Medica e Biometria, Universita` degli Studi di
Milano
20133 Milan, Italy
Grant Support: By the Italian Association for Cancer Research, Milan,
Italy.
References
1. Chen WY, Colditz GA, Rosner B, Hankinson SE, Hunter DJ, Manson JE, et al.
Use of postmenopausal hormones, alcohol, and risk for invasive breast cancer. Ann
Intern Med. 2002;137:798-804. [PMID: 12435216]
2. La Vecchia C, Negri E, Parazzini F, Boyle P, Fasoli M, Gentile A, et al. Alcohol and
breast cancer: update from an Italian case-control study. Eur J Cancer Clin Oncol.
1989;25:1711-7. [PMID: 2632254]
3. Ferraroni M, Decarli A, Franceschi S, La Vecchia C. Alcohol consumption and risk
of breast cancer: a multicentre Italian case-control study. Eur J Cancer.
1998;34:1403-9. [PMID: 9849424]
4. La Vecchia C, Pagano R, Negri E, Decarli A. Determinants of alcohol consumption
in Italy [Letter]. Int J Epidemiol. 1987;16:295-6. [PMID: 3610459]
5. Ferraroni M, Decarli A, Franceschi S, La Vecchia C, Enard L, Negri E, et al.
Validity and reproducibility of alcohol consumption in Italy. Int J Epidemiol. 1996;
25:775-82. [PMID: 8921456]
Update in Hospital Medicine
TO THE EDITOR: Regarding the section on avoiding femoral line
placement in Flansbaum and Huddlestons Update in hospital med-
icine (1), am I the only one who sees the folly of leaving a femoral
line in place for more than 4 days? In the study reviewed (2), femoral
lines were used for an average of 9.3 days!
I argue that in the short run a femoral line is far safer than a
subclavian line. The complications associated with femoral lines all
occur after 72 hours. Line infections are rare in this time window. If
short-term access is needed, it makes more sense to use the femoral
vein. If access may be needed for more than 72 hours, a subclavian
line should be used. I use femoral lines for all of my patients with
diabetic ketoacidosis. They dont need the line longer than 72 hours,
and they dont get pneumothorax.
I would love to see a study that compares complication rates
between subclavian lines left in longer than 5 days and femoral lines
pulled in less than 72 hours. We all know that the infection rate and
thrombotic rate will both be lower with the femoral line. If central
access will be needed for less than 72 hours, I argue that the femoral
vein is better.
Todd Painton, MD
Appleton Medical Center
Appleton, WI 54911
References
1. Flansbaum BE, Huddleston JM. Update in hospital medicine. Ann Intern Med.
2002;137:814-22. [PMID: 12435218]
2. Merrer J, De Jonghe B, Golliot F, Lefrant JY, Raffy B, Barre E, et al. Complications
Table. Odds Ratios for Breast Cancer in Postmenopausal Women, by Alcohol Intake and Postmenopausal Hormone Use
Alcohol Intake Postmenopausal
Hormone Use
All Postmenopausal Women Women Who Reported
Natural Menopause
Women with
Breast Cancer
Controls Odds Ratio
(95% CI)*
Odds Ratio (95% CI)*
None (abstainers) Never 970 1152 1† 1†
Ever 97 82 1.48 (1.08–2.04) 1.39 (0.95–2.05)
1 drink per day Never 1140 1133 1.19 (1.05–1.35) 1.21 (1.05–1.39)
Ever 148 129 1.41 (1.08–1.83) 1.35 (0.99–1.85)
2 drinks per day Never 792 759 1.23 (1.07–1.41) 1.30 (1.11–1.51)
Ever 63 45 1.60 (1.07–2.40) 2.32 (1.40–3.82)
3 drinks per day Never 327 252 1.62 (1.33–1.96) 1.56 (1.26–1.93)
Ever 36 20 2.25 (1.27–3.99) 2.95 (1.43–6.11)
* Derived from multiple logistic regression models including terms for age, study center, calendar year of interview, education, smoking habit, body mass index, age at
menarche, type of menopause, parity age at rst birth, oral contraceptive use, history of benign breast diseases, and family history of breast cancer in rst-degree relatives.
Reference category.
Letters
602 7 October 2003 Annals of Internal Medicine Volume 139 Number 7 www.annals.org
of femoral and subclavian venous catheterization in critically ill patients: a randomized
controlled trial. JAMA. 2001;286:700-7. [PMID: 11495620]
IN RESPONSE: Reducing problems related to central venous catheter
placement is a high priority, and we agree with Dr. Painton that
appropriate patient screening is prudent and may help avoid needless
line-related complications. Typically, patients with signicant co-
morbid conditions who are seen in the intensive care unit have
longer hospital stays, in addition to continued needs for intravenous
access. The patients in the study by Merrer and colleagues (1) reect
this and, as a result, required longer placement of both subclavian
and femoral lines. The investigators stated that catheters were re-
moved at the discretion of the ICU [intensive care unit] team when
they were no longer needed or if an adverse event occurred.
Whether greater reductions in catheter duration were possible is un-
clear.
In critically ill patients without peripheral access in whom brief
needs for central line placement can be predicted (probably a limited
subset), a strategy favoring anatomic sites with lower complication
rates would be appropriate. While infectious and thrombotic com-
plications are always a risk, it is unlikely that these problems all
occur after 72 hours, and good judgment should direct the location
of any intravascular device. If avoiding pneumothorax is the sole
concern, subclavian access should be attempted at the discretion of
the physician. Ultrasound guidance also reduces the potential for
complications (2).
In patients with diabetic ketoacidosis, such as those Dr. Painton
describes, large-bore peripheral lines should be the optimal choice for
access. They will both minimize complications and maximize uid
resuscitation rates if the patients are very ill.
Bradley E. Flansbaum, DO, MPH
Columbia Presbyterian Medical Center
New York, NY 10032
Jeanne M. Huddleston, MD
Mayo Clinic
Rochester, MN 55905
References
1. Merrer J, De Jonghe B, Golliot F, Lefrant JY, Raffy B, Barre E, et al. Complications
of femoral and subclavian venous catheterization in critically ill patients: a randomized
controlled trial. JAMA. 2001;286:700-7. [PMID: 11495620]
2. Randolph AG, Cook DJ, Gonzales CA, Pribble CG. Ultrasound guidance for
placement of central venous catheters: a meta-analysis of the literature. Crit Care Med.
1996;24:2053-8. [PMID: 8968276]
Acute Migraine Treatment Guideline
TO THE EDITOR: I have had migraines for 30 years and therefore
read Snow and colleagues article on migraine management and pre-
vention (1) with interest. I have used almost all of the medications
mentioned in the article and continue to get migraines at least once
per week, sometimes twice. My migraines are characterized by nau-
sea, occasional vomiting, photophobia, and intense right-side frontal
pain, along with a sense of unease. There is no aura. The triptans I
have takensumatriptan, naratriptan, and rizatriptan do work
with varying onset of action and sometimes rebound pain. I have also
used acetaminophen, butalbital, and caffeine (Fioricet, Novartis,
Basel, Switzerland); nonsteroidal anti-inammatory drugs; acetamin-
ophen; and even zolpidem to allow me to get to sleep when I have a
headache that is not responding.
-Blockers do not lessen the sever-
ity or frequency of my attacks. I have even tried cold showers, usually
to no avail. Menopause did not affect my attacks, nor did hormone
replacement therapy.
After reading several articles on use of botulinum toxin type A
(Botox, Allergan, Inc., Irvine, California) for the treatment of mi-
graine and other chronic headaches, I asked my husband, a derma-
tologist, to inject my frontalis area bilaterally. I received 16 U of
botulinum toxin type A and was headache-free for 6 weeks. I then
developed a severe migraine that lasted for several days. Another set
of injections was given during an attack, and although the attack was
not aborted, I subsequently enjoyed another 6 weeks of freedom. I
had not gone for such a long period without a headache since I was
25 years of age.
Binder and associates (2) examined the effectiveness of botuli-
num toxin type A in 106 women and noted a complete response rate
of 51% (mean response duration, 4.1 months) among the 77 women
who had true migraine, according to American Headache Society
criteria. Ten women also had an acute response to therapy during
attacks. In another study of botulinum toxin therapy in 134 patients
who had migraine, tension, or chronic daily headaches more than 15
days per month, 88% improved and 92% of those who had a series
of 4 treatments at 3-month intervals responded (3).
The mechanism of action of botulinum toxin type A for mi-
graine relief is unknown but is thought to be related to acetylcholine
inhibition and a blocking action on the parasympathetic nervous
system (2). Side effects are rare and mild (4). However, according to
the dermatology literature, blocking antibodies can develop; I do not
know whether this would negate the effects for headache. Neither
Snow and colleagues (1) nor a recent review by Goadsby and co-
workers (5) mentioned botulinum toxin type A as a potential pre-
ventive medication for migraines. I believe that its use should be
carefully studied, since it appears to be an effective treatment.
Catherine Marino, MD
New Jersey Medical SchoolUniversity of Medicine & Dentistry of
New Jersey
Newark, NJ 07103
References
1. Snow V, Weiss K, Wall EM, Mottur-Pilson C. Pharmacologic management of acute
attacks of migraine and prevention of migraine headache. Ann Intern Med. 2002;137:
840-9. [PMID: 12435222]
2. Binder WJ, Brin MF, Blitzer A, Schoenrock LD, Pogoda JM. Botulinum toxin type
A (BOTOX) for treatment of migraine headaches: an open-label study. Otolaryngol
Head Neck Surg. 2000;123:669-76. [PMID: 11112955]
3. Troost TB. Presented at Annual Meeting of the American Headache Society, Seattle,
Washington, 18 June 2002.
4. Silberstein SD. Review of botulinum toxin type A and its clinical applications in
migraine headache. Expert Opin Pharmacother. 2001;2:1649-54. [PMID: 11825307]
5. Goadsby PJ, Lipton RB, Ferrari MD. Migraine current understanding and treat-
ment. N Engl J Med. 2002;346:257-70. [PMID: 11807151]
IN RESPONSE: Dr. Marino provides a very interesting account of her
journey toward achieving relief from her migraines. Happily, she has
found a preventive therapy that is effective for her. Dr. Marino cites
Letters
www.annals.org 7 October 2003 Annals of Internal Medicine Volume 139 Number 7 603
several reports on the use of botulinum toxin therapy in migraine
headache and asks why it was not included in the evidence review for
the American College of Physicians guidelines. First, I must point
out that the Colleges guideline is based on an exhaustive systematic
review of the evidence, performed under the auspices of U.S. Head-
ache Consortium (1, 2). These evidence reviews covered published
studies up until the year 1998. In addition, only trials that were
judged to be well-designed randomized, controlled trials could be
included (3). In order for a recommendation to be made, many such
trials directly relevant to the recommendation had to yield a consis-
tent pattern of ndings. Thus, the study by Binder and associates (4)
that Dr. Marino cites would necessarily be excluded from the review
because of its design (nonrandomized, uncontrolled, open-label).
Since completion of our review, a single randomized, double-
blind, controlled trial of the use of botulinum toxin type A in mi-
graine prevention has been published (5). Silberstein and associates
studied 123 patients with a history of 2 to 8 moderate to severe
migraine attacks per month. Participants were randomly assigned to
receive 25 U or 75 U of botulinum toxin type A injection or injec-
tion of vehicle control. The authors concluded that pericranial injec-
tion of 25 U safely and substantially reduced migraine frequency (at
3 months) and severity (at 2 and 3 months). Of interest, those
treated with 75 U showed no signicant effects. Even if this trial had
been available at the time of our review, however, we could not make
a recommendation on the basis of a single small study. Further large-
scale randomized, controlled studies are needed to conrm these
results, identify the most efcacious doses, and demonstrate long-
term efcacy and safety.
Vincenza Snow, MD
American College of Physicians
Philadelphia, PA 19106
References
1. Matchar DB, Young WB, Rosenberg JH, Pietrzak MP, Silberstein SD, et al. Evi-
dence-based guidelines for migraine headache in the primary care setting: pharmaco-
logical management of acute attacks. 2000. Available at www.aan.com/professionals
/practice/guidelines.cfm
2. Ramadan NM, Silberstein SD, Freitag FG, Gilbert TT, Frishberg BM. Evidence-
based guidelines for migraine headache in the primary care setting: pharmacological
management for prevention of migraine. 2000. Available at www.aan.com/professionals
/practice/guidelines.cfm
3. McCrory DC, Matchar DB, Gray RN, Rosenberg JH, Silberstein SD. Evidence-
based guidelines for migraine headache: overview of program description and method-
ology. 2000. Available at www.aan.com/public/practiceguidelines/headache_gl.htm.
4. Binder WJ, Brin MF, Blitzer A, Schoenrock LD, Pogoda JM. Botulinum toxin type
A (BOTOX) for treatment of migraine headaches: an open-label study. Otolaryngol
Head Neck Surg. 2000;123:669-76. [PMID: 11112955]
5. Silberstein S, Mathew N, Saper J, Jenkins S for the Botox Migraine Clinical Re-
search Group. Botulinum toxin type A as a migraine preventive treatment. Headache.
2000;40:445-50.
CLINICAL OBSERVATION
Editor’s Note: The lead author of the following Clinical Observa-
tion was 1 of a dozen Associates of the American College of Physicians
selected to present a clinical vignette at the 2002 Annual Session in
Philadelphia. We are proud to present this case report through a special
arrangement with the Council of Associates of the College.
An Unusual Case of Ischemic Bowel
TO THE EDITOR: Case Report: A 67-year-old woman presented with
acute abdominal pain that had persisted for 12 hours. The pain was
sharp and generalized throughout the abdomen with associated nau-
sea and vomiting. The patients medical history included myocardial
infarction and hypercholesterolemia, and she was taking metoprolol,
lisinopril, atorvastatin, and estrogenprogesterone. The patient was
in mild distress; her blood pressure was 149/63 mm Hg, her pulse
was 74 beats/min, and her respiratory rate was 22 breaths/min. She
had a slightly distended abdomen, hypoactive bowel sounds, dif-
fusely tender epigastrium, rebound, and guarding. Rectal examina-
tion revealed no masses, and stool was guaiac positive. The physical
examination was otherwise unremarkable.
Initial laboratory tests showed a leukocyte count of 19 10
9
cells/L, 85% of which were neutrophils. Results of Sequential Mul-
tiple Analysis-7, lactic acid, amylase, and liver function tests were all
within normal limits. Abdominal computed tomography demon-
strated dilated proximal small bowel with thickened and edematous
Figure.
Small bowel on computed tomography and an inflamed
vein on pathologic section.
Top. Abdominal computed tomography scan showing small-bowel dila-
tation and thickening (arrow) with mucosal enhancement. Bottom.
Medium-sized vein with exuberant inammation surrounding the vessel
wall and a thrombus in lumen (right). A muscular artery is unaffected
(left). (Hematoxylin eosin; original magnication, 100.)
Letters
604 7 October 2003 Annals of Internal Medicine Volume 139 Number 7 www.annals.org
walls (Figure, top). At emergency exploratory laparotomy, 60 cm of
necrotic proximal small bowel was resected. Histopathologic exami-
nation revealed acute vasculitis with thrombosis of the mesenteric
veins. Surrounding the veins was an inammatory cell inltrate com-
posed of numerous neutrophils, eosinophils, and histiocytes with a
partial hemorrhagic infarct. Arteries were not involved (Figure, bot-
tom). Results of tests for antineutrophil cytoplasmic antibodies and
antinuclear antibodies were negative. Erythrocyte sedimentation rate
was 16 mm/h. There was no evidence of systemic vasculitis. The
patient received no further treatment and remained well 6 months
after surgery.
Discussion: Most cases of mesenteric ischemia are due to supe-
rior mesenteric embolism, arterial thrombosis, nonocclusive isch-
emia, or mesenteric venous thrombosis. Less commonly, the cause
may be classied in 1 of 5 broad categories: mechanical injury, drugs,
hematologic disease, vasculitides, and other (for example, postcoro-
nary artery bypass or peritoneal dialysis) (1). Most vasculitides of the
gastrointestinal tract are secondary to systemic vasculitis (2). Patients
in whom vasculitis is suspected should be tested for systemic vascu-
litis.
While localized gastrointestinal vasculitis is unusual, venulitis is
decidedly rare. In the largest review of localized gastrointestinal vas-
culitis, localized polyarteritis nodosa was the most common cause,
accounting for more than 50% of all cases (3). Vasculitis affecting
only the veins accounted for 19% of cases. Isolated mesenteric venu-
litis is also a rare disorder; fewer than 50 cases have been reported in
the literature (4). The typical patient is older than 40 years of age
and has acute or subacute onset of abdominal pain and diarrhea
followed by peritonitis. Surgical resection is required in all cases.
Histopathologic characteristics consist of lymphocytic inltration
and thrombosis of the inamed veins. The arteries are not involved,
and eosinophils are seen in up to 70% of cases. The cause of the
disease is unclear (5).
Localized mesenteric venulitis is found in the literature under
several different names, including idiopathic enterocolic lymphocytic
phlebitis, mesenteric inammatory veno-occlusive disease, intramu-
ral mesenteric venulitis, idiopathic colonic phlebitis, enterocolic lym-
phocytic phlebitis, and giant-cell granulomatous phlebitis (6). Al-
though histologic differences exist among cases, the common feature
is localized vasculitis affecting the veins and sparing the arteries. The
individual variations in histologic characteristics raise the possibility
of an unusual type of venulitis with several different causes or, alter-
natively, a single disorder characterized by a spectrum of histologic
change (7).
Conclusion: This case illustrates several important points. Vas-
culitis may occur in a localized segment of the gastrointestinal tract,
and removal of the affected bowel is the only treatment required. In
addition, vasculitis may be conned to the veins. A venous source of
intestinal ischemia is rarely suspected and may be overlooked on
angiography (8).
Michael Reinig, DO
Paul Arcand, MD
Henry Soto, MD
Robert Yood, MD
St. Vincent Hospital
Worcester, MA 01608
References
1. Schwartz LB, Gewertz BG. Mesenteric Ischemia. Philadelphia: WB Saunders; 1997:
471-80.
2. Lie JT. Vasculitis and the gut: unwitting partners or strange bedfellows [Editorial].
J Rheumatol. 1991;18:647-9. [PMID: 1865408]
3. Burke AP, Sobin LH, Virmani R. Localized vasculitis of the gastrointestinal tract.
Am J Surg Pathol. 1995;19:338-49. [PMID: 7872432]
4. Martinet O, Reis ED, Joseph JM, Saraga E, Gillet TM. Isolated granulomatous
phlebitis: rare cause of ischemic necrosis of the colon: report of a case. Dis Colon
Rectum. 2000;43:1601-3. [PMID: 11089601]
5. Haber MM, Burrell M, West AB. Enterocolic lymphocytic phlebitis. Clinical, ra-
diologic, and pathologic features. J Clin Gastroenterol. 1993;17:327-32. [PMID:
8308222]
6. Saraga E, Bouzourenne H. Enterocolic (lymphocytic) phlebitis: a rare cause of
intestinal ischemic necrosis: a series of six patients and review of the literature. Am J
Surg Pathol. 2000;24:824-9. [PMID: 10843284]
7. Chergui MH, Vandeperre J, Van Eeckhout P. Enterocolic lymphocytic phlebitis: a
case report. Acta Chir Belg. 1997;97:293-6. [PMID: 9457320]
8. Genta RM, Haggitt RC. Idiopathic myointimal hyperplasia of mesenteric veins.
Gastroenterology. 1991;101:533-9. [PMID: 2065929]
CORRECTIONS
Correction: Treatment of Chronic Hepatitis C in a State
Correctional Facility
In an article on treatment outcomes for incarcerated persons
with hepatitis C virus infection (1), the response rate for all patients
who completed treatment and had data available 6 months after
treatment should have been reported as 40% (26 of 65 patients)
rather than 46% (26 of 57 patients).
Reference
1. Allen SA, Spaulding AC, Osei AM, Taylor LE, Cabral AM, Rich JD. Treatment of
chronic hepatitis C in a state correctional facility. Ann Intern Med. 2003;138:187-90.
[PMID: 12558357]
Correction: National Kidney Foundation Practice Guidelines
for Chronic Kidney Disease
In the National Kidney Foundation practice guidelines for
chronic kidney disease (1), the CockcroftGault equation is printed
incorrectly on page 143. It should be C
Cr
(mL/min)
[(140 age) weight]/72 S
Cr
(0.85 if female), where C
Cr
is
creatinine clearance, S
Cr
is serum creatinine concentration in mg/dL,
age is in years, and weight is in kg.
Reference
1. Levey AS, Coresh J, Balk E, Kausz AT, Levin A, Steffes MW, et al. National Kidney
Foundation practice guidelines for chronic kidney disease: evaluation, classication,
and stratication. Ann Intern Med. 2003;139:137-47. [PMID: 12859163]
Letters
www.annals.org 7 October 2003 Annals of Internal Medicine Volume 139 Number 7 605
Finding Ping
TO THE EDITOR: This letter is written as a follow-up to an earlier
essay (1). The encounter with Jiajia occurred in May 2001. When I
returned to the United States in June, I initiated a search for her. In
July, the U.S. Consulate General in Chengdu responded, providing
the name of Jiajia’s father and his address in a village near Chong-
qing. I sent him a letter, in English, with no real expectation of a
reply. In November, a letter came from him, in Chinese, that in-
cluded a photograph of Jiajia.
A Chinese graduate student translated the letter, which stated
that Jiajia was doing well but that she had been born with only 1
lung and had therefore been prone to many colds and to pneumonia.
The graduate student introduced me to several of his Chinese
friends. One, Xuexian Yan, a physician from Chongqing, had both
graduated from and worked in the medical school there. He offered
to contact physicians there to facilitate Jiajia’s care. Although it
seemed there was little curative potential, we thought that preventive
and acute care requirements could be bolstered. Jiajia’s father had
written, “Jiajia is better compared with when we met at the airplane.
We are worried whether she would face more difficulty and bitter-
ness in the future. By all means, we promise to bring Jiajia a healthy
and normal life, no matter how hard it would be. This is the biggest
wish of us as her parents.”
The now deeply involved Xuexian made telephone contact with
a professor at the Children’s Hospital in Chongqing who said he was
willing to see Jiajia. After making many other telephone calls, Xue-
xian finally reached Jiajia’s parents on the last day of February 2002.
He learned that Jiajia had died in October after contracting an in-
fectious disease and developing a high fever. She had been in the
county People’s Hospital, and her mother had been with her.
We have continued to communicate by telephone and by mail
with Jiajia’s parents. They do have a son, now 12. Her father is 39,
and her mother is 30. Whether they will have another child is un-
known. They have sent us additional pictures of Jiajia, and memories
of her remain very much alive both with her family and with her
friends. Although she lived only 18 months, she left her mark and
deeply affected the lives of those around her.
Alexander C. McLeod, MD, MBA
Nashville, TN 37205-0451
Reference
1. McLeod AC. Finding Ping. Ann Intern Med. 2003;138:432-3. [PMID: 12614098]
Priapism Induced by Proton-Pump Inhibitors and
Misoprostol
TO THE EDITOR: To my knowledge, sexual side effects from antiul-
cer medications have been reported only once in the medical litera-
ture, in the case of a 77-year-old man taking omeprazole and isordil
who developed painful nocturnal erections lasting up to 36 hours
(1). I describe what may be the second documented case of proton-
pump inhibitor–induced priapism and the first case of priapism re-
lated to misoprostol.
A 61-year-old man taking etodolac, atenolol, pravastatin, and
aspirin was prescribed esomeprazole, 40 mg/d, to treat gastritis so
that he could continue taking etodolac for severe noncardiac chest
pain. An uncomfortable nocturnal erection lasting 2 to 6 hours de-
veloped after each of the 6 times that he took a dose of esomeprazole.
On further questioning, the patient reported that he had had the
same experience with rabeprazole 2 years earlier, but his physician at
the time had not believed him. Misoprostol was substituted for es-
omeprazole at an initial dosage of 100
g twice per day; the dose was
slowly titrated upward. When the dose had reached 400
g twice per
day, the patient had nocturnal erections lasting 2 to 6 hours each
time he took misoprostol (3 times in all). By this time, the noncar-
diac chest pain had resolved, and therapy with etodolac and miso-
prostol was discontinued. At 6-month follow-up, the patient had had
no further episodes of priapism, and he confirmed that the disorder
had developed only while he was taking proton-pump inhibitors and
misoprostol.
This patient’s sustained erections probably reflect 2 different
physiologic pathways. Omeprazole causes calcium-channel– depen-
dent relaxation of isolated corpus cavernosum, while misoprostol
causes comparable relaxation that is prostaglandin mediated (2, 3).
Similar mechanisms may be at work in rare persons who are unusu-
ally susceptible to substituted benzimidazole adenosine triphosphate
inhibitors and prostaglandin E
1
analogues. Priapism can be a medical
emergency, resulting in penile infarction. Therefore, clinicians need
to take seriously any reports of priapism during therapy with proton-
pump inhibitors or misoprostol, especially since relaxation of corpus
cavernosum can be demonstrated in vitro for both classes of medi-
cations.
Joseph M. Alisky, MD, PhD
Marshfield Clinic
Marshfield, WI 54449-5790
References
1. Dutertre JP, Soutif D, Jonville AP, Cadenne M, Valat JP, Autret E. Sexual distur-
bances during omeprazole therapy [Letter]. Lancet. 1991;338:1022. [PMID:
1681330]
2. Sarioglu Y, Yildirim S, Utkan T, Yildirim MK, Uma S. Evidence of relaxant effect
of omeprazole in rabbit corpus cavernosum in vitro. Life Sci. 2000;66:1411-21.
[PMID: 11210716]
3. Moreland RB, Kim NN, Nehra A, Parulkar BG, Traish A. Misoprostol induces
relaxation of human corpus cavernosum smooth muscle: comparison to prostaglandin
E1. Int J Impot Res. 2000;12:107-10. [PMID: 11052637]
E-606 Annals of Internal Medicine Volume • Number www.annals.org
Copyright © American College of Physicians 2003.
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Objective.—To assess the safety and efficacy of botulinum toxin type A (BOTOX; Allergan, Inc) in the prevention of migraine. Background.—Current migraine preventive therapies are often unsatisfactory because of their limited efficacy, adverse effects, and drug interactions. Botulinum toxin type A injections often reduce the pain associated with conditions such as cervical dystonia, achalasia, rectal fissures, and myofascial pain syndrome. An open-label, noncontrolled study of botulinum toxin type A suggested benefits for patients with migraine. Design and Methods.—This was a double-blind, vehicle-controlled study of 123 subjects with a history of two to eight moderate-to-severe migraine attacks per month, with or without aura. Participants were randomized to receive single administrations of vehicle or botulinum toxin type A, 25 U or 75 U, injected into multiple sites of pericranial muscles at the same visit. During a 1-month baseline period and for 3 months following injection, subjects kept daily diaries in which they recorded migraine frequency, migraine severity, and the occurrence of migraine-associated symptoms. Results.—Compared with vehicle treatment, subjects in the 25-U botulinum toxin type A treatment group showed significantly fewer migraine attacks per month, a reduced maximum severity of migraines, a reduced number of days using acute migraine medications, and reduced incidence of migraine-associated vomiting. Both the 25-U and 75-U botulinum toxin type A groups were significantly better than the vehicle group on subject global assessment. Botulinum toxin A treatment was well tolerated, with only the 75-U treatment group exhibiting a significantly higher rate of treatment-related adverse events than vehicle. Conclusions.—Pericranial injection of botulinum toxin type A, 25 U, was found to be a safe treatment that significantly reduced migraine frequency, migraine severity, acute medication usage, and associated vomiting.
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