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Letters to the Editor

Thromboembolic Events Secondary to Estrogen Therapy

TO THE EDITOR: The excellent review of recurrent thrombosis and hypercoagulability¹ failed to mention the increased risk of thromboembolic events associated with use of unopposed estrogen therapy or estrogen-progestin hormone replacement therapy, or with endogenous estrogen dominance relative to progesterone.

The increased risk of thromboembolic events secondary to estrogen therapy has long been known by experienced physicians. A recent letter¹ reports a venous thromboembolic risk 2.0 to 3.6 times higher in estrogen-progestin hormone replacement therapy users than in nonusers.¹ A well-referenced review article³ presents strong evidence that higher fibrinogen levels, higher blood viscosity, and less filterable, stiffer red blood cells occur during the follicular phase of the menstrual cycle than during the progesterone-rich secretory phase.

Thus, solid research indicates that (1) estrogen is a potent risk factor in thromboembolic events and (2) progestins (foreign, synthetic progesterone-like compounds) offer little protection against estrogen-induced thromboembolic events, whereas progesterone is protective. It would have been appropriate for Drs. Harris and Abramson to include this knowledge in Table 1 of their article.

JOHN R. LEE, M.D.
9620 Bodega Hwy.
Sebastopol, CA 95472

REFERENCES

1. Harris JM, Abramson N. Evaluation of recurrent thrombosis and hypercoagulability. Am Fam Physician 1997;56:1591-6.
2. Grady D, Hulley SB, Furberg C. Venous thromboembolic events associated with hormone replacement therapy [Letter]. JAMA 1997;278:477.
3. Hrushesky WJ. Breast cancer, timing of surgery, and the menstrual cycle: call for prospective trial.
   J Women Health 1996;5:555-66.

IN REPLY: We are grateful to Dr. Lee for the comments regarding the association of estrogenic factors and hypercoagulability. Indeed, estrogens and estrogen analogs, such as tamoxifen (Nolvadex) are associated with deep venous thrombosis and pulmonary emboli.

It was our purpose to review the primary coagulation disorders. However, as long as Dr. Lee raises the subject of estrogenic influences, we would like to reemphasize a point we made: estrogen-associated hypercoagulation may be related to primary coagulation defects. Women with known abnormalities of the protein S and C pathways (including factor V leiden) are at greater risk for thrombosis when estrogens are used.¹ Future epidemiologic data might reveal that a number of women in the general population who develop hypercoagulability with the use of estrogen therapy (or with use of tamoxifen) have unrecognized coagulation abnormalities.

NEIL ABRAMSON, M.D.
Baptist Regional Cancer Institute
1235 San Marco Blvd., Ste. 3
Jacksonville, FL 32207

REFERENCE

1. Olivieri O, Frisco S, Manzato F, Guella A, Bernardi F, Lunghi B, et al. Resistance to activated protein C in healthy women taking oral contraceptives. Br J Haematol 1995;91:465-70.

ECG Findings and Hypertrophic Cardiomyopathy

TO THE EDITOR: It was great to see the excellent two-part series on common cardiovascular problems in the young.^1,2 However, I disagree with the interpretation rendered for the electrocardiogram (ECG) shown in Figure 1 of the second article in this series.

The legend for this figure reads as follows: "ECG from a 12-year-old girl with hypertrophic cardiomyopathy. Note the presence of sinus rhythm and wide, bizarre QRS complexes. The recording is at half standard, so the complexes are actually twice as large as displayed. The ECG is abnormal in over 90 percent of patients with hypertrophic cardiomyopathy. The most common abnormalities are left ventricular hypertrophy, ST-segment alterations, T-wave inversion, large Q waves and the peculiar diminution of R waves in the lateral precordial leads seen in this patient."

Close inspection of lead V1 in this tracing shows a short PR interval, slurring of the intial portion of the QRS complex (a delta wave) and QRS widening. Although delta waves are not well seen in many of the other leads in this tracing, I believe there is slurring of the initial part of the QRS in leads V4 and V5. In addition, the multiple deflections in the inferior leads may represent partially negative delta waves. I therefore believe that this ECG is highly suggestive of Wolff-Parkinson-White (WPW) syndrome.

While I fully agree that most patients with hypertrophic cardiomyopathy have an abnormal ECG, I do not feel that the tracing shown in Figure 1 is representative of what one should expect to find with this abnormality, other than the slight increased association of a familial form of WPW that is seen with hypertrophic cardiomyopathy.

KEN GRAUER, M.D.
Family Practice Residency Program
University of Florida College of Medicine
625 S.W. Fourth Ave.
Gainesville, FL 32614

REFERENCE

1. Gutgesell HP, Barst RJ, Humes RA, Franklin WH, Shaddy RE. Common cardiovascular problems in the young: Part I. Murmurs, chest pain, syncope and irregular rhythms. Am Fam Physician 1997; 56:1825-30.
2. Gutgesell HP, Atkins DL, Day RW. Common cardiovascular problems in the young: Part II. Hypertension, hypercholesterolemia and preparticipation screening of athletes. Am Fam Physician 1997; 56:1993-8.

IN REPLY: Dr. Grauer correctly points out that the ECG in Figure 1 of the second part of our review on common cardiovascular problems in the young appears to show preexcitation. The patient in question has marked septal hypertrophy and mild left ventricular outflow obstruction by echocardiography but has never complained of tachycardia. It illustrates our point that the ECG is almost always abnormal in hypertrophic cardiomyopathy, with preexcitation being one of the abnormalities that may occur.

HOWARD P. GUTGESELL, M.D.
Division of Pediatric Cardiology
University of Virginia Children's Medical Center
Box 386
Charlottesville, VA 22908

Gamma-Hydroxy Butyrate

TO THE EDITOR: Gamma-hydroxy butyrate is an increasingly popular illicit drug used by body builders for its alleged anabolic effects and by recreational drug users for its effects on the central nervous system. When purchased as a powder, it may be called Somatomax PM or sodium oxybate. Gamma-hydroxy butyrate also has a number of street names, including "liquid ecstasy," "grievous bodily harm," "GBH," and "liquid X." At selected body building gyms, night clubs and "rave" halls, gamma-hydroxy butyrate is sold pre-mixed in small glass jars. At high doses, its sedative effect and ability to produce muscle relaxation and hypotonia, along with its amnestic effect, have been exploited in the practice known as "date rape." The onset of action is usually within 15 minutes, and effects resolve within eight hours.

Gamma-hydroxy butyrate is a four-carbon fatty acid endogenous metabolite of gamma amino butyric acid, a central nervous system depressant. It is present in the brain at about one thousandth of the concentration of its parent compound. Gamma-hydroxy butyrate increases the level of dopamine in the brain and produces its effects by unknown mechanisms.¹ At higher doses (above 30 mg per kg, or about two capfuls of powder), it may produce loss of strength, a trance-like state and amnesia.

Street lore and eyewitness accounts of gamma-hydroxy butyrate ingestion describe a lag period, after which the user becomes limp and drops to the floor. Ingesting more than three capfuls or mixing gamma-hydroxy butyrate with alcohol or other intoxicants may cause recurrent vomiting and central nervous system depression, which may lead to stupor or coma. Respiratory depression has been reported.¹

Some experts believe that daily ingestion of doses of about two or more capfuls (30 to 50 mg per kg) can lead to addiction. The craving has been described by those using it to be somewhat similar to that of cocaine.

During the 12-month period ending September 1996, poison control centers in New York, Dallas and Galveston, Tex., received reports of 69 acute poisonings and one death attributed to ingestion of gamma-hydroxy butyrate.² Appropriate warnings have been printed in various medical journals, including state medical journals.^3-5 There are now 14 documented fatalities caused by gamma-hydroxy butyrate, often in association with sublethal doses of alcohol (personal communication, Dr. James Tollinei).

Two states (Rhode Island and Georgia) have classified gamma-hydroxy butyrate as a Schedule I drug (no proven clinical use and high potential for abuse), and several other states are considering similar action.

The drug can not be detected with standard urinalyses used to test for drugs of abuse, because it requires gas chromatography for detection.⁶ Gamma-hydroxy butyrate should be added to the list of illicit drugs that can cause syncope and coma. Ingestion should be considered in body builders who present to the emergency department with such symptoms. No known antidote to gamma-hydroxy butyrate intoxication exists. Naloxone (Narcan, Talwin) has been tried but without success.

RICHARD H. SCHWARTZ, M.D.
Department of Family Medicine
Medical College of Virginia
MCV Station
Richmond, VA 23298

REFERENCES

1. Gamma hydroxy butyrate poisoning. Medical Letter 1991;33:8.
2. Gamma hydroxy butyrate use--New York and Texas, 1995-1996. MMWR Morb Mortal Wkly Rep 1997;46:281-3.
3. Nightingale SL. Warning about GHB. JAMA 1991; 265:1802.
4. Chin MY, Kreutzer RA, Dyer JE. Acute poisoning from gamma-hydroxybutyrate in California. West J Med 1992;156:380-4.
5. Steele MT, Watson WA. Acute poisoning from gamma hydroxybutyrate (GHB). Missouri Med 1995;92:354-7.
6. Lettieri JT, Fung HL. Evaluation and development of gas chromatographic procedures for the determination of gamma-hydroxy butyrate acid and gamma-butyrolactone. Biochem Med 1978;20:70-80.

Bacterial Meningitis and Antimicrobial Therapy

TO THE EDITOR: Tunkel and Scheld¹ suggest that when bacterial meningitis is suspected, "initiation of antimicrobial therapy optimally should begin within 30 minutes of the patient's presentation to the hospital." The authors qualify the statement by noting that no definitive study has correlated a delay in the initiation of therapy with a worsened outcome. Little evidence has suggested that delays of one to two hours in antibiotic treatment lead to adverse outcomes.

Dr. Kallio and colleagues² compared the outcome of children three months to 15 years of age in whom the diagnosis of meningitis was made immediately with the outcome in those in whom the diagnosis was delayed up to four days. No difference was found in the outcomes measured at six months. The study did not address the interval from diagnosis to treatment. The statistical and medicolegal issues of this study were debated in a subsequent letter to the editor by Dr. Wenner, with a reply from Dr. Kallio and his associates.³

Dr. Meadow and colleagues⁴ investigated the actual time from patient presentation to administration of antibiotics. The study setting consisted of two university-affiliated pediatric emergency departments that were staffed by residents, fellows and attending physicians. The median time from presentation to administration of antibiotics in children with meningitis was two hours. Only one of 93 patients received treatment within 30 minutes, and only 15 received treatment within 60 minutes of initial presentation. No significant correlation was found between the time elapsed before treatment and outcome.

Drs. Talan and Zibulewsky⁵ performed a similar study of 122 patients, ranging in age from one month to 60 years of age or older, in two teaching hospitals. Patients were evaluated by pediatric, internal medicine or emergency medicine residents and/or emergency medicine attending physicians. The mean time from registration to antibiotic administration was 2.7 hours. The authors did not attempt to correlate treatment timing with outcome.

A literature review performed by Radetsky⁶ addressed delays in diagnosis and treatment. Evaluation included 22 studies of different design, involving a total of 4,707 patients. The findings showed that in patients with "insidious" or nonspecific symptoms at onset, a delay in treatment of three to five days did not result in adverse sequelae; in patients with "fulminant meningitis," a delay in therapy was not connected with outcome; and in patients with "clinically overt nonfulminant meningitis," an "excessive" delay in initiating therapy increased the risk for permanent injury. "Excessive" delay was not defined.

The goal of physicians should be to diagnose and initiate the proper treatment of meningitis as soon as possible. Failure to do so may possibly place the patient at risk for adverse outcome and the physician at risk for medicolegal inquiry. It would not be reasonable to delay the diagnosis and treatment of bacterial meningitis, but many factors contribute to the length of time from a patient's presentation to treatment. Standards of care should be based on data and should reflect the realities of typical practice settings.

ROBERT B. HASH, M.D.
Mercer University School of Medicine
1550 College St.
Macon, GA 31207

REFERENCES

1. Tunkel AR, Scheld WM. Issues in the management of bacterial meningitis. Am Fam Physician 1997; 56:1355-62.
2. Kallio MJ, Kilpi T, Anttila M, Peltola H. The effect of a recent previous visit to a physician on outcome after childhood bacterial meningitis. JAMA 1994; 272:787-91.
3. Wenner WJ Jr. Diagnostic delays with bacterial meningitis [Letter]. JAMA 1995;273:621-2.
4. Meadow WL, Lantos J, Tanz RR, Mendez D, Unger R, Wallskog P. Ought "standard care" be the "standard of care"? A study of the time to administration of antibiotics in children with meningitis. Am J Dis Child 1993;147:40-4.
5. Talan DA, Zibulewsky J. Relationship of clinical presentation to time to antibiotics for the emergency department management of suspected bacterial meningitis. Ann Emerg Med 1993;22:1733-8.
6. Radetsky M. Duration of symptoms and outcome in bacterial meningitis: an analysis of causation and the implications of a delay in diagnosis. Pediatr Infect Dis J 1992;11:694-8.

IN REPLY: We agree with Dr. Hash that no definitive study has correlated a delay in the initiation of antimicrobial therapy with a worsened outcome in patients with bacterial meningitis. He cites several studies to support this statement, which are all flawed given their retrospective nature. Even in the large retrospective review by Radetsky,¹ in the subgroup of patients with clinically apparent meningitis and documented neurologic findings, there were insufficient data to establish any correlation between duration of symptoms and outcome. Furthermore, Radetsky did not separate the data based on causative organism. This is critical since Haemophilus influenzae type b meningitis is associated with a mortality rate of 3 to 6 percent, whereas patients with meningitis caused by Streptococcus pneumoniae have a mortality rate ranging from 19 to 26 percent.²

Other studies have supported the concept of rapid administration of antimicrobial therapy. One such study³ was a retrospective analysis of 46 consecutive patients with meningococcal disease before presentation to the hospital; none of the 13 patients who were given parenteral penicillin by the referring physician died, while eight deaths occurred among 33 patients who were admitted without such initial treatment. Another retrospective study⁴ reviewed hospital notes and laboratory and public health medical department records of patients in Southwest England who were presumed to have meningococcal meningitis. Patients who were given parenteral benzylpenicillin by general practitioners before hospital admission had a lower mortality rate than patients treated later (5 percent versus 9 percent); the mortality rate was also lower in patients who presented with a hemorrhagic rash (5 percent versus 12 percent). Although these data are retrospective in nature and did not specifically review patients with meningitis, they suggest that early administration of antimicrobial therapy to patients with meningococcal disease improves outcome. Furthermore, in a retrospective review⁵ by the British Society for the Study of Infection of 305 patients with bacterial meningitis, mortality rates were lower in the patients who received antimicrobial therapy before admission than in those treated later (2 percent versus 12 percent).

Dr. Hash also makes the point that early administration (within 30 minutes) of antimicrobial therapy in patients with bacterial meningitis does not reflect the realities of typical practice settings; this was suggested by two of the trials he cited. However, these studies were also retrospective in nature. We feel they highlight the importance of educating physicians to recognize the likelihood of bacterial meningitis as soon as possible to begin appropriate therapy.

In the absence of clinical data and in view of the fact that ethical concerns preclude performance of a prospective, randomized trial of the time from presentation to administration of antimicrobial therapy in patients with bacterial meningitis, what is the optimal timing of administration of antimicrobial therapy that should be recommended? Our suggestion that antimicrobial therapy should optimally be administered within 30 minutes of the patient's presentation to the hospital was not meant as a recommendation for the standard of care in the medicolegal sense. We feel that this recommendation will serve to alert health care professionals to the importance of considering the diagnosis of bacterial meningitis in the right clinical setting and administering antimicrobials as rapidly as possible.

When patients with bacterial meningitis present for medical attention, all that is known is the duration of symptoms--not the duration of bacterial meningitis. Many patients who are eventually diagnosed with bacterial meningitis and who have had symptoms for more than three to five days may not have had bacterial meningitis for that entire period of time. In contrast, patients with fulminant presentations may have had bacterial meningitis long before presentation.

We agree with Dr. Hash that failure to rapidly diagnose and treat the patient with bacterial meningitis may only possibly place the patient at risk for an adverse outcome. However, we feel that the only reasonable course, in the best interest of the patient and in the absence of clinical data, is emergent diagnosis and rapid initiation of antimicrobial therapy.

ALLAN R. TUNKEL, M.D., PH.D.
Department of Medicine
Allegheny University of the Health Sciences
3300 Henry Ave.
Philadelphia, PA 19129

W. MICHAEL SCHELD, M.D.
University of Virginia School of Medicine
Charlottesville, VA 22908

REFERENCES

1. Radetsky M. Duration of symptoms and outcome in bacterial meningitis: an analysis of causation and the implications of a delay in diagnosis. Pediatr Infect Dis J 1992;11:694-8.
2. Tunkel AR, Scheld WM. Acute meningitis. In: Mandell GL, Bennett JE, Dolin R, eds. 4th ed. Principles and practice of infectious diseases. New York: Churchill Livingstone, 1995:831-65.
3. Strang JR, Pugh EJ. Meningococcal infections: reducing the case fatality rate by giving penicillin before admission to hospital. BMJ 1992;305:141-3.
4. Cartwright K, Reilly S, White D, Stuart J. Early treatment with parenteral penicillin in meningococcal disease. BMJ 1992;305:143-7.
5. The Research Committee of the British Society for the Study of Infection. Bacterial meningitis: causes for concern. J Infect 1995;30:89-94.

Copyright 1998 by the American Academy of Family Physicians.
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