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A Pulseless Hand: Accidental Epinephrine Injection

TO THE EDITOR: While I was working in an emergency room in Kewanee, Ill., a mother brought in her three-year-old child with a short history of a cold feeling in her right hand. Examination showed delayed capillary refill and decreased pulsation of the extremity. Because arterial thrombosis was suspected, the hand surgery service was contacted.

On further questioning, the child revealed that she had been well until she had placed her hand inside her mother's purse. Inside the purse we found a self-propelling epinephrine injector (Epi E-Z Pen), which we assumed had triggered an injection into the child's hand. Local infiltration was performed with phentolamine (Regitine) in a dosage of 1 mg per kg. Return of color and restoration of pulse occurred within three minutes. Accidental injection of epinephrine is expected to be a rare occurrence, but one that requires an index of suspicion for diagnosis and immediate management referral.

MICHAEL A. AHEARN, M.D.
Family Health Clinic of the Tri-County Area
336 Front St.
Galva, IL 61434

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Reducing Complications in Type 2 Diabetes

TO THE EDITOR: I wish to expand on several points in a recent article on reducing the complications in type 2 (non-insulin­dependent) diabetes.¹ The authors cite the results of the Diabetes Control and Complications Trial (DCCT), which studied glycemic control in patients with type 1 (insulin-dependent) diabetes, and discuss its implications for patients with type 2 diabetes. However, there is now a similar study of glycemic control performed in patients with type 2 diabetes that is more relevent to other patients with type 2 diabetes.² The study randomized 110 patients with type 2 diabetes to intensive or conventional insulin treatment for six years and found reductions in nephropathy, retinopathy and neuropathy that were similar to those found in the DCCT.² The glycemic threshold to prevent these complications was a hemoglobin A_1c level less than 6.5 percent.

Though glycemic control is important, the importance of blood pressure control, at least in the prevention of diabetic nephropathy, cannot be overemphasized. The goal for patients with type 2 diabetes is to maintain a blood pressure less than 130/85 mm Hg, with further reductions as tolerated.³ Angiotensin-converting enzyme (ACE) inhibitors are recommended as first-line therapy for antihypertensive treatment, since they lower glomerular capillary pressure and preserve glomerular filtration rate more than can be explained by their blood pressure effects alone.⁴

In one important ACE inhibitor study, Ravid and colleagues⁵ randomized 94 patients with type 2 diabetes who were normotensive and had normal renal function and microalbuminuria to enalapril maleate (Vasotec), in a dosage of 10 mg per day or placebo, and followed them over five years. While the enalapril group's average protein excretion remained stable at approximately 140 mg per 24 hours, the placebo group's protein excretions increased from 123 to 310 mg per 24 hours.⁵ The American Diabetes Association (ADA) supports the use of ACE inhibitors when type 2 diabetes is accompanied by microalbuminuria and normal blood pressure; for those who have progressed from microalbuminuria to proteinuria, the ADA also recommends dietary protein reductions to 0.8 g per kg per day or 10 percent of calories.³

The recent lowering of the fasting blood glucose cutoff for diagnosing diabetes to 126 mg per dL (6.9 mmol per L)⁶ or greater should allow for earlier diagnosis of diabetes and more effective secondary prevention of complications. Recently, the NIH has launched a multicenter primary prevention trial, the Diabetes Prevention Program (DPP), to find the best way to prevent type 2 diabetes. Successful primary prevention could be the most effective method yet of reducing the microvascular complications of diabetes. While we await the results of the DPP, efforts should be focused on the screening of high risk individuals with fasting blood sugars, the aggressive control of blood pressure and blood sugar and the appropriate use of ACE inhibitors in patients with type 2 diabetes.

STEVEN J. POIRIER, M.D.
Zuni Indian Health Service Hospital
P.O. Box 467
Zuni, NM 87327

REFERENCES

1. Susman JL, Helseth LD. Reducing the complications of type II diabetes: a patient-centered approach. Am Fam Physician 1997;56:471-80.
2. Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, et al. Intensive insulin therapy prevents to progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract 1995; 28:103-17.
3. American Diabetes Association: Clinical Practice Recommendations 1996. Diagnosis and management of nephropathy in patients with diabetes mellitus. Diabetes Care 1996;19(Suppl 1):S103-6.
4. Kasiske BL, Kalil RS, Ma JZ, Liao M, Keane WF. Effect of antihypertensive therapy on the kidney in patients with diabetes: a meta-regression analysis. Ann Intern Med 1993;118:129-38.
5. Ravid M, Savin H, Jutrin I, Bental T, Katz B, Lishner M. Long-term stabilizing effect of angiotensin-converting enzyme inhibition on plasma creatinine and on proteinuria in normotensive type II diabetic patients. Ann Intern Med 1993;118:577-81.
6. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997;20:1183-97.

IN REPLY: We appreciate Dr. Poirier's comments on our article and wish to briefly clarify several important points. Ohkubo and colleagues¹ do provide significant additional evidence for our assertion that microvascular complications in type 2 diabetes are linked to hyperglycemia. However, this study is limited by the small sample size (110 patients) and the inclusion of only nonobese, Japanese, insulin-treated patients. This study also fails to resolve the question of the effects of tighter glycemic control using insulin on macrovascular complications.

We do agree with Dr. Poirier's emphasis on the importance of controlling blood pressure and preventing nephropathy. Nonetheless, we continue to believe that a patient-centered approach may necessitate trade-offs between ideal biomedical management and patient preferences. As Dr. Poirier suggests, the lowering of the fasting blood glucose cutoff for diagnosing diabetes to 126 mg per dL (6.9 mmol per L) or greater will provide an opportunity to diagnose diabetes earlier.² We hope physicians can use this extra lead time to educate their patients, to gain a better understanding of their priorities and to facilitate negotiation of mutually agreed upon goals for management.

JEFFREY L. SUSMAN, M.D.
LYNN HELSETH
University of Nebraska Medical Center
600 S. 42nd St.
Omaha, NE 68198-3075

REFERENCES

1. Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract 1995;28:103-17.
2. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997;20:1183-97.

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Antibiotic Therapy and Serum Digoxin Toxicity

to the editor: In the article on serum digoxin concentration,¹ the discussion under the eighth question (is the patient receiving medications that interact with digoxin?) states that digoxin is metabolized by certain bacteria, such as Eubacterium lentum, which exist in the intestinal flora of approximately 10 percent of the population. It goes on to state that treatment of these patients with antibiotics such as erythromycin and tetracycline can eradicate intestinal flora and cause as much as a twofold increase in the serum digoxin concentration. Since the bacterium metabolizes digoxin, does this mean that these patients ordinarily have a lower serum digoxin concentration while taking the same dose of digoxin as patients who do not have colonization with Eubacterium lentum? Since 1966 I have never observed nor have I heard of any other physician observing a patient with an adverse reaction involving digoxin and tetracycline or erythromycin. How significant is this effect?

PAUL A. CONSTANTINE, M.D.
St. Joseph Medical Group
1095 Irvine Blvd.
Tustin, CA 92780

REFERENCE

1. Cauffield JS, Gums JG, Grauer K. The serum digoxin concentration: ten question to ask. Am Fam Physician 1997;56:495-503.

IN REPLY: Digoxin is metabolized to inactive metabolites, called digoxin reduction products, in approximately 10 percent of patients.¹ These digoxin reduction products are excreted in the urine. As stated in our article, this reduction is presumed to be performed by bacteria such as Eubacterium lentum, which colonize the gut of a minority of patients.² The digoxin reduction products can be detected by clinical assay. Studies detailing the effects of administering oral antibiotics to patients producing digoxin reduction products are limited. In one study,¹ patients receiving erythromycin demonstrated as much as a doubling of serum digoxin concentrations on the seventh day of an erythromycin regimen. In these patients, production of digoxin reduction products dropped significantly. The interaction appears to be more significant when poorly absorbed formulations, such as tablets, are used in comparison with elixir or intravenous preparations.¹

Several cases of digoxin toxicity resulting from concomitant administration of broad-spectrum antibiotics have been reported. In one case,³ involving an 86-year-old woman who was receiving oral digoxin therapy in a dosage of 0.25 mg once daily, trough digoxin concentration increased from 1.9 ng per mL (2.4 nmol per L) to 5.1 ng per mL (6.5 nmol per L) after she had received six days of therapy with erythromycin in a dosage of 250 mg four times daily. The only symptom of digoxin toxicity that she experienced was persistent lethargy. Her symptoms resolved one week after digoxin was discontinued. Other patients experienced symptoms of digoxin toxicity, such as nausea and vomiting, after receiving antibiotic therapy.^4,5,

These case reports suggest that the risk of digoxin toxicity in patients with digoxin reduction products may be increased by factors such as the baseline serum concentration and other factors that influence digoxin metabolism and elimination, such as renal function, age and use of medications that can increase serum digoxin concentrations. Because of the inability to conveniently identify patients at risk for digoxin toxicity, it is recommended that patients receiving digoxin have serum digoxin concentrations monitored at baseline and after completing therapy with broad-spectrum antibiotics.

JOHN G. GUMS, PHARM. D.
Department of Pharmacy Practice
University of Florida
625 S.W. Fourth Ave.
Gainesville, FL 32601

REFERENCES

1. Lindenbaum J, Rund DG, Butler VP Jr, Tse-Eng D, Saha JR. Inactivation of digoxin by the gut flora: reversal by antibiotic therapy. N Engl J Med 1981; 305:789-94.
2. Cauffield JS, Gums JG, Grauer K. The serum digoxin concentration: ten questions to ask. Am Fam Physician 1997;56:495-503.
3. Morton MR, Cooper JW. Erythromycin-induced digoxin toxicity. DICP 1989;23:668-70.
4. Friedman HS, Bonventre MV. Erythromycin-induced digoxin toxicity [Letter]. Chest 1982;82:202.
5. Maxwell DL, Gilmour-White SK, Hall MR. Digoxin toxicity due to interaction of digoxin with erythromycin. BMJ 1989;298:572. *

The editors of AFP welcome input concerning topics of current medical interest and feedback in response to articles and other material published in AFP. Send letters to Jay Siwek, M.D., Editor, American Family Physician, 8880 Ward Pkwy., Kansas City, MO 64114; fax: 816-333-0303; e-mail: afplet@aafp.org. Please include your complete address, telephone number and fax number. Letters should be double-spaced, fewer than 500 words and limited to one table or figure and six references. Letters submitted for publication in AFP must not be submitted to any other publication. Letters pertaining to AFP subject matter must be received within two months of publication. Any financial associations or other possible conflicts of interest must be disclosed at time of submission. Submission of a letter constitutes transfer of copyright to the American Academy of Family Physicians. The editors reserve the right to edit correspondence to meet style and space requirements.

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