284
Epitomes Important Advances in Clinical Medicine
Emergency Medicine The Scientific Board ofthe California Medical Association presents the following inventory of items ofprogress in emergency medicine. Each item, in the judgment of a panel ofknowledgeable physicians, has recently become reasonably firmly established, both as to scientific fact and important clinical significance. The items are presented in simple epitome, and an authoritative reference, both to the item itselfand to the subject as a whole, is generally given for those who may be unfamiliar with a particular item. The purpose is to assist busy practitioners, students, researchers, or scholars to stay abreast of these items ofprogress in emergency medicine that have recently achieved a substantial degree ofauthoritative acceptance, whether in their own field ofspecial interest or another. The items ofprogress listed below were selected by the Advisory Panel to the Section on Emergency Medicine ofthe California Medical Association, and the summaries were prepared under its direction. Reprint requests to Division of Scientific and Educational Activities, California Medical Association, PO Box 7690, San Francisco, CA 94120-7690
Zidovudine for Prophylaxis of Human Immunodeficiency Virus Infection After Accidental Exposure THE POSSIBLE RISK of the transmission of human immunodeficiency virus (HIV) to health care workers following accidental exposure to contaminated blood and body fluids is a prominent concern. Pooled data from ten prospective studies suggest that the incidence of seroconversion after occupational exposure is 0.37%, or less than 1 case of infection per 250 exposures. Zidovudine is a thymidine analogue that inhibits the viral enzyme reverse transcriptase and also terminates viral-induced DNA synthesis, thus acting as a potent inhibitor of HIV replication. Administering zidovudine has been shown to improve the quality of and prolong life in patients with advanced HIV infection. It delays the destruction of CD4 lymphocytes, the onset of opportunistic infections, and progression to the acquired immunodeficiency syndrome in patients with early and asymptomatic HIV infection. Thus, it appears logical that the early prophylactic administration of zidovudine after accidental HIV exposure might prevent lymphocyte infection and provide an "antidote" for personnel with such exposure. By many criteria, however, zidovudine would be an unlikely agency for postexposure prophylaxis. Zidovudine is an inhibitor of viral replication and functions virostatically by preventing future replication cycles, thus seeming to be best suited to preventing the progression of established infection. Experimental agents exist that prevent HIV entry into lymphocytes-soluble CD4 antigen, dextran sulfate, and heparin-and that selectively destroy HIV-infected cells (GLQ233). These agents may eventually be approved for individual or combined postexposure prophylaxis. Therefore, recommendations made regarding postexposure prophylaxis must be considered dynamic and interim in nature, pending future research. Only limited studies of zidovudine postexposure prophylaxis have been done in both animals and humans, with inconclusive results. Reports have been published of cases of the failure of zidovudine postexposure prophylaxis after accidental, albeit massive, exposure to HIV. The Burroughs Wellcome Company, makers of zidovudine, has initiated a
double-blind, placebo-controlled study of health care workwith such exposure who were given six weeks of zidovudine prophylaxis after the exposure. This study has shown no HIV seroconversion in 84 experimental and control subjects, but the absence of seroconversion in this small group is not
ers
surprising.
As data from studies in both animals and humans are currently inadequate, rationales can be made for and against zidovudine postexposure prophylaxis. The rationale for prophylaxis includes the severity and mortality of established HIV infection, the documented antiviral effect of zidovudine in cases of established HIV infection, and preliminary data from studies in animals suggesting a modification of retroviral infection by zidovudine. The rationale against prophylaxis includes the lack of zidovudine virucidal activity, lack ofdata showing efficacy in postexposure prophylaxis, limited data on toxicity in uninfected persons, and the carcinogenic properties of zidovudine in rats and mice. Current insight into factors associated with the increased risk of occupational infection is limited, and data collection aimed at exposure and risk stratification, that is, types and route of exposure, body fluid type, volume, age of specimen, stage of illness of donor, and use of zidovudine by donor, is needed. Identifying a type of exposure associated with a higher infection rate (5% to 10%) would advance our knowledge on postexposure risk, define a patient group for therapeutic intervention, and greatly reduce the number of subjects necessary for powerful studies on postexposure prophylaxis. Models for institutional postexposure programs are more thoroughly described in the accompanying references. If desired, zidovudine therapy should be instituted as soon as possible after exposure, based on data from animals and the knowledge that intracellular HIV infection in CD4 lymphocytes has been established four hours after exposure. The National Institutes of Health use a regimen of 200 mg every four hours (six times a day) for 42 days, and the University of California, San Francisco, General Hospital Medical Center uses 200 mg every four hours (five times a day, skipping the 4 AM dose) for 28 days. Short-term toxicities of zidovudine
include
marrow
suppression-anemia, thrombocytopenia,
WESTERN JOURNAL OF MEDICINE THE THI
o
SEPTEMBER 1991
0
155
0
granulocytopenia-gastrointestinal symptoms, rashes, constitutional symptoms, and polymyositis. Long-term side effects, such as carcinogenesis and teratogenic effects on future offspring, are unknown. This is of concern because most occupational exposures occur in women of childbearing age. Future research needs in postexposure prophylaxis include stratifying the risk factors for occupational infection, developing better animal models of HIV infection, designing controlled human studies to determine if zidovudine postexposure prophylaxis or other agents are effective, defining optimal dosing and duration of chemoprophylaxis, determining the long-term toxicity of chemoprophylactic agents, and establishing the duration of follow-up needed to detect HIV infection in workers choosing postexposure prophylaxis. LOUIS S. BINDER, MD El Paso, Texas JAMES A. CHAPPELL, MD
Lubbock, Texas REFERENCES Henderson DK, Gerberding JL: Prophylactic zidovudine after occupational exposure to the human immunodeficiency virus: An interim analysis. J Infect Dis 1989; 160:321-327 Lange JMA, Boucher CAB, Hollack CEM, et al: Failure of zidovudine prophylaxis after accidental exposure to HIV-1. N Engl J Med 1990; 322:1375-1377 US Department of Health and Human Services, Public Health Service: Public Health Service statement on management of occupational exposure to human immunodeficiency virus, include considerations regarding zidovudine postexposure use. MMWR 1990; 39:1-14
Magnesium and Acute Myocardial Infarction THE ROLE OF MAGNESIUM in cardiovascular disease has received widespread attention. The relationship between hypomagnesemia and arrhythmias has been well documented. Administering intravenous magnesium is now routine treatment in patients with digitalis toxicity who have ventricular arrhythmias and torsades de pointes. Several investigators have also noted the association between magnesium deficiency and coronary artery disease. Magnesium deficiency may even predispose a patient to infarction. An increased risk for thrombosis, increased peripheral vascular resistance, and a promotion of cholesterol deposits have all been associated with a magnesium-deficient state. In the 1950s and 1960s, there were reports of the beneficial effects of magnesium in treating acute myocardial infarction in uncontrolled clinical trials. Since 1984, there have been six randomized, doubleblind studies using clinical controlled intervention and one follow-up mortality study of the use of intravenous magnesium in patients with acute myocardial infarctions. An early study of 76 patients with myocardial infarctions showed that those treated with magnesium infusions needed substantially lower doses of an antiarrhythmic agent than did controls. Ofanother 130 patients with verified acute myocardial infarction, those randomly assigned to the magnesium infusion group had a 21% incidence of arrhythmias compared with 47% in the placebo group (P = .003). A one-year follow-up study of 270 of 273 patients with suspected myocardial infarction showed death from ischemic heart disease occurred in 28% ofthe placebo group as opposed to 15% in the magnesium-treated group (P = .006). Of note, this reduction was almost solely due to a reduction in the mortality within the first 30 days after inclusion in the study. Another study of 185 patients with possible myocardial infarction showed a decrease in mortality and incidence of arrhythmias in the magnesium-treated group. It has also been
285
3
reported that a single 2.4-gram dose of intravenous magnesium sulfate aborted potentially lethal arrhythmias during the first 24 hours after admission for myocardial infarction in 7 of 48 patients (15%), whereas 16 of46 patients (35%) receiving placebo had similar arrhythmias (P = .02). Another recent report showed patients treated with a continuous infusion of magnesium after a myocardial infarction had significantly fewer episodes of ventricular tachycardia (7 of 25) than did controls (18 of 23) (P = .0001). Most recently, in a study of 103 patients, 48 hours of continuous magnesium infusion produced no statistical difference between the incidence of tachyarrhythmias and conduction disturbances in a treated group versus controls. In-hospital mortality figures, 2% (1 patient) in the magnesium-treated group and 17% (9 patients) in the placebo group, were statistically significant (P < .01), but death was attributed to hemodynamic factors rather than arrhythmias. No adverse effects of magnesium infusion have been reported. In all of the noted clinical trials, there was no significant difference in serum magnesium levels between treatment and placebo groups. Thus, the serum value appears to be an inaccurate assessment of the intracellular environment. More accurate results using lymphocyte levels, muscle biopsy concentrations, and magnesium intravenous loading tests have been described. Postulated mechanisms that continue to gather empiric support and explain the benefits of magnesium infusion in acute myocardial infarction include dilating coronary arteries, inhibiting myocardial calcium overload, preventing arrhythmia, inhibiting platelet aggregation, reducing infarct size, and preventing coronary spasm. CONNIE MITCHELL, MD Sacramento, California
REFERENCES Ceremuzynski L, Jurgiel R, Kulakowski P, Gebalska J: Threatening arrhythmias in acute myocardial infarction are prevented by intravenous magnesium sulfate. Am Heart J 1989; 118:1333-1334 Dubey A, Solomon R: Magnesium, myocardial ischaemia and arrhythmias: The role of magnesium in myocardial infarction. Drugs 1989; 37:1-7 Rasmussen HS, Gronbaek M, Cintin C, Balslov S, Norregard P, McNair P: Oneyear death rate in 270 patients with suspected acute myocardial infarction, initially treated with intravenous magnesium or placebo. Clin Cardiol 1988; 11:377-381 Schechter M, Hanoch H, Marks N, Behar S, Kaplinsky E, Rabinowitz B: Beneficial effect of magnesium sulfate in acute myocardial infarction. Am J Cardiol 1990; 66: 271-274
Preventing and Controlling Violence in Emergency Departments THERE IS WIDESPREAD concern regarding the problem of aggression and violence directed toward staff in hospital emergency departments. Concern over this issue is underscored by a 1987 American Medical Association House of Delegates resolution calling for increased hospital security measures. Until recently, virtually no objective data had been collected about the incidence and magnitude of this problem. The available evidence now suggests that emergency department violence is both widespread and substantial and that many institutions are improperly prepared to deal with it. A six-month prospective study at the Edinburgh Royal Infirmary accident and emergency department (annual volume, 65,000) showed 102 episodes of violence, half of which involved both verbal abuse and physical assault directed against a staffmember. Ofall incidents recorded, 37% occurred between 10 PM and 2 AM. A British National Health Service employee survey found
Epitomes Important Advances in Clinical Medicine
Emergency Medicine The Scientific Board ofthe California Medical Association presents the following inventory of items ofprogress in emergency medicine. Each item, in the judgment of a panel ofknowledgeable physicians, has recently become reasonably firmly established, both as to scientific fact and important clinical significance. The items are presented in simple epitome, and an authoritative reference, both to the item itselfand to the subject as a whole, is generally given for those who may be unfamiliar with a particular item. The purpose is to assist busy practitioners, students, researchers, or scholars to stay abreast of these items ofprogress in emergency medicine that have recently achieved a substantial degree ofauthoritative acceptance, whether in their own field ofspecial interest or another. The items ofprogress listed below were selected by the Advisory Panel to the Section on Emergency Medicine ofthe California Medical Association, and the summaries were prepared under its direction. Reprint requests to Division of Scientific and Educational Activities, California Medical Association, PO Box 7690, San Francisco, CA 94120-7690
Zidovudine for Prophylaxis of Human Immunodeficiency Virus Infection After Accidental Exposure THE POSSIBLE RISK of the transmission of human immunodeficiency virus (HIV) to health care workers following accidental exposure to contaminated blood and body fluids is a prominent concern. Pooled data from ten prospective studies suggest that the incidence of seroconversion after occupational exposure is 0.37%, or less than 1 case of infection per 250 exposures. Zidovudine is a thymidine analogue that inhibits the viral enzyme reverse transcriptase and also terminates viral-induced DNA synthesis, thus acting as a potent inhibitor of HIV replication. Administering zidovudine has been shown to improve the quality of and prolong life in patients with advanced HIV infection. It delays the destruction of CD4 lymphocytes, the onset of opportunistic infections, and progression to the acquired immunodeficiency syndrome in patients with early and asymptomatic HIV infection. Thus, it appears logical that the early prophylactic administration of zidovudine after accidental HIV exposure might prevent lymphocyte infection and provide an "antidote" for personnel with such exposure. By many criteria, however, zidovudine would be an unlikely agency for postexposure prophylaxis. Zidovudine is an inhibitor of viral replication and functions virostatically by preventing future replication cycles, thus seeming to be best suited to preventing the progression of established infection. Experimental agents exist that prevent HIV entry into lymphocytes-soluble CD4 antigen, dextran sulfate, and heparin-and that selectively destroy HIV-infected cells (GLQ233). These agents may eventually be approved for individual or combined postexposure prophylaxis. Therefore, recommendations made regarding postexposure prophylaxis must be considered dynamic and interim in nature, pending future research. Only limited studies of zidovudine postexposure prophylaxis have been done in both animals and humans, with inconclusive results. Reports have been published of cases of the failure of zidovudine postexposure prophylaxis after accidental, albeit massive, exposure to HIV. The Burroughs Wellcome Company, makers of zidovudine, has initiated a
double-blind, placebo-controlled study of health care workwith such exposure who were given six weeks of zidovudine prophylaxis after the exposure. This study has shown no HIV seroconversion in 84 experimental and control subjects, but the absence of seroconversion in this small group is not
ers
surprising.
As data from studies in both animals and humans are currently inadequate, rationales can be made for and against zidovudine postexposure prophylaxis. The rationale for prophylaxis includes the severity and mortality of established HIV infection, the documented antiviral effect of zidovudine in cases of established HIV infection, and preliminary data from studies in animals suggesting a modification of retroviral infection by zidovudine. The rationale against prophylaxis includes the lack of zidovudine virucidal activity, lack ofdata showing efficacy in postexposure prophylaxis, limited data on toxicity in uninfected persons, and the carcinogenic properties of zidovudine in rats and mice. Current insight into factors associated with the increased risk of occupational infection is limited, and data collection aimed at exposure and risk stratification, that is, types and route of exposure, body fluid type, volume, age of specimen, stage of illness of donor, and use of zidovudine by donor, is needed. Identifying a type of exposure associated with a higher infection rate (5% to 10%) would advance our knowledge on postexposure risk, define a patient group for therapeutic intervention, and greatly reduce the number of subjects necessary for powerful studies on postexposure prophylaxis. Models for institutional postexposure programs are more thoroughly described in the accompanying references. If desired, zidovudine therapy should be instituted as soon as possible after exposure, based on data from animals and the knowledge that intracellular HIV infection in CD4 lymphocytes has been established four hours after exposure. The National Institutes of Health use a regimen of 200 mg every four hours (six times a day) for 42 days, and the University of California, San Francisco, General Hospital Medical Center uses 200 mg every four hours (five times a day, skipping the 4 AM dose) for 28 days. Short-term toxicities of zidovudine
include
marrow
suppression-anemia, thrombocytopenia,
WESTERN JOURNAL OF MEDICINE THE THI
o
SEPTEMBER 1991
0
155
0
granulocytopenia-gastrointestinal symptoms, rashes, constitutional symptoms, and polymyositis. Long-term side effects, such as carcinogenesis and teratogenic effects on future offspring, are unknown. This is of concern because most occupational exposures occur in women of childbearing age. Future research needs in postexposure prophylaxis include stratifying the risk factors for occupational infection, developing better animal models of HIV infection, designing controlled human studies to determine if zidovudine postexposure prophylaxis or other agents are effective, defining optimal dosing and duration of chemoprophylaxis, determining the long-term toxicity of chemoprophylactic agents, and establishing the duration of follow-up needed to detect HIV infection in workers choosing postexposure prophylaxis. LOUIS S. BINDER, MD El Paso, Texas JAMES A. CHAPPELL, MD
Lubbock, Texas REFERENCES Henderson DK, Gerberding JL: Prophylactic zidovudine after occupational exposure to the human immunodeficiency virus: An interim analysis. J Infect Dis 1989; 160:321-327 Lange JMA, Boucher CAB, Hollack CEM, et al: Failure of zidovudine prophylaxis after accidental exposure to HIV-1. N Engl J Med 1990; 322:1375-1377 US Department of Health and Human Services, Public Health Service: Public Health Service statement on management of occupational exposure to human immunodeficiency virus, include considerations regarding zidovudine postexposure use. MMWR 1990; 39:1-14
Magnesium and Acute Myocardial Infarction THE ROLE OF MAGNESIUM in cardiovascular disease has received widespread attention. The relationship between hypomagnesemia and arrhythmias has been well documented. Administering intravenous magnesium is now routine treatment in patients with digitalis toxicity who have ventricular arrhythmias and torsades de pointes. Several investigators have also noted the association between magnesium deficiency and coronary artery disease. Magnesium deficiency may even predispose a patient to infarction. An increased risk for thrombosis, increased peripheral vascular resistance, and a promotion of cholesterol deposits have all been associated with a magnesium-deficient state. In the 1950s and 1960s, there were reports of the beneficial effects of magnesium in treating acute myocardial infarction in uncontrolled clinical trials. Since 1984, there have been six randomized, doubleblind studies using clinical controlled intervention and one follow-up mortality study of the use of intravenous magnesium in patients with acute myocardial infarctions. An early study of 76 patients with myocardial infarctions showed that those treated with magnesium infusions needed substantially lower doses of an antiarrhythmic agent than did controls. Ofanother 130 patients with verified acute myocardial infarction, those randomly assigned to the magnesium infusion group had a 21% incidence of arrhythmias compared with 47% in the placebo group (P = .003). A one-year follow-up study of 270 of 273 patients with suspected myocardial infarction showed death from ischemic heart disease occurred in 28% ofthe placebo group as opposed to 15% in the magnesium-treated group (P = .006). Of note, this reduction was almost solely due to a reduction in the mortality within the first 30 days after inclusion in the study. Another study of 185 patients with possible myocardial infarction showed a decrease in mortality and incidence of arrhythmias in the magnesium-treated group. It has also been
285
3
reported that a single 2.4-gram dose of intravenous magnesium sulfate aborted potentially lethal arrhythmias during the first 24 hours after admission for myocardial infarction in 7 of 48 patients (15%), whereas 16 of46 patients (35%) receiving placebo had similar arrhythmias (P = .02). Another recent report showed patients treated with a continuous infusion of magnesium after a myocardial infarction had significantly fewer episodes of ventricular tachycardia (7 of 25) than did controls (18 of 23) (P = .0001). Most recently, in a study of 103 patients, 48 hours of continuous magnesium infusion produced no statistical difference between the incidence of tachyarrhythmias and conduction disturbances in a treated group versus controls. In-hospital mortality figures, 2% (1 patient) in the magnesium-treated group and 17% (9 patients) in the placebo group, were statistically significant (P < .01), but death was attributed to hemodynamic factors rather than arrhythmias. No adverse effects of magnesium infusion have been reported. In all of the noted clinical trials, there was no significant difference in serum magnesium levels between treatment and placebo groups. Thus, the serum value appears to be an inaccurate assessment of the intracellular environment. More accurate results using lymphocyte levels, muscle biopsy concentrations, and magnesium intravenous loading tests have been described. Postulated mechanisms that continue to gather empiric support and explain the benefits of magnesium infusion in acute myocardial infarction include dilating coronary arteries, inhibiting myocardial calcium overload, preventing arrhythmia, inhibiting platelet aggregation, reducing infarct size, and preventing coronary spasm. CONNIE MITCHELL, MD Sacramento, California
REFERENCES Ceremuzynski L, Jurgiel R, Kulakowski P, Gebalska J: Threatening arrhythmias in acute myocardial infarction are prevented by intravenous magnesium sulfate. Am Heart J 1989; 118:1333-1334 Dubey A, Solomon R: Magnesium, myocardial ischaemia and arrhythmias: The role of magnesium in myocardial infarction. Drugs 1989; 37:1-7 Rasmussen HS, Gronbaek M, Cintin C, Balslov S, Norregard P, McNair P: Oneyear death rate in 270 patients with suspected acute myocardial infarction, initially treated with intravenous magnesium or placebo. Clin Cardiol 1988; 11:377-381 Schechter M, Hanoch H, Marks N, Behar S, Kaplinsky E, Rabinowitz B: Beneficial effect of magnesium sulfate in acute myocardial infarction. Am J Cardiol 1990; 66: 271-274
Preventing and Controlling Violence in Emergency Departments THERE IS WIDESPREAD concern regarding the problem of aggression and violence directed toward staff in hospital emergency departments. Concern over this issue is underscored by a 1987 American Medical Association House of Delegates resolution calling for increased hospital security measures. Until recently, virtually no objective data had been collected about the incidence and magnitude of this problem. The available evidence now suggests that emergency department violence is both widespread and substantial and that many institutions are improperly prepared to deal with it. A six-month prospective study at the Edinburgh Royal Infirmary accident and emergency department (annual volume, 65,000) showed 102 episodes of violence, half of which involved both verbal abuse and physical assault directed against a staffmember. Ofall incidents recorded, 37% occurred between 10 PM and 2 AM. A British National Health Service employee survey found
