REPORTS ON THERAPY
Intravenous Diazoxide Therapy in Hypertensive Crisis
WALTER J. MCDONALD, MD GORDON SMITH, MD” JAMES W. WOODS, MD H. MITCHELL PERRY, MD, FACC BYRON D. DANIELSON, MD+ Portland, Oregon Boston, Massachusetts Chapel Hill, North Carolina St. Louis, Missouri Minneapolis, Minnesota
Ninety-one doses of diazoxide were administered intravenously to 41 patients with hypertensive crises. Diastolic blood pressure was reduced from an average of 139 to 98 mm Hg within 10 minutes. On the basis of a retrospective analysis of the response of diastolic blood pressure, it was possible to determine within 10 minutes of injection whether a second dose would be required. Therapy was judged to be effective in 38 of 41 patients; 35 percent of injections were ineffective. Concomitant administration of furosemide was not shown to have a beneficial antihypertensive effect. Mean blood urea nitrogen was 59.5 mg/lOO ml initially and was not significantly diff’erent 2 weeks after therapy. None of the patients demonstrated clinical evidence of diazoxide-induced deterioration of coronary circulation. Electrocardiograms obtained 2 weeks after diazoxide therapy failed to show evidence of new ischemic changes. Only 9 percent of patients complained of side effects, and these were transient and relatively innocuous. It is concluded that diazoxide is both safe and efficacious in the management of hypertensive crises.
The introduction of the benzothiadiazine derivative diazoxide has been a significant advance in the therapeutic approach to the hypertensive crisis. Several reports1-8 attest to the efficacy and safety of this compound. The rapidity with which control of blood pressure is achieved has led to a reevaluation of the therapeutic goals in managing the severely hypertensive patient. To evaluate further the effectiveness and safety of diazoxide in the clinical setting, a multicenter study was undertaken. Patients presenting with severe hypertension were treated with intravenously administered diazoxide and carefully evaluated over the ensuing 2 weeks. The results demonstrated that diazoxide safely, rapidly and effectively reduces blood pressure and is useful in treating most hypertensive crises. Methods From the Portland Veterans Administration Hospital and University of Oregon Health Sciences Center, Portland, Oregon; Boston University Medical Center, Boston, Massachusetts; University of North Carolina School of Medicine, Chapel Hill, North Carolina; Veterans Administration Hospital, St. Louis, Missouri; and the Renal Section, Hennepin County Hospital, Minneapolis, Minnesota. Manuscript received January 24, 1977; revised manuscript received March 8, 1977, accepted March 16, 1977. + Present address: Cheshire, Connecticut. t Present address: Dakota Clinic, Fargo, North Dakota. Address for reprints: Walter J. McDonald, MD, Portland Veterans Administration Hospital, Portland, Oregon 97207.
and Materials
Protocol: Five centers participated in the study. Forty-one patients, judged to have hypertension of sufficient severity to warrant rapid reduction of blood pressure, were entered into the protocol. Age, sex, race, weight, concurrent disease, medications, basal blood pressure and pulse were recorded. Blood was drawn for determinations of glucose, urea nitrogen, uric acid and creatinine levels. Electrocardiograms and chest X-ray films were obtained. A total of 91 doses of diazoxide were administered intravenously to the study group of 41 patients. Eighty-nine doses were injected over a period not exceeding 30 seconds, and 2 doses over a 1 minute period. In 11 instances, the dose was less than, and in 4 instances greater than, 300 mg; in the remaining 76 injections, the dose was 300 mg. Blood pressure, pulse and symptoms were recorded 2,5,10,15,45 and 75 minutes and 2,4,8,12,24,36 and 48 hours after injection. Concurrently administered antihypertensive medications were recorded. The variables cited were monitored over the succeeding 2 weeks. Mean blood pressure was calculated from the formula: mean blood pressure = diastolic blood pressure plus one third of pulse pressure.
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ET AL.
Three patients received more than one course of therapy. Seventy-five percent of the courses consisted of one or two injections. Nine patients were without concurrent disease. Four patients had a history of coronary artery disease and four a history of occlusive cerebrovascular disease. Seventeen had significant renal dysfunction, but none was undergoing long-term dialysis at the initiation of this study. The remaining diagnoses were varied and unrelated to the cardiovascular system. Three patients died within 2 months of diazoxide therapy. These deaths, occurring 8,23 and 54 days, respectively, after treatment, appeared to be unrelated to diazoxide therapy.
TABLE I Number
of Courses
and Injections
per Course
Injections (no.)
Courses (no.)*
1 2 3 4 5 6 Total
22 13 6 2 1 2 46
A course of treatment is defined as a series of injections, no two of which are more than 120 hours apart. l
Results Blood pressure: For purposes of analysis, the patients were classified into three groups: those who received one injection (18 patients) and those who received two (13 patients) or more (10 patients) injections. The blood pressure response of patients receiving a single injection of diazoxide is shown in Figure 1. Four of the patients in this group had two courses of therapy. The average (i standard error of the mean) pretreatment systolic, diastolic and mean blood pressures were 229 f 4.4, 139 f 3.5 and 169 f 3.9 mm Hg, respectively. Within 10 minutes, average systolic and diastolic pressures were reduced to 166 f 6.9 and 98 f 4.0 mm Hg, respectively. Generally, blood pressure remained at these levels for the first 48 hours after therapy. The response of mean blood pressure in 13 patients receiving two injections is shown in Figure 2. The initial mean blood pressure of 178 f 4.6 mm Hg is not different from that observed in patients requiring only a single injection. The reduction in blood pressure resulting from the first injection in this group of patients was maximal at 2 minutes, decreasing to 139 f 7.5 mm Hg. The subsequent rise toward pretreatment values necessitated the second injection. The mean pressure decreased to 128 f 8.8 mm Hg within 2 minutes after injection
A single course of d&oxide therapy was arbitrarily defined as a single injection or a series of injections, no two of which were more than 120 hours apart. Several patients received more than one course of diazoxide therapy. Assessment of effectiveness: Each investigator subjectively assessed the effectiveness of diazoxide therapy in the patients for whom he was responsible. In addition, objective data were obtained to corroborate and support the clinical assessment. An injection was classified effective if diastolic blood pressure decreased by more than 30 mm Hg or to less than 100 mm Hg within the first 10 minutes of administration and if the reduction was sustained for at least 75 minutes. Transient effectiveness was defined as a similar reduction of blood pressure not sustained for 75 minutes. An ineffective iniection was one that failed to result in this decrement of blood pressure. Demographic data: Forty-one patients aged 23 to 71 years were studied. There were 26 men and 15 women whose weights ranged from 47.3 to 128.2 kg. The number of injections per course and the courses of injections are shown in Table I.
Omin.
2
5
10
1
15
45
L
75
,
2hr.
I
4
L I
8
12
I
24
TIME
410
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FIGURE 1. Systolic, diastolic and mean blood pressure standard error of the mean) in 18 patients receiving a single injection of diazoxide.
(zk
DIAZOXIDE
IN HYPERTENSION-MCDONALD
ET AL.
r
FIGURE 2. Mean blood pressure (zb standard error of the mean) in 13 patients receiving two injections of diazoxide. Response to the first injection is-plotted for only 75 minutes because of insufficient observations beyond that
L
,
i
I
Omin.
2
5
L I 10
15
I
I
45
75
I
I
t
I
2hr.
4
8
12
1 24
J 40
TIME
time.
of the second dose. Subsequently, the blood pressure tended to decrease during the next 48 hours. The mean blood pressure response observed in 10 patients receiving more than two injections is illustrated in Figure 3. The changes in pressure induced by the first and last doses are shown. Response to the first dose was inadequate and this was apparent in most cases within 75 minutes. The last in-
jection generally resulted in a rapid initial reduction of mean pressure and a subsequent progressive decrease over the next 48 hours. Effectiveness of diazoxide therapy: Each investigator was asked to assess subjectively the effectiveness of diazoxide therapy in the patients for whom he was responsible. By these criteria, diazoxide was judged effective in 38 of 41 patients.
o-o
Lad
lnl.ctlon
140
1
100
FIGURE 3. Mean blood pressure (AZstandard error of the mean) in 10 patients receiving more than two injections of diazoxide. Data from first and last injections are plotted. Response to the first injection is plotted for 15 minutes only because of insufficient observations beyond that time.
1 w
L
1
I
I
I
I
Omin.
2
5
10
15
I
45
I
75
I
2 hr.
I
1
I
I
4
8
12
24
I 48
TIME
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The data were further analyzed to determine how frequently the diastolic pressure reduction obtained within the first 10 minutes of injection was within 10 mm Hg of the lowest diastolic reading obtained within the first 2 hours. After the first injection of diazoxide, 40 of 41 patients (97 percent) fulfilled these criteria. For the second or subsequent injections, the corresponding figure was 36 of 45 patients (80 percent). If the observation period for second or subsequent injections was extended from 10 to 15 minutes, the diastolic pressure in 39 of 45 patients (87 percent) was within 10 mm Hg of the lowest obtained reading. In no instance did diastolic pressure, after 10 minutes, decrease by more than 30 mm Hg during the subsequent 2 hours. In only six patients was diazoxide given within 30 minutes of a previous injection. In none of these patients was the response to the second dose greater than the response to the first. Influence of renal function on blood pressure response: The response to the first injection of d&oxide was evaluated as a function of pretreatment levels of blood urea nitrogen and creatinine. Data were sufficient in 36 of the 41 patients to permit analysis. Eighteen patients had an effective response to the first injection; mean blood urea nitrogen and creatinine were 62 and 5.4 mg/lOO ml, respectively, for these patients. For the 16 patients who failed to respond, mean blood urea nitrogen and creatinine were not significantly different (65 and 6.3 mg/lOO ml, respectively). Two of the injections were transiently effective and mean blood levels for these patients were 24 and 1.9 mg/lOO ml, respectively. The response to d&oxide in these patients did not correlate with pretreatment renal function. Concomitant use of furosemide: Although no attempt was made to control the use of other orally administered antihypertensive agents, the response to d&oxide was analyzed with respect to the concomitant use of furosemide. Seventy-seven injections could be analyzed; furosemide was administered in conjunction with 48 of these. Forty-three percent of the
TABLE II Time When Maximal Reduction in Diastolic Pressure Was Obtained After ihe First, Second or Subsequent Injection of Diazoxide Time After Injections tmin)
no.
%
no.
%
no.
%
75 120 Total
; 40
5 100
0” 23
17 0 100
; 19
:: 100
Injections Second
First
Subsequent
Figures in parentheses refer to percent of injections eliciting maximal response at that time. Of the 91 injections 9 could not be analyzed because of insufficient data.
With use of the more objective criteria, 84 of the 91 injections could be classified; missing data points made it impossible to classify the remaining 7 injections. By these criteria, 47 injections (55 percent) were effective and 8 (10 percent) were transiently effective. Twenty-nine injections (35 percent) were classified ineffective. Expressed as milligrams per kilogram, the doses for these three groups were 4.9,4.7 and 4.0, respectively, not significantly different from each other. Time of maximal blood pressure reduction: Each response to diazoxide was analyzed to determine when, within 4 hours of injection, maximal diastolic pressure reduction was obtained (Table II). Fifty percent of first injections resulted in a maximal reduction of diastolic pressure within 15 minutes. Similar patterns were observed after 23 second injections and the 19 third or subsequent injections.
,
Omin.
I
1
2
5
I
i
10 15
45
I
75
,
2hr.
I
4
I
8
1
12
I
24
TIME
412
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FIGURE 4. Change in heart rate in patients receiving a single dose of diazoxide.
DIAZOXIDE IN HYPERTENSION-MCDONALD
TABLE III Pulse Rate Before Diazoxide and Maximal Percent Increase and Decrease After Administration of Diazoxide in Patients Receiving Single or Multiple Injections (mean f standard error of the mean) Initial Pulse Rate Ibeatslmin) Single injection (no.) Multiple injections (no.)
100.7 f 4.9 17 102.2 f 3.2 65
Maximal % Increase 3 f 3.6 E.8 56
f 2.1’
Maximal % Decrease 20.3 f 4.0’ :‘,.5 f 2.3’ 56
Difference from initial pulse rate (P < 0.01). Data are based on the first 48 hours after injections. l
injections were successful when furosemide was simultaneously administered and 57 percent were effective when the diuretic drug was not utilized. In this series, furosemide could not be shown to favorably affect the response of diazoxide. Response of heart rate to diazoxide (Fig. 4 and Table III): Pulse rate initially decreased slightly after administration of diazoxide but returned to pretreatment levels by 10 minutes. A gradual decrease ensued and the rate decreased below pretreatment values by 8 hours. The maximal percent increase in pulse rate shown in Table III was significant only for the group receiving multiple doses. The maximal decrease in heart
rate was significant in patients receiving either single or multiple injections of diazoxide. Concomitant use of sympathetic blocking agents did not appear to influence significantly the subsequent response of heart rate to diazoxide. Funduscopic findings: Changes in retinopathy 2 weeks after therapy are shown in Table IV. Ninety percent of the patients had either grade 3 or grade 4 retinopathy (KeithWagener-Barker classification ) before therapy; 2 weeks after therapy only 51 percent had retinopathy of equal severity. Effect of diazoxide on glucose metabolism: The mean blood glucose before administration of diazoxide was 133.4 mg/lOO ml. The highest mean glucose value obtained during the first 48 hours after therapy was 139.8 mg/lOO ml. The highest glucose value obtained during therapy in any individual patient was 308 mg/lOO ml, which represented an increase from the value of 223 mg/lOO ml before therapy. In this series of patients, diazoxide did not have a major detrimental effect on glucose metabolism. Alterations in renal function induced by therapy: Mean blood urea nitrogen and creatinine values were 58 and 5.5 mg/lOO ml, respectively, before administration of diazoxide. Two weeks after diazoxide therapy, these values were un-
ET AL.
changed (59 and 5.7 mg/lOO ml, respectively). Only eight patients demonstrated an increase in blood urea nitrogen of more than 50 percent above the pretreatment level and a tendency for the level to rise after therapy. Only one patient had a more
than 30 percent increase in creatinine. Electrocardiographic effect of diazoxide: Thirty-nine of 41 patients had electrocardiographic evaluation before diazoxide therapy. Only one had a normal electrocardiogram. Of the remaining 38 patients, 4 had ST-T wave changes compatible with ischemia and an additional 2 had evidence of previous myocardial infarction. No patient had symptoms suggesting acute coronary artery disease. During therapy, one patient had angina that occurred 20 minutes after administration of diazoxide, at a time when blood pressure was 250/158 mm Hg. This episode was not believed to be diazoxide-induced. Electrocardiograms were obtained in 35 patients 2 weeks after diazoxide therapy; no tracing demonstrated deterioration attributable to ischemia. Other adverse effects (Table V): Only 8 of 91 injections (9 percent) were associated with side effects. The most serious of these was transient weakness of the right arm and hand that rapidly resolved.
Discussion Mean reduction in blood pressure: For all injections of diazoxide, diastolic pressure decreased an average of 28 mm Hg (20 percent) within 2 minutes. For patients receiving only one injection of diazoxide, diastolic pressure decreased an average of 41 mm Hg (29 percent). These changes in diastolic pressure compare with previously reported decreases of 164 and 50 mm Hg5 and 37 percent2 For all injections, the reduction of mean pressure within 2 minutes of diazoxide therapy was 33 mm Hg (20 percent). Comparable figures for patients receiving only one injection were 38 mm Hg (28 percent). These figures are similar to those previously reported, which ranged from 19 to 40 percent.1,6-10 Effectiveness: Subjectively, diazoxide was judged effective in 38 of 41 patients. Objectively, 55 percent of injections were effective, 10 percent transiently effective and 35 percent ineffective. By comparison, Miller et al.,” using similar criteria, reported that 78.5 percent of injections were effective, 7.7 percent transiently effective and only 13.8 percent ineffective. Diazoxide is frequently used with potent diuretic agents to counteract its sodium-retaining properties and augment its antihypertensive effect. In this study we could not demonstrate that effectiveness was improved
TABLE IV
Changesin Retinopathy’ 2 Weeks After Diazoxide Therapy After Therapy Before
Nor-
Therapy ma1 iI III IV Totals l
I
II
:::
:::
.i
1
1
7 6 15
‘i’
'i'
III
IV
Patient Not Available Totals
'ii
::. ..:
." 2
2 13
5”
6”
1
TABLE V Patient Complaints and Side Effects Related to Therapy
z 21 16 41
Classification according to criteria of Keith, Wagener and Bark-
er.
September 1977
Injections (no.) 3 : : 1
Complaints Nausea and vomiting Nausea Warmth after injections Orthostasis Venous irritation Weakness in hand and arm
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ET AL.
by the addition of furosemide to the therapeutic regimen. The reason for this striking finding is not clear. Although no data are available, it is possible that this might be explained either by patient selection or by careful attention to fluid balance. In either case, the data demonstrate that the use of potent diuretic drugs in conjunction with diazoxide is frequently unnecessary. Diastolic blood pressure has been reported to decrease maximally between 2 and 10 minutes after injectionof diazoxide.2 Although this was generally true in our study group, the greatest decrease in blood pressure was delayed at least 15 minutes after 35 percent of the injections. Nevertheless, after 97 percent of first injections and 80 percent of second or subsequent injections, the diastolic pressure observed within the first 10 minutes of injection was within 10 mm Hg of the lowest blood pressure level obtained during the subsequent 2 hours. Of those patients whose subsequent blood pressure measurements were significantly lower than those observed within 10 minutes, the further decrement never exceeded 30 mm Hg. Pulse rate: Several investigators’l-l5 have demonstrated that intravenous administration of diazoxide causes a significant increase in heart rate within 5 minutes of injection. It is not known whether this chronotropic effect is mediated by direct stimulation of the beta receptor sites in the heart or indirectly by stimulating carotid baroreceptor activity. In our study, administration of diazoxide resulted in a decrease in heart rate. The difference between these results and those previously reported may reflect the initial condition of patients. For example, the mean pulse rate before treatment in our cooperative study patients was 101 beats/min, in contrast to 74 beats/min reported in the patients of Bhatia and Frohlich.li It is possible that our study patients were initially under a greater degree of sympathetic stimulation and therefore less likely to respond to further sympathetic stimulation. Retinopathy: The finding that approximately 40 percent of patients with retinopathy showed improvement during the posttreatment period of 2 weeks is not surprising and attests to the effectiveness of antihypertensive therapy. Small hemorrhages, soft exudates and papilledema have been demonstrated to clear within several weeks of control of blood pressure.3@ Larger retinal lesions may take many months to clear. Renal function: Previous investigators3v17-lg have reported at least transient increases in blood urea nitrogen associated with reduction of blood pressure. Although progressive renal deterioration has been observed with aggressive antihypertensive therapy,r7,1s several recent reports have emphasized the reversible nature of the induced azotemia.3*1g Mrozcek et a1.,5 for example, reported increases of 19 and 17 percent, respectively, in mean blood urea nitrogen and creatinine 2 weeks after the initiation of intensive antihypertensive therapy. The increase was greater in those patients with initial blood urea nitrogen values greater than 60 mg/ 100 ml. Seven months after therapy, however, mean blood urea nitrogen and creatinine values were 35 and 414
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of CARDIOLOGY
4.5 percent, respectively, lower than pretreatment measurements. In contrast to these findings, our patients demonstrated no increase in either mean blood urea nitrogen or creatinine 2 weeks after the initiation of therapy. Although this difference in findings does not appear to be related to the degree and rapidity of blood pressure reduction, an explanation is not readily apparent. Electrocardiographic effects: A recent report20 noted that 7 of 14patients receiving d&oxide exhibited significant ST-T changes within 15 minutes of drug administration. Five of these patients also manifested chest discomfort and one had evidence of an acute myocardial infarction. Our results do not corroborate these findings and, in this respect, agree with the data of Miller et a1.2 None of our patients manifested either electrocardiographic or clinical cardiac deterioration. Although we believe that diazoxide is contraindicated in patients with an acute coronary artery syndrome, in most other settings it does not appear to have a significantly adverse effect on myocardial oxygenation. Side effects: The incidence of drug-related side effects (9 percent) is comparable with the, previously reported incidence rate of 12 percent.2 Of note is the minor nature of these side effects. Only one reported symptom was related to cerebrovascular or coronary insufficiency. The infrequency of these side effects, despite the presence of severe coronary and cerebral atherosclerotic disease in at least 25 percent of the patients, may reflect the hemodynamic effects of this drug. Coincident with the induced reduction of blood pressure, cardiac output has been reported to increase by as much as 55 to 75 percent and peripheral resistance to decrease dramatically. 7,g Additional protection from symptoms of coronary insufficiency may be provided by increased coronary blood fl~wl~,~l and the dramatic reduction in afterload on the heart. There were no episodes of severe hyperglycemia, blood sugar never attaining values greater than 308 mg/lOO ml. Clinical implications: Diazoxide continues to enjoy a reputation for both safety and efficacy. In an average hypertensive adult, 300 mg of diazoxide intravenously will result in a significant reduction in blood pressure in more than 50 percent of patients. The effectiveness of diazoxide can be gauged within 10 to 15 minutes of injection. Sodium retention may be countered with the use of potent diuretic agents. Blood glucose should be carefully monitored, but hyperglycemia occurs infrequently; other side effects are also uncommon. Renal function in most patients remains relatively stable in the immediate posttreatment period. Other manifestations of severe hypertensive diseases, such as retinopathy and tachycardia, are at least partially and rapidly reversed. Diazoxide appears to be an excellent drug for the initial treatment of the majority of clinically encountered hypertensive crises. Acknowledgments Diazoxide was supplied as Hyperstat I.V. by Schering Corporation, Kenilworth, New Jersey. The assistance of Ms. Velda Bevel and Ms. Ann Irwin in typing the manuscript is gratefully acknowledged.
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DIAZOXIDE IN HYPERTENSION-MCDONALD ET AL.
References 1. Finnerty FA: Hypertensive encephalopathy. Am Heart J 75: 559-563, 1968 2. Miller WE, Gifford RW, Humphrey DC, et al: Management of severe hypertension with intravenous injections of d&oxide. Am J Cardiol 241870-875, 1969 3. Yroczek WJ, Davidov M, Gavrilovich L, et al: The value of aggressive therapy in the hypertensive patient with azotemia. Circulation 40:893-904. 1969 4. Thomson AE, Nickerson M, Gaskell P, et al: Clinical observations on an antihypertensive chlorothiazkfe analogue devoid of diuretic activity. Can Med Assoc J 87:1306-1310, 1962 5. Saker BM, Matthew TH, Eremln J, et al: Diazoxide in the treatment of acute hypertensive emergency. Med J Aust 1:592-593,1968 6. Hamby WM, Jankowski JG, Pouget JM, et al: Intravenous use of diazoxide in the treatment of severe hypertension. Circulation 37:169-174, 1968 7. Finnerty FA: Newer antihypertensive drugs. Med Clin North Am 481329-333, 1964 8. Sellers EM, ftskovitz HD: Acute hypotensive use of diazoxide (abstr). Circulation 28:801, 1963 9. Finnerty FA, Kakviatos N, Tuckman J, et al: Clinical evaluation of diazoxide: a new treatment for acute hypertension. Circulation 28:203-208, 1963 10. Diazoxide: a review of its pharmacologic properties and therapeutic use in hypertensive crises. Drugs 2:78-137, 1971 11. Bhatia S, Frohlich ED: A hemodynamic comparison of agents useful in hypertensive emergencies (abstr). Clin Pharmacol Ther 12:287, 1971
12. Rubin AA, Roth FE, Taylor RM, et al: Pharmacology of d&oxide, an antihypertensive, non-diuretic benzothiadiazine. J Pharmacol Exp Ther 136:344-352.1962 13. Naylor WG, Mclnnes I, Swann JB, et al: Some effects of the hypotensive drug diazoxide on the cardiovascular system. Am Heart J 75:223-232, 1968 14. Bartorelli C, Gargano N, Leonetti G, et al: Hypotensive and renal effects of diazoxide, a sodium retaining benzothiadiazine compound. Circulation 27:895-903, 1963 15. Wilson WR, Gkun R: The acute hemodynamic effects of d&oxide in man. Circulation 28:89-93, 1963 16. Hedge JV, Golfery cf: Retinal soft exudates. Q J Med 33117-131, 1964 17. Harrington MB, Kincaid-Smith P: Results of treatment in malignant hypertension: a seven-year experience in 94 cases. Br Med J 2: 969-980, 1959 18. Dollery CT: Malignant hypertension. In, Treatment of Hypertension (Pickering GW, Cranston WI, Pears MA, ed). Springfield, Illinois, Charles C Thomas, 1961, p 47 19. Woods JW, Blythe WB: Management of malignant hypertension complicated by renal insufficiency. N Engl J Med 277:57-61, 1967 20. Kanada SA, Kanada W, Hutchinson RA, et al: Angina-like syndrome with diazoxide therapy for hypertensive crisis. Ann Intern Med 84:696-699, 1976 2 1. Scott JC, Cowley AW: The effect of diazoxide on coronary blood flow. Am J Cardiol 24:865-869, 1969
September 1977
The American Journal of CARDIOLOGY
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415
Intravenous Diazoxide Therapy in Hypertensive Crisis
WALTER J. MCDONALD, MD GORDON SMITH, MD” JAMES W. WOODS, MD H. MITCHELL PERRY, MD, FACC BYRON D. DANIELSON, MD+ Portland, Oregon Boston, Massachusetts Chapel Hill, North Carolina St. Louis, Missouri Minneapolis, Minnesota
Ninety-one doses of diazoxide were administered intravenously to 41 patients with hypertensive crises. Diastolic blood pressure was reduced from an average of 139 to 98 mm Hg within 10 minutes. On the basis of a retrospective analysis of the response of diastolic blood pressure, it was possible to determine within 10 minutes of injection whether a second dose would be required. Therapy was judged to be effective in 38 of 41 patients; 35 percent of injections were ineffective. Concomitant administration of furosemide was not shown to have a beneficial antihypertensive effect. Mean blood urea nitrogen was 59.5 mg/lOO ml initially and was not significantly diff’erent 2 weeks after therapy. None of the patients demonstrated clinical evidence of diazoxide-induced deterioration of coronary circulation. Electrocardiograms obtained 2 weeks after diazoxide therapy failed to show evidence of new ischemic changes. Only 9 percent of patients complained of side effects, and these were transient and relatively innocuous. It is concluded that diazoxide is both safe and efficacious in the management of hypertensive crises.
The introduction of the benzothiadiazine derivative diazoxide has been a significant advance in the therapeutic approach to the hypertensive crisis. Several reports1-8 attest to the efficacy and safety of this compound. The rapidity with which control of blood pressure is achieved has led to a reevaluation of the therapeutic goals in managing the severely hypertensive patient. To evaluate further the effectiveness and safety of diazoxide in the clinical setting, a multicenter study was undertaken. Patients presenting with severe hypertension were treated with intravenously administered diazoxide and carefully evaluated over the ensuing 2 weeks. The results demonstrated that diazoxide safely, rapidly and effectively reduces blood pressure and is useful in treating most hypertensive crises. Methods From the Portland Veterans Administration Hospital and University of Oregon Health Sciences Center, Portland, Oregon; Boston University Medical Center, Boston, Massachusetts; University of North Carolina School of Medicine, Chapel Hill, North Carolina; Veterans Administration Hospital, St. Louis, Missouri; and the Renal Section, Hennepin County Hospital, Minneapolis, Minnesota. Manuscript received January 24, 1977; revised manuscript received March 8, 1977, accepted March 16, 1977. + Present address: Cheshire, Connecticut. t Present address: Dakota Clinic, Fargo, North Dakota. Address for reprints: Walter J. McDonald, MD, Portland Veterans Administration Hospital, Portland, Oregon 97207.
and Materials
Protocol: Five centers participated in the study. Forty-one patients, judged to have hypertension of sufficient severity to warrant rapid reduction of blood pressure, were entered into the protocol. Age, sex, race, weight, concurrent disease, medications, basal blood pressure and pulse were recorded. Blood was drawn for determinations of glucose, urea nitrogen, uric acid and creatinine levels. Electrocardiograms and chest X-ray films were obtained. A total of 91 doses of diazoxide were administered intravenously to the study group of 41 patients. Eighty-nine doses were injected over a period not exceeding 30 seconds, and 2 doses over a 1 minute period. In 11 instances, the dose was less than, and in 4 instances greater than, 300 mg; in the remaining 76 injections, the dose was 300 mg. Blood pressure, pulse and symptoms were recorded 2,5,10,15,45 and 75 minutes and 2,4,8,12,24,36 and 48 hours after injection. Concurrently administered antihypertensive medications were recorded. The variables cited were monitored over the succeeding 2 weeks. Mean blood pressure was calculated from the formula: mean blood pressure = diastolic blood pressure plus one third of pulse pressure.
September1977
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DIAZOXIDE IN HYPERTENSION-MCDONALD
ET AL.
Three patients received more than one course of therapy. Seventy-five percent of the courses consisted of one or two injections. Nine patients were without concurrent disease. Four patients had a history of coronary artery disease and four a history of occlusive cerebrovascular disease. Seventeen had significant renal dysfunction, but none was undergoing long-term dialysis at the initiation of this study. The remaining diagnoses were varied and unrelated to the cardiovascular system. Three patients died within 2 months of diazoxide therapy. These deaths, occurring 8,23 and 54 days, respectively, after treatment, appeared to be unrelated to diazoxide therapy.
TABLE I Number
of Courses
and Injections
per Course
Injections (no.)
Courses (no.)*
1 2 3 4 5 6 Total
22 13 6 2 1 2 46
A course of treatment is defined as a series of injections, no two of which are more than 120 hours apart. l
Results Blood pressure: For purposes of analysis, the patients were classified into three groups: those who received one injection (18 patients) and those who received two (13 patients) or more (10 patients) injections. The blood pressure response of patients receiving a single injection of diazoxide is shown in Figure 1. Four of the patients in this group had two courses of therapy. The average (i standard error of the mean) pretreatment systolic, diastolic and mean blood pressures were 229 f 4.4, 139 f 3.5 and 169 f 3.9 mm Hg, respectively. Within 10 minutes, average systolic and diastolic pressures were reduced to 166 f 6.9 and 98 f 4.0 mm Hg, respectively. Generally, blood pressure remained at these levels for the first 48 hours after therapy. The response of mean blood pressure in 13 patients receiving two injections is shown in Figure 2. The initial mean blood pressure of 178 f 4.6 mm Hg is not different from that observed in patients requiring only a single injection. The reduction in blood pressure resulting from the first injection in this group of patients was maximal at 2 minutes, decreasing to 139 f 7.5 mm Hg. The subsequent rise toward pretreatment values necessitated the second injection. The mean pressure decreased to 128 f 8.8 mm Hg within 2 minutes after injection
A single course of d&oxide therapy was arbitrarily defined as a single injection or a series of injections, no two of which were more than 120 hours apart. Several patients received more than one course of diazoxide therapy. Assessment of effectiveness: Each investigator subjectively assessed the effectiveness of diazoxide therapy in the patients for whom he was responsible. In addition, objective data were obtained to corroborate and support the clinical assessment. An injection was classified effective if diastolic blood pressure decreased by more than 30 mm Hg or to less than 100 mm Hg within the first 10 minutes of administration and if the reduction was sustained for at least 75 minutes. Transient effectiveness was defined as a similar reduction of blood pressure not sustained for 75 minutes. An ineffective iniection was one that failed to result in this decrement of blood pressure. Demographic data: Forty-one patients aged 23 to 71 years were studied. There were 26 men and 15 women whose weights ranged from 47.3 to 128.2 kg. The number of injections per course and the courses of injections are shown in Table I.
Omin.
2
5
10
1
15
45
L
75
,
2hr.
I
4
L I
8
12
I
24
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FIGURE 1. Systolic, diastolic and mean blood pressure standard error of the mean) in 18 patients receiving a single injection of diazoxide.
(zk
DIAZOXIDE
IN HYPERTENSION-MCDONALD
ET AL.
r
FIGURE 2. Mean blood pressure (zb standard error of the mean) in 13 patients receiving two injections of diazoxide. Response to the first injection is-plotted for only 75 minutes because of insufficient observations beyond that
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of the second dose. Subsequently, the blood pressure tended to decrease during the next 48 hours. The mean blood pressure response observed in 10 patients receiving more than two injections is illustrated in Figure 3. The changes in pressure induced by the first and last doses are shown. Response to the first dose was inadequate and this was apparent in most cases within 75 minutes. The last in-
jection generally resulted in a rapid initial reduction of mean pressure and a subsequent progressive decrease over the next 48 hours. Effectiveness of diazoxide therapy: Each investigator was asked to assess subjectively the effectiveness of diazoxide therapy in the patients for whom he was responsible. By these criteria, diazoxide was judged effective in 38 of 41 patients.
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140
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FIGURE 3. Mean blood pressure (AZstandard error of the mean) in 10 patients receiving more than two injections of diazoxide. Data from first and last injections are plotted. Response to the first injection is plotted for 15 minutes only because of insufficient observations beyond that time.
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The American Journal of CARDIOLOGY
Volume 40
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DIAZOXIDE IN HYPERTENSION-MCDONALD
ET AL.
The data were further analyzed to determine how frequently the diastolic pressure reduction obtained within the first 10 minutes of injection was within 10 mm Hg of the lowest diastolic reading obtained within the first 2 hours. After the first injection of diazoxide, 40 of 41 patients (97 percent) fulfilled these criteria. For the second or subsequent injections, the corresponding figure was 36 of 45 patients (80 percent). If the observation period for second or subsequent injections was extended from 10 to 15 minutes, the diastolic pressure in 39 of 45 patients (87 percent) was within 10 mm Hg of the lowest obtained reading. In no instance did diastolic pressure, after 10 minutes, decrease by more than 30 mm Hg during the subsequent 2 hours. In only six patients was diazoxide given within 30 minutes of a previous injection. In none of these patients was the response to the second dose greater than the response to the first. Influence of renal function on blood pressure response: The response to the first injection of d&oxide was evaluated as a function of pretreatment levels of blood urea nitrogen and creatinine. Data were sufficient in 36 of the 41 patients to permit analysis. Eighteen patients had an effective response to the first injection; mean blood urea nitrogen and creatinine were 62 and 5.4 mg/lOO ml, respectively, for these patients. For the 16 patients who failed to respond, mean blood urea nitrogen and creatinine were not significantly different (65 and 6.3 mg/lOO ml, respectively). Two of the injections were transiently effective and mean blood levels for these patients were 24 and 1.9 mg/lOO ml, respectively. The response to d&oxide in these patients did not correlate with pretreatment renal function. Concomitant use of furosemide: Although no attempt was made to control the use of other orally administered antihypertensive agents, the response to d&oxide was analyzed with respect to the concomitant use of furosemide. Seventy-seven injections could be analyzed; furosemide was administered in conjunction with 48 of these. Forty-three percent of the
TABLE II Time When Maximal Reduction in Diastolic Pressure Was Obtained After ihe First, Second or Subsequent Injection of Diazoxide Time After Injections tmin)
no.
%
no.
%
no.
%
75 120 Total
; 40
5 100
0” 23
17 0 100
; 19
:: 100
Injections Second
First
Subsequent
Figures in parentheses refer to percent of injections eliciting maximal response at that time. Of the 91 injections 9 could not be analyzed because of insufficient data.
With use of the more objective criteria, 84 of the 91 injections could be classified; missing data points made it impossible to classify the remaining 7 injections. By these criteria, 47 injections (55 percent) were effective and 8 (10 percent) were transiently effective. Twenty-nine injections (35 percent) were classified ineffective. Expressed as milligrams per kilogram, the doses for these three groups were 4.9,4.7 and 4.0, respectively, not significantly different from each other. Time of maximal blood pressure reduction: Each response to diazoxide was analyzed to determine when, within 4 hours of injection, maximal diastolic pressure reduction was obtained (Table II). Fifty percent of first injections resulted in a maximal reduction of diastolic pressure within 15 minutes. Similar patterns were observed after 23 second injections and the 19 third or subsequent injections.
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The American Journal of CARDIOLOGY
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48
FIGURE 4. Change in heart rate in patients receiving a single dose of diazoxide.
DIAZOXIDE IN HYPERTENSION-MCDONALD
TABLE III Pulse Rate Before Diazoxide and Maximal Percent Increase and Decrease After Administration of Diazoxide in Patients Receiving Single or Multiple Injections (mean f standard error of the mean) Initial Pulse Rate Ibeatslmin) Single injection (no.) Multiple injections (no.)
100.7 f 4.9 17 102.2 f 3.2 65
Maximal % Increase 3 f 3.6 E.8 56
f 2.1’
Maximal % Decrease 20.3 f 4.0’ :‘,.5 f 2.3’ 56
Difference from initial pulse rate (P < 0.01). Data are based on the first 48 hours after injections. l
injections were successful when furosemide was simultaneously administered and 57 percent were effective when the diuretic drug was not utilized. In this series, furosemide could not be shown to favorably affect the response of diazoxide. Response of heart rate to diazoxide (Fig. 4 and Table III): Pulse rate initially decreased slightly after administration of diazoxide but returned to pretreatment levels by 10 minutes. A gradual decrease ensued and the rate decreased below pretreatment values by 8 hours. The maximal percent increase in pulse rate shown in Table III was significant only for the group receiving multiple doses. The maximal decrease in heart
rate was significant in patients receiving either single or multiple injections of diazoxide. Concomitant use of sympathetic blocking agents did not appear to influence significantly the subsequent response of heart rate to diazoxide. Funduscopic findings: Changes in retinopathy 2 weeks after therapy are shown in Table IV. Ninety percent of the patients had either grade 3 or grade 4 retinopathy (KeithWagener-Barker classification ) before therapy; 2 weeks after therapy only 51 percent had retinopathy of equal severity. Effect of diazoxide on glucose metabolism: The mean blood glucose before administration of diazoxide was 133.4 mg/lOO ml. The highest mean glucose value obtained during the first 48 hours after therapy was 139.8 mg/lOO ml. The highest glucose value obtained during therapy in any individual patient was 308 mg/lOO ml, which represented an increase from the value of 223 mg/lOO ml before therapy. In this series of patients, diazoxide did not have a major detrimental effect on glucose metabolism. Alterations in renal function induced by therapy: Mean blood urea nitrogen and creatinine values were 58 and 5.5 mg/lOO ml, respectively, before administration of diazoxide. Two weeks after diazoxide therapy, these values were un-
ET AL.
changed (59 and 5.7 mg/lOO ml, respectively). Only eight patients demonstrated an increase in blood urea nitrogen of more than 50 percent above the pretreatment level and a tendency for the level to rise after therapy. Only one patient had a more
than 30 percent increase in creatinine. Electrocardiographic effect of diazoxide: Thirty-nine of 41 patients had electrocardiographic evaluation before diazoxide therapy. Only one had a normal electrocardiogram. Of the remaining 38 patients, 4 had ST-T wave changes compatible with ischemia and an additional 2 had evidence of previous myocardial infarction. No patient had symptoms suggesting acute coronary artery disease. During therapy, one patient had angina that occurred 20 minutes after administration of diazoxide, at a time when blood pressure was 250/158 mm Hg. This episode was not believed to be diazoxide-induced. Electrocardiograms were obtained in 35 patients 2 weeks after diazoxide therapy; no tracing demonstrated deterioration attributable to ischemia. Other adverse effects (Table V): Only 8 of 91 injections (9 percent) were associated with side effects. The most serious of these was transient weakness of the right arm and hand that rapidly resolved.
Discussion Mean reduction in blood pressure: For all injections of diazoxide, diastolic pressure decreased an average of 28 mm Hg (20 percent) within 2 minutes. For patients receiving only one injection of diazoxide, diastolic pressure decreased an average of 41 mm Hg (29 percent). These changes in diastolic pressure compare with previously reported decreases of 164 and 50 mm Hg5 and 37 percent2 For all injections, the reduction of mean pressure within 2 minutes of diazoxide therapy was 33 mm Hg (20 percent). Comparable figures for patients receiving only one injection were 38 mm Hg (28 percent). These figures are similar to those previously reported, which ranged from 19 to 40 percent.1,6-10 Effectiveness: Subjectively, diazoxide was judged effective in 38 of 41 patients. Objectively, 55 percent of injections were effective, 10 percent transiently effective and 35 percent ineffective. By comparison, Miller et al.,” using similar criteria, reported that 78.5 percent of injections were effective, 7.7 percent transiently effective and only 13.8 percent ineffective. Diazoxide is frequently used with potent diuretic agents to counteract its sodium-retaining properties and augment its antihypertensive effect. In this study we could not demonstrate that effectiveness was improved
TABLE IV
Changesin Retinopathy’ 2 Weeks After Diazoxide Therapy After Therapy Before
Nor-
Therapy ma1 iI III IV Totals l
I
II
:::
:::
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1
1
7 6 15
‘i’
'i'
III
IV
Patient Not Available Totals
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." 2
2 13
5”
6”
1
TABLE V Patient Complaints and Side Effects Related to Therapy
z 21 16 41
Classification according to criteria of Keith, Wagener and Bark-
er.
September 1977
Injections (no.) 3 : : 1
Complaints Nausea and vomiting Nausea Warmth after injections Orthostasis Venous irritation Weakness in hand and arm
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DIAZOXIDE
IN HYPERTENSION-MCDONALD
ET AL.
by the addition of furosemide to the therapeutic regimen. The reason for this striking finding is not clear. Although no data are available, it is possible that this might be explained either by patient selection or by careful attention to fluid balance. In either case, the data demonstrate that the use of potent diuretic drugs in conjunction with diazoxide is frequently unnecessary. Diastolic blood pressure has been reported to decrease maximally between 2 and 10 minutes after injectionof diazoxide.2 Although this was generally true in our study group, the greatest decrease in blood pressure was delayed at least 15 minutes after 35 percent of the injections. Nevertheless, after 97 percent of first injections and 80 percent of second or subsequent injections, the diastolic pressure observed within the first 10 minutes of injection was within 10 mm Hg of the lowest blood pressure level obtained during the subsequent 2 hours. Of those patients whose subsequent blood pressure measurements were significantly lower than those observed within 10 minutes, the further decrement never exceeded 30 mm Hg. Pulse rate: Several investigators’l-l5 have demonstrated that intravenous administration of diazoxide causes a significant increase in heart rate within 5 minutes of injection. It is not known whether this chronotropic effect is mediated by direct stimulation of the beta receptor sites in the heart or indirectly by stimulating carotid baroreceptor activity. In our study, administration of diazoxide resulted in a decrease in heart rate. The difference between these results and those previously reported may reflect the initial condition of patients. For example, the mean pulse rate before treatment in our cooperative study patients was 101 beats/min, in contrast to 74 beats/min reported in the patients of Bhatia and Frohlich.li It is possible that our study patients were initially under a greater degree of sympathetic stimulation and therefore less likely to respond to further sympathetic stimulation. Retinopathy: The finding that approximately 40 percent of patients with retinopathy showed improvement during the posttreatment period of 2 weeks is not surprising and attests to the effectiveness of antihypertensive therapy. Small hemorrhages, soft exudates and papilledema have been demonstrated to clear within several weeks of control of blood pressure.3@ Larger retinal lesions may take many months to clear. Renal function: Previous investigators3v17-lg have reported at least transient increases in blood urea nitrogen associated with reduction of blood pressure. Although progressive renal deterioration has been observed with aggressive antihypertensive therapy,r7,1s several recent reports have emphasized the reversible nature of the induced azotemia.3*1g Mrozcek et a1.,5 for example, reported increases of 19 and 17 percent, respectively, in mean blood urea nitrogen and creatinine 2 weeks after the initiation of intensive antihypertensive therapy. The increase was greater in those patients with initial blood urea nitrogen values greater than 60 mg/ 100 ml. Seven months after therapy, however, mean blood urea nitrogen and creatinine values were 35 and 414
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1977
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Journal
of CARDIOLOGY
4.5 percent, respectively, lower than pretreatment measurements. In contrast to these findings, our patients demonstrated no increase in either mean blood urea nitrogen or creatinine 2 weeks after the initiation of therapy. Although this difference in findings does not appear to be related to the degree and rapidity of blood pressure reduction, an explanation is not readily apparent. Electrocardiographic effects: A recent report20 noted that 7 of 14patients receiving d&oxide exhibited significant ST-T changes within 15 minutes of drug administration. Five of these patients also manifested chest discomfort and one had evidence of an acute myocardial infarction. Our results do not corroborate these findings and, in this respect, agree with the data of Miller et a1.2 None of our patients manifested either electrocardiographic or clinical cardiac deterioration. Although we believe that diazoxide is contraindicated in patients with an acute coronary artery syndrome, in most other settings it does not appear to have a significantly adverse effect on myocardial oxygenation. Side effects: The incidence of drug-related side effects (9 percent) is comparable with the, previously reported incidence rate of 12 percent.2 Of note is the minor nature of these side effects. Only one reported symptom was related to cerebrovascular or coronary insufficiency. The infrequency of these side effects, despite the presence of severe coronary and cerebral atherosclerotic disease in at least 25 percent of the patients, may reflect the hemodynamic effects of this drug. Coincident with the induced reduction of blood pressure, cardiac output has been reported to increase by as much as 55 to 75 percent and peripheral resistance to decrease dramatically. 7,g Additional protection from symptoms of coronary insufficiency may be provided by increased coronary blood fl~wl~,~l and the dramatic reduction in afterload on the heart. There were no episodes of severe hyperglycemia, blood sugar never attaining values greater than 308 mg/lOO ml. Clinical implications: Diazoxide continues to enjoy a reputation for both safety and efficacy. In an average hypertensive adult, 300 mg of diazoxide intravenously will result in a significant reduction in blood pressure in more than 50 percent of patients. The effectiveness of diazoxide can be gauged within 10 to 15 minutes of injection. Sodium retention may be countered with the use of potent diuretic agents. Blood glucose should be carefully monitored, but hyperglycemia occurs infrequently; other side effects are also uncommon. Renal function in most patients remains relatively stable in the immediate posttreatment period. Other manifestations of severe hypertensive diseases, such as retinopathy and tachycardia, are at least partially and rapidly reversed. Diazoxide appears to be an excellent drug for the initial treatment of the majority of clinically encountered hypertensive crises. Acknowledgments Diazoxide was supplied as Hyperstat I.V. by Schering Corporation, Kenilworth, New Jersey. The assistance of Ms. Velda Bevel and Ms. Ann Irwin in typing the manuscript is gratefully acknowledged.
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DIAZOXIDE IN HYPERTENSION-MCDONALD ET AL.
References 1. Finnerty FA: Hypertensive encephalopathy. Am Heart J 75: 559-563, 1968 2. Miller WE, Gifford RW, Humphrey DC, et al: Management of severe hypertension with intravenous injections of d&oxide. Am J Cardiol 241870-875, 1969 3. Yroczek WJ, Davidov M, Gavrilovich L, et al: The value of aggressive therapy in the hypertensive patient with azotemia. Circulation 40:893-904. 1969 4. Thomson AE, Nickerson M, Gaskell P, et al: Clinical observations on an antihypertensive chlorothiazkfe analogue devoid of diuretic activity. Can Med Assoc J 87:1306-1310, 1962 5. Saker BM, Matthew TH, Eremln J, et al: Diazoxide in the treatment of acute hypertensive emergency. Med J Aust 1:592-593,1968 6. Hamby WM, Jankowski JG, Pouget JM, et al: Intravenous use of diazoxide in the treatment of severe hypertension. Circulation 37:169-174, 1968 7. Finnerty FA: Newer antihypertensive drugs. Med Clin North Am 481329-333, 1964 8. Sellers EM, ftskovitz HD: Acute hypotensive use of diazoxide (abstr). Circulation 28:801, 1963 9. Finnerty FA, Kakviatos N, Tuckman J, et al: Clinical evaluation of diazoxide: a new treatment for acute hypertension. Circulation 28:203-208, 1963 10. Diazoxide: a review of its pharmacologic properties and therapeutic use in hypertensive crises. Drugs 2:78-137, 1971 11. Bhatia S, Frohlich ED: A hemodynamic comparison of agents useful in hypertensive emergencies (abstr). Clin Pharmacol Ther 12:287, 1971
12. Rubin AA, Roth FE, Taylor RM, et al: Pharmacology of d&oxide, an antihypertensive, non-diuretic benzothiadiazine. J Pharmacol Exp Ther 136:344-352.1962 13. Naylor WG, Mclnnes I, Swann JB, et al: Some effects of the hypotensive drug diazoxide on the cardiovascular system. Am Heart J 75:223-232, 1968 14. Bartorelli C, Gargano N, Leonetti G, et al: Hypotensive and renal effects of diazoxide, a sodium retaining benzothiadiazine compound. Circulation 27:895-903, 1963 15. Wilson WR, Gkun R: The acute hemodynamic effects of d&oxide in man. Circulation 28:89-93, 1963 16. Hedge JV, Golfery cf: Retinal soft exudates. Q J Med 33117-131, 1964 17. Harrington MB, Kincaid-Smith P: Results of treatment in malignant hypertension: a seven-year experience in 94 cases. Br Med J 2: 969-980, 1959 18. Dollery CT: Malignant hypertension. In, Treatment of Hypertension (Pickering GW, Cranston WI, Pears MA, ed). Springfield, Illinois, Charles C Thomas, 1961, p 47 19. Woods JW, Blythe WB: Management of malignant hypertension complicated by renal insufficiency. N Engl J Med 277:57-61, 1967 20. Kanada SA, Kanada W, Hutchinson RA, et al: Angina-like syndrome with diazoxide therapy for hypertensive crisis. Ann Intern Med 84:696-699, 1976 2 1. Scott JC, Cowley AW: The effect of diazoxide on coronary blood flow. Am J Cardiol 24:865-869, 1969
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