482 Episodes in 257 Patients; Experience of Three Years
Paul M. Beigelman, M.D., Los Angeles
SUMMARY
There were 340 episodes of severe diabetic ketoacidosis in 257 patients, July 1, 1965 to June 30, 1968. Fatality in thirty-two cases was associated with significantly elevated admission serum glucose, urea nitrogen, osmolality and age. Major associated causes of death were infection and myo- cardial infarction. Twenty episodes of acute pancreatitis, with only two deaths, demonstrated severe morbidity and marked elevation of serum glucose and urea nitrogen. Four- teen of the twenty occurred in alcoholics. There were eleven episodes in ten pregnant women, with one maternal and seven fetal deaths. Admission serum potassium, recorded in 336 episodes, was markedly elevated in 22 per cent and decreased in 4 per cent. Including all multiple admissions, there were 482 episodes; forty had hypoglycemic reactions, none with fatality or severe morbidity. Nine cases of non- ketotic hyperosmolar coma, with five deaths, demonstrated very high admission serum glucose, urea nitrogen, and osmo- lality levels. DIABETES 20:490-500, July, 1971.
Severe diabetic ketoacidosis is defined by the Diabetes Service of LAC-USC Medical Center* as a state of keto- acidosis with serum bicarbonate decreased to levels of io mEq./L or less. This degree of diabetic ketoacidosis, even without mental obtundation, has been designated by some authorities as "diabetic coma".1
Admission data on 340 sequential episodes of severe diabetic ketoacidosis in 257 patients admitted between July 1, 1965 and June 30, 1968 are presented. Particu- lar emphasis is given to factors leading to death in thirty-two of these patients. None of these fatalities was
From the Departments of Medicine and Pharmacology, School of Medicine, University of Southern California, Los Angeles, California.
*Los Angeles County-University of Southern California Med- ical Center.
caused by cerebral edema. Also, certain conditions asso- ciated with severe diabetic ketoacidosis are discussed, in- cluding myocardial infarction, alcoholism, pancreatitis, therapy with oral agents, and hypoglycemia.
Additional admissions, numbering 142, occurred in certain of the patients who had multiple admissions for severe diabetic ketoacidosis before or after the prin- cipal three-year study period. Inclusion of these yielded a total of 482 episodes in the 257 patients, if time limits are ignored. These data are utilized to ascertain the effect of multiple admissions upon mortality rate.
Nine cases of hyperosmolar nonketotic coma, admitted to the Diabetes Service between July 1, 1965 and June 30, 1968, -are also presented for comparison with the ketoacidotic patients.
The therapeutic technics utilized by this Diabetes Ser- vice are based on careful monitoring of vital signs and chemical status. Individualized, vigorous therapy is em- phasized with large intravenous doses of insulin ad- ministered in the earlier phases of treatment, followed by smaller subcutaneous doses until ketosis is corrected. Deficits of water, sodium, and potassium may be pro- found, requiring rapid and aggressive parenteral replace- ment therapy. Large doses of parenteral potassium, care- fully monitored, also may be necessary. Shock, infec- tions, and hypoglycemia must be diagnosed immediately and treated vigorously. These therapeutic approaches are fully presented in a separate communication2 which also summarizes briefly fifty-one episodes of severe diabetic ketoacidosis in forty-six patients admitted between Janu- ary 1 and April 30, 1968. The fifty-one episodes sum- marized in the treatment paper are included in the present report.
RESULTS
1. Findings on admission The age range in this series was fourteen to eighty-
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PAUL M. BEIGELMAN, M.D.
four years. The mean age of thirty-eight was within the range of mean ages, twenty-nine to forty-two, reported in other series.3'8 The mean admission serum glucose levels reported by others,3'8 371-597 mg./ioo cc, were less than the mean value of 705 mg./ioo cc. observed in this institution. The mean admission serum urea nitro- gen in this series, 35 mg./ioo cc, was slightly higher than mean values of 30-33 mg./ioo cc. in other se- ries.6'8'9' A minor factor possibly contributing to these discrepancies is the use, in previous smdies, of whole blood for glucose and urea determinations, which are lower than equivalent serum values. Mean admission serum potassium levels reported by others, 4.6-5.7 mEq./ L,3-5'9 were in the same range as the mean potassium of this series, 5.3 mEq./L. The mean admission serum sodium in this institution, 131 mEq./L., was within the range reported elsewhere, 131-138 mEq./L. 3-r>-9 In earlier reports, mean admission leucocyte counts were 16,900-21,900 per cu. mm.,3-15'8 closely agreeing with the value observed in this series, 18,387 per cu. mm. The patients of Zieve and Hill6 had a mean admis- sion hemoglobin of 13.9 gm. per cent, slightly lower than the 14.7 gm. per cent observed in this series. Mean admission respiratory rate of 30/min., pulse rate of 115/min., and temperature of 98.5 ° F. are in good agreement with values of other series.3'6
2. Causes Many of the episodes reported in this series of cases
had multiple causes, and frequently the cause was un- known. Discontinuance of therapy and infection were the two most common causes of severe diabetic keto- acidosis in this and other series.1'3'4'6'8'9 The third most common cause in this series was diabetes mellitus not being diagnosed before admission. This group consti- tuted 28 per cent of fatalities, 13 per cent of nonfatal episodes (15 per cent of total episodes), and nearly 20 per cent of the 257 subjects admitted during the three-year study period. Other institutions have reported a high frequency (10 to 35 per cent) of diabetes mel- litus being diagnosed at time of admission for keto-
3. Treatment (table 1) The mean dose of insulin administered in this series
(540 units) was within the widely variable twelve to twenty-four hour range of others, 148-1,280 units.3"5'8'9
The smallest insulin dose (20 units) was given in a puzzling case with definite hyperglycemia and ketoacid- osis, excellent response to parenteral bicarbonate therapy and diet, and no evidence of diabetes mellitus at time of discharge. The highest dose was 10,700 units in a fatal case complicated by pneumonia and pancreatitis.
Mean fluid volume infused was 6 L, the range being 0-18. Mean sodium given was 530 mEq., the range being 0-620. Mean potassium administered was 165 mEq., the range being 0-620.
The amounts of insulin, fluid and electrolytes given were designed in each instance to relieve ketosis and correct fluid and electrolyte deficits. Correction of ketosis (disappearance of ketonuria) occurred, on the average, in seventeen hours (range three to forty-four hours). 4. Characteristics of fatal cases
Fatal and nonfatal cases of severe diabetic ketoacidosis admitted July 1, 1965 to June 30, 1968 are compared in table 2.
During the three-year period, 32 of the 340 episodes (9 per cent) terminated fatally (death in thirty-one days or less after admission). The patient mortality rate, 32 of 257, was 13 per cent. There were more episodes of severe diabetic ketoacidosis in women than in men, but the male mortality rate was greater. There was no relation of mortality to presence or absence of a family history of diabetes. Mortality was higher with increased age and with increase of serum glucose, urea nitrogen, and osmolality. Similar associations, particularly with age, have been noted in other series.3'4-6-10"13
The mean pulse rate and diastolic blood pressure were lower in fatal cases. The depression of pulse rate was probably due to greater frequency of bradycardia, less than 50/min., or cardiac standstill. The lower mean diastolic blood pressure in the fatal cases probably re- flected the increased frequency of severe hypotension and shock in such patients.
Clinical coma, characterized by the patient's not re- sponding to pain or to loud voice commands, was more frequent in fatal cases. A relationship between uncon- sciousness and mortality has been frequently re- ported.1'4'6-8-9'11'14"17 Severe hypotension, designated as a diastolic blood pressure of zero, was related to mortality
TABLE 1 Summary of therapy
Therapy Insulin (units) Potassium (mEq.) Fluid (liters) Sodium (mEq.) Time for correction of
ketosis (hours)
3-44t
*To nearest five units or 5 mEq. tTo nearest 0.5 L. tTo nearest hour.
JULY, 197 I 491
TABLE 2
Age
Comatose Semicomatose
995±72 7±1 1/16
62±6 5.4±0.2 132±2 320±98 357±6
29±1 100±7 110±10 58±5
Per centt
31 59
31 13
16 3.1
Number 308
174 134
291 302 302 302
32±1 5.3±0.1 131±0 242±51 323±1
30±l 117±1 125±1 71 ±1
Per cent
56 44
3 11
2 6
<.001 N.S.
<.001 N.S.
* Number of episodes. t Standard error of mean. tPer cent of total fatal or total nonfatal. § Probability of significance of difference between means for clinical and chemical findings in fatal and nonfatal "coma"
episodes. Computed by X2 or Student f-test. "P" values from Fisher's Tables (Fisher and Yates Statistical Tables, Hatner Publishing Co., New York, 1953).
Serum glucose (mg./100 cc.) Serum nitrogen (mg./lOO cc.) ||2(Na+ + K+) + + **Not significant (N.S.).
18 2.8
in severe diabetic ketoacidosis, but moderate hypotension, arbitrarily designated as a systolic pressure of less than ioo mm./Hg and diastolic blood pressure between o and 50 mm./Hg, was not. An association between hypotension and mortality has been reported by others.4-6-8'11-14-16
Among the nonfatal cases in this series, mean serum glucose levels were significantly lower in individuals with thirteen to twenty-eight episodes each compared to those admitted only once in severe diabetic keto- acidosis (table 3). Most deaths occurred during the first or second admission. The much higher survival rate of individuals with multiple admissions probably re-
flects their relative youth. Younger, "brittle" diabetics more frequently endure episodes of diabetic ketoacidosis which may be severe as measured by degree of acidosis, but are usually characterized by mild hyperglycemia, little or no azotemia, and few complications. 5. Survival time and conditions associated with mortality
The time intervals between admission and death in the thirty-two fatal cases varied from one and one-half hours to thirty-one days. Six died within six hours of admis- sion; four, seven to twelve hours after admission; eight, within twelve to forty-eight hours; seven, within two to seven days; and seven, within seven to thirty-one days.
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per individual 1 2 3 4 5 6 7 9
10 13 19 28
PAUL M. BEIGELMAN, M.D.
occurring in an individual.
Number of individuals
183 36 13 9 6 1 2 1 2 2 1 1
Nonfatal Number of
6 14 9
Serum glucose*
Mean±S.E.M 710±22 708±47 568±28 650±46 709 ±44 613±115 654±76 791±167 766±67 537±37 503±32 361±34
glucose levels episodes in 257
.t Pi*
N.S. <.001
<.001 <.001 <.001
<.01 <.001
*Mg./100 cc. tStandard error of mean. ^Probability of significance of difference between means of multiple "coma" episodes per individual compared with mean
of single episode per individual. Computed by Student /-test. "P" from Fisher's Tables. §Probability of difference between means of death and survival being significant. Computed by Student /-test. "P" from
Fisher's Tables.
The two major contributing factors in death were acute myocardial infarction and infection (table 4 ) . Bacter- emia with sepsis occurred in three subjects wfth pneu- monia, and in the single case of pyelonephritis. Four subjects were diagnosed as dying of uncomplicated severe diabetic ketoacidosis. The uncomplicated mortality rate of severe diabetic ketoacidosis may be computed as four of 340 episodes (1 per cent) or four of 257 subjects (1.5 per cent).
The importance of associated complications in the mortality of severe diabetic ketoacidosis has been fre-
TABLE 4 Major contributing causes of death in thirty-two
fatal cases of severe diabetic ketoacidosis
Coronary artery disease: Myocardial infarction Occlusive coronary artery disease
Infection: Pneumonia or pneumonitis Pyelonephritis with gram-negative
septicemia Mucormycosis
metastases
Number
1
Autopsy
* Questionable as to cause of death.
quently emphasized.1'3'4-6"15'18'19 Also, many of the fatal cases in this series had extremely complicated courses with multiple factors contributing to death. A detailed study of these deaths, including pathological findings, is being prepared. 6. Myocardial infarction
Seven of eleven subjects admitted with acute myocar- dial infarction and severe diabetic ketoacidosis expired. Autopsies performed on six of the seven fatal cases confirmed the diagnosis of myocardial infarction. Mean admission serum osmolality, age, admission serum glu- cose, urea nitrogen, and sodium values were higher in fatal cases (table 5). Two of the seven fatal cases dem- onstrated marked hypotension, with unobtainable dia- stolic blood pressure. In three of the seven fatal cases, death occurred within two hours of admission. One pa- tient, with evidence of lactic acidosis in addition to keto- sis, died twelve days after admission. It is possible that ketosis was not a major factor contributing to the acido- sis and death in this person.
Death in seven of eleven subjects with myocardial infarction emphasizes the particularly ominous prognosis of this complication. It should be emphasized also that the four subjects who survived were very ill.
The association of vascular thrombosis and death in diabetic ketoacidosis has been pointed out in particular by Fitzgerald et al.20 Myocardial infarction with shock in diabetics, even without ketoacidosis, is associated with a very poor prognosis.21 Vascular stasis and hemoconcen- tration secondary to marked hyperglycemia and hyper-
JULY, 1971 493
TABLE 5 Acute myocardial infarction associated with severe diabetic ketoacidosis
Age Serum glucose (mg./lOO ml.) Serum urea nitrogen (mg. per cent) Serum potassium (mEq./L.) Serum sodium (mEq./L.) Serum osmolality
No.* 7 7 7 7 7 7
Fatal Mean+S.E.Mt
Range 32-82
No. 4 4 4 4 4 4
Nonfatal Mean±S.E.M.
Range 26-60
510-1,050 18-51
*Number of episodes. tStandard error of mean.
osmolarity could be important factors in the genesis of coronary arterial thrombosis associated with severe dia- betic ketoacidosis. If vascular stasis is important, it is puzzling, then, that pulmonary embolism is seen so rarely. There was only one fatal case in this series, and it is questionable whether pulmonary embolism was the cause of death in this individual. 7. Alcoholism and pancreatitis
Forty-two alcoholic patients were admitted with fifty- three episodes of severe diabetic ketoacidosis (table 6 ) . In fourteen episodes there was presumed acute pancrea- titis, including one fatality, with typical abdominal find- ings and markedly elevated serum amylase levels. The diagnosis of acute pancreatitis may be difficult, the ele-
• vated serum amylase level (above 300 Somogyi units) reflecting a possible "chemical" pancreatitis with no overt pathological changes. The diagnosis was provi- sionally accepted or excluded on the basis of the highest serum amylase level, which was usually the admission value. These cases were associated with marked eleva- tions of serum glucose, urea nitrogen, and amylase.
Sixteen of the forty-two alcoholic subjects had no previous diagnosis of diabetes mellitus, a higher fre- quency than among nonalcoholics admitted in severe diabetic ketoacidosis. There were definite histories of hypoglycemia in seven, acute or chronic pancreatitis in
fifteen, and pancreatic calcification was noted in roent- genograms of two patients. Acute delirium tremens was observed during five episodes. Three of six alcoholic subjects with evidence of hepatic cirrhosis died shortly after admission. All four alcoholic subjects with severe infection expired.
There were six additional cases of presumed acute pancreatitis in nonalcoholic subjects. Mean admission values for all twenty cases of pancreatitis, including the alcoholics, were: age, forty years; serum glucose, 909 mg. / ioo cc; urea nitrogen, 50 mg. / ioo cc; amylase, 1,067 Somogyi units; potassium, 5.1 mEq./L; sodium, 125 mEq./L; and osmolality, 324. Chemical data of al- coholic compared to nonalcoholic subjects with acute pancreatitis was not markedly different. There was a 10 per cent mortality rate, two of twenty expiring. One of the two had an exceedingly complex course with pneumonia, and severe insulin resistance playing im- portant roles in his demise. Other institutions have em- phasized the severe morbidity of acute pancreatitis, which was encountered in this series. The mortality rate in this series was considerably lower than that reported by others.22"25
8. Surgery
Five patients developed severe ketoacidosis after sur- gery. The procedures were one embolectomy, two leg
TABLE 6 Severe diabetic ketoacidosis associated with alcoholism (53 episodes)
Age (years) Serum glucose (mg./lOO ml.) Serum urea nitrogen (mg. per cent) Serum potassium (mEq./L.) Serum sodium (mEq./L.) Serum amylase (Somogyi units) Osmolality Insulin therapy (units)
No
Fatal (6)* .t Mean+S.E.M.t
49+3 870 + 170
57 + 13 4.6+0.6 128+5 339 334 + 14 423 + 110
Pancreatitis (14)* No.
Mean +S.E.M. 42+3
124+10 1,131+292
320+7 745 + 113
Nonfatal (34) No. Mean +S.E.M. 34 34 34 34 33 21 33 34
41+2 657+49 33+3 5.5+0.2 130±l 119 + 18 325+4 423+50
*Fatal episode of pancreatitis included in both fatal and pancreatitis series. tNumber of episodes. tStandard error of mean.
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Urea Serum Potas- nitro-
glucose HCO3 sium gen Age (mg./ (mEq./ (mEq./ (mg./ (yrs.) 28 28
100 cc.) 430 330
100 c 8 10
Ace- Dura- tone Insulin tion of (dilu- Sodium dosage pregnancy tion) (mEq./L.) (units) (months)
36
27
615
300
7.4
3.4
35
14
1:32
300
440
4.2
4.7
15
19
1:8
1:16
142
132
130
430
Comment Hyperemesis gravidarum. Fetal demise at six months. Discharged three weeks after "coma." Fetus probably dead on admission. Cesarean section two months later. Viable eight-month old male. Complete abortion. Mediasti- nal emphysema. Survival of four-pound pre- mature newborn. Cesarean section and hyste- rectomy. Fetal death. Spontaneous labor. Death of fetus. Stillborn one day after admis- sion.
Maternal death. Recurrence of coma twenty-four hours after admission. Fetal death. Cesarean section at eight months. Viable infant.
amputations, a pancreatectomy for pancreatic carcinoma, followed within four days by onset of newly diagnosed diabetes mellitus with acidosis, and incision and drain- age of a large (12 cm.) abscess of the thigh. Two sub- jects died, one fifty hours after admission due to acute myocardial infarction; the other expired four days after onset of gram-negative bacteremia.
One of the nonfatal cases, a twenty-six-year-old male requiring embolectomy shortly after admission, survived acute myocardial infarction. Gangrene of the left foot developed despite the embolectomy, and a left below- knee amputation was performed one month after ad- mission. 9. Pregnancy
Ten pregnant women were admitted to LAC-USC Medical Center eleven times in severe diabetic keto- acidosis, one having two episodes during a single preg- nancy (table 7 ) . Severe ketoacidosis occurred between the first and eighth months of pregnancy.
One of the ten women expired five hours after therapy was begun for recurrence of severe ketoacidosis success- fully treated twenty-four hours earlier. Pulmonary edema,
presumably due to severe coronary arteriosclerosis (diag- nosed at autopsy), was the cause of death. The fetus also died.
One subject, admitted twice during the course of her pregnancy, had hyperemesis gravidarum. Fetal demise occurred in the sixth month of her pregnancy, one month after recovery from the second episode of severe ketoacidosis.
Only three of the ten fetuses survived. One four- pound, live, newborn infant was delivered by induction during the seventh month of pregnancy, three months after recovery from the episode of severe ketoacidosis. The other two surviving infants were delivered by cesarean section, one two months and the other a few days after maternal recovery from severe ketoacidosis. Deliveries were at the eighth and ninth months of pregnancy.
The very high fetal fatality rate associated with severe maternal ketoacidosis is striking. Knowles et al.26 re- ported fetal and neonatal mortality in six of eleven pregnancies complicated by severe maternal ketoacidosis characterized by serum bicarbonate levels of < 15
JULY, 197 I 495
TABLE 8 Change from insulin to oral hypoglycemic agents
three days or less before admission (seven episodes)
Number* Mean ± SEMf
TABLE 9 Admission serum potassium of 336 episodes
Age , Serum glucose (mg./lOO cc.) Serum urea nitrogen (mg./lOO cc.) Serum sodium (mEq./L.) Serum potassium (mEq./L.) Osmolality Coma insulin dosage (units)
7 7 6 5 7 5 7
47 ± 6 819 ± 118 56 ± 10
122 ±4 6.4 ± A 331±6
466 ± 105
* Number of episodes. f Standard error of mean.
mEq./L. Kyle27 summarized the literature on the sub- ject and computed a fetal loss rate of 64.5 per cent associated with maternal diabetic "coma".
One pregnant woman, after severe ketoacidosis re- quiring 1,350 units of insulin, and complicated by pneumonia, was discharged on diet without requiring drug therapy. She had delivered an eight-month still- born fetus one day after admission.
The subject with the complete abortion at one month of gestation also had mediastinal emphysema. A de- tailed description of this case has been given previ- ously.28
10. Previous therapy ivith oral hypoglycemic agents Seven episodes of severe ketoacidosis occurred less
than three days after therapy was changed from insulin to oral hypoglycemic agents (table 8) . The oral agents prescribed were chlorpropamide (500-750 mg./day) in three subjects, and tolbutamide in four. All seven sur- vived and were discharged from the hospital with in- sulin prescribed in dosages of 15-85 units per day. The need for caution and constant surveillance when chang- ing from insulin to oral agents is emphasized.
Long-term oral agent therapy, ranging from two weeks to five years, preceded twelve nonfatal and three fatal episodes of severe diabetic ketoacidosis. 11. Potassium
Table 9 summarizes admission serum potassium levels obtained in 336 of the 340 episodes of severe diabetic ketoacidosis. Levels were elevated ( > 6.0 mEq./L.) in 73 (22 per cent) episodes, low (<3-5 mEq./L.) in 13 (4 per cent), and within a range of approximate normality (3.5-6.0 mEq./L.) in 250 (74 per cent). Greatly elevated levels (above 7.0 mEq./L.) were ob- served in 17 (6 per cent) of all nonfatal episodes, and 5 (16 per cent) of all fatalities. The association of fatality and greatly elevated serum potassium level pos- sibly reflected circulatory failure and diminished renal function. It was previously reported from this institu- tion that admission serum potassium levels were high in
Approximately normal (3.5-6.0 mEq./L.)
Markedly elevated (> 6.0 mEq./L.)
Nonfatal (305)
250 74
73 22
13 4
* Number of episodes. t Per cent of nonfatal episodes. t Per cent of fatal episodes. § Per cent of total episodes.
39 per cent, normal in 43 per cent, and low in 18 per cent of severely ketoacidotic cases.29 Another study from LAC-USC Medical Cente,r revealed very low (below 2.9 mEq./L.) admission serum potassium levels in 2 per cent of the episodes.30
The highest parenteral potassium dose in this series, 620 mEq. in sixteen hours, was given to a subject whose admission serum potassium level, 4.5 mEq./L., was some- what lower than the mean of 5.3 mEq./L. Other cases with low, or relatively low, admission serum potassium levels also required larger amounts than usual of par- enteral petassium. The experience of this institution, therefore, would support other studies31*35 emphasizing the need to greatly increase parenteral potassium ad- ministration in subjects with low admission serum potas- sium levels. These reports emphasize that potassium de- pletion may be so profound as to require considerably greater amounts of potassium than the 100-200 mEq. per twelve to twenty-four hours usually advocated.2-36
The maximum amount administered was 715 mEq. in twenty-four hours.33
In an extension of the principal study, acute changes of serum potassium levels during treatment were ana- lyzed in thirty-nine episodes of severe diabetic keto- acidosis admitted between December 22, 1961 and June 15, 1968. The mean admission serum potassium level, 5.4 mEq./L. (range 3.3-7.3 mEq./L), was higher than all subsequent mean serum potassium levels. The lowest mean serum potassium level (3.9 mEq./L.) was observed approximately four hours after admission. The range of lowest serum potassium levels was 2.5-4.9 mEq./L. Harwood5 reported similar findings with a mean serum potassium of 5.7 (range 2.0-8.8) mEq./L before treatment, and subsequent decline to a mean of 3.4 mEq./L. after treatment.
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12. Hypoglycemia Hypoglycemia, denned as serum glucose levels of less
than 50 mg./ioo cc, occurred during treatment in 40 of all 482 episodes (8 per cent) of severe diabetic keto- acidosis. The lowest serum glucose level observed was 9 mg./ioo cc. There was no direct association between hypoglycemia and death or severe morbidity. Hypo- glycemia occurred in individuals aged twelve to eighty- three years (mean, thirty-four). Admission serum glu- cose levels ranged from 72 to 1,520 mg./ioo cc. (mean, 604 mg./ioo cc). The interval between commencement of therapy and occurrence of hypoglycemia varied from four to twenty-six hours (mean, thirteen hours). Cumu- lative insulin dose at the time of hypoglycemia ranged from 40 to 1,400 units (mean, 400 units). None of these variables was related to the occurrence of hypo- glycemia. Bortz and Spoont9 reported a lower incidence, four of 213 episodes (2 per cent), of "significant" hypo- glycemia. 13. Subjects requiring no drug therapy after treatment of the acute episodes of severe diabetic ketoacidosis
Eight patients were aglycosuric, and required no drug therapy at time of discharge or within two months after the acute episode. Seven of the eight subjects- had had no personal history, and none had a family history, of diabetes mellitus. Three subjects were alcoholic, two with acute pancreatitis.
The mean age, forty-seven years (range thirty-five to sixty-nine), was greater than that of subjects with non- fatal, severe ketoacidosis who continued to require long- term therapy for diabetes mellitus. Admission mean values of serum glucose, 584 mg./ioo cc. (range 290- 1,020); urea nitrogen, 30 mg./ioo cc. (range 18-51); potassium, 4.7 mEq./L. (range 3.9-7.4); sodium, 133 mEq./L. (range 111-151); bicarbonate, 6 mEq./L. (range <5- io ) ; ketone, 1/16 dilution (range 1/6- 1/32); and insulin dosage, 485 units (range 20-1,480) did not differ markedly from those of subjects requiring long-term therapy.
Recently, Genuth37 reported two cases with prolonged clinical remission of diabetes in adults following suc- cessful therapy of severe diabetic ketoacidosis. These re- missions were characterized by normal fasting blood sugar levels, and marked rise of plasma immunoreactive insulin after administration of glucose, tolbutamide, or glucagon. It is not known to what extent glucose toler- ance may have improved in the present cases. 14. Nonketotic hyperosmolar coma
Nine cases of nonketotic hyperosmolar coma, defined on the basis of a serum osmolality of 380 or more and absence of ketoacidosis, were admitted to the Diabetes
TABLE Hyperosmolar
Serum urea nitro- gen (mg./lOOcc.)
Serum potassium (mEq./L.)
Serum sodium (mEq./L.)
Serum bicarbonate (mEq./L.)
66 ± 8 402 ± 7
N.S. >.O2, <.05
* Standard error of mean. t Probability of significance of difference between means of
fatal and nonfatal cases.- N.S. (Not significant).
Service between July 1, 1965 and June 30, 1968 (table 10). Probably, numerous other cases were admitted to LAC-USC Medical Center during this period, but were either not recognized or reported. Five of the nine cases died, confirming the high mortality rate reported by others.38-39 In contrast to severe diabetic ketoacidosis, there was no association in these cases between mortality and elevated serum glucose (range, 670-2075 mg./ioo cc) , urea nitrogen (range, 43-308 mg./ioo cc) , or os- molality levels (range, 383-594). Also, there was no marked difference in age (range, 46-79), or insulin dos- age (range, 70-1200) between fatal and nonfatal cases. Considerably larger amounts of parenteral fluid were ad- ministered in the surviving (mean, 7.3 L. and range, 4.5-8.5 L.) as compared with the fatal nonketotic "coma" cases (mean, 4.8 L. and range, 3.5-5.9 L). One of the four nonfatal and three of the five fatal cases had a past history of known diabetes mellitus. All four surviving subjects were discharged on drug therapy for diabetes mellitus.
DISCUSSION
This series of patients in severe diabetic ketoacidosis is characterized by the frequency of severe hypergly- cemia, azotemia, and elevated serum osmolality. Acidosis was marked in that all cases selected had serum bicarb- onate values of 10 mEq./L. or less, with arterial blood pH determinations as low as 6.81, performed on many individuals.
The rationale of therapy in this series is presented in a separate communication.2 Insulin requirements were usu-
JULY, 1971 497
SEVERE DIABETIC KETOACIDOSIS (DIABETIC "COMA")
ally very high (mean, 540). Previous studies40-41 have indicated that smaller insulin doses are usually as effec- tive as larger amounts, but recent experience at this in- stitution and elsewhere indicates the value of higher doses.1-3-5-7-9'12-13
The relatively low mortality rates of 9 per cent (340 episodes) and 13 per cent (257 patients) may be at- tributed in part to the intensive therapy. Careful mon- itoring probably accounted for the infrequency of severe hypoglycemia, pulmonary edema, or hyperkalemia.
There have been reports of fatal cerebral edema de- veloping in severe diabetic ketoacidosis following insti- tution of therapy.42'46 In certain of these reports, fatal cerebral edema may have been associated with persistent hypokalemia, acidosis, or other metabolic derangement. No instance of fatality due to cerebral edema could be
confirmed in the present series, either clinically or by necropsy. This observation, associated with the emphasis given rapid correction of metabolic and electrolyte ab- normalities in this institution, would support Bradley and Young's denial47 of allegations that aggressive ther- apy is the sole or principal cause of this fatal compli- cation.
Four cases of a usually benign clinical entity (media- stinal and subcutaneous emphysema) occurring in this series, have been reported separately.27 An additional case has been recently presented.48
The larger series reported during the last two decades from Los Angeles, London, Cincinnati, Philadelphia, Paris, and Sydney indicate a fairly constant mortality rate in severe diabetic ketoacidosis ranging from 9 per cent to 16 per cent (table n ) . Considerable improvement
TABLE 11 Summary of mortality rates in severe diabetic ketoacidosis: Survey of literature
Study Number
18 19 20 21 22
23 24 25 26
140 172 61 69
42 67 32 30
44 25 5
31 15 8
Cincinnati
Philadelphia
New York New York Seattle Seattle Boston Cincinnati Cincinnati London, England Sydney, Australia
Boston Melbourne, Australia Melbourne, Australia Baltimore Paris, France
Paris, France Philadelphia San Francisco Los Angeles
Years 1923-66 1923-34 1923-29
1952-55 1952-55 1956-67 1958-59 1959-62
1963-67 1960-64 1964-68 1965-68
Hudson et al.18
Hudson et al.18
Shaw et al.41
Derot and Tchobroutsky12
Assan et al.18
Bortz et al.9
Kiraly et al.54
Present series
*Mortality rate 4.6 per cent between 1946 and 1966 (Joslin Clinic). tCases with serum bicarbonate levels of <15 mEq./L. included. Remainder of series based on bicarbonate levels of
approximately 10 mEq./L. or less.
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PAUL M. BEIGELMAN, M.D.
has been reported from certain institutions as more intensive therapeutic regimens have been instituted. It has been suggested that a higher mortality rate is to be expected in the larger county or city hospitals as com- pared with the more selective private or university hospitals.3-8
ACKNOWLEDGMENT
The helpful advice of Helen E. Martin, M.D., Chief of the Diabetes Service until December 31, 1968, is gratefully acknowledged.
This study was assisted by grants from the Diabetes Association of Southern California, U.S. Public Health Service Grant AM06510-07, a nd University of South- ern California Medical School Grant RR-05356-09, 53-5120-5837.
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