Severe Diabetic Ketoacidosis (Diabetic "Coma ) - Diabetes

Severe Diabetic Ketoacidosis (Diabetic "Coma95)

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 in257 patients, July 1, 1965 to June 30, 1968. Fatality inthirty-two cases was associated with significantly elevatedadmission 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 andmarked elevation of serum glucose and urea nitrogen. Four-teen of the twenty occurred in alcoholics. There were elevenepisodes in ten pregnant women, with one maternal andseven fetal deaths. Admission serum potassium, recorded in336 episodes, was markedly elevated in 22 per cent anddecreased 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, demonstratedvery high admission serum glucose, urea nitrogen, and osmo-lality levels. DIABETES 20:490-500, July, 1971.

Severe diabetic ketoacidosis is defined by the DiabetesService of LAC-USC Medical Center* as a state of keto-acidosis with serum bicarbonate decreased to levels ofio mEq./L or less. This degree of diabetic ketoacidosis,even without mental obtundation, has been designatedby some authorities as "diabetic coma".1

Admission data on 340 sequential episodes of severediabetic ketoacidosis in 257 patients admitted betweenJuly 1, 1965 and June 30, 1968 are presented. Particu-lar emphasis is given to factors leading to death inthirty-two of these patients. None of these fatalities was

From the Departments of Medicine and Pharmacology,School of Medicine, University of Southern California, LosAngeles, 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 incertain of the patients who had multiple admissions forsevere diabetic ketoacidosis before or after the prin-cipal three-year study period. Inclusion of these yieldeda total of 482 episodes in the 257 patients, if time limitsare ignored. These data are utilized to ascertain the effectof multiple admissions upon mortality rate.

Nine cases of hyperosmolar nonketotic coma, admittedto the Diabetes Service between July 1, 1965 and June30, 1968, -are also presented for comparison with theketoacidotic patients.

The therapeutic technics utilized by this Diabetes Ser-vice are based on careful monitoring of vital signs andchemical status. Individualized, vigorous therapy is em-phasized with large intravenous doses of insulin ad-ministered in the earlier phases of treatment, followed bysmaller 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 immediatelyand treated vigorously. These therapeutic approaches arefully presented in a separate communication2 which alsosummarizes briefly fifty-one episodes of severe diabeticketoacidosis 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 thepresent report.

RESULTS

1. Findings on admissionThe 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 therange of mean ages, twenty-nine to forty-two, reportedin other series.3'8 The mean admission serum glucoselevels reported by others,3'8 371-597 mg./ioo cc, wereless than the mean value of 705 mg./ioo cc. observedin this institution. The mean admission serum urea nitro-gen in this series, 35 mg./ioo cc, was slightly higherthan mean values of 30-33 mg./ioo cc. in other se-ries.6'8'9' A minor factor possibly contributing to thesediscrepancies is the use, in previous smdies, of wholeblood for glucose and urea determinations, which arelower than equivalent serum values. Mean admissionserum potassium levels reported by others, 4.6-5.7 mEq./L,3-5'9 were in the same range as the mean potassiumof this series, 5.3 mEq./L. The mean admission serumsodium in this institution, 131 mEq./L., was within therange reported elsewhere, 131-138 mEq./L. 3-r>-9 Inearlier reports, mean admission leucocyte counts were16,900-21,900 per cu. mm.,3-15'8 closely agreeing withthe 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 lowerthan the 14.7 gm. per cent observed in this series.Mean admission respiratory rate of 30/min., pulse rateof 115/min., and temperature of 98.5 ° F. are in goodagreement with values of other series.3'6

2. CausesMany of the episodes reported in this series of cases

had multiple causes, and frequently the cause was un-known. Discontinuance of therapy and infection werethe two most common causes of severe diabetic keto-acidosis in this and other series.1'3'4'6'8'9 The third mostcommon cause in this series was diabetes mellitus notbeing diagnosed before admission. This group consti-tuted 28 per cent of fatalities, 13 per cent of nonfatalepisodes (15 per cent of total episodes), and nearly20 per cent of the 257 subjects admitted during thethree-year study period. Other institutions have reporteda 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 totwenty-four hour range of others, 148-1,280 units.3"5'8'9

The smallest insulin dose (20 units) was given in apuzzling case with definite hyperglycemia and ketoacid-osis, excellent response to parenteral bicarbonate therapyand diet, and no evidence of diabetes mellitus at timeof discharge. The highest dose was 10,700 units in afatal case complicated by pneumonia and pancreatitis.

Mean fluid volume infused was 6 L, the range being0-18. Mean sodium given was 530 mEq., the range being0-620. Mean potassium administered was 165 mEq., therange being 0-620.

The amounts of insulin, fluid and electrolytes givenwere designed in each instance to relieve ketosis andcorrect 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 ketoacidosisadmitted July 1, 1965 to June 30, 1968 are comparedin table 2.

During the three-year period, 32 of the 340 episodes(9 per cent) terminated fatally (death in thirty-onedays or less after admission). The patient mortality rate,32 of 257, was 13 per cent. There were more episodesof severe diabetic ketoacidosis in women than in men,but the male mortality rate was greater. There was norelation of mortality to presence or absence of a familyhistory of diabetes. Mortality was higher with increasedage and with increase of serum glucose, urea nitrogen,and osmolality. Similar associations, particularly withage, have been noted in other series.3'4-6-10"13

The mean pulse rate and diastolic blood pressure werelower in fatal cases. The depression of pulse rate wasprobably due to greater frequency of bradycardia, lessthan 50/min., or cardiac standstill. The lower meandiastolic blood pressure in the fatal cases probably re-flected the increased frequency of severe hypotensionand shock in such patients.

Clinical coma, characterized by the patient's not re-sponding to pain or to loud voice commands, was morefrequent 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 adiastolic blood pressure of zero, was related to mortality

TABLE 1Summary of therapy

TherapyInsulin (units)Potassium (mEq.)Fluid (liters)Sodium (mEq.)Time for correction of

ketosis (hours)

Number ofObservations

325314322322

325

Mean

540*165*6t

530*

17t

Range

20-10,7000-620*0-180-1,460

3-44t

*To nearest five units or 5 mEq.tTo nearest 0.5 L.tTo nearest hour.

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SEVERE DIABETIC KETOACIDOSIS (DIABETIC "COMA")

TABLE 2

Comparison of fatal with nonfatal episodes

Age

SexWomenMen

Chemical data:Serum glucose (mg./lOOcc.)Serum bicarbonate (mEq./L.)Serum acetone (dilution)Serum urea nitrogen

(mg./lOOcc.)Serum potassium (mEq./L.)Serum sodium (mEq./L.)Serum amylase (Somogyi units)Osmolality (calculated) ||

Physical findings:RespirationPulseSystolic blood pressureDiastolic blood pressureLoss of consciousness:

ComatoseSemicomatose

Hypotension:SevereModerate

Number*32

1319

323222

323130

926

29313131

104

51

Fatal (32)Mean ±S.E.M.t54±2

995±727±11/16

62±65.4±0.2132±2320±98357±6

29±1100±7110±1058±5

Percentt

3159

3113

163.1

Number308

174134

308308268

304305274126287

291302302302

1035

, 717

Nonfatal (308)

Mean ± SEM36±1

675±176±01/16

32±15.3±0.1131±0242±51323±1

30±l117±1125±171 ±1

Percent

5644

311

26

P§

<.001

<.001N.S.**N.S.

<.001N.S.N.S.N.S.

<.001

N.S.>.01, <.O2

N.S.>.01, <.O2

<.001N.S.

<.001N.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, HatnerPublishing 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 thanioo mm./Hg and diastolic blood pressure betweeno and 50 mm./Hg, was not. An association betweenhypotension and mortality has been reported byothers.4-6-8'11-14-16

Among the nonfatal cases in this series, mean serumglucose levels were significantly lower in individualswith thirteen to twenty-eight episodes each comparedto those admitted only once in severe diabetic keto-acidosis (table 3). Most deaths occurred during thefirst or second admission. The much higher survival rateof individuals with multiple admissions probably re-

flects their relative youth. Younger, "brittle" diabeticsmore frequently endure episodes of diabetic ketoacidosiswhich 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 withmortality

The time intervals between admission and death in thethirty-two fatal cases varied from one and one-half hoursto 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 toseven days; and seven, within seven to thirty-one days.

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Number of"coma" episodes

per individual12345679

10131928


TABLE 3Relationship of fatality rate and admission serum

occurring in an individual.

Number ofindividuals

1833613961212211

NonfatalNumber of

"coma"episodes

16064393629

6149

20261928

Total of 482

Serumglucose*

Mean±S.E.M710±22708±47568±28650±46709 ±44613±115654±76791±167766±67537±37503±32361±34

glucose levelsepisodes in 257

.t Pi*

N.S.<.001

N.S.N.S.N.S.N.S.N.S.N.S.

<.001<.001<.001

to number ofindividuals.

Number23

8

1

episodes

FatalSerumglucose

Mean±S.E.M.960±89

l,102±48

750

P2§

<.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 acutemyocardial infarction and infection (table 4 ) . Bacter-emia with sepsis occurred in three subjects wfth pneu-monia, and in the single case of pyelonephritis. Foursubjects were diagnosed as dying of uncomplicated severediabetic ketoacidosis. The uncomplicated mortality rateof severe diabetic ketoacidosis may be computed as fourof 340 episodes (1 per cent) or four of 257 subjects(1.5 per cent).

The importance of associated complications in themortality of severe diabetic ketoacidosis has been fre-

TABLE 4Major contributing causes of death in thirty-two

fatal cases of severe diabetic ketoacidosis

Coronary artery disease:Myocardial infarctionOcclusive coronary artery disease

Infection:Pneumonia or pneumonitisPyelonephritis with gram-negative

septicemiaMucormycosis

Diabetic ketoacidosisAcute renal failureCerebrovascular accidentAcute pancreatitisHyperthyroidism (toxic goiter.)Pulmonary embolism and infarctionCarcinoma of pancreas with

metastases

Number

71

8

11423211

1

Autopsy

61

5

111

1—

11*

1

* Questionable as to cause of death.

quently emphasized.1'3'4-6"15'18'19 Also, many of the fatalcases in this series had extremely complicated courseswith multiple factors contributing to death. A detailedstudy of these deaths, including pathological findings, isbeing 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 casesconfirmed the diagnosis of myocardial infarction. Meanadmission serum osmolality, age, admission serum glu-cose, urea nitrogen, and sodium values were higher infatal 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 thatketosis was not a major factor contributing to the acido-sis and death in this person.

Death in seven of eleven subjects with myocardialinfarction emphasizes the particularly ominous prognosisof this complication. It should be emphasized also thatthe four subjects who survived were very ill.

The association of vascular thrombosis and death indiabetic ketoacidosis has been pointed out in particularby Fitzgerald et al.20 Myocardial infarction with shock indiabetics, even without ketoacidosis, is associated witha very poor prognosis.21 Vascular stasis and hemoconcen-tration secondary to marked hyperglycemia and hyper-

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TABLE 5Acute myocardial infarction associated with severe diabetic ketoacidosis

AgeSerum glucose (mg./lOO ml.)Serum urea nitrogen (mg. per cent)Serum potassium (mEq./L.)Serum sodium (mEq./L.)Serum osmolality

No.*777777

FatalMean+S.E.Mt

59±12l,061±197

61 + 115.5±0.5130±2354+13

Range32-82

597-2,16024-1053.9-7.5126-138325-420

No.444444

NonfatalMean±S.E.M.

46+12893 + 128

34+156.5+0.4129+3314+9

Range26-60

510-1,05018-51

5.6-7.6122-137294-322

*Number of episodes.tStandard error of mean.

osmolarity could be important factors in the genesis ofcoronary arterial thrombosis associated with severe dia-betic ketoacidosis. If vascular stasis is important, it ispuzzling, then, that pulmonary embolism is seenso rarely. There was only one fatal case in this series,and it is questionable whether pulmonary embolism wasthe 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. Thediagnosis of acute pancreatitis may be difficult, the ele-

• vated serum amylase level (above 300 Somogyi units)reflecting a possible "chemical" pancreatitis with noovert pathological changes. The diagnosis was provi-sionally accepted or excluded on the basis of the highestserum amylase level, which was usually the admissionvalue. These cases were associated with marked eleva-tions of serum glucose, urea nitrogen, and amylase.

Sixteen of the forty-two alcoholic subjects had noprevious diagnosis of diabetes mellitus, a higher fre-quency than among nonalcoholics admitted in severediabetic ketoacidosis. There were definite histories ofhypoglycemia in seven, acute or chronic pancreatitis in

fifteen, and pancreatic calcification was noted in roent-genograms of two patients. Acute delirium tremens wasobserved during five episodes. Three of six alcoholicsubjects with evidence of hepatic cirrhosis died shortlyafter admission. All four alcoholic subjects with severeinfection expired.

There were six additional cases of presumed acutepancreatitis in nonalcoholic subjects. Mean admissionvalues for all twenty cases of pancreatitis, including thealcoholics, were: age, forty years; serum glucose, 909mg. / 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 acutepancreatitis was not markedly different. There was a10 per cent mortality rate, two of twenty expiring. Oneof the two had an exceedingly complex course withpneumonia, and severe insulin resistance playing im-portant roles in his demise. Other institutions have em-phasized the severe morbidity of acute pancreatitis, whichwas encountered in this series. The mortality rate in thisseries was considerably lower than that reported byothers.22"25

8. Surgery

Five patients developed severe ketoacidosis after sur-gery. The procedures were one embolectomy, two leg

TABLE 6Severe 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)OsmolalityInsulin therapy (units)

No

66666266

Fatal (6)*.t Mean+S.E.M.t

49+3870 + 170

57 + 134.6+0.6128+5339334 + 14423 + 110

Pancreatitis (14)*No.

1414141413141314

Mean +S.E.M.42+3

943 + 11349 + 85.2+0.3

124+101,131+292

320+7745 + 113

Nonfatal (34)No. Mean +S.E.M.3434343433213334

41+2657+4933+35.5+0.2130±l119 + 18325+4423+50

*Fatal episode of pancreatitis included in both fatal and pancreatitis series.tNumber of episodes.tStandard error of mean.

494 DIABETES, VOL. 20, NO. 7

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TABLE 7Pregnancy in severe diabetic ketoacidosis

UreaSerum Potas- nitro-

glucose HCO3 sium genAge (mg./ (mEq./ (mEq./ (mg./(yrs.)2828

100 cc.)430330

L.)88

L.)4.94.4

100 c810

Ace- Dura-tone Insulin tion of(dilu- Sodium dosage pregnancytion) (mEq./L.) (units) (months)

36

27

615

300

7.4

3.4

35

14

1:32

132131129

135

5565

615

355

18

34

23

35

36

31

290

360

305

714

810

695

5

<5

5

5

6

5

4.3

4.9

4.0

5.0

4.0

4.6

5

14

18

32

19

34

1:16

1:8

1:32

1:8

1:32

1:8

127

136

137

350

125

200

450

1,350

1,050

1

4

2

8

I

5

23

Means:29

300

440

4.2

4.7

15

19

1:8

1:16

142

132

130

430

CommentHyperemesis gravidarum.Fetal demise at six months.Discharged three weeks after"coma." Fetus probably deadon admission.Cesarean section two monthslater. Viable eight-month oldmale.Complete abortion. Mediasti-nal emphysema.Survival of four-pound pre-mature newborn.Cesarean section and hyste-rectomy. Fetal death.Spontaneous labor. Death offetus.Stillborn one day after admis-sion.

Maternal death. Recurrence ofcoma twenty-four hours afteradmission. Fetal death.Cesarean section at eightmonths. Viable infant.

amputations, a pancreatectomy for pancreatic carcinoma,followed within four days by onset of newly diagnoseddiabetes 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 acutemyocardial infarction; the other expired four days afteronset of gram-negative bacteremia.

One of the nonfatal cases, a twenty-six-year-old malerequiring embolectomy shortly after admission, survivedacute myocardial infarction. Gangrene of the left footdeveloped 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-USCMedical Center eleven times in severe diabetic keto-acidosis, one having two episodes during a single preg-nancy (table 7 ) . Severe ketoacidosis occurred betweenthe first and eighth months of pregnancy.

One of the ten women expired five hours after therapywas 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 fetusalso died.

One subject, admitted twice during the course of herpregnancy, had hyperemesis gravidarum. Fetal demiseoccurred in the sixth month of her pregnancy, onemonth after recovery from the second episode of severeketoacidosis.

Only three of the ten fetuses survived. One four-pound, live, newborn infant was delivered by inductionduring the seventh month of pregnancy, three monthsafter recovery from the episode of severe ketoacidosis.The other two surviving infants were delivered bycesarean section, one two months and the other a fewdays after maternal recovery from severe ketoacidosis.Deliveries were at the eighth and ninth months ofpregnancy.

The very high fetal fatality rate associated with severematernal ketoacidosis is striking. Knowles et al.26 re-ported fetal and neonatal mortality in six of elevenpregnancies complicated by severe maternal ketoacidosischaracterized by serum bicarbonate levels of < 15

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TABLE 8Change from insulin to oral hypoglycemic agents

three days or less before admission (seven episodes)

Number* Mean ± SEMf

TABLE 9Admission 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.)OsmolalityComa insulin dosage (units)

7765757

47 ± 6819 ± 11856 ± 10

122 ±46.4 ± A331±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 centassociated with maternal diabetic "coma".

One pregnant woman, after severe ketoacidosis re-quiring 1,350 units of insulin, and complicated bypneumonia, was discharged on diet without requiringdrug therapy. She had delivered an eight-month still-born fetus one day after admission.

The subject with the complete abortion at one monthof gestation also had mediastinal emphysema. A de-tailed description of this case has been given previ-ously.28

10. Previous therapy ivith oral hypoglycemic agentsSeven episodes of severe ketoacidosis occurred less

than three days after therapy was changed from insulinto oral hypoglycemic agents (table 8) . The oral agentsprescribed were chlorpropamide (500-750 mg./day) inthree 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. Theneed for caution and constant surveillance when chang-ing from insulin to oral agents is emphasized.

Long-term oral agent therapy, ranging from two weeksto five years, preceded twelve nonfatal and three fatalepisodes of severe diabetic ketoacidosis.11. Potassium

Table 9 summarizes admission serum potassium levelsobtained in 336 of the 340 episodes of severe diabeticketoacidosis. Levels were elevated ( > 6.0 mEq./L.) in73 (22 per cent) episodes, low (<3-5 mEq./L.) in13 (4 per cent), and within a range of approximatenormality (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, and5 (16 per cent) of all fatalities. The association offatality and greatly elevated serum potassium level pos-sibly reflected circulatory failure and diminished renalfunction. It was previously reported from this institu-tion that admission serum potassium levels were high in

Approximatelynormal(3.5-6.0 mEq./L.)

Markedly elevated(> 6.0 mEq./L.)

Definitely low« 3 . 5 mEq./L.)

Nonfatal(305)

Num- Perber* centf

227 74

66 22

12 4

Fatal(31)

Num- Perber centt

23 74

7 22

1 4

Total(336)

Num- Perber cent§

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 percent of severely ketoacidotic cases.29 Another study fromLAC-USC Medical Cente,r revealed very low (below2.9 mEq./L.) admission serum potassium levels in 2per cent of the episodes.30

The highest parenteral potassium dose in this series,620 mEq. in sixteen hours, was given to a subject whoseadmission serum potassium level, 4.5 mEq./L., was some-what lower than the mean of 5.3 mEq./L. Other caseswith low, or relatively low, admission serum potassiumlevels also required larger amounts than usual of par-enteral petassium. The experience of this institution,therefore, would support other studies31*35 emphasizingthe 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 considerablygreater 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. intwenty-four hours.33

In an extension of the principal study, acute changesof serum potassium levels during treatment were ana-lyzed in thirty-nine episodes of severe diabetic keto-acidosis admitted between December 22, 1961 andJune 15, 1968. The mean admission serum potassiumlevel, 5.4 mEq./L. (range 3.3-7.3 mEq./L), was higherthan all subsequent mean serum potassium levels. Thelowest mean serum potassium level (3.9 mEq./L.) wasobserved approximately four hours after admission. Therange of lowest serum potassium levels was 2.5-4.9mEq./L. Harwood5 reported similar findings with a meanserum potassium of 5.7 (range 2.0-8.8) mEq./L beforetreatment, and subsequent decline to a mean of 3.4mEq./L. after treatment.

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12. HypoglycemiaHypoglycemia, denned as serum glucose levels of less

than 50 mg./ioo cc, occurred during treatment in 40of all 482 episodes (8 per cent) of severe diabetic keto-acidosis. The lowest serum glucose level observed was9 mg./ioo cc. There was no direct association betweenhypoglycemia 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 commencementof therapy and occurrence of hypoglycemia varied fromfour to twenty-six hours (mean, thirteen hours). Cumu-lative insulin dose at the time of hypoglycemia rangedfrom 40 to 1,400 units (mean, 400 units). None ofthese 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 treatmentof the acute episodes of severe diabetic ketoacidosis

Eight patients were aglycosuric, and required no drugtherapy at time of discharge or within two months afterthe acute episode. Seven of the eight subjects- had hadno personal history, and none had a family history, ofdiabetes mellitus. Three subjects were alcoholic, twowith acute pancreatitis.

The mean age, forty-seven years (range thirty-five tosixty-nine), was greater than that of subjects with non-fatal, severe ketoacidosis who continued to require long-term therapy for diabetes mellitus. Admission meanvalues 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, 133mEq./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 requiringlong-term therapy.

Recently, Genuth37 reported two cases with prolongedclinical remission of diabetes in adults following suc-cessful therapy of severe diabetic ketoacidosis. These re-missions were characterized by normal fasting bloodsugar levels, and marked rise of plasma immunoreactiveinsulin after administration of glucose, tolbutamide, orglucagon. 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, definedon the basis of a serum osmolality of 380 or more andabsence of ketoacidosis, were admitted to the Diabetes

TABLEHyperosmolar

NonfatalCases (4)

Mean ± SEM*AgeSerum osmolalitySerum glucose(mg./lOOcc.)

Serum urea nitro-gen (mg./lOOcc.)

Serum potassium(mEq./L.)

Serum sodium(mEq./L.)

Serum bicarbonate(mEq./L.)

Therapy:Insulin (units)Fluid (liters)

66 ± 8402 ± 7

1,293 ± 341

95 ± 11

4.3 ± 0.5

144 ± 6

25 ± 3

624 ± 2217.3 ± 0.9

10"coma"

FatalCases (5)

Mean ± SEM*64 ± 5

409 ± 22

1,158 ± 122

140 ± 45

5.1 ± 0.8

142 ± 4

22 ± 4

408 ± 1514.8 ± 0.4

PtN.S.N.S.

N.S.

N.S.

N.S.

N.S.

N.S.

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 (table10). Probably, numerous other cases were admitted toLAC-USC Medical Center during this period, but wereeither not recognized or reported. Five of the nine casesdied, confirming the high mortality rate reported byothers.38-39 In contrast to severe diabetic ketoacidosis,there was no association in these cases between mortalityand elevated serum glucose (range, 670-2075 mg./ioocc) , urea nitrogen (range, 43-308 mg./ioo cc) , or os-molality levels (range, 383-594). Also, there was nomarked 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 thefour nonfatal and three of the five fatal cases had a pasthistory of known diabetes mellitus. All four survivingsubjects were discharged on drug therapy for diabetesmellitus.

DISCUSSION

This series of patients in severe diabetic ketoacidosisis characterized by the frequency of severe hypergly-cemia, azotemia, and elevated serum osmolality. Acidosiswas marked in that all cases selected had serum bicarb-onate values of 10 mEq./L. or less, with arterial bloodpH determinations as low as 6.81, performed on manyindividuals.

The rationale of therapy in this series is presented in aseparate communication.2 Insulin requirements were usu-

JULY, 1971 497

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ally very high (mean, 540). Previous studies40-41 haveindicated 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 higherdoses.1-3-5-7-9'12-13

The relatively low mortality rates of 9 per cent (340episodes) 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 severehypoglycemia, 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, fatalcerebral edema may have been associated with persistenthypokalemia, acidosis, or other metabolic derangement.No instance of fatality due to cerebral edema could be

confirmed in the present series, either clinically or bynecropsy. This observation, associated with the emphasisgiven rapid correction of metabolic and electrolyte ab-normalities in this institution, would support Bradleyand 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 thisseries, have been reported separately.27 An additionalcase has been recently presented.48

The larger series reported during the last two decadesfrom Los Angeles, London, Cincinnati, Philadelphia,Paris, and Sydney indicate a fairly constant mortality ratein severe diabetic ketoacidosis ranging from 9 per centto 16 per cent (table n ) . Considerable improvement

TABLE 11Summary of mortality rates in severe diabetic ketoacidosis: Survey of literature

StudyNumber

123

4

567

8

91011121314151617

1819202122

23242526

Number ofEpisodes

1,2167481

60

31584

165

107

10060325367

1401726169

42673230

133

15414925

340

FatalityNumber Per cent

871110

25

1052373

29

131301

44255

11

221

12

16

23210

32

71512

42

332744

27

132901

31158

16

53137

12

151409

CityBostonRochester, Minn.Buffalo

Cincinnati

Los Angeles -MinneapolisPhiladelphia

Philadelphia

New YorkNew YorkSeattleSeattleBostonCincinnatiCincinnatiLondon, EnglandSydney, Australia

BostonMelbourne, AustraliaMelbourne, AustraliaBaltimoreParis, France

Paris, FrancePhiladelphiaSan FranciscoLos Angeles

Years1923-661923-341923-29

1923-37

1930-401930-481931-36

1941

1940-511952-571942-491948-521944-501947-511952-561948-631950-55

1952-551952-551956-671958-591959-62

1963-671960-641964-681965-68

ReferenceMarble*49

Baker4

Bowen andHekimian50

Owens andRockwern17

Collen14

Zieve and Hill6

Dillon andDyer8

Beardwood andRouse15

Pines51

Pines51

Crampton et al.52

Crampton et al.52

Harwood5

Skillman et al.7

Skillman et al.7

Nabarro53

Greenaway andRead"Cohen et al.3

Hudson et al.18

Hudson et al.18

Shaw et al.41

Derot andTchobroutsky12

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.

498 DIABETES, VOL. 2O, NO. 7

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has been reported from certain institutions as moreintensive therapeutic regimens have been instituted. Ithas been suggested that a higher mortality rate is to beexpected in the larger county or city hospitals as com-pared with the more selective private or universityhospitals.3-8

ACKNOWLEDGMENT

The helpful advice of Helen E. Martin, M.D., Chiefof the Diabetes Service until December 31, 1968, isgratefully acknowledged.

This study was assisted by grants from the DiabetesAssociation of Southern California, U.S. Public HealthService Grant AM06510-07, a nd University of South-ern California Medical School Grant RR-05356-09,53-5120-5837.

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Severe Diabetic Ketoacidosis (Diabetic "Coma ) - Diabetes