THE CRITICALLY ILL CHILD: DIABETIC KETOACIDOSIS AND COMA

(1)

THE

CRITICALLY

ILL CHILD:

DIABETIC

KETOACIDOSIS

AND

COMA

Robert Schwartz, M.D.

From the Department of Pediatrics, Case Western Reserve University School of Medicine at Cleveland Metropolitan General Hospital, Cleveland, Ohio

The author was supported in part by a grant ( HD-03290) from the National Institute of Child Health

and Human Development, and by the National Institute of Arthritis and Metabolic Diseases (

5-Ti-AM-5:356).

ADDRESS: 3395 Scranton Road, Cleveland, Ohio 44109.

DIAGNOSIS

AND

TREATMENT

902

D IABETIC ACIDO5IS, even with coma, may not be so alarming in implications as are some other critical problems previously presented in this series. Yet it certainly be-longs among the critical illnesses, demand-ing as it does prompt action to restore a

delicate physiological balance. Because the therapeutic response is very sensitive to pre-cise management, improper therapy may be

all the more dangerous. Management of diabetic coma therefore confronts the

pedi-atrician with a more dramatic challenge than

either the early recognition of diabetes in the previously normal child or the prevention of ketoacidosis in those with known diabetes; both of which should be more common prob-lems. The mortality rate in diabetic acidosis and coma is admittedly very low. It should

be nonexistent.

The frequency of presentation with

ke-toacidosis in children with diabetes mellitus

has been variously reported as low as 18%

by Danowski’ and as high as 52% by

Jack-son.2 Knowles3 indicated that 45% of diabe-tic children had serum carbon dioxide con-centrations of less than 20 mM/L at the initial episode of diabetes. In his observa-tions. recurrence of attacks varied widely; no subsequent acidosis occurred in 46% of

the children; whereas 13% had 10 attacks

or more each to account for almost half of all attacks tabulated. Knowles found acido-sis most prevalent in the first 5 years of

known diabetes regardless of age at

diagno-sis and in the teen years regardless of dura-tion.3 Severe ketoacidosis

( serum

CO2 < 10 mM/L and coma occur in less than 20% of initial admissions.1

PATE-IOPHYSIOLOGY

While the fundamental common bio-chemical basis for hereditary juvenile dia-betes mellitus remains to be elucidated, the

nonvascular metabolic derangements can in large measure be attributed to defective

in-sulin secretion.

The metabolic derangements which re-sult concern:

(

1

) volume

depletion, both

extracellular and intracellular; (2

) osmotic

alterations between volume compartments;

(

3) acid-base disequilibrium with acidosis and buffer depletion; and (4) caloric defi-ciency, i.e., “metabolic starvation.”

Immunoreactive insulin measurements

indicate low normal values in plasma, which fail to rise in response to several stimuli

(

glucose, arginine, tolbutamide

)

.

Although a physiological recovery may oc-cur after initial treatment, permanent

defi-ciency of insulin secretion follows within

weeks to months after onset. The several

re-sultant physiological disturbances are well

shown by two diagrams

(

Fig. 1 and 2

)

re-produced by courtesy of Dr. Rachmiel Lev-inc.

Insulin deprivation

(

Fig. 1

) is associated

with impairment of peripheral utilization of carbohydrates, caused in part by defective glucose uptake in insulin sensitive tissues, especially muscle and adipose tissue. In

ad-dition, decreased synthesis of glycogen in the liver and increased synthesis of glucose from amino acids

(

gluconeogenesis

) raise

the hepatic glucose output. These two fac-tors, coupled with a continuing and

some-times

increased

dietary intake of

carbohy-drate, result in hyperglycemia. Since

(2)

‘lAlN

e. ‘‘

FIG. 1. Pathophysiological effects of insulin deprivation. (Reproduced by

permission of Dr. R. Levine, and Ciba Corporation). Not shown is the

pro-duction of hydrogen ions due to organic acids (including “ketones” ).

Ke-tones do not “bind sodium,” but are associated with cation at physiological

pH, and to a large extent appear in the urine in this form.

cose contributes to the effective osmotic

pressure of the extracellular fluid,

hyper-glycemia is associated with cellular

dehy-dration as cell water shifts to the extra-cellular compartment. In the kidney the

hyperglycemia results in a filtered glucose

load exceeding the reabsorptive mechanism

of tubular transport, thus producing an

“os-motic”

or “solute”

diuresis.

This in turn

ob-ligates both water and electrolyte

( sodium

and chloride

) loss and results

in

extracellu-lar fluid depletion when there is also a

fail-ure of intake. As the derangement

pro-gresses, additional solute for excretion is

derived from protein catabolism

( urea)

and the ketoacidosis (organic acids

), both

(3)

COMA 904

Fic. 2. Ketoacidosis in diabetes. (Reproduced by permission of Dr. R. Levine

(111(1 Ciba COr/)OratiOfl). Substitution of ketone acids for “ketones” and cation

for “base” would clarify terminology concepts.

(Fig. 2) decreased lipogenesis and

in-creased lipolysis occur. The latter produces an excess of nonesterified or free fatty acids (NEFA) which, bound to albumin, are transported in the plasma to the liver and

other tissues for further metabolism. In the liver, increased degradation of fatty acids to two carbon fragments (acetyl coenzyme

A ) is associated with increased formation of

organic acids, especially “ketone acids” (

B-hydroxybutyric, aceto-acetic acids ). The

latter, as relatively strong organic acids

(pK’s a)proximately 4.7 ) , interact with

ccl-lular and extracellular buffers and, at physi-ological pH’s, exist principally in ionized

form rather than as free organic acid.

The magnitude of systemic metabolic

aci-dosis is dependent upon the rate of organic

acid synthesis and metabolism coupled with renal compensatory mechanisms for

excret-ing hydrogen ion. Three factors, urinary pH

gradient, titratable acidity ( determined by

concentration of organic acids and

(4)

partic-DIAGNOSIS AND TREATMENT

ularly affect the rate at which systemic

buffers are depleted. When hydrogen ion production exceeds the total of these three limiting mechanisms, acidosis proceeds inexorably toward an unphysiological state no longer compatible with cellular function.

Buffer depletion in metabolic acidosis is

evident in part in the measured bicarbonate

concentration of plasma. The so-called

plasma anion gap is an approximation of

or-ganic acid accumulation in the plasma. This is derived by determining the difference in the sum of measured cations and anions.

The measured cations are sodium and po-tassium, while the anions are chloride,

bi-carbonate, and protein. Protein equivalents are equal to 2.43 times the serum protein concentration in grams per 100 milliliters.

: cations- anions equals

( [Na] -F [K]) ) - ([Cl],, + [HCO:;IJp

+ 2.43 {Pr})

The total buffer deficit of the body is the

resultant of two major components. One, represented by the loss of volume including

osmolar ( Na, K, Cl ) and buffer (HCO3) components, requires replacement from

cx-ogenous sources; the other, represented by organic “ketone” acids within the body, is a

measure of potential buffer. When

lipogen-esis is increased and lipolysis decreased by

administration of insulin and glucose, not

only is organic acid (hydrogen ion ) pro-duction diminished, but also the “ketone ac-ids” in peripheral tissues are metabolized to

CO2 and H20 and the regeneration of sonic buffer occurs. However, the initial bicar-bonate concentration alone cannot be relied upon to predict quantitatively the buffer re-generation with therapy.

While the principal alterations expressed

above relate primarily to extracellular vol-ume depletion and metabolic acidosis, hy-pertonicity and loss of cellular volume are accompanied by depletion of potassium.

Though such depletion is frequent and sig-nificant, it may not be reflected in the initial

serum potassium concentration, which may even be elevated. Electrolyte deficits previ-ously measured by balance techniques in

children6 and adultsTs with severe

diabe-tic acidosis were found by Darrow9 to be

(per kilogram body weight):

H2O

100 gm

Na Cl K

8 mEq 6 mEq 6-10 mEq

CLINICAL AND LABORATORY FINDINGS

The onset of symptoms associated with

juvenile diabetes mellitus itself may vary in duration from 1 to 2 days to as long as

sev-eral months before the appearance of

clini-cally significant ketoacidosis, although in

most instances the duration is less than 1

month. Polyuria and polydipsia are, of

course, the most common symptoms;

poly-phagia, nocturia, and weight loss may be somewhat less evident. Infections and

emo-tional upsets may be contributing factors.

The rapidity of progression from carbohy-drate intolerance to ketoacidosis is so

unpredictable that continuous medical sur-veillance is recommended once the

diagno-sis of diabetes mellitus is suspected, with

laboratory studies initially not only to

es-tablish the diagnosis but also to assess the degree of metabolic derangements,

espe-cially in those aspects which require

emer-gency therapy. The diagnosis of diabetes

mellitus is confirmed by the indentification

of glucosuria and ketonuria in the presence

of a blood sugar (glucose) above 150 mg

per 100 ml.

Vomiting, with the attendant absence of

fluid and calorie intake, is an ominous symp-torn which signals rapid deterioration and

progression to serious acidosis and coma. The early phases of acidosis may produce no gross changes in the character of respira-tion; however, by the time moderate

acido-sis (serum CO2 < 15 mM/L) supervenes

definite increase in depth and rate is ap-parent. With severe acidosis (CO2 < 10

mM/L ), the characteristic Kussmaul

acido-tic breathing is grossly and alarmingly

ob-vious.

(5)

reaching 2.5 to 10 mM/L in severe

acido-sis.* Under these circumstances, there is

marked depression of the actual

bicarbon-ate concentration, while the tension of car-bon dioxide is also depressed ( values of 10

to 20 mm Hg ) in presence of compensatory hyperventilation. Plasma ketones are

ele-vated and approximate the bicarbonate

depression. A rapid bedside test has been

de-scribed by Lee and Dunca&#{176} which quanti-fies plasma ketone levels by serial dilution

of plasma (1:1, 1:2, 1:4, 1:8, and so forth) and reaction with nitroprusside reagent. Since the latter does not react with

B-hy-droxybutyrate (which may account for 35

to 50% of plasma ketones ), the test is

semi-quantitative at best, but serves as a useful guide to adequacy of therapy. Diminution

in the concentration of plasma ketones is usually reflected in a lessening of the meta-bolic acidosis and an improvement in the

bicarbonate concentration.

In diabetic ketoacidosis, hyperglycemia

may vary from 150 to as high as 2,000 mg

glucose! 100 ml. Most frequently, a range

of values from 250 to 600 mg/100 ml is ob-served. While the concentration of sodium in plasma is usually normal or slightly de-creased, marked elevations of blood glucose are associated with a reciprocal decrease in

sodium concentration. The value of chlo-ride tends to parallel that of sodium. As al-ready noted, plasma potassium initially is normal or even slightly elevated (5.5 to 6.0 mEq/L ) in association with dehydration

and metabolic acidosis. In the rare case of abnormally decreased plasma potassium, particular attention to early therapy with potassium is indicated.

Signs of dehydration (decreased skin tur-gor, softened eyeballs, dry mucous mem-branes ) are not obvious until acute weight loss of at least 5% has occurred. In diabetic

acidosis occurring a month or more after the onset of unsuspected diabetes, signs of

0 For those laboratories using the micro pH

electrodes and the Astrup technique, familiarity

with terminology and concepts such as buffer base

(excess or deficit ) and standard bicarbonate is

indicated.

undernutrition predominate and weight loss

alone is not a valid measure of fluid deficit. When dehydration is severe (15% body

weight loss ), signs of circulatory

insuffici-ency with hypotension and tachycardia

may be present. Azotemia may reflect circu-latory inadequacy and decreased renal

per-fusion as well as the additional urea pro-duction from increased protein catabolism.

Hyperlipidemia, including hypercho-lesterolemia, may be very marked (15 to 25 gm total lipids per 100 ml plasma ),

espe-cially in patients with prolonged onset.

Lactescence (milky plasma ) should be

rec-ognized when drawing the initial blood sample or suspected by finding lipemia reti-nalis on physical examination. Hyperlipe-mia not only interferes with

spectrophoto-metric analysis of hemoglobin but also results in falsely low laboratory measure-ments of electrolytes and other aqueous phase substances because of volume dis-placement.1’ Thus markedly but

decep-tively low serum sodium values (± 100

mEq/L) may be reported in the presence of very high blood glucose levels associated with hyperlipemia.

The state of consciousness may be as var-ied as other signs; however, in advanced ketoacidosis, semicoma or coma is evident. Differential diagnosis is seldom a problem.

In rare instances, similar findings may occur following a head injury or in salicylate in-toxication in young children, and the

change in respiratory character sometimes is mistaken for a sign of primary respiratory

disease such as pneumonia in young chil-dren. But once diabetes mellitus is thought

of, the only possible diagnostic problem

may arise from the occasional abdominal

pain of acidosis and the question of appen-dicitis in a known diabetic.

THERAPY

Treatment of the child with diabetic

acidosis is always urgent, perhaps more so

(6)

par-DIAGNOSIS AND TREATMENT

f Ames Company.

ticular emphasis on circulatory sufficiency

and the extent of metabolic acidosis. Once the diagnosis has been confirmed (rapid

blood glucose assessment may be made at the bedside with Dextrostixf ), initial fluids,

given primarily to expand circulatory

vol-ume, should consist of isotonic sodium in a balanced anion solution (Cl-HCO3 2: 1) at

a rapid rate of 20 ml/kg in the first 30 to 60 minutes. If severe acidosis is present (pH

< 7.15 and/or carbon dioxide content, com-bining power, or actual bicarbonate

concen-tration less than 8 mM,’L), sodium

bicar-bonate should then be given in a dose of 2 mEq/kg body weight. This is easily accom-plished with the 7%% sodium bicarbonate so-lution which contains 44.6 mEq in 50 ml

(approximately 1 mEq/ml) . Direct

admin-istration of this solution, with its osmolar

load of 892 X 2 mOs/L may raise the

effec-tive osmotic pressure of extracellular fluid enough to dehydrate brain and other cells further. Therefore dilution with distilled water is recommended: 50 ml of 73%

so-dium bicarbonate to 250 ml distilled water results in a solution of 149 mEq!L ( isotonic

sodium bicarbonate). Initial therapy should avoid glucose administration especially if

marked hyperglycemia ( > 300 mg per 100

ml ) is present.

Correction of the ketoacidosis and hyper-glycemia is dependent upon reversal of the

pathophysiological mechanisms by insulin administration, which is given

simultane-ously with therapy for circulatory

insuffici-ency and severe acidosis. This begins with

an empiric administration of crystalline or

regular insulin in a dosage of 3 to 4 units

per kilogram body weight for patients with severe acidosis and coma; lesser doses to 1 unit/kg are administered to patients less critically ill. Initial insulin is given by two routes : approximately half intravenously,

the remainder subcutaneously.

Urgency in attention to circulatory

insuf-ficiency and acidosis should not lead to

ne-glect of requirements for free water,

neces-sary in the presence of hyperosmolality as

well as for correction of the significant

neg-ative water balance from hyperventilation

and renal excretion. Such water may be provided by dilution of the electrolyte

solu-tion.

A program of therapy must be devised

once initial emergency treatment has com-menced. A detailed flow or data sheet containing critical clinical observations (

es-pecially body weight, BP, P, R ) and

labora-tory data (pH, CO2, blood glucose, ketones,

Na, K, BUN, Hb ) is essential to

manage-ment. The frequency of observations de-pends upon the degree of critical concern;

thus, while circulatory insufficiency is

pres-ent or potential, BP, P, and R are observed at least every 10 to 15 minutes. While aci-dosis is present, respiration is observed cv-cry 15 minutes and pH, CO2, and ketones observed every 3 hours until significant im-provement, whereupon the interval is

in-creased. Blood sugar may be followed at 1-to 3-hour intervals at the bedside until sta-bilization at normoglycemia is assured.

Body weight, Hb, and BUN need not be observed more frequently than every 12 hours. The recording of fluid balance must be meticulous and initially includes only

in-travenous fluids and urine; other volumes must subsequently be recorded. In addition, a balance of electrolytes, sodium, potassium

bicarbonate and of glucose should be ascer-tamed every 6 hours. Urine volumes may be collected separately, but cumulative

pen-ods of 6 hours are more practical. After the initial 24 hours of therapy, daily cumulative

balances suffice.

The details of therapy are similar to those

for other derangements of electrolyte

physiology and are calculated from : (1)

previous deficit; (2 ) maintenance needs;

and (3) continuing abnormal losses.

(1) Since rapid restoration of the cellular

deficit is not possible because of limitations

of potassium administration, initial treat-ment is directed toward extracellular fluid

restoration. According to the data of

Dar-row,9 approximately half the estimated

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TABLE II

INITIAL EMERGENCY THERAPY

‘FABLE III

C0vrINUING THEHA PY % FTER Eu EHG ENCY PHASE

. Isotonic Na . Electrolyte

Joiume .

Data Solution Free Water

701day mi/day mEq/day mt/day

First 4 hours Total S . 730 1.950 .5 1.800 Minusfirsthour 1,000 1,000 151) 0 Remainder q.730 930 1 4t ..5 1 . 800

TABLE I

WATER AND SoDIu1 REQUIREMENTS FOR FIRST

24 Houas OF THERAPY

Data Volume mi/day I,olonic Na Solution mL,’day Na mEqiday Electrolyte Free Water mi/day

Maintenance 1,500 300 5 1,OO

Abnormal losses up to

50% maintenance 750 150 .5 600

ECFdeficit5oinl/kg 1,500 1,300 qq 0

Total 3,750 1,950 1,800

(2 ) Maintenance needs may be

deter-mined by a variety of techniques ( based on

surface area, calories metabolized, weight, or age ) , with an approximately similar range of values. Each physician must

nec-ognize the virtues and limitations of that system which he prefers. They may be

sum-manized to include: ( a ) 1,500 to 1,800 ml!

M2/24 hours; or (b) 150 ml! 100 cal

metabo-lized/24 hours; or ( c) insensible water losses

+ 10 to 50 ml/kg/24 hours; urine losses

-I- 10 to 50 ml!kg!24 hours, with a total of 20 to 100 ml/kg/24 hours; ( d ) 100 - 3X

(X = age in years ) ml!kg/24 hours. Main-tenance fluids preferably contain 3 volume of isotonic solution of sodium salts and % free water ( as 5 to 10% glucose solution).

Data I.I ul Isotonic A\a Solution ml

,.

mEq Electrolyte Free JJatt’r ml

Isotonic NaC) 0 mi/kg 600 600 90 0

and/or

Na HCO3 Q mEq/kg 400 400 60 0

Total 1.000 1,000 150 0

Potassium in a concentration of 20 to 30 mEq/L is also included.

(3) Continuing abnormal water losses due to hyperventilation and urinary output are highly variable and best assessed from acute

changes in body weight relative to fluid balance.

The above recommendations may be sum-marized (Table I ) in an example for a 30

kg (1 M2) child in severe ketoacidosis. This results for the first 24 hours of therapy

( when no glucose is to be given) in a

solu-tion which is approximately half isotonic so-dium solution plus supplemental potassium. Practically, the initial hour of therapy must be subtracted from the above to determine remaining requirements. Thus, assuming the above patient had circulatory insuffici-ency and severe acidosis and was treated

promptly and adequately, see Table II for what he would have received in the first

hour.

Under these circumstances and to avoid

acute fluid overloads, the volume of isotonic sodium chloride should be reduced to 10 ml 1kg and would be replaced in part by the isotonic sodium bicarbonate solution. If the total volumes ( maximal) are as noted

above, then the fluids to be given by the

end of the first 24 hours will include those already administered plus the remainder in

Table III.

The remainder now represents

approxi-mately one-third isotonic sodium and

two-thirds water instead of the half isotonic so-dium for the total first 24 hours of therapy. The second phase of therapy (1 to 6 hours

post admission ) is directed primarily

to-ward expansion of extracellular volume and correction of acidosis ( insulin and sodium

bicarbonate).

Total fluids of the first day of therapy

may be planned so that one-half to two-thirds of the remainder are administered in

the initial 12 hours and the rest in the 5cc-ond half day. Thus in the above example,

1,375 ml total fluid remain for the first 12

(8)

first hour ) these would be: 688 ml fluid, 238

ml isotonic sodium solution. The remaining solution must contain some additional

so-lute, otherwise it is dangerously hypotonic.

Since glucose is not recommended in

pres-ence of very high glucose concentrations, this may be achieved with 5% fructose

(450 ml) . If not, an exception must be made to the 24 hour requirements given above and only 238 ml ( an equal volume)

of free water administered; the requisite additional free water administration being

deferred for a later phase of therapy when glucose solution may be provided.

Once blood glucose concentration has fallen to 300 mg/100 ml or less (initially hourly determinations are suggested), then the appropriate vehicle is glucose as 5 or 10% solution in place of either fructose or

free water alone, with appropriate

electro-lyte.

Serial electrocardiograms are checked

every 2 hours for (1) depression of the ST segment and lowering, flattening or

inver-sion of the T wave; (2) prolongation of the

Q-T interval; (3) presence of an elevated, broad, or diphasic U wave which may be responsible for the impression of a pro-longed Q-T interval; (4 ) occasional prolon-gation of the P-R interval; as indication of

hypokaliemia. Since potassium therapy is

not usually recommended for the first 4 to 6 hours of treatment because of initial hyper-kaliemia, at approximately 4 hours post therapy, potassium chloride or phosphate is

added in a concentration of 30 to 40 mEq/

L. If symptomatology of hypokaliemia

( muscle weakness or ileus ) or very low

se-rum values are observed (‘( 3.0 mEq/L),

higher concentrations of potassium may be indicated. If concentrations exceeding 40 mEq!L are administered, careful

monitor-ing of plasma potassium concentration is added to the two hourly ECG to avoid

car-diotoxicity.

Insulin must be administered

subcutane-ously at least every 3 hours in a decreasing

amount until ketosis is cleared, which may require 12 to 24 hours. When presenting

findings are severe, the initial dose may be

repeated once and then decreased by 50% each subsequent period. At low levels of

in-sulin (< 5 U ), a small 3 to 6 hourly dosage

should still be maintained to avoid rebound

of ketonunia. A decrease in blood glucose is not sufficient reason alone for discontinuing

insulin administration; rather, the amount of glucose administered parenterally should

be increased from 5 to 10 or greater percent

solution. Monitoring of blood glucose at the bedside will serve to anticipate and correct

hypoglycemia with glucose therapy.

Parenteral fluids are continued until the

patient is free of ketones and aglycosuric.

Even in the absence of vomiting, oral fluids

should not be begun in the initial 12 hours or even then if the sensoniuni is uncleared. Once consciousness is fully restored, fluids containing potassium may be introduced by

mouth. Orange juice contains 40 mEq/L

po-tassium and 10% carbohydrate. Amounts of

fluids and dosages of insulin during the

sec-ond 24-hour period are dependent upon

rate of repair of the estimated deficit and continuing losses. By this time, the extracel-lular deficit is usually minimal and

begin-fling repair of cellular deficit through

intro-duction of higher calories and protein

orally may proceed. Regular insulin is

pre-ferred for an additional 24-hour period at

regular intervals preceding oral intake.

Pc-nods exceeding 6 hours duration without

insulin are to be avoided. By the third day,

a planned dietary regimen may be

intro-duced with long acting insulin. Further

management is dependent upon many

fac-tors other than those considered above,

among them are especially the education

and adjustment of the patient and family.

Nevertheless the efficiency and skill with

which the preceding more critical illness has

been managed will remain significant fac-tors in the subsequent course and care of the patient.

REFERENCES

1. Danowski, T. S. : Diabetes Mellitus with

(9)

Balti-910

more: The \Villiams and Wilkins Co., p. 128,

1957.

2. Jackson, R. L., Hardin, R. C., Walker, G. L.,

Hendricks, A. B., and Kelly, H. C. :

De-generative changes in young diabetics in

relationship to level of control. Proc. Amer.

Diabetes Ass., 9:307, 1949.

3. Knowles, H. C., Jr., Guest, G. M., Lampe, J.,

Kessler, M., and Skiliman, T. G. : The

course of juvenile diabetes treated with

un-measured diet. Diabetes, 14:239, 1965.

4. Parker, M. L., Pildes, R. S., Chao, K. L.,

Cornblath, M., and Kipnis, D. M. : Juvenile

diabetes mellitus, a deficiency of insulin.

Diabetes, 17:27, 1968.

5. Butler, A. M., Talbot, N. B., Barnett, C. H., Stanbury’, J. B., and MacLachlan, E. A.:

Metabolic studies in diabetic coma. Trans.

Ass. Amer. Physicians, 60: 102, 1947.

6. Darrow, D. C., and Pratt, E. L. : Retention of

water and electrolyte during recovery in a

patient with diabetic acidosis. J. Pediat.,

4:688, 1942.

7. Atchley, D. W., Loeb, R. F., Richards, D. W.,

Benedict, E. M., and Driscoll, M. E. :On

dia-betic acidosis: A detailed study of electrolyte

balance following the withdrawal and

re-establishment on insulin therapy. J. Clin.

Invest., 12:297, 1933.

8. Nabarro, J. D. N., Spencer, A. G., and Stowers,

J. M.: Metabolic studies in severe diabetic

ketosis. Quart. J. Med. N.S., 21:225,

1952.

9. Darrow, D. C.: A Guide to Learning Fluid

Therapy. Springfield, Illinois: Charles C

Thomas, 1964.

10. Lee, C. T., and Duncan, G. C. : Diabetic coma:

The value of a simple test for acetone in the

plasma; an aid to diagnosis and treatment.

Metabolism, 5: 144, 1956.

11. Aibrink, M. J., Hald, P. M., Man, E. B., and

Peters, J. P.: The displacement of serum

water by lipids of hyperlipemic serum. A

new method for the rapid determination

of serum water. J. Clin. Invest., 34:1483,

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1971;47;902

Pediatrics

Robert Schwartz