PEDIATRICS Vol. 59 No. 5 May 1977 733
Low-Dose
Intravenous
Insulin
Infusion
Versus
Subcutaneous
Insulin
Injection:
A Controlled
Comparative
Study
of Diabetic
Ketoacidosis
Stenvert L. S. Drop, M.D., Bertrand J. M. Duval-Arnould, M.D., Alan E. Gober, M.D.,
Joseph H. Hersh, M.D., Paul T. McEnery, M.D., and Harvey C. Knowles, M.D.
From the Department of Pediatrics (Time Children sHospital Research Foundation), (Tniversitt/ of Cincinnati
College of %fe(licine and time Cincinnati Children s 1Iopital Medical Center
ABSTRACT. Fourteen patients, 5 to 17 years old, with 18
episodes of uncomplicated diabetic ketoacidosis were
randomly allocated and studied prospectively. The study
group received 0.1 units of insulin per kilogram of body
weight per hour as a continuous intravenous infusion: the
control group received insulin subcutaneously. In both
groups, a gradual fall in serum glucose and ketone levels was
achieved. Senim ketones persisted longer in the intravenous
group. No colriplications were encountered. The study
suggests that both regimliens of insulin administration are
equally effective, but a low-dose constant infusion m,iay
provide more simplified and controlled nianagemnent than
the standard subcutaneous regimen. Pediatrics, 59:733-738,
1977, DIABETES, INSULIN, DIABETIC KETOACII)OSIS.
Accepted regimens of insulin administration
for management of patients who have diabetic
ketoacidosis vary widely from one medical center
to the other. Recent reports’7 on the use of
constant intravenous infusion of small amounts of
insulin primarily in adults suggest this to be an
improved method of insulin administration for patients having ketoacidosis. A prospective study was initiated at the Cincinnati Children’s
Hospital to compare the efficacy and safety of the
current regimen of subcutaneous insulin therapy to that with continuous low-dose insulin infusion
in the treatment of diabetic ketoacidosis in the
pediatric age group. Under the close supervision
of this study protocol, both regimens of insulin
administration were safe and effective, but the
low-dose infusion of insulin resulted in a more
simplified and controlled management of the child with diabetic ketoacidosis.
MATERIALS AND METHODS
Patients
Fourteen patients from 5 to 17 years old who had mild to moderate uncomplicated diabetic
ketoacidosis and who were admitted to the
Cincinnati Children’s Hospital during July 1975
to March 1976 were randomly allocated to either a study or control regimen of insulin thei’apy
(Table I). One patient was studied twice, another
four times. The conditions required for inclusion ill the study were the following: blood glucose
level in excess of 400 mg/100 ml, ketonemia,
(Received July 16; revision accepted for publication
September 15, 1976.)
ADDRESS FOR REPRINTS: (P.T.McE.) Children’s Hospital
Research Foundation, Cincinnati, Ohio 45229.
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TABLE I
SERUM AND CAPILLARY BLOOD VALUES IN STUDY GROUP AND CONTROL GROUP
Patient Age
(yr)
Precious Daily
Insulin
Dosage
Initial Serum Values
A
Capillary Blood
pH Pco2
(mm Hg) ,
Glucose Blood Urea Ni-Total Carbon Potassium
(mgi 1(X) ml) trogen Dioxide (mEqlLiter)
(mg/1()O iiml) (mEqlLiter)
Ketones
1 13 40 units lente
Control Group I Subcutaneous Insulin
575 23 5.0 5.8 + + + 7.23 21
2 11 40 units NPH 494 28 5.1 4.6 + + 7.07 17
3 15 65 units lente 804 23 3.4 5.1 + + + 6.89 23
4 11 New diabetic 400 13 2.7 4.9 + 7.20 35
5 15 75 units lente 549 14 2.8 7.2 + 6.98 14
6 8 20 units NPH 858 24 13.5 5.3 + + 7.35 29
7 14 48 units lente 741 31 5.0 6.0 + 7.08 17
8 11 New diabetic 563 17 17.9 6.3 + 7.43
9 5 New diabetic 708 28 6.7 6.4 + + 7.23 18
10 8 New diabetic
Study Group/Intravenous insulin
995 30 6.0 5.3 + + 7.10 22
11 15 New diabetic 769 28 4.4 5.3 + + + 7.12
12 13 75 units lente 516 21 15.6 5.2 + + 7.39 26
13 15 75 units lente 556 14 3.8 5.1 + + 7.02 12
14 16 80 units lente 510 19 6.2 5.2 + + 7.20 12
15 15 80 units lente 522 20 16.0 6.1 + + 6.85 12
16 16 95 units lente 586 19 4.0 4.6 + + 7.15 13
17 17 80 units lente 526 20 4.0 6.6 + 7.16 21
18 6 New diabetic 909 18 6.8 4.2 + + + 7.33 20
ketonunia, glucosuria, and, for this study, absence
of profound diabetic coma. Informed consent was
obtained from the patients, their parents or guardians, and the referring pediatrician.
Intravenous Fluid Replacement
In all patients, rehydration was begun with
isotonic saline at a rate of 360 mI/sq m of body
surface area given over 30 to 45 minutes, followed
l)y isotonic saline over the next three hours at a
rate of 270 mI/sq ni/hr. During the second three
hours, 0.45% saline was given in either 2.5% or 5%
dextrose in water, the latter as the blood glucose
level approached 250 mg/mI. Six to eight hours
after admission, 0.23% saline in 5% dextrose
(
Normosol) was infused at a rate of 150 nil/sqrn/hr. Potassium supplement was started
approx-imately one hour after initiating fluid therapy at a
rate of 3.3 mEq/sq ui/hr. In four patients in
whom the initial blood pH was 7.00 or less,
sodium bicarbonate was administered at a rate of
1 inEq per kilogram of body weight per four
hours.
Insulin Therapy
Assignment of patients to the insulin infusion
study group or the standard subcutaneous insulin
therapy control group was decided by
randomiza-tion in order of presentation to the emergency
room, using a random digits table.8 In both groups
of patients, insulin therapy was withheld until
results of initial studies were known and the
initial 30 to 90 minutes of rehydration were
completed.
Study Group
The insulin infusate was prepared by adding 50
units of crystalline insulin (0.5 ml of Iletin) to a
solution set containing 100 ml of normal saline.
The intravenous line containing the insulin was
flushed with at least 40 ml of the solution. With a
Harvard pump, the insulin was infused at a rate of
0.2 ml per kilogram of body weight per hour (0.1 units per kilogram of body weight per hour) via a
four-way stopcock directly into the intravenous
Control Group
700 - T
I
0 IV.
500
-400
-::: l I
0 I 2 3 4 5 6 7 8 9 10
HOURS
FIG. 1. Serum glucose levels versus time of treatment of
diabetic acidosis.
ARTICLES 735
four hours imniediately before use. The rate of insulin administration was independent of the
intravenous fluid line rate. The insulin infusion
was continued until the blood glucose level had
fallen to 200 to 250 mg/100 ml. Thereafter,
subcutaneous insulin therapy was given
i;nmedi-ately according to the regimen as described
below.
Following the initial rehydration, crystalline
insulin, 0.9 to 1.8 units/kg, was given according to
the currently accepted regimen of this medical
center. Initially, one third of the dose was given as
an intravenous boltis and the rest was given
subcutaneously. Thereafter, 0.1 to 0.25 units/kg
was administered subcutaneously every two to six hours, according to results of blood and urine glucose and ketone levels and the judgment of the
investigators.
Adsorption of Infused Insulin
The amount of insulin lost by adhesion to the
plastic tubing during the period of insulin infusion
was assayed. The tubing was flushed with 20 ml of insulin infusate, 0.5 units of insulin per milliliter of solution, and then the infusion was maintained
at 2 ml/hr for four hours. A saniple of the solution
at the termination of the infusion line was assayed for insulin concentration on four different infu-sion preparations. The average final insulin level was 0.42 units/iiil, which represents a loss of 18%
of the insulin by adherence to the systeni, a loss
comparable to that previously reported.
Monitoring of Patient and Therapy
Initial studies included blood count; urinalysis;
determination of blood glucose level by
Dextro-stix, serum glucose level by the glucose oxidase
method (DuPont ACA), qualitative serum ketone
levels by Acetest, and serum bicarbonate, sodium,
potassium, chloride, creatinine, and blood urea
nitrogen levels; arteriolized capillary blood gas
determination of pH, Pco9, and base excess; and
determination of urine glucose and ketone levels
by Clinitest and Labstix, respectively. A lead II
electrocardiogram was obtained on each patient
initially and at six hours after admission. In all
new patients, serum insulin levels at 0, 3, and 6
hours of therapy were measured by
radioimmu-noassay. Most of the initial studies were repeated
during the therapy, with the blood glucose levels
estimated every 30 minutes with a Dextrostix
reflectancemeter (Amesmeter) and seruni
gin-cose and ketone levels determined hourly. Voided
urine was tested for glucose and ketones at least
every two hours. Vital signs and state of
consciousness were recorded hourly, and fluid
intake and output were quantitated every four
hours.
Data Analysis
The curves in blood glucose and ketone levels
and the rise in blood pH were compared by
covariant analysis. The logarithms of blood
glucose values were used since the curves
deflected from linearity in the untransformed
state. Tests for significance of difference were
made on mean slopes and mean elevations. Initial
mean and eight- or nine-hour mean values of
blood glucose, ketones, and pH of the two groups
were tested for significant differences by the t test.
RESULTS
Serum Glucose
As illustrated in Figure 1, there was in both groups a steady drop of the serum glucose
concentration. The mean value of the curve of the
patients treated subcutaneously with insulin was
significantly lower (P < .01) than the values of
the patients treated intravenously with insulin.
There was no difference in the slopes of the
curves.
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No patient experienced difficulties of insulin
therapy due to either the intravenous infusion or
subcutaneous route of administration. None
expe-rienced hypokalemia as determined by a serum
potassium level of less than 3.5 mEq/liter or ECG
T wave changes. All had improvement in serum
glucose levels without symptoms of hypoglycemia or episodes of hypoglycemic “overshoot.” The
insulin rate in one patient was increased to 0.2
units per kilogram of body weight per hour
during the second hour of therapy because of
failure of the serum glucose level to fall at least 50
mg/ 100 ml during the first hour of insulin
infu-sion. None of the children were treated in an
intensive care unit, and nursing personnel did not
consider the procedure of intravenous insulin
infusion to involve more care than the subcuta-neous regimen once the process was started.
DISCUSSION
As with other new ideas and regimens of
medical therapy, the use of continuous
intrave-nous infusion of small amounts of insulin in the
treatment of diabetic ketoacidosis appears
theo-retically to be a more physiologic therapy than
the current regimen of subcutaneous insulin
injec-tions. Recent reports’37 and editorials2’#{176}’2 have
advanced the ease, safety, and efficacy of this
method of treatment primarily in adults and have
also appropriately cautioned against the pitfalls
of this therapy and the lack of controlled studies
in promulgating its benefits. Our results suggest
that both regimens of insulin administration are
equally effective in the treatment of children with
mild to moderately severe diabetic ketoacidosis,
but the ease of control and almost predictable
course in the decrease of serum glucose levels by
the continuous infusion therapy suggest that this
regimen may be more beneficial.
It should be noted though that in this closely
monitored study there was no statistical
differ-ence in the rate of fall in serum glucose and
ketone levels or in the final absolute serum
glucose level changes when comparing the two
regimens. The serum ketones actually persisted
longer in the intravenous group, possibly due to
the absence of the initial bolus of intravenous
insulin in the study group. This gap between the
correction of serum glucose level and elimination
of serum ketones has also been noted by Soler et
al.7 and Page et al. in those patients treated with
low-dose infusion. In these studies and ours, an
initial intravenous bolus of insulin was not
7.1
0369
HOURS
Fm:. 2. Serum pH versus time of treatmiient of diabetic
acidosis.
Blood pH
There were no statistical differences between
the two groups (Fig. 2).
Serum Ketones
The mean value of the curve of serum ketone
levels throughout treatment was lower and
ketones disappeared from the serum sooner in the
group of patients treated subcutaneously with
insulin (Fig. 3). There was no difference, however,
in the rate of disappearance of the ketones from
the seruni.
Serum Insulin
In new diabetics, serum insulin levels before
treatment ranged from 0 to 3 jtU/ml and at three
and six hours of treatment ranged between 18 and
45 tU/ml in the three patients who received
subcutaneous insulin therapy and 29 to 50 jiU/ml
in two patients who received insulin intrave-nously.
0 l.V.
3-
2-I
I
I
I
I
I
I
I
I
I
I
0
I
2
3
4
5
6
7
8
9
10
HOURS
FIG. 3. Serum ketone levels versus time of treatment of diabetic acidosis.
ARTICLES
737I :SmalI
2
Moderate
3
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utilized. In those patients treated with intermit-tent intravenous boluses of insulin, the gap and absolute times of resolution of ketosis were
signif-icantly shorter than with continuous low-dose
insulin therapy alone.7 The low peripheral
intra-venous infusion of insulin may not be adequate
enough to reverse the state of increased hepatic
gluconeogenic and ketogenic processes, since the
liver under normal physiologic conditions and
state of hydration has a substantially higher
concentration of insulin than the peripheral
tissues.13 The beneficial effect of an initial bolus of
insulin has been reported by Semple et al.’ and
Kaufman et al.,2 who were able to correct the
ketosis before the plasma glucose level had fallen
to 200 mg/100 ml.
The major question unanswered in the present
study is whether the continuous low-dose insulin
infusion represents an improvement in the
morbidity and the mortality of severe diabetic
ketoacidosis. The intravenous insulin half-life of
three to five minutes facilitates control of the rate
of fall of serum glucose level regardless of age,
weight, or degree of complicating medical illness.
In fact, the critically ill ketoacidotic patients who
were excluded from this study may be better
treated with intravenous insulin doses in view of
the absence of delay of effect and when there may
be late depot insulin effects, which are often seen
when the subcutaneous regimen is used in the dehydrated patient in shock. We found that the
relatively immediate effect from a change in the
amount of insulin infusion allows for better
control of insulin therapy. The rate of insulin
infusate of 0. 1 units per kilogram of body weight
per hour appeared to achieve a gradual fall of
serum glucose level in most children, but in one
patient the rate was increased to 0.2 units/kg/hr
after failure of the glucose level to fall at least 50
mg/100 ml during the first hour of insulin
infu-sion. Because of the short half-life of insulin
administered intravenously, the need for
imme-diate institution of a subcutaneous insulin
regimen at the point of discontinuing the insulin
infusate should be emphasized.
REFERENCES
1. Genuth SM: Constant intravenous insulin infusion in
diabetic ketoacidosis. JAMA 2.33: 1348, 1973.
2. Kaufman JA, Keller MA, Nyhan WL: Diabetic ketosis
and acidosis: The continuous infusion of low doses
of insulin. J Pediatr 87:846, 1975.
3. Kidson \V, Casey J, Kraegen E, Lazarus L: Treatment of
severe diabetes mellitus by insulin infusion. Br Med
J 2:691, 1974.
4. Page M, Alberti KG, Greenwood R, et al: Treatment of
diabetic coma with continuous low-dose infusion of
insulin. Br Med J 2:687, 1974.
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5. Piters K, Goodman J,Bessman A: Treatment of diabetic
ketoacidosis with continuous low-dose intravenous
insulin. Diabetes 24(suppl 2):396, 1975.
6. Semple PF, White C, Manderson \\‘G: Continuous
intravenous infusion of small doses of insulin in
treatment of diabetic ketoacidosis. Br Med J2:694,
1974.
7. Soler NC, Fitzgerald MG, Wright AD, MaIms JM:
Comparative study of different insulin regimens in
nianagement of diabetic ketoacidosis. Lancet
2:1221, 1975.
8. The Rand Corporation: A Million Random Digits With
100,000 Normal Deviates. New York, Free Press,
1955, p 89.
9. Weisenfeld 5, Podolsky S, Goldsniith L, Ziff L:
Adsorp-tion of insulin to infusion bottles and tubing.
Diabetes 17:766, 1968.
10. Routine treatnient for diabetic ketoacidosis. JAMA
223:1381, 1973.
11. Felig P: Insulin: Rates and routes of delivery. N EngI J
Med 291:1031, 1974.
12. Madison LL: Low-dose insulin, a plea for caution. N
Engl J Med 294:393, 1976.
13. Tchobroutsky G, in Malaisse WJ, Pirart J (eds):
Diabetes, publication 312. International Congress
Series, Amsterdam, North-Holland, 1974, p 667.
ACKNOWLEDGMENT
We wish to thank Dr. J. Loggie for her critical review of
the study protocol, private pediatricians for referring their
patients, the Children’s Hospital house staff for their
invalu-able cooperation in the care of the patients, and S. McCurry and D. Lachenman for secretarial assistance in the
prepara-tion of the mnanuscript.
ERRATUM
In the article by Say et al. in the January issue (59: 123, 1977),
“trichorhino-phalangeal” was misspelled in the title, the first line of text, the table of
1977;59;733
Pediatrics
T. McEnery and Harvey C. Knowles
Stenvert L. S. Drop, Bertrand J. M. Duval-Arnould, Alan E. Gober, Joseph H. Hersh, Paul
Controlled Comparative Study of Diabetic Ketoacidosis
Low-Dose Intravenous Insulin Infusion Versus Subcutaneous Insulin Injection: A
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