European Journal of Internal Medicine 47 (2018) 14–16

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European Journal of Internal Medicine

journal homepage: www.elsevier.com/locate/ejim

Narrative Review

Basal insulin for the management of diabetic ketoacidosis

Leonid Barski ⁎, Evgenia Brandstaetter, Iftach Sagy, Alan Jotkowitz
Department of Internal Medicine F, Soroka University Medical Center, Beer–Sheva, Israel

a r t i c l e i n f o a b s t r a c t

Article history: Due to its pharmacokinetic properties, it has been suggested that long-acting insulin analogues may have a role in
Received 2 June 2017 facilitating the transition from continuous intravenous insulin infusion to subcutaneous maintenance therapy in
Received in revised form 20 July 2017 patients with DKA for prevention of rebound hyperglycemia, particularly if there are high insulin requirements.
Accepted 27 August 2017
Concomitant administration of basal insulin analogues with regular insulin infusion accelerates ketoacidosis res-
Available online 31 August 2017
olution and prevents rebound hyperglycemia.
Keywords:
Several studies have investigated the use of basal insulin in the management of DKA. Studies have been instituted
Diabetic ketoacidosis on pediatric patients and adult patients.
Long-acting basal insulin analogues These studies reveal that co-administration of basal insulin in combination with an insulin infusion in the acute
management of DKA is feasible.
Basal insulin co-administration with regular insulin infusion was well tolerated, associated with faster resolution
of acidosis without any adverse effects; patients required a shorter duration of intravenous insulin infusion and
had a lower total dose of intravenous insulin and significantly decreased hyperglycemia after discontinuation of
the intravenous insulin. This could potentially lead to a shorter ICU length of stay and reduced costs in the treat-
ment of DKA.
However, this approach may be associated with an increased risk of hypokalemia.
The current literature on this management approach is incomplete, due to its many limitations (retrospective na-
ture, small sample size, nonrandomized design).
Additional prospective randomized studies are needed on this new therapeutic approach in the management pa-
tients with DKA.
© 2017 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

1. Introduction
In the last decade, the mortality rate from diabetic ketoacidosis
(DKA) has declined due to improvements in its management. The use
of standardized written guidelines for therapy has resulted in a mortal-
ity rate lower than 5% [1–4].
Long-acting insulin analogues enable a once-daily dosing in patients
with diabetes mellitus (DM), thus providing a basal insulin component
[5,6].
Due to its pharmacokinetic properties, it has been suggested that
this type of insulin may have a role in facilitating the transition from
continuous intravenous (IV) insulin infusion to subcutaneous (SC)
maintenance therapy in patients with DKA.
Transition from IV insulin infusion to SC insulin injections frequently
results in rebound hyperglycemia, particularly if there are high insulin
requirements. Furthermore, because of the short half-life of IV insulin,
technical errors during the transitional phase of the insulin infusion
⁎ Corresponding author at: Department of Medicine F, Soroka University Medical
Center, P.O. Box 151, Beer-Sheva 84101, Israel.
E-mail address: lbarski@bgu.ac.il (L. Barski).
can adversely affect the recovery process of DKA, specifically the occur-
rence of rebound hyperglycemia [7]. Extensive data indicate that uncon-
trolled hyperglycemia is associated with adverse outcomes in critically
ill patients. For example, rebound hyperglycemia has the potential to in-
crease the concentration of ketone bodies rather than decrease it, fur-
ther delaying resolution of DKA and increasing length of stay in
addition to increasing the risk of mortality and morbidity [7].
Concomitant administration of basal insulin analogues with regular
insulin infusion accelerates ketoacidosis resolution and prevents re-
bound hyperglycemia [8].
Glargine, a soluble long-acting insulin analogue, exhibits physiolog-
ical pharmacokinetic and pharmacodynamic characteristics [9]: it is a
peakless insulin, that lasts for nearly 24 h, has lower intersubject
variability compared with other types of intermediate- and long-
acting insulins (such as Neutral Protamine Hagedorn – NPH – insulin,
and Ultralente) and it closely mimics continuous subcutaneous insulin
infusion (CSII), the gold standard of basal insulin replacement [10].
Therefore, the use of basal insulin such as glargine may be associated
with several beneficent effects in the management of patients with DKA.
Several studies have investigated the use of basal insulin in the
management of DKA. Studies have been instituted on experimental

http://dx.doi.org/10.1016/j.ejim.2017.08.025
0953-6205/© 2017 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
 L. Barski et al. / European Journal of Internal Medicine 47 (2018) 14–16
investigations, and have been performed using animal models (cats),
pediatric patients and adult patients.
The addition of long-acting insulin during IV insulin infusion for
treatment of DKA appears to be safe, as the number of hypoglycemic
events does not differ [7].
2. Animal models
There are several studies on animal models confirming the useful-
ness of the management of DKA with basal insulin.
Gallagher BR et al. performed a pilot study comparing a protocol using
intermittent administration of glargine and regular insulin to a continu-
ous rate infusion of regular insulin in cats with naturally occurring DKA.
The authors concluded that intermittent short- and long-acting insulin
injection was useful for the treatment of cats with DKA [11].
In another study, Marshall RD et al. investigated intramuscular
glargine with or without concurrent subcutaneous administration for
the treatment of feline DKA. The important finding of this study was
that treatment with IM glargine combined with or without SC glargine
was effective in the management of feline DKA and may provide an al-
ternative to regular insulin [12].
3. Pediatric patients
Shankar V et al. studied the effect of subcutaneous administration of
insulin glargine in the early phase of DKA on the rate of resolution of ac-
idosis and intravenous insulin infusion requirement in children with
moderate and severe diabetic ketoacidosis.
This was a retrospective cohort trial of 71 pediatric patients with
moderate and severe DKA, during which 12 patients received
0.3 units/kg of subcutaneous insulin glargine within 6 h of admission
and 59 were treated following a standard protocol with intravenous
regular insulin.
Glargine treated patients had shorter insulin infusion time (14.8 ±
6.0 h vs 24.4 ± 9.0 h), lower total infused insulin dose (43.0 ± 31.6 U
vs 89.4 ± 68.8 U), and shorter total hospital stay (3.2 ± 1.0 days vs
3.72 ± 1.06 days). Glargine co-administration with regular insulin infu-
sion was associated with faster resolution of acidosis without any ad-
verse effects (12.4 ± 2.9 h vs 17.1 ± 6.2 h).
This study demonstrated that children treated with insulin glargine
during the initial presentation of DKA had a faster resolution of acidosis
and required a shorter duration of intravenous insulin infusion and
needed a lower total dose of intravenous insulin. This could potentially
lead to a shorter ICU length of stay and reduced costs in the treatment of
DKA [13].
The study is limited by its retrospective nature and small sample
size.
Harrison VS et al. performed a retrospective chart review of 149 pa-
tients aged 2 to 21 years, presenting with DKA. Patients were divided
into distinct groups: those with preexisting DM type 1, and those with
new onset DM type 1. In each group children who received glargine
more than 4 h before discontinuation of IV insulin infusion were com-
pared with those who received glargine less than 2 h, or no subcutane-
ous insulin, before cessation of infusion.
The authors concluded that co-administration of glargine early with
intravenous regular insulin in the course of DKA treatment is well toler-
ated, not associated with an increased risk of hypoglycemia or cerebral
edema and convenient for discharge planning; however, this approach
is associated with an increased risk of hypokalemia [14].
The limitations of this study are due to its retrospective nature and
non-randomized design.
4. Adult patients
Hsia E et al. performed a prospective, randomized, controlled study
of 61 diabetic patients, comparing 31 patients treated with regular
15
insulin infusion and 30 patients treated with regular insulin infusion
plus 0.25 U/kg of daily glargine [9]. It is important to note that only 25
patients in this study had DKA and all subjects with DKA had DM type
1. The remainder of patients received intravenous insulin for postoper-
ative management of diabetes after kidney, liver, or lung transplanta-
tion (n = 25); or for the management of hyperglycemia associated
with other surgeries or infections (n = 11).
The length of insulin infusion was lower in the glargine group (35 h
vs 42 h), though not statistically significant. Total insulin infusion within
the 24 h before discontinuation was similar in both groups. At least one
episode of rebound hyperglycemia occurred in 94% of control group
subjects and only in 33% of the glargine group during the 12 h following
insulin infusion discontinuation.
The authors concluded that administration of subcutaneous insulin
glargine during intravenous insulin infusion significantly decreased hy-
perglycemia after discontinuation of the IV insulin. The differences in re-
bound rates were highly significant for at least 12 h after transition to
subcutaneous insulin regimens. Glargine insulin administered concom-
itantly with the intravenous insulin infusion was equally effective in the
DKA and non-DKA patients [15].
Limitations of this study include a relatively small number of pa-
tients as well as a mixed cohort of both medical and surgical patients.
Doshi P et al. performed a prospective, randomized, controlled pilot
trial comparing co-administration of insulin glargine and intravenous
insulin (experimental) with intravenous insulin (standard care control).
The study included 40 patients with DKA (20 in control group and 20 in
experimental group) hospitalized in emergency departments in two
hospitals in Texas. All patients received IV insulin. Additionally, the ex-
perimental group was given SC insulin glargine within 2 h of diagnosis.
The primary outcome was time to closure of the anion gap (less to 12).
Secondary outcomes were hospital length of stay, ICU length of stay,
rate of ICU admission, and incidence of hypoglycemia (defined as less
60 mg/dl during 24 h after AG closure).
The authors concluded that co-administration of glargine in combi-
nation with an insulin infusion in the acute management of DKA is fea-
sible. Further study is needed to determine the true efficacy in terms of
time to closure of anion gap and hospital length of stay. Also, using basal
insulin for the management of patients with DKA may result in cost sav-
ings due to a decrease in ICU utilization. The limitation of this study is
that it was a pilot trial planned to develop preliminary estimates of dif-
ferences in outcomes using a limited sample size. Another limitation is
that subjects were enrolled based on availability of the research team,
leading to a convenience sample of patients [16].
Although there is no evidence, the Joint British Diabetes Societies
guidelines for the management of diabetic ketoacidosis recommend
continuation of long-acting analogues during the initial management
of DKA providing background insulin when intravenous insulin is
discontinued. This recommendation is based on the assumption that
basal insulin in normal daily dose is unlikely to adversely affect the
blood glucose response to the intravenous insulin infusion and should
facilitate a smoother transition from the intravenous insulin infusion
to subcutaneous insulin.
This potentially limits rebound hyperglycemia and ketogenesis
when intravenous insulin is stopped and may avoid excess length of
stay [17].
ADA recommendations for management of patients with DKA rec-
ommend using basal insulins only in the period of transition from intra-
venous to subcutaneous insulin in regime of basal bolus: basal insulin
(glargine or detemir) and rapid acting insulin analogs (lispro, aspart
or glulisine) [18].
5. Conclusions
Co-administration of basal insulin in combination with an insulin in-
fusion in the acute management of DKA is feasible.
16 L. Barski et al. / European Journal of Internal Medicine 47 (2018) 14–16
Basal insulin co-administration with regular insulin infusion was
well tolerated, associated with faster resolution of acidosis without
any adverse effects; patients required a shorter duration of intravenous
insulin infusion and had a lower total dose of intravenous insulin and
significantly decreased hyperglycemia after discontinuation of the in-
travenous insulin. This could potentially lead to a shorter ICU length of
stay and reduced costs in the treatment of DKA.
However, this approach may associate with an increased risk of
hypokalemia.
The current literature on this management approach is incomplete,
due to its many limitations (retrospective nature, small sample size,
non-randomized design).
In addition, it is not well understood whether treatment of DKA pa-
tients with basal insulin should begin early, during the initial presenta-
tion of DKA, together with intravenous infusion of regular insulin or in
the period closer to the transition from intravenous to subcutaneous
regimen.
Additional prospective randomized studies are needed on this new
therapeutic approach in the management patients with DKA.
References
[1] Kitabchi AE. Low-dose insulin therapy in diabetic ketoacidosis: fact or fiction. In:
DeFronzo R, editor. Diabetes metabolism reviews. New York: John Wiley, Sons;
1989. p. 337–63.
[2] Kitabchi AE, Umpierrez GE, Murphy MB, et al. Management of hyperglycemic crises
in patients with diabetes. Diabetes Care 2001;24:131–53.
[3] Umpierrez GE, Kelly JP, Navarrete JE, Casals MM, Kitabchi AE. Hyperglycemic crises
in urban blacks. Arch Intern Med 1997;157:669–75.
[4] Kitabchi AE, Umpierrez GE, Murphy MB. Diabetes ketoacidosis and hyperglycemic
hyperosmolar state. In: DeFronzo RA, Ferrannini E, Keen H, Zimmet P, editors. Inter-
national textbook of diabetes mellitus. 3rd ed. Chichester, UK: John Wiley, Sons, Ltd;
2004. p. 1101–19.
[5] McKeage K, Goa KL. Insulin glargine: a review of its therapeutic use as a long-acting
agent for the management of type 1 and 2 diabetes mellitus. Drugs 2001;61:
1599–624.
[6] Dunn CJ, Plosker GL, Keating GM, McKeage K, Scott LJ. Insulin glargine: an updated
review of its use in the management of diabetes mellitus. Drugs 2003;63:1743–78.
[7] Bunn S, Halm M. Long-acting insulin on the road to recovery with diabetic
ketoacidosis. Am J Crit Care 2016;25(3):277–80.
[8] Cardoso L, Vicente N, Rodrigues D, Gomes L, Carrilho F. Controversies in the manage-
ment of hyperglycemic emergencies in adults with diabetes. Metab Clin Exp 2017;
68:43–54.
[9] Porcellati F, Rosetti P, Busciantella NR, et al. Comparison of pharmacokinetics and
dynamics of the long-acting insulin analogs glargine and detemir at steady state in
type 1 diabetes. Diabetes Care 2007;30:2447–52.
[10] Lepore M, Pampanelli S, Fanelli C, et al. Pharmacokinetics and pharmacodynamics of
subcutaneous injection of long-acting human insulin analog glargine, NPH insulin,
and ultralente human insulin and continuous subcutaneous infusion of insulin
lispro. Diabetes 2000;49(12):2142–8.
[11] Gallagher BR, Mahony OM, Rozanski EA, Buob S, Freeman LM. A pilot study compar-
ing a protocol using intermittent administration of glargine and regular insulin to a
continuous rate infusion of regular insulin in cats with naturally occurring diabetic
ketoacidosis. J Vet Emerg Crit Care (San Antonio) 2015;25(2):234–9.
[12] Marshall RD, Rand JS, Gunew MN, Menrath VH. Intramuscular glargine with or with-
out concurrent subcutaneous administration for treatment of feline diabetic
ketoacidosis. J Vet Emerg Crit Care (San Antonio) 2013;23(3):286–90.
[13] Shankar V, Haque A, Churchwell KB, Russell W. Insulin glargine supplementation
during early management phase of diabetic ketoacidosis in children. Intensive
Care Med 2007;33(7):1173–8.
[14] Harrison VS, Rustico S, Palladino AA, Ferrara C, Hawkes CP. Glargine co-
administration with intravenous insulin in pediatric diabetic ketoacidosis is safe
and facilitates transition to a subcutaneous regimen. Pediatr Diabetes 2016. http://
dx.doi.org/10.1111/pedi.12462.
[15] Hsia E, Seggelke S, Gibbs J, et al. Subcutaneous administration of glargine to diabetic
patients receiving insulin infusion prevents rebound hyperglycemia. J Clin
Endocrinol Metab 2012;97:3132–7.
[16] Doshi P, Potter AJ, De Los Santos D, Banuelos R, Darger BF, Chathampally Y. Prospec-
tive randomized trial of insulin glargine in acute management of diabetic
ketoacidosis in the emergency department: a pilot study. Acad Emerg Med 2015;
22(6):657–62. http://dx.doi.org/10.1111/acem.12673.
[17] Savage MW, Dhatariya KK, Kilvert A, et al, Joint British Diabetes Societies. Joint Brit-
ish Diabetes Societies guideline for the management of diabetic ketoacidosis. Diabet
Med 2011;28(5):508–15. http://dx.doi.org/10.1111/j.1464-5491.2011.03246.x.
[18] Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult pa-
tients with diabetes. Diabetes Care 2009;32:1335.