Elsevier

Journal of Critical Care

Volume 30, Issue 2, April 2015, Pages 437.e1-437.e6
Journal of Critical Care

Electronic Articles
Insulin infusion therapy in critical care patients: Regular insulin vs short-acting insulin. A prospective, crossover, randomized, multicenter blind study,☆☆

https://doi.org/10.1016/j.jcrc.2014.10.019Get rights and content

Abstract

Introduction

The aim of this multicenter, prospective, randomized, crossover trial is to compare, in critical care patients receiving insulin infusion therapy (IIT), the pharmacodynamic of Humulin insulin (Hlin), currently used as “standard of care,” and Humalog insulin (Hlog), a shorter acting insulin formulation. This was measured as extent and duration of the carryover effect of insulin treatment, with the latter calculated as ratio between blood glucose concentration (BGC) reduction during and after IIT.

Materials and methods

Twenty-eight patients treated in an intensive care unit and receiving full nutritional support were randomly assigned to Hlin or Hlog as first treatment. Insulin was infused at a constant rate in patients presenting with BGC greater than or equal to 180 mg/dL (0.04 U/kg per hour) and was discontinued when BGC was less than or equal to 140 mg/dL (therapeutic BGC drop). Further reductions in BGC after discontinuation of insulin infusion were recorded (postinfusional BGC drop). During the study period, whole blood BGC was measured every 30 minutes. A minimal 6-hour washout interval was maintained between treatments with the 2 types of insulin. The primary end point was the extent (calculated as ratio between the therapeutic BGC drop and the postinfusional BGC drop) and duration of the carryover effect.

Results

Treatment with Hlog, as compared with Hlin, was associated with a less profound carryover effect as well as a briefer duration of carryover (median, 0.40 vs 0.62; P < .001; median, 1 vs 1.5 hours; P < .001).

Conclusions

The use of constant Hlog infusion for IIT, when compared with Hlin at the same dose, is associated with a less profound carryover effect on BGC after discontinuation of IIT, a briefer duration of carryover, a faster BGC drop during infusion, and a quicker BGC rise after discontinuation. These characteristics suggest that Hlog IIT may be preferable for use in critically ill patients.

Introduction

Insulin infusion therapy (IIT) is widely used as “standard of care” to treat hyperglycemia in critical care patients [1], [2]. This therapeutic approach leads to reduced morbidity and to a higher survival rate in some subgroups of critical care patients but is also associated with a substantial risk of inducing hypoglycemia [3], [4], [5]. Various strategies have been used to minimize the risk of iatrogenic-induced hypoglycemia during IIT including wider glycemia target ranges, sliding scale insulin titration, increased frequency of blood glucose concentration (BGC) measurements, and a higher caloric intake [6], [7], [8]. Whether these therapeutic measures do indeed provide greater safety margins remains controversial as does their impact on clinical benefit of IIT [9], [10].

Clinical application of IIT is usually accomplished with regular human insulin (Hlin) (HumulinR; Eli Lilly, Indianapolis, IN) continuous infusion [11], [12]. Shorter acting insulin formulations, such as lispro insulin (Hlog) (Humalog; Eli Lilly) have faster onset and offset kinetics than Hlin and may thus be more suitable for IIT in critical care patients [13], [14], [15]. The molecular structure of Hlog is characterized by a change in the amino acid sequence of the insulin B chain—with proline in position 28 and lysine in position 29 inverted Lys(B28),Pro(B29). This pharmacokinetic profile, which resembles that of endogenous insulin, leads to a faster rise in plasma concentration, a higher peak concentration, and a shorter duration of action than Hlin [12], [13], [16], [17]. The use of Hlog in patients receiving chronic insulin therapy is associated with a faster BGC reduction when infusion is started and a reduced “residual effect” when infusion is stopped [18]. In the critical care setting, a similar effect may be potentially beneficial due to a decreased risk of hypoglycemia in the carryover phase, after insulin infusion is discontinued. However, controlled clinical data on the use of shorter acting insulin formulations in critical care patients are lacking.

We describe the effect of short-acting insulin on blood glucose during continuous infusion and after discontinuation of infusion in critically ill patients, compared with that of regular insulin (the current standard of care).

Section snippets

Materials and methods

This prospective, randomized, crossover, multicenter, clinical trial received institutional review board approval for human research from the University of Rome “La Sapienza,” Italy (approval March 28, 2013, protocol no. 390/13, Chairman: Prof. Aldo Isidori) and from the Valencia University Hospital Institutional Review Board (President Dr Antonio Pelaez) and was registered at the clinicaltrials.gov (NCT 02165566). Written informed consent was obtained from the patients or their next of kin

Patients

A total of 36 patients were randomized to 1 of the 2 treatments. Five patients assigned as first treatment to Hlin and 3 patients assigned to Hlog had no subsequent severe hyperglycemia (BGC > 180 mg/dL) and were, therefore, not assigned to the other treatment (see Fig. 2 for CONSORT diagram). Twenty-eight patients were treated with both Hlog and Hlin. Demographic and clinical data are summarized in Table 1. During the study period, all patients received only parenteral nutrition with a mean

Discussion

In this prospective randomized pilot study performed in critical care patients, the clinical effects of IIT with Hlog or Hlin—during and after insulin infusion—were compared. With Hlog, as compared with Hlin, during insulin infusion, the rate of BGC reduction was faster, and after insulin discontinuation, the extent and duration of carryover effect were more limited and the rate of BGC increase was more rapid. These results suggest that shorter acting insulin analogs such as Hlog have a safer

Conclusions

In conclusion, in ICU patients, the use of short-acting insulin Hlog for IIT at a fixed dose, when compared with Hlin at the same dose, is associated with a less profound carryover effect on BGC after insulin infusion is discontinued. The use of Hlog, when compared with Hlin, is also associated with a higher rate of BGC reduction during insulin infusion—leading to faster attainment of the target BGC range—a shorter duration of carryover and a higher rate of BGC increase after insulin infusion

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    ☆☆

    Disclosure: The authors have no conflicts of interest. No corporate funds have been used to support this study.

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