Inadequate suspension of neutral protamine Hagendorn (NPH) insulin in pens

doi:10.1016/S0140-6736(98)12459-5

The Lancet

Volume 354, Issue 9190, 6 November 1999, Pages 1604-1607

https://doi.org/10.1016/S0140-6736(98)12459-5 Get rights and content

Summary

Background

Neutral protamine Hagedorn (NPH) insulin is one of the most commonly used insulins in insulin pens. NPH in pen cartridges is in a two-phase solution with either a solvent or a short-acting insulin, and needs adequate mixing for complete resuspension. We assessed whether NPH insulin is accurately resuspended by patients and the association of suspension errors with diabetes control

Methods

109 patients (39 with type 1 diabetes) who had received conventional diabetic education had the NPH content of their cartridges measured by an optical system; a control cartridge was designated as 100%. A questionnaire was used to assess clinical details and insulin suspension habits. After the information about residual insulin error was known, all 109 patients were instructed to resuspend their insulin by rolling and tipping the pen 20 times. 52 patients were randomly selected to have cartridges re-analysed 3 months or 6 months later and to complete another questionnaire.

Findings

Only 10 (9%) of 109 patients tipped and rolled their pen more than ten times. NPH insulin content ranged from 5% to 214% and varied by more than 20% in 71 (65%) of 109 cartridges. There was no relation between inadequate suspension and the frequency of hypoglycaemic episodes (r=0·2, p=0·08). For all patients, there was a correlation between the absolute error of NPH suspension and cycles of rolling and tipping the pen (r=−0·23, p<0·05). After education on resuspending the pen's contents, data were available from 44 of 52 patients; suspension errors decreased in 35 (80%), were unchanged in three (7%), and increased in six (13%). The 35 patients with improved NPH insulin suspension had fewer mean hypoglycaemic episodes per month compared with the previous period (0·4 [SD 0·1] vs 1·0 [0·3], p<0·05). Mean HbA1c values in patients with improved suspension quality did not differ from baseline (8·4% [0·3] vs 8·9% [0·4], p=0·07). Mixing of NPH insulin by a mechanical device showed that at least 20 cycles were necessary before complete resuspension was obtained

Interpretation

Inadequate NPH insulin suspension is common. We recommended that patients tip pens that contain NPH insulin at least 20 times, since inadequate mixing may impair diabetes control.

Introduction

Modern insulin regimens aim to mimic physiological insulin profiles. Intermediate-acting insulin should provide basal insulin requirements, whereas short-acting insulin is given preprandially to cover food intake. This kind of insulin provision is deemed conventional intensified-insulin therapy and is highly effective in short-term and long-term diabetes control.1, 2, 3

For many patients with diabetes, insulin pens, which were developed to facilitate multiple daily injections of short-acting insulin in intensified treatment regimens, are the most convenient way to administer insulin.4, 5 With the introduction of pens with intermediate-acting insulin and premixed insulin combinations, insulin pens have become the most widely used device for insulin injection. The most commonly used intermediate-acting isophane insulin is neutral protamine Hagedorn (NPH). NPH cartridges for pens contain a predetermined ratio of NPH insulin and solvent or NPH in combination with a short acting soluble insulin—ie, these are two-phase solutions. The recommendation given to patients is to suspend NPH insulin by tipping the pen and gently rolling it in the palms of the hands before use until a complete suspension is achieved. However, the specific number of cycles is not provided by all manufacturers.⁶

We evaluated the completeness of insulin resuspension by NPH insulin-pen users and its effect on glycaemic control and hypoglycaemic events.

Section snippets

Methods

We assessed NPH insulin suspension in 109 insulin-dependent patients (39 with type 1 diabetes, 70 with type 2 diabetes). These patients were from seven medical practices (n=65) and the outpatient clinics of seven hospitals (n=44) in southern Germany. The study was approved by the local ethical committees. All patients had received a conventional education on the use of insulin pens and had used insulin for median of 10 years (interquartile range [IQR] 5–17).

After informed consent, patients

Results

Patient details and clinical data at baseline are shown in table 1. All patients with type 1 and 59 (84%) of patients with type 2 diabetes stated that they resuspended their NPH insulin before injection either by rolling and tipping or by shaking the pen at least five times; only ten patients tipped and rolled their pen more than ten times.

The NPH insulin content varied by more than 20% (range 5–214%) from the nominal value in the control cartridges in 71 (65%) of 109 patients (figure 1). Low

Discussion

We found that inadequate resuspension of NPH insulin before pen injection is common among diabetic patients treated with insulin. Patients who improved their technique for insulin resuspension had significantly fewer hypoglycaemic episodes than those that did not improve.

Other studies have reported impaired glycaemic control7, 8 and underdosing of insulin⁹ in patients using pen injectors. Hardy and colleagues¹⁰ reported a deterioration in glycaemic control in women who were changed to insulin

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Citation Excerpt :
To improve the efficiency of the process, they have placed miniaturized beads in the cartridges to aid the mixing [5]. However, Jehle et al. [6] have demonstrated that up to 91% of NPH-treated patients either do not perform the resuspension procedure or do it inappropriately, with deleterious consequences for blood glucose control. NPH is characterized by highly variable pharmacokinetics (PK) and pharmacodynamics (PD) in patients with diabetes [2,7].
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Early ReportInadequate suspension of neutral protamine Hagendorn (NPH) insulin in pens

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Methods

Results

Discussion

Lancet

J Adolesc Health

Diabetes Res Clin Pract

Patient Educ Couns

Med Clin North Am

The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus

N Engl J Med

The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent mellitus

N Engl J Med

Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes

Lancet

A randomized trial of the efficacy and acceptability of a pen injector

Diabet Med

Insulin pen: mightier than syringe?

Lancet

Early Report
Inadequate suspension of neutral protamine Hagendorn (NPH) insulin in pens