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\begin{document}

\title{Evaluation of Regular Insulin Adsorption to Polypropylene Bag and
Polyvinyl Chloride Infusion Set}



\author[1]{Nursel Sürmelioğlu}%
\author[2]{Merve Nenni}%
\author[3]{Ahmet Fırat}%
\author[4]{Kutay Demirkan}%
\author[3]{Dilek Özcengiz}%
\affil[1]{Cukurova University}%
\affil[2]{Affiliation not available}%
\affil[3]{ Faculty of Medicine, Çukurova University }%
\affil[4]{Hacettepe University Faculty of Pharmacy}%


\vspace{-1em}



  
  \date{May 18, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Aim Clinical application of insulin infusion therapy is usually
accomplished with regular human insulin. It is known that the regular
insulin adsorbed to the hydrophobic surfaces and different approaches
were implemented into the clinical practices. It was aimed to evaluate
the rate of adsorption of insulin to PP bags and PVC infusion sets and
stability of insulin during the infusion. Methods 100 IU insulin was
added to PP bags containing 100 ml of 0.9\% NaCl solution(n = 6). The
infusion was started at a rate of 2 ml/h using infusion sets in the PVC
structure. Insulin quantification was performed in the samples taken
both from the bag and from the end tip of the infusion set during
infusion. The stability of insulin solutions stored at room (+24\selectlanguage{ngerman}°C) and
refrigerator (+4°C) temperatures were compared. Samples were analyzed
using reverse-phase high-performance liquid chromatography. Results No
statistically significant difference was found between the
concentrations of the samples taken from the bags stored at room and
refrigerator temperatures at the 4th, 12th, and 24th hours
(p\textgreater{}0.05). It was seen that the adsorption rate of insulin
to PVC set was 57\% and PP bags is at most 5\% at the 24th hour.
Conclusion When PP bags are used for insulin infusion, it is predicted
that 24-hour change can be made instead of frequent change. In addition,
losses caused by the high rate of insulin adsorption to PVC infusion
sets should be considered and PP infusion sets would be the better
option to use if available.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Evaluation of Regular Insulin Adsorption to Polypropylene Bag
and Polyvinyl Chloride Infusion Set}

\textbf{Running Title:} Clinical application of insulin infusion

Nursel S\selectlanguage{ngerman}ürmelio\selectlanguage{polish}ğ\selectlanguage{english}lu\textsuperscript{1}, Merve Nenni\textsuperscript{2},
Ahmet F\selectlanguage{polish}ı\selectlanguage{english}rat\textsuperscript{3}, Kutay Demirkan\textsuperscript{4}, Dilek
\selectlanguage{ngerman}Özcengiz\textsuperscript{3}

\textsuperscript{1} Department of Clinical Pharmacy, Faculty of
Pharmacy, Çukurova University

\textsuperscript{2} Department of Analytical Chemistry, Faculty of
Pharmacy, Çukurova University

\textsuperscript{3} Department of Intensive Care, Faculty of Medicine,
Çukurova University

\textsuperscript{4} Department of Clinical Pharmacy, Faculty of
Pharmacy, Hacettepe University

\textbf{Corresponding author}

Nursel Sürmelio\selectlanguage{polish}ğ\selectlanguage{english}lu, PhD

Department of Clinical Pharmacy, Faculty of Pharmacy, \selectlanguage{ngerman}Çukurova
University, 01380, Sar\selectlanguage{polish}ı\selectlanguage{ngerman}çam, Adana, Turkey

Tel: +90-533-054-69-01

e-mail: \emph{nurselisci@gmail.com}

\textbf{Conflict of interest:} The authors declare that they have no
conflict of interest.

\textbf{Financial Disclosure} : The authors declared that this study has
received no financial support.

\textbf{Author Contributions} : N.S and K.D. designed the study and
conducted the literature review. M.N. performed the data analysis. All
authors interpreted the study data. N.S., M.N. and A.F. wrote the first
draft of the manuscript. K.D. and D.Ö. provided critical revisions to
the manuscript. All of the authors approved the final version of the
manuscript.

Parts of this study were presented in abstract form at the 16. National
Internal and Surgical Sciences Intensive Care Congress and 8th Eurasian
Intensive Care Meeting, Antalya, Turkey, 13-16 November 2019

\textbf{Abstract}

\textbf{Aim}

Clinical application of insulin infusion therapy is usually accomplished
with regular human insulin. It is known that the regular insulin
adsorbed to the hydrophobic surfaces and different approaches were
implemented into the clinical practices. It was aimed to evaluate the
rate of adsorption of insulin to PP bags and PVC infusion sets and
stability of insulin during the infusion.

\textbf{Methods}

100 IU insulin was added to PP bags containing 100 ml of 0.9\% NaCl
solution(n = 6). The infusion was started at a rate of 2 ml/h using
infusion sets in the PVC structure. Insulin quantification was performed
in the samples taken both from the bag and from the end tip of the
infusion set during infusion. The stability of insulin solutions stored
at room (+24°C) and refrigerator (+4°C) temperatures were compared.
Samples were analyzed using reverse-phase high-performance liquid
chromatography.

\textbf{Results}

No statistically significant difference was found between the
concentrations of the samples taken from the bags stored at room and
refrigerator temperatures at the 4th, 12th, and 24th hours
(p\textgreater{}0.05). It was seen that the adsorption rate of insulin
to PVC set was 57\% and PP bags is at most 5\% at the 24th hour.

\textbf{Conclusion}

When PP bags are used for insulin infusion, it is predicted that 24-hour
change can be made instead of frequent change. In addition, losses
caused by the high rate of insulin adsorption to PVC infusion sets
should be considered and PP infusion sets would be the better option to
use if available.

\textbf{What is already known about this topic?}

\begin{itemize}
\tightlist
\item
  It is known that the regular insulin adsorbed to the surfaces of
  polyvinyl chloride bags and infusion sets, which are generally used in
  hospitals, and not to the polypropylene surfaces.
\item
  There are different data about the adsorption rates and approaches
  were implemented into the clinical practices in the literature.
\item
  There is a lack of information regarding the stability of the insulin
  solution at room temperature.
\end{itemize}

\textbf{What does this article add?}

\begin{itemize}
\tightlist
\item
  As a result of the study, it has been determined that insulin
  solutions are stable at both room and refrigerator temperatures over
  24 h storage.
\item
  It has been determined that the rate of adhesion of insulin to
  polyvinyl chloride surface is different from that stated in the
  literature.
\item
  These results may change the clinical practice.
\end{itemize}

\textbf{Introduction}

Hyperglycemia is common in critically ill patients and is a modifiable
risk factor that increases morbidity and mortality {[}1-4{]}. For many
years, optimal treatment of hyperglycemia has been discussed in
intensive care units {[}5{]}. The American Clinical Endocrinologists
Association and the American Diabetes Association recommend keeping
glucose levels between 140-180 mg/dL for glycemic control in critically
ill patients {[}6,7{]}. In critically ill patients, continuous iv
insulin infusion has been shown to be the best route to achieve glycemic
targets and prevent glycemic fluctuations {[}7{]}. Clinical application
of insulin infusion therapy is usually accomplished with regular human
insulin {[}2,8{]}. It is known that the regular insulin adsorbed to the
surfaces of polyvinyl chloride (PVC) bags and infusion sets, which are
generally used in hospitals, and not to the polypropylene (PP) surfaces.
However, there are different data about the adsorption rates in the
literature {[}9-16{]}. Therefore different approaches were implemented
into the clinical practices, such as changing the bag every 4 or 12
hours, to minimize the adsorption of insulin to the bag during the
infusion {[}17-19{]}.

In this study, it was aimed to evaluate the rate of adhesion of insulin
solutions to PP bags and PVC infusion sets and stability times at room
temperature (+24° C) during the infusion.

\textbf{Methods}

Chemicals

\selectlanguage{polish}İ\selectlanguage{english}nsulin (Humulin R, Lilly\textsuperscript{?}), PP bags
(Polifarma\textsuperscript{?}) and PVC infusion sets
(Sapphire\textsuperscript{?}) were obtained from a pharmaceutical
warehouse. All the chemicals were analytical grade on preparing buffers
and solutions. Acetonitrile was purchased from Merck (Darmstadt,
Germany). Ultrapure water was purchased from the Milli-Q water system
(Barnstead, USA).

Analytical Conditions

Chromatographic methods for insulin are included in the Turkish
Pharmacopoeia {[}20{]}. In this study, insulin was analyzed by reverse
phase high performance liquid chromatography (RP-HPLC) which the assay
was validated according to international guidelines {[}21{]}. Briefly,
the LC system (Agilent 1220 Infinity II) consisted of a gradient pump, a
degasser, and a UV detector (Thermo Separation Products, USA). The
separations were achieved by a C18 Phenomenex column (250 x 4.6 mm,
100\selectlanguage{ngerman}Å, 5 \selectlanguage{greek}µ\selectlanguage{english}m i.d.) at room temperature. The mobile phase was
acetonitrile:phosphate buffer (50:50 v/v, pH:3.0, 10 mM) and, solutions
delivered at a flow rate of 1mL/min which gave the optimum
chromatographic conditions. Injection volume was 20 \selectlanguage{greek}μ\selectlanguage{english}L and UV detection
was performed at 214 nm.

Sample Preparation

In the study, solutions containing 1 IU/mL concentration (n = 6) were
prepared by adding 100 IU insulin to PP bags containing 100 ml of 0.9\%
NaCl solution. Also, PVC infusion sets were used. In the experimental
setup established in accordance with clinical practice, the infusion
rate of the solutions was determined as 2 IU/hour through the infusion
pump. 600 \selectlanguage{greek}µ\selectlanguage{english}L samples were taken from the bag at the beginning of the
infusion (hour 0), as well as from the bag and at the end tip of the
infusion set at the end of the 1st, 2nd, 4th, 12th and 24th hours. In
each sample taken, insulin quantification was made. This experimental
procedure was carried out simultaneously with 6 separate insulin
solutions prepared at room temperature. As a result of the analysis of
the samples taken from each bag and set at specified times, the
adsorption rates of insulin to PP bag and PVC infusion set were
evaluated.

Also, to evaluate the stability of insulin solutions at room temperature
during infusion, the analysis results of samples taken from insulin
solutions stored at room (+25\selectlanguage{ngerman}°C) and refrigerator (+4°C) temperatures at
0, 4, 12 and 24 hours were compared.

Statistical analysis

Statistical evaluation was performed using Student's t-test and
the\emph{p} values \selectlanguage{english}[?]0.05 were considered statistically significant. In
the beginning (0 hours), insulin solutions in PP bags are the control
group.

\textbf{Results}

The samples required to evaluate the amount of insulin adsorbed to PP
bags were collected simultaneously from 6 separate infusion bags. In the
analysis of these samples, the insulin concentration rate of 100\% was
accepted at baseline (0 hours). The insulin concentration rates of the
samples taken from PP bags at the 1st, 2nd, 4th, 12th, and 24th hours of
the infusion were determined as 95\%, 98\%, 98\%, 95\%, and 100\%,
respectively (Table 1).

The samples required to evaluate the amount of insulin adsorbed to the
PVC infusion set were collected simultaneously from the end tips of the
6 separate infusion sets. The insulin concentrations of the samples
collected at the 1st, 2nd, 4th, 12th, and 24th hours of the infusion
were determined as 43\%, 40\%, 30\%, 21\% and 35\%, respectively (Table
1).

To evaluate the stability of the insulin solution at room temperature,
the insulin concentrations of the solutions in PP bags stored at room
(+25degC)and at refrigerator (+4degC) temperatures were compared. The
insulin concentration in the PP bag, stored at + 4deg C, was initially
considered 100\% (0 hours). No statistically significant difference was
found between the concentrations of the samples taken from the bags
stored at room and refrigerator temperatures at the 4th, 12th, and 24th
hours (p\textgreater{}0.05) (Figure 1).

\textbf{Discussion}

Adsorption is a nonspecific phenomenon that occurs with every solid
particle. This phenomenon is particularly important with insulin,
because it alters the rate of drug delivery to patient, and finally
impacts glycemic control {[}18{]}. In order to minimize insulin loss due
to adsorption and optimal glycemic control, appropriate clinical
practices should be determined according to the rate of insulin adsorbed
to the bag and set used during infusion.

In this study, the insulin concentration rates of the samples taken from
PP bags at the 1st, 2nd, 4th, 12th, and 24th hours were determined as
95\%, 98\%, 98\%, 95\%, and 100\%, respectively. Accordingly, it has
been shown that the rate of insulin adsorption to PP bags is at most
5\%, and this rate decreases after the first hour of infusion. In a
study by Jakobson et al. it was shown that insulin adsorbed 10\% to the
PP bag at the first hour of infusion, and then this rate was decreased
while insulin was administered at a rate of 1 ml/h. Similarly, the
maximum adsorption rate was achieved at the 1st hour and then reduction
was determined in both studies {[}10{]}. The difference between the
maximum adsorption rates is thought to result from the difference in
infusion rates. It is reported that the rate of adsorption increases
with a slower infusion rate {[}10,16-22{]}.

The insulin concentration of the samples taken from the end tip of the
PVC infusion set, at the 1st, 2nd, 4th, 12th, and 24th hours were
detected as 43\%, 40\%, 30\%, 21\% and 35\%, respectively. Accordingly,
it was seen that the adsorption rate of insulin to PVC set was 57\% at
the 1st hour and 65\% at the 24th hour. In the study conducted by Zahid
et al., it was shown that the adsorption rate of insulin to the PVC
neonatal tube was approximately 55\% at 3 hours and 15\% at 24 hours
{[}16{]}. It is thought that the high adsorption rate determined in our
study may be due to the surface area difference of the sets used in both
studies. In the study of Trissel et al., it was reported that the
24-hour adsorption rate of insulin to the PVC bag was 35\%. However, in
Trissel's study, the sample was taken from the PVC bag at the beginning
and after 24 hours storage, not during infusion {[}15{]}. Although the
methods of both studies are different, it has been shown that the
maximum adsorption rate was within the first 4 hours and then reduction
in this rate was detected. So, changing the bag every 4 hours, which is
frequently applied in clinical practice, leads to an increase in insulin
loss.

It is thought that changing PVC and PP bags every 24 hours is more
appropriate in terms of both preventing insulin loss and reducing
workload. Besides, economic advantages of changing insulin solution bag
every 24 hours versus 4 hours should be considered in terms of
minimization of manpower (time spend for administration frequency and
preparation), sources (bag and solution) and insulin loss. However, the
stability of the insulin solution is of concern when using the bags for
24 hours. Also, there is no information on the stability of the insulin
solution at room temperature in the package insert. As a result of the
analysis, the insulin solution has been shown to maintain its stability
for 24 hours at room temperature.

\textbf{Conclusion}

As a result of the study, it has been determined that insulin solutions
are stable at both room and refrigerator temperatures over 24 h storage.
When PP bags are used for insulin infusion, it is predicted that 24-hour
change can be made instead of frequent change. In addition, losses
caused by the high rate of insulin adhesion to PVC infusion sets should
be considered and PP infusion sets would be the better option to use if
available.

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\end{enumerate}

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