- Email: [email protected]
Adsorption of insulin onto infusion sets used in adult intensive care unit and neonatal care settings
diabetes research and clinical practice 80 (2008) e11–e13
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/diabres
Brief report
Adsorption of insulin onto infusion sets used in adult intensive care unit and neonatal care settings Najam Zahid a, Kevin M.G. Taylor a,*, Hardyal Gill a, Fiona Maguire b, Rob Shulman b a b
Department of Pharmaceutics, School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, UK Pharmacy Department, University College Hospital, University College London Hospitals NHS Foundation Trust, Euston Road, London, UK
article info
abstract
Article history:
Introduction: Insulin adsorption onto infusion equipment may affect glycaemic control.
Received 21 February 2008
Methods: The change in insulin concentration during delivery through tubing employed for
Accepted 23 February 2008
adult ICU and neonatal patients was determined using continuous flow UV analysis.
Published on line 18 April 2008
Results: Insulin adsorption depended on tubing composition, dimensions and flow rate, being highest for neonatal polyvinylchloride tubing at low flow rates.
Keywords:
Conclusion: In continuous insulin therapy, we should consider the nature of the infusion set
Adsorption
and flow rate. # 2008 Elsevier Ireland Ltd. All rights reserved.
Assay Injecting equipment Insulin
1.
Introduction
Tight glycaemic control in adult long-stay critically ill patients using intensive insulin therapy reduces absolute mortality [1,2]. However, target glycaemia may be difficult to achieve in clinical practice [3]. A low infusion rate of insulin is used in neonatal hyperglycaemia if blood–glucose concentrations are persistently high, and in the management of neonatal diabetes [4]. Insulin adsorption onto infusion equipment may affect glucose control [5], possibly leading to hyperglycaemia [6,7]. Adsorption may depend on infusion flow rate and concentration [7]. Over time, protein adsorption onto injecting equipment increases until binding regions reach saturation [8], with maximum adsorption occurring in the first 30–60 min [9]. The clinical significance of this in the adult ICU and neonatal settings is uncertain [8].
In this study, adsorption of insulin onto infusion sets used in the adult ICU and for neonatal insulin delivery at University College Hospital (UCH), London, at clinically relevant flow rates was analyzed. The effect of tubing composition and dimensions were also considered.
2.
Methods
Soluble human insulin (Actrapid1, 100 U/ml, Novo Nordisk) was diluted to 1 U/ml in 0.9% NaCl, prepared from HPLC grade water (Fisher Scientific) and sodium chloride (Sigma–Aldrich). The UV absorbance of insulin solutions passing through a continuous flow UV detector (Agilent Technologies 1200 Series) was measured at 210 nm. Insulin adsorption onto adult ICU infusion tubing (Cardinal Health, polyethylene (PE) 200 cm 0.9 mm internal diameter, prime volume 1.6 ml) was
* Corresponding author. E-mail address: [email protected] (Kevin M.G. Taylor). 0168-8227/$ – see front matter # 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2008.02.013
e12
diabetes research and clinical practice 80 (2008) e11–e13
determined at rates of 0.5 and 1 ml/h over 24 h, and at 4 ml/h for 10 h. Neonatal tubing extension sets (Alaris Medical Systems, polyvinylchloride (PVC) 150 cm 0.5 mm internal diameter, 0.4 ml prime volume) at 0.1 and 0.5 ml/h were investigated over 24 h. The UV cell was purged with 0.9% NaCl and a baseline achieved for 0.9% NaCl delivered from a 50 ml BD PlastipakTM syringe, in a B. Braun1 Space PerfusorTM Pump, via the tubing at the selected flow rate. An initial (100%) UV absorbance for the insulin solution was determined by running insulin from the syringe directly into the UV cell. Following purging and new baseline acquisition, a BD syringe containing insulin was attached to the same tubing used for achieving baseline, placed in the infusion pump and connected to the UV cell. The desired flow rate and infusion time for each experiment were entered on the pump and results collected. Each experiment was repeated four times. Insulin adsorption onto the syringe was quantified over 24 h using HPLC with a Jupitor 300, 5 mm C18, 250 mm 4.6 mm column (Phenomenex), mobile phase of 30% HPLC grade acetonitrile (Fisher Scientific) and 0.1% trifluroacetic acid (TFA, Sigma–Aldrich) in 70% HPLC grade water, and UV detection at 210 nm.
3.
Results
At a flow rate of 0.5 ml/h, insulin was adsorbed onto the PE ICU tubes, such that the concentration flowing from the tubing was 86.23% of that in the syringe after the first 30 min, and
Fig. 1 – Mean (WS.E.M.) insulin recovery from polyethylene tubing used in the adult ICU.
only achieved a steady state of 100% of initial concentration after approximately 600 min (Fig. 1). At 1 ml/h, the initial insulin concentration was 95.08% and took around 400 min to reach 100%. At 4 ml/h, the initial concentration was 99.06% and approximately 200 min were required to reach steady state. For the PVC neonatal tubing, at a flow rate of 0.5 ml/h, the insulin concentration reached a minimum of 63.30% of the syringe concentration (Fig. 2). At 0.1 ml/h the initially measured concentration was 54.19% after 180 min. At both flow rates, the concentration of insulin had not reached 100% of the syringe concentration at 24 h. The HPLC methodology indicated that there was a loss of 1.99% of insulin by surface adsorption to the syringe.
4.
Discussion
The relatively small loss of insulin on the syringe indicates that the majority of insulin loss observed in this study resulted from adsorption to tubing. Maximum loss of insulin in tubing occurred at the beginning of infusion as previously described [9], with recovery of insulin increasing as adsorption sites are saturated [8]. The flow rate had a considerable effect on insulin loss. At low rates, there was greater opportunity for interaction with plastic surfaces. Comparing the two tubings at 0.5 ml/h, adsorption was substantially greater for the neonatal microbore PVC tubing, through which insulin concentration never reached 100%. The tubing used in the adult ICU was lined with polyethylene, which at 0.5 ml/h, adsorbed insulin to a lesser extent than PVC. Overall, most adsorption occurred within 30 min for PVC, but up to 180 min for PE tubing. The two tubings differed in length and internal diameter. The PVC tube had a larger surface area to volume ratio (5.890 10 3 m2: 1 ml) than PE tubing (3.534 10 3 m2: 1 ml), giving greater opportunity for insulin adsorption. There was less variability in insulin adsorption at higher flow rates, suggesting these may give more predictable insulin delivery, helping to maintain a tight glycaemic control. At low rates and especially in neonatal patients, the concentration of insulin administered to patients could be substantially reduced, having implications for glycaemic control and consequently morbidity and mortality. In conclusion, our study demonstrated the profound effect of flow rate, tubing composition and surface area to volume ratio on insulin adsorption. The clinical significance of this level of adsorption on glycaemic control in adult ICU and especially neonatal patients needs to be analysed. As PVC tubes adsorbed insulin to a greater extent than PE tubing during this investigation, it has been recommended that PE tubes should be used at UCH. Previously, priming of tubing with insulin solutions enhanced insulin delivery by interacting with non-specific binding sites at low flow rates [7], indicating an alternative strategy to reduce insulin adsorption.
Conflict of interest Fig. 2 – Mean (WS.E.M.) insulin recovery from PVC tubing used for neonatal patients.
The authors declare that they have no conflict of interest.
diabetes research and clinical practice 80 (2008) e11–e13
references
[1] G. Van den Berghe, P. Wouters, F. Weekers, C. Verwaest, F. Bruyninckx, M. Schetz, et al., Intensive insulin therapy in critically ill patients, N. Eng. J. Med. 345 (2001) 1359–1367. [2] G. Van den Berghe, A. Wilmer, G. Hermans, G. Meersseman, P. Wouters, L. Milants, et al., Intensive insulin therapy in the medical ICU, N. Eng. J. Med. 354 (2006) 449–461. [3] R. Shulman, S.J. Finney, C. O’Sullivan, P.A. Glynne, R. Greene, Tight glycaemic control: A prospective observational study of a computerised decision-supported intensive insulin therapy protocol, Crit. Care 11 (2007) R75. [4] BNF for Children. Drugs used in diabetes. BMJ Publishing Group Ltd. and RPS Publishing, London, 2006, pp. 398–403. [5] S. Ley, J. Ammann, C. Herder, M. Hartmann, D. KindgenMilles, Variable adsorption of insulin at catheter materials
[6]
[7]
[8]
[9]
e13
used in intensive care units: polyethylene versus polyurethane—possible cause for hypoglycemia during intensive insulin treatment? Crit. Care 11 (2007) P127. M.P. Hewson, V. Nawadra, J.R. Oliver, et al., Insulin infusions in the neonatal unit: delivery variation due to adsorption, J. Paed. Child Health 36 (2000) 216–220. M. Fuloria, M.A. Friedberg, R.H. Durant, J.L. Aschner, Effect of flow rate and insulin priming on the recovery of insulin from microbore infusion tubing, Pediatrics 102 (1998) 1401–1406. J. Brange, Physical stability of proteins, in: S. Frokjaer, L. Hovgaard (Eds.), Pharmaceutical Formulation Development of Peptides and Proteins, Taylor & Francis Ltd., Cornwall, 2000, pp. 89–109. L.A. Trissel, Handbook on Injectable Drugs, 13th ed., American Society of Health-System Pharmacists, Bethesda, 2005, pp. 864–871.
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/diabres
Brief report
Adsorption of insulin onto infusion sets used in adult intensive care unit and neonatal care settings Najam Zahid a, Kevin M.G. Taylor a,*, Hardyal Gill a, Fiona Maguire b, Rob Shulman b a b
Department of Pharmaceutics, School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, UK Pharmacy Department, University College Hospital, University College London Hospitals NHS Foundation Trust, Euston Road, London, UK
article info
abstract
Article history:
Introduction: Insulin adsorption onto infusion equipment may affect glycaemic control.
Received 21 February 2008
Methods: The change in insulin concentration during delivery through tubing employed for
Accepted 23 February 2008
adult ICU and neonatal patients was determined using continuous flow UV analysis.
Published on line 18 April 2008
Results: Insulin adsorption depended on tubing composition, dimensions and flow rate, being highest for neonatal polyvinylchloride tubing at low flow rates.
Keywords:
Conclusion: In continuous insulin therapy, we should consider the nature of the infusion set
Adsorption
and flow rate. # 2008 Elsevier Ireland Ltd. All rights reserved.
Assay Injecting equipment Insulin
1.
Introduction
Tight glycaemic control in adult long-stay critically ill patients using intensive insulin therapy reduces absolute mortality [1,2]. However, target glycaemia may be difficult to achieve in clinical practice [3]. A low infusion rate of insulin is used in neonatal hyperglycaemia if blood–glucose concentrations are persistently high, and in the management of neonatal diabetes [4]. Insulin adsorption onto infusion equipment may affect glucose control [5], possibly leading to hyperglycaemia [6,7]. Adsorption may depend on infusion flow rate and concentration [7]. Over time, protein adsorption onto injecting equipment increases until binding regions reach saturation [8], with maximum adsorption occurring in the first 30–60 min [9]. The clinical significance of this in the adult ICU and neonatal settings is uncertain [8].
In this study, adsorption of insulin onto infusion sets used in the adult ICU and for neonatal insulin delivery at University College Hospital (UCH), London, at clinically relevant flow rates was analyzed. The effect of tubing composition and dimensions were also considered.
2.
Methods
Soluble human insulin (Actrapid1, 100 U/ml, Novo Nordisk) was diluted to 1 U/ml in 0.9% NaCl, prepared from HPLC grade water (Fisher Scientific) and sodium chloride (Sigma–Aldrich). The UV absorbance of insulin solutions passing through a continuous flow UV detector (Agilent Technologies 1200 Series) was measured at 210 nm. Insulin adsorption onto adult ICU infusion tubing (Cardinal Health, polyethylene (PE) 200 cm 0.9 mm internal diameter, prime volume 1.6 ml) was
* Corresponding author. E-mail address: [email protected] (Kevin M.G. Taylor). 0168-8227/$ – see front matter # 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2008.02.013
e12
diabetes research and clinical practice 80 (2008) e11–e13
determined at rates of 0.5 and 1 ml/h over 24 h, and at 4 ml/h for 10 h. Neonatal tubing extension sets (Alaris Medical Systems, polyvinylchloride (PVC) 150 cm 0.5 mm internal diameter, 0.4 ml prime volume) at 0.1 and 0.5 ml/h were investigated over 24 h. The UV cell was purged with 0.9% NaCl and a baseline achieved for 0.9% NaCl delivered from a 50 ml BD PlastipakTM syringe, in a B. Braun1 Space PerfusorTM Pump, via the tubing at the selected flow rate. An initial (100%) UV absorbance for the insulin solution was determined by running insulin from the syringe directly into the UV cell. Following purging and new baseline acquisition, a BD syringe containing insulin was attached to the same tubing used for achieving baseline, placed in the infusion pump and connected to the UV cell. The desired flow rate and infusion time for each experiment were entered on the pump and results collected. Each experiment was repeated four times. Insulin adsorption onto the syringe was quantified over 24 h using HPLC with a Jupitor 300, 5 mm C18, 250 mm 4.6 mm column (Phenomenex), mobile phase of 30% HPLC grade acetonitrile (Fisher Scientific) and 0.1% trifluroacetic acid (TFA, Sigma–Aldrich) in 70% HPLC grade water, and UV detection at 210 nm.
3.
Results
At a flow rate of 0.5 ml/h, insulin was adsorbed onto the PE ICU tubes, such that the concentration flowing from the tubing was 86.23% of that in the syringe after the first 30 min, and
Fig. 1 – Mean (WS.E.M.) insulin recovery from polyethylene tubing used in the adult ICU.
only achieved a steady state of 100% of initial concentration after approximately 600 min (Fig. 1). At 1 ml/h, the initial insulin concentration was 95.08% and took around 400 min to reach 100%. At 4 ml/h, the initial concentration was 99.06% and approximately 200 min were required to reach steady state. For the PVC neonatal tubing, at a flow rate of 0.5 ml/h, the insulin concentration reached a minimum of 63.30% of the syringe concentration (Fig. 2). At 0.1 ml/h the initially measured concentration was 54.19% after 180 min. At both flow rates, the concentration of insulin had not reached 100% of the syringe concentration at 24 h. The HPLC methodology indicated that there was a loss of 1.99% of insulin by surface adsorption to the syringe.
4.
Discussion
The relatively small loss of insulin on the syringe indicates that the majority of insulin loss observed in this study resulted from adsorption to tubing. Maximum loss of insulin in tubing occurred at the beginning of infusion as previously described [9], with recovery of insulin increasing as adsorption sites are saturated [8]. The flow rate had a considerable effect on insulin loss. At low rates, there was greater opportunity for interaction with plastic surfaces. Comparing the two tubings at 0.5 ml/h, adsorption was substantially greater for the neonatal microbore PVC tubing, through which insulin concentration never reached 100%. The tubing used in the adult ICU was lined with polyethylene, which at 0.5 ml/h, adsorbed insulin to a lesser extent than PVC. Overall, most adsorption occurred within 30 min for PVC, but up to 180 min for PE tubing. The two tubings differed in length and internal diameter. The PVC tube had a larger surface area to volume ratio (5.890 10 3 m2: 1 ml) than PE tubing (3.534 10 3 m2: 1 ml), giving greater opportunity for insulin adsorption. There was less variability in insulin adsorption at higher flow rates, suggesting these may give more predictable insulin delivery, helping to maintain a tight glycaemic control. At low rates and especially in neonatal patients, the concentration of insulin administered to patients could be substantially reduced, having implications for glycaemic control and consequently morbidity and mortality. In conclusion, our study demonstrated the profound effect of flow rate, tubing composition and surface area to volume ratio on insulin adsorption. The clinical significance of this level of adsorption on glycaemic control in adult ICU and especially neonatal patients needs to be analysed. As PVC tubes adsorbed insulin to a greater extent than PE tubing during this investigation, it has been recommended that PE tubes should be used at UCH. Previously, priming of tubing with insulin solutions enhanced insulin delivery by interacting with non-specific binding sites at low flow rates [7], indicating an alternative strategy to reduce insulin adsorption.
Conflict of interest Fig. 2 – Mean (WS.E.M.) insulin recovery from PVC tubing used for neonatal patients.
The authors declare that they have no conflict of interest.
diabetes research and clinical practice 80 (2008) e11–e13
references
[1] G. Van den Berghe, P. Wouters, F. Weekers, C. Verwaest, F. Bruyninckx, M. Schetz, et al., Intensive insulin therapy in critically ill patients, N. Eng. J. Med. 345 (2001) 1359–1367. [2] G. Van den Berghe, A. Wilmer, G. Hermans, G. Meersseman, P. Wouters, L. Milants, et al., Intensive insulin therapy in the medical ICU, N. Eng. J. Med. 354 (2006) 449–461. [3] R. Shulman, S.J. Finney, C. O’Sullivan, P.A. Glynne, R. Greene, Tight glycaemic control: A prospective observational study of a computerised decision-supported intensive insulin therapy protocol, Crit. Care 11 (2007) R75. [4] BNF for Children. Drugs used in diabetes. BMJ Publishing Group Ltd. and RPS Publishing, London, 2006, pp. 398–403. [5] S. Ley, J. Ammann, C. Herder, M. Hartmann, D. KindgenMilles, Variable adsorption of insulin at catheter materials
[6]
[7]
[8]
[9]
e13
used in intensive care units: polyethylene versus polyurethane—possible cause for hypoglycemia during intensive insulin treatment? Crit. Care 11 (2007) P127. M.P. Hewson, V. Nawadra, J.R. Oliver, et al., Insulin infusions in the neonatal unit: delivery variation due to adsorption, J. Paed. Child Health 36 (2000) 216–220. M. Fuloria, M.A. Friedberg, R.H. Durant, J.L. Aschner, Effect of flow rate and insulin priming on the recovery of insulin from microbore infusion tubing, Pediatrics 102 (1998) 1401–1406. J. Brange, Physical stability of proteins, in: S. Frokjaer, L. Hovgaard (Eds.), Pharmaceutical Formulation Development of Peptides and Proteins, Taylor & Francis Ltd., Cornwall, 2000, pp. 89–109. L.A. Trissel, Handbook on Injectable Drugs, 13th ed., American Society of Health-System Pharmacists, Bethesda, 2005, pp. 864–871.