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Performance of modern syringe infusion pump assemblies at low infusion rates in the perioperative setting
British Journal of Anaesthesia, xxx (xxx): xxx (xxxx) doi: 10.1016/j.bja.2019.10.007 Advance Access Publication Date: xxx Laboratory Investigation
LABORATORY INVESTIGATION
Performance of modern syringe infusion pump assemblies at low infusion rates in the perioperative setting Martina Baeckert1,y, Martin Batliner2,y, Beate Grass3, Philipp K. Buehler1, Marianne Schmid Daners2, Mirko Meboldt2 and Markus Weiss1,* 1
Department of Anaesthesia, University Children’s Hospital Zurich, Zurich, Switzerland, 2Product Development Group
Zurich, ETH Zurich, Zurich, Switzerland and 3Department of Paediatric Intensive Care and Neonatology, University Children’s Hospital Zurich, Zurich, Switzerland *Corresponding author. E-mail: [email protected] y
These authors contributed equally to this article.
Abstract Background: Syringe infusion pumps are used for the precise continuous administration of intravenous drugs. Their compliance and mechanical deficiencies have been found to cause considerable start-up delays, flow irregularities during vertical displacement, as well extensive delays of occlusion alarms at low infusion rates. The aim of this study was to evaluate the performance of several modern syringe infusion pumps at low infusion rates and the impact on drug concentration. Methods: Seven currently marketed syringe infusion pump assemblies were assessed in an in vitro study during start-up, vertical displacement manoeuvres, and infusion line occlusion at a set flow rate of 1 ml h1. The measured data were used as input for a pharmacokinetic simulation modelling plasma concentration during a standard neonatal continuous epinephrine infusion. Results: The mean time from starting the infusion pump to steady-state flow varied from 89 to 1622 s. The zero-drug delivery time after lowering the pump ranged from 145 to 335 s. In all assemblies tested, occlusion alarm delays and measured flow irregularities during vertical displacement manoeuvres resulted in relevant deviations in plasma epinephrine concentration (>25%) as calculated by the pharmacokinetic simulation model. Conclusion: Problems with the performance of syringe infusion pump assemblies can have considerable impact on plasma drug concentration when highly concentrated short-acting cardiovascular drugs are administered at low flow rates. The problems, which affected all assemblies tested, are mainly related to the functional principle of syringe infusion pumps and will only partially be solved by incremental improvements of existing equipment. Keywords: continuous; infusion; infusion pump; low flow; paediatric anaesthesia; paediatric critical care; syringe
Editor’s key points When intravenous drugs are administered by a syringe driver infusion pump, performance accuracy depends on several factors. In small children, in whom low infusion rates are usually required, errors may result in significant differences in achieved plasma drug concentrations.
The authors studied the flow characteristics of several assemblies comprising commercially available syringe pumps, syringes, and administration sets at a set flow rate of 1 ml h1. At these flow rates, inaccuracies were noted on startup, after vertical displacement manoeuvres and on line occlusion.
Received: June 6, 2019; Accepted: 8 October 2019 © 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved. For Permissions, please email: [email protected]
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Syringe infusion pumps are used in critical care medicine and anaesthesia for the continuous intravenous administration of short-acting cardiovascular drugs. In the paediatric setting, highly concentrated drug solutions are administered at low infusion rates (1 ml h1) to prevent fluid overload, particularly in neonates and infants. Accordingly, precise and regular fluid delivery is essential to avoid haemodynamic disturbances. For almost 20 yr, the compliance and mechanical shortcomings of syringe infusion pump assemblies have been identified as causing considerable start-up delays, flow irregularities during vertical displacement, and delays in occlusion alarm times.1e11 However, these have so far only been investigated individually; a comprehensive assessment, including their impact on plasma drug concentration, is lacking. The aim of this study was to evaluate the performance of a large range of currently available modern syringe infusion pump assemblies during start-up, vertical displacement, and infusion line occlusion. Secondly, we aimed to investigate the effect of flow alterations of a standard neonatal epinephrine infusion on plasma drug concentration, using a numerical pharmacokinetic simulation model.
Methods In autumn of 2017, local distributors were asked to provide their currently marketed syringe infusion pump assemblies for use in paediatric critical care and anaesthesia. In total, seven different syringe infusion pump assemblies, including a 50 ml infusion syringe and a low-compliant, stiff 200 cm infusion line extension, from six different manufacturers were included (Table 1). One syringe infusion pump assembly was tested using an infusion line extension without (assembly BD) and with (assembly BD plus) a disc being inserted in the pressure transducer slot of the pump.
Experimental set-up 1 An in vitro set-up was used to evaluate start-up performance and flow characteristics during vertical pump displacement (Fig. 1a). The 50 ml syringe with corresponding infusion line extension filled with distilled water was connected to two serial flow sensors (SLS-1500 and SLI0430; Sensirion AG, Staefa, Switzerland). The output of the second sensor was connected to a fluid chamber filled with 13 cm of distilled water above the infusion syringe outlet level to simulate a central venous pressure of 10 mm Hg. No anti-siphon valves were used. Measured flow values (ml s1) from both sensors were simultaneously recorded on a personal computer 70 times per second using specific software provided by the manufacturer. Data obtained from the SLI-0430 flow sensor were used for flow analysis, and data from the SLS-1500, for measuring retrograde and anterograde infusion volumes.
Start-up experiments The 50 ml syringe was placed in the syringe pump and connected to the corresponding 200 cm infusion line. Thereafter, start-ups at 1 ml h1 were performed either with or without an initial priming bolus of 1 ml fluid from the syringe pump and with or without activating the FastStart mode of the syringe pump, if available, detachable, or both. FastStart mode has been developed and introduced to reduce drive gear slack of the syringe pump and gaps between the syringe barrel flanges and the pump housing. Its principle ranges from application of a fixed simple bolus to sophisticated interaction of plunger force and line pressure after starting the syringe infusion pump.10 The following parameters were measured. Time to first fluid delivery (T1) was defined as the time from activating the start button until the flow sensors registered a first continuous forward flow at 5% of steady-state fluid delivery.
Table 1 Infusion syringe pump assemblies included in the study. The tested assemblies included a syringe infusion pump, a 50 ml infusion syringe and a 200 cm non-compliant infusion line. Syringe pump
Infusion syringe
Infusion line
Assembly 1 (Arcomed)
Syramed mSP6000, Arcomed AG (Regensdorf, Switzerland)
Assembly 2 (BBraun)
Perfusor Space, B. Braun (Melsungen, Germany)
Assembly 3 (BD)
Alaris CC Plus Guardrails, CareFusion (Rolle, Switzerland)
Assembly 4 (BD Plus)
Alaris CC Plus Guardrails, CareFusion (Rolle, Switzerland)
Assembly 5 (Codan)
A616S InCare, Codan Argus AG (Baar, Switzerland)
Assembly 6 (Fresenius)
Agilia SP MC, Fresenius Kabi AG (Bad Homburg, Germany)
Assembly 7 (Theramed)
Terufusion Type SS TE-SS800, Terumo Europe N. V. (Leuven, Belgium)
Syramed 50 ml (60 ml), REF 8300026718, Henke-Sass, Wolf GmbH (Tuttlingen, Germany) Original Perfusor Syringe 50 ml, REF 8728852F-06, B. Braun (Melsungen, Germany) BD Plastipak 50 ml, REF 300865, Becton Dickinson and Company (Drogheda, Ireland) BD Plastipak 50 ml, REF 300865, Becton Dickinson and Company (Drogheda, Ireland) Codandsingle-use syringe; 50e60 ml LUER-LOCK, REF 62.8426 Codan Medical ApS (Rodby, Denmark) Injectomat Syringe 50 ml, REF 9000711, Fresenius Kabi AG (Bad Homburg, Germany) Terumo Syringe 50 ml, REF SSþ50L1, Terumo Europe N. V. (Leuven, Belgium)
Syramed Line, PE, 200 cm, REF APEF202, Fresenius Kabi AG (Bad Homburg, Germany) Original Perfusor Line, PE, 200 cm, REF 8723060, B. Braun (Melsungen, Germany) Extension Set, PE/PVC, 200cm, REF PB-G40720, Cair LGL (Lissieu, France) Extension Set with Pressure Disk, PE/PVC, 200 cm, REF G30302M, CareFusion (Rolle, Switzerland) Extension Set, 200 cm, REF 71.4002, Codan Medizinische € te GmbH & Co KG Gera (Lensahn, Germany) Syramed Line, PE, 200 cm, REF APEF202, Fresenius Kabi AG (Bad Homburg, Germany) Terex Extension Set, 200 cm, REF EXþ200TN1FL, RoweMed AG (Parchim, Germany)
Low flow performance of modern syringe pumps
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Fig 1. Schematic of experimental set-up: (a) in vitro set-up for start-up and vertical displacement manoeuvres, (b) in vitro set-up for infusion line occlusion and assembly compliance, and (c) for isolated syringe compliance. (1) Syringe infusion pump; (2) 50 ml infusion syringe; (3) 200 cm infusion line; (4) flow sensor SLS-1500; (5) flow sensor SLI-0430; (6) sampling glass; (7) PC; (8) three-way stopcock; (9) invasive blood pressure transducer; (10) anaesthesia monitor; (11) central venous catheter; (12) electronic balance; (13) infusion syringe holder; and (14) 5 ml injection syringe.
Time to steady-state fluid delivery (T2) was assessed as the time from activating the start button of the syringe pump until reaching 95% or, for the start-up bolus, 105% of steady-state fluid delivery.
subsequently elevated by 50 cm, whereupon the anterograde infusion volume (V2) delivered within 60 s was assessed.
Experimental set-up 2 Vertical syringe pump displacements After establishing steady-state flow at zero level, the syringe infusion pump assembly was lowered by 50 cm. The resulting retrograde aspiration volume (V1), the time from lowering the infusion pump until the first continuous forward movement of fluid (zero flow time; T3), and the time from lowering the infusion pump until the retrograde aspiration volume was reinfused (zero-drug delivery time; T4) were measured. Afterwards, the syringe infusion pump was placed back at zero level and, after steady-state flow had been re-established,
A second in vitro set-up was used to measure times until various pressure levels were reached with the distal infusion line occluded and the release bolus after re-opening the occlusion (Fig. 1b). Each of the seven syringe infusion pump assemblies were filled with 50 ml sterile water and connected by a stopcock to a central venous catheter (Seldiflex 4Fr - 11 cm; Prodimed, Le Plessis Boucard, France). A three-way stopcock with a blood pressure transducer (TruWave; Edwards Lifesciences, Irvine, CA, USA) was inserted between the infusion line and the catheter. The pressure transducer was connected to a vital sign monitor (S/5TM anaesthesia monitor; Datex-
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Ohmeda, Helsinki, Finland). After establishing steady-state conditions at 1 ml h1 flow rate, the three-way stopcock was set to occlude the syringe outflow. The times from steadystate flow until reaching a pressure of 20, 40, 60, 80, and 100 mm Hg (T5) were measured. At 100 mm Hg occlusion pressure, the three-way stopcock was re-opened. Assuming a specific density of 999.83 kg m3 for water at 22 C room temperature and 1 bar ambient pressure, the volume of fluid (V3) released through the catheter tip into the sampling glass was measured gravimetrically by using an electronic balance (sensitivity 0.0001 g; AT261 DeltaRange; Mettler Toledo, Schwerzenbach, Switzerland) and expressed in ml. The compliance of the syringe infusion pump assembly was calculated from the occlusion release bolus and occlusion pressure. Two identical syringe infusion pumps (A/B) were tested per assembly, and all experiments were performed with new infusion syringes and extension lines for each run. Measurements performed at a set flow rate of 1 ml h1 were repeated five times with both pumps (A/B) for all experiments and each assembly in randomised order.
used; this was translated into a one-compartment model, predicting the plasma epinephrine concentration as presented by Oualha and coworkers.12 The inputs to the simulation were measured flow raw data (no moving average), body weight, and drug concentration of the epinephrine infusion. The body weight was chosen to be 3 kg, and the chosen epinephrine concentration administered at a flow rate of 1 ml h1 corresponded to the continuous application of 0.1 mg kg1 min1. Output was the epinephrine plasma concentration. Data processing and simulation were carried out using a custom simulation model implemented through a numerical computing tool (MATLAB 2016a; The MathWorks Inc., Natick, MA, USA). Start-up time until reaching 95% of steady-state plasma epinephrine concentration (T6) and maximum decrease and increase of plasma epinephrine during vertical displacements were calculated for the two different syringe infusion pump assemblies. Furthermore, zero-drug delivery time until the plasma epinephrine concentration decreased by 25%, which is reported to cause haemodynamic disturbances, was calculated.13
Experimental set-up 3 For all assemblies studied (BD and BD plus have the same syringe, and thus were only evaluated once) the isolated infusion syringe compliance at 100 mm Hg occlusion pressure was measured by mounting the 50 ml infusion syringes into a selfmade syringe holder that prevented movement of plunger and syringe housing during pressure changes (Fig. 1c). The infusion syringes were pressurised to 100 mm Hg pressure by adding sterile water via a 5 ml syringe through a three-way stopcock. At 100 mm Hg the latter was opened to the balance system. The volume released (V4) through the catheter tip into the sampling glass was measured gravimetrically using an electronic balance to estimate infusion syringe compliance. Ten pieces of each infusion syringe brand were measured twice in randomised order (20 measurements per syringe brand).
Data analyses and calculations The high sampling rate of the flow sensors revealed the oscillations in the real-time flow signal. To determine the parameters from T1 to T4 accurately, the signal had to be further processed by using a trailing moving average filter with a window length of 10 s for all pumps except the Arcomed assembly. To account for the latter’s pronounced oscillations (forward movement every 56 s at 1 ml h1 flow rate), a 30 s window was necessary.
Statistical analyses The Wilcoxon rank sum test was used to compare start-up times T1 and T2 with and without an initial priming bolus, FastStart mode, or both, for each assembly, as selectable by the syringe pump. The non-parametric KruskaleWallis test was used to test the difference between the seven assemblies for T5 and V3 during occlusion pressure testing in each assembly. Furthermore, KruskaleWallis test was used to test for differences between the four settings in the Arcomed assembly for T3, T4, V1, and V2 during vertical displacement manoeuvres. Dunn’s test with Holm adjustment was used for pairwise comparisons. A linear mixed model was run to test independence of data for the two distinct pump models (A/B) used in each assembly and experiment. The Pearson correlation coefficient between measured parameters and calculated compliance was also computed. All analyses were performed with the R programming language (version 3.3.3; https://www. R-project.org/).
Results A total of 160 start-up runs, 70 vertical displacement manoeuvres, and 70 occlusion pressure time and pressure release tests were performed and included in the analyses. The null model indicated that most of the time the withinmodel variance (pumps A/B) was higher than the betweenmodel variance, which suggested independence of data.
Pharmacokinetic simulation To demonstrate the effect of continuous epinephrine administration on plasma concentration during start-up and vertical displacement manoeuvres, additional runs were conducted using the Codan and Fresenius assemblies (Table 1). Here, start-ups were performed after delivering a priming bolus of 1 ml, with FastStart activated if available, and at a flow rate of 1 ml h1. After >120 min, the syringe infusion pump assembly was physically lowered by 50 cm, then placed back at zero level and finally elevated by 50 cm. A simulation model based on the pharmacokinetic response of 39 children to an epinephrine infusion was
Start-up performance There were different patterns in start-up behaviour among the six syringe pump brands investigated (Table 2). The FastStart could be manually deactivated in only one syringe pump brand (Arcomed), in another brand the FastStart was automatically deactivated if a priming bolus was delivered (Fresenius), and in all other tested assemblies the FastStart was either unchangeably activated or not available. Overall, median start-up times (T1) ranged from 1.9 to 522.7 s, and median times to steady-state flow (T2) ranged from 88.1 to 1622.4 s (Table 2).
522.69 (5.19e692.44) 1622.35 (1355.78e2011.65) 2.06* (1.74e2.66) 88.07*** (64.89e112.22)
e
e
86.52 (8.09e456.27) 962.98** (611.12e1467.77) 3.62 (3.2e4.73) 106.07*** (77.69e163.24)
e
e
8.98 (5.2e12.48) 385.56 (324.26e660.04) 4.24** (3.41e5.22) 670.84 (308.46e715.16) e e
e e
e e
e
e
Theramed Fresenius Codan
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With FastStart activated, the priming bolus significantly improved T1 in the Theramed (P¼0.019) and Codan (P¼0.004) assemblies but not in others. Similarly, T2 was significantly reduced by a bolus in both BD assemblies (P<0.01 and P<0.05) and in the Theramed (P<0.001) and in the Codan (P<0.001) assemblies. In the Fresenius assembly, the combination priming bolus without FastStart (setting C) was superior to FastStart without priming bolus (setting D) for T1 (P¼0.007) but not for T2. T1 and T2 did not differ significantly among the four settings A, B, C, and D in the Arcomed assembly.
Vertical displacement manoeuvres Zero flow and zero drug delivery times (T3, T4), retrograde aspiration (V1), and anterograde infusion volumes (V2) during vertical displacement all differed significantly among the seven assemblies (P<0.001) (Fig. 2; Supplementary Appendix SI). The Codan assembly had the shortest and the Fresenius assembly the longest zero-drug delivery times (T4). V1 ranged from 0.01 ml up to 0.0415 ml, whereas V2 varied from 0.0978 to 0.1648 ml.
e
e
e
e
e
e
4.83 (3.66e6.22) 806.65 (461.09e1009.12) 5.75 (4.52e7.63) 396.78** (302.55e440.28)
e
1.88 (1.42e4.34) 306.32 (185.21e405.45) 2.84 (2.33e3.72) 151.98 (136.43e273.12)
7.97 (3.73e48.11) 1131.45 (806.6e1302.88) 7.31 (5.44e9.55) 323.52* (195.14e466.22)
e e
T2 (s)
T1 (s) (þB/þFS) D
(eB/þFS) C
B
T2 (s)
T2 (s)
T1 (s)
e T1 (s) (þB/eFS)
T2 (s)
e
20.30 (3.66e27.21) 482.89 (465.64e582.19) 5.96 (2.95e10.37) 466.82 (200.65e541.29) 4.43 (3.18e8.06) 352.02 (108.39e420.48) 4.68 (3.06e8.39) 381.35 (142.05e534.19) T1 (s) (eB/eFS) A
Parameter
Assembly
e
BD BBraun Arcomed
BD Disk
Infusion line occlusion
Setting
Table 2 Results of start-up performance tested in seven syringe infusion pump assemblies. Start-up delay times T1 (time to first fluid delivery) and T2 (time to steady-state flow) with (þB) and without (eB) an initial fluid bolus after placing the 50 ml infusion syringe into the syringe pump and with (þFS) and without (eFS) activated FastStart mode of the syringe pump, if available and selectable. Values are median (inter-quartile range) in seconds (*P<0.05; **P<0.01; ***P<0.001).
Low flow performance of modern syringe pumps
The time (T5) until an occlusion pressure of 100 mm Hg was reached, and occlusion release boluses (V3) and the calculated compliance of each assembly differed significantly between the seven assemblies (P<0.001) (Fig. 3 and Supplementary Appendix SII). The Codan assembly with the lowest compliance showed the shortest occlusion pressure times and smallest release volumes, whereas the Fresenius assembly, which had with the highest compliance, demonstrated the longest occlusion pressure times and largest boluses. There were strong positive correlations between assembly compliance and zero-drug delivery time and between compliance and anterograde infusion bolus (V2) (r¼0.807, P<2.2e16 and r¼0.732, P¼6.093e13). Including a pressure disc in the BD plus had no effect on calculated assembly compliance.
Isolated syringe compliance Similar to the whole syringe pump assembly, the isolated syringe compliance differed significantly between the six brands (P<0.001). Most of the isolated syringe compliances corresponded to the whole syringe infusion pump assembly, except in the BD infusion syringe (Fig. 3 and Supplementary Appendix SIII).
Pharmacokinetic simulation The calculated model of epinephrine plasma concentrations (0.1 mg kg1 min epinephrine delivery rate; 1 ml h1 flow rate) during start-up and vertical displacement manoeuvres is presented in Figure 4. A start-up time (T2) of 108 s in the Codan assembly resulted in duration of 665 s until 95% of the targeted plasma concentration was reached (T6). With the Fresenius assembly, a T2 of 291 s led to a T6 of 898 s. Lowering the syringe pump by 50 cm resulted in a 39.3% decrease in plasma epinephrine concentration in the Codan assembly and a 63% decrease in the Fresenius assembly. Elevating the pump by 50 cm caused a sudden, temporary increase of up to 145.1% and 183.9%, respectively, of steady-state epinephrine plasma concentration. The zero-drug delivery time at 1 ml h1 flow
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Fig 2. Results of fluid delivery during vertical displacement manoeuvres (50 cm below/50 cm above zero level) at 1 ml h1 flow rate set. Measured zero flow times (T3), zero-drug delivery times (T4), retrograde aspiration volumes (V1), and anterograde infusion volumes (V2) after vertical pump displacement manoeuvres for each of the seven syringe infusion pump assemblies tested at four different set-ups. Boxplot with median (red line), inter-quartile range (blue box), the range of adjacent values (whiskers), and outliers (þ).
rate until plasma epinephrine concentration decreases by 25% was calculated to be 55 s.
Discussion This comprehensive in vitro study investigated the performance of seven modern syringe infusion pump assemblies during start-up, vertical displacement manoeuvres, and infusion line occlusion. We observed large differences between the tested assemblies and between different runs within the same assembly. Start-up delays for 50 ml infusion syringes at a set flow rate of 1 ml h1 with and without activated FastStart mode were considerable and in agreement with earlier published data.10,11 In all but the Arcomed assembly, delivery of an initial priming bolus (before starting the pump at regular flow rate) considerably improved start-up performance. This indicates that there are still mechanical and gear shortcomings. It may also explain the considerable variation in start-up times between individual runs within the same assembly and is also supported by the lacking correlation of compliance with startup behaviour. As an exception, the Arcomed assembly has, via
optimised design, shown improvement over an earlier version of the pump.10 All of the seven syringe infusion pump assemblies tested revealed a zero-drug delivery time >55 s, which leads to a decrease of more than 25% in the prior steady-state plasma drug concentration, thereby resulting in potentially significant haemodynamic disturbances.13 The finding that there was a strong positive correlation between calculated compliance and zero-drug delivery time and with the anterograde infusion bolus implies that the behaviour observed during vertical displacement is mainly caused by the compliance of the whole assembly. In addition, the plasma epinephrine concentration decreased by 39.3% even with a less compliant syringe (Codan assembly) compared with 63% with the more compliant infusion syringe (Fresenius assembly).7 Similarly, the plasma epinephrine concentration after an elevation was related to the compliance of the syringe infusion pump assembly. Besides flow interruption with a decrease in plasma drug concentration after lowering the infusion pump assembly, a further issue is the 20e40 ml of blood aspirated into a smallbore catheter lumen for 3e6 min, which raises the risk of intraluminal catheter thrombosis or even occlusion if not flushed out by other infusion fluids.
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Fig 3. Results of infusion line occlusion at 1 ml h1 flow rate set. Upper left: simple linear regression plots of times from steady-state flow until reaching occlusion pressures of 20, 40, 60, 80, and 100 mm Hg. Upper right: box plots of times from steady-state flow until occlusion pressures of 100 mm Hg were reached. Lower left: box plots of calculated compliances for each of the seven assemblies tested. Lower right: box plots of calculated compliances for each of the seven infusion syringes investigated. Box plots with median (red line), inter-quartile range (blue box), the range of adjacent values (whiskers), and outliers (þ).
The time to occlusion pressure of different levels varied considerably among the assemblies tested and can mainly be explained by the measured infusion assembly compliances, which is in agreement with earlier findings.7 Modern syringe infusion pumps feature occlusion pressure alarms that are either activated at a pre-set alarm level by an increase in driving pressure of typically 30 cm H2O, or can be set to a certain value above current driving pressure. However, in all pumps, the time of a pressure increase of 20 mm Hg measured at any occlusion pressure level exceeded 55 s zero-drug delivery times, leading to a clinically significant 25% decrease in plasma epinephrine concentration. The released occlusion volume might also cause harm, which would be most pronounced in the smallest patients. In the present study only stiff, low-compliant infusion lines were used in all assemblies. The infusion line compliance of stiff infusion lines has been studied and shown not to have a relevant impact on flow irregularities during vertical displacement and time duration to set off the occlusion alarm.3,8 Our results show that the isolated infusion syringe contributed about 25e60% to the whole assembly compliance, indicating that there are considerable
differences in compliance among the infusion pumps. Both significant differences among different brands of infusion syringes or syringe infusion pumps have been reported and discussed in the past, and found to relate to the design and construction of the equipment tested.7,9 The extensive differences among infusion syringes and syringe pumps should prompt industrial manufacturers to analyse and improve their equipment. Unfortunately, conventional testing of syringe pump performance does not allow the detection of these shortcomings. As a consequence, regulations related to syringe infusion pump testing should be adapted accordingly by official bodies, at least for low flow applications. In the past, on the basis of several scientific publications, some major design flaws in syringe infusion pumps were eliminated, the drive gear slack of the pumps was minimised, and FastStart options were added to newer syringe infusion pumps. However, this study reveals that the problems with start-up performance, flow irregularities and risks with vertical displacement of the assembly, and prolonged occlusion alarm time persist at low flow rates. From a technical standpoint, there have been no significant changes in syringe
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Fig 4. Measured flow rate and calculated epinephrine concentration during start-up and vertical displacement (50 cm below/50 cm above zero level) of the syringe infusion pump assembly set at 1 ml h1 flow rate corresponding to 0.1 mg kg1 min1 continuous epinephrine infusion in a neonate with a body weight of 3 kg. (a) Codan assembly; (b) Fresenius assembly; T2, time from starting the syringe infusion pump until reaching 95% steady-state flow; T4, zero-drug delivery time; T6, time from starting the syringe infusion pump until achieving 95% of the targeted plasma epinephrine concentration; V2, anterograde infusion volume.
infusion pump technology that might eliminate the problems identified, although syringe pump manufacturers were asked to improve their equipment.14,15 In clinical practice, it is crucial to raise awareness and to teach countermeasures to overcome these problems, such as the prevention of vertical syringe pump displacement and delivery of a priming bolus before starting the syringe infusion pump. Recently, a Food and Drug Administration (FDA) communication on syringe pump problems with flow
continuity at low infusion rates has addressed the serious clinical consequences.16 Among other things, the selection of smaller syringes is recommended to reduce the compliance of infusion.4,6,11 However, the use of smaller syringes, even of a 20 or 30 ml syringe, would impact clinical practice, as this would lead to more frequent changes of syringe with associated haemodynamically relevant interruptions of the infusion and increased risk for central venous catheter infections.17e19
Low flow performance of modern syringe pumps
Other approaches have been proposed in the literatures that address the compliance issue of syringe infusion pumps. The micro-volumetric pump reduces the syringe to a small, non-compliant 10-ml container leading to enhanced performance during start-up and vertical displacement.20 Another approach involving the use of two syringe pumps at different flow rates, whose respective outflows are joined at a vented manifold controlled by a computer-executed algorithm, has been proposed to achieve an accelerated start-up.21 However, clinical applicability remains moot. Another countermeasure is the use of an in-line filter, increasing driving pressure, which helps reduce the delays and flow irregularities described above at very low infusion rates.22 Finally, antisiphon valves have been tested to avoid retrograde fluid flow during the lowering of the syringe infusion pump assembly. Anti-siphon valves may prevent aspiration boluses after the lowering of the syringe pump, but they cause a considerable prolongation of zero-drug delivery times, because they need an additional opening pressure beyond the valve’s operating pressure. Moreover, with the reopening of the valve an infusion bolus is released, itself increasing the risk of flow irregularities.23 The in vitro experiment presented here has several limitations. The flow irregularities in a real patient also depend on fluctuations in central venous pressure, on other infusion pumps delivering drugs through the same catheter lumen, and on the viscosity of the infusate.24 These factors were not considered in our study. Furthermore, the pharmacokinetic response to an epinephrine infusion is subject to considerable inter-individual variabilities, which the numerical model does not account for, being obtained by approximating the data of 39 patients. When patient variability was taken into account, the deviations in plasma drug concentration observed far exceed the threshold of 25%, which is considered clinically significant; this, however, does not invalidate the general conclusion.13 Furthermore, the pharmacokinetics of the numerical model is governed mainly by the half-life time of the drug, which is comparable to the values found in the literature. In conclusion, this study revealed that problems with the performance of syringe infusion pump assemblies have remained almost unsolved and that they may have considerable impact on plasma drug concentrations when highly concentrated, short-acting cardiovascular drugs are administered at low flow rates. The considerable differences between infusion syringes and syringe pumps compliance from different manufacturers indicate that there is room for improvement. However, as the problems are mainly related to the functional principle of syringe infusion pumps affecting all tested assemblies, these problems will only partially be solved by incremental improvements in existing equipment.
Author’s contributions Conception and design: MBae, MBat, PKB, MW. Acquisition of data: MBae, MBat, PKB, MW. Analysis and interpretation of data: MBae, MBat, BG, MSD, MM, MW. Writing up of the first draft of the manuscript: MBae, MBat. Revising the manuscript: BG, PKB, MSD, MM. Drafting the final version of the manuscript: MW. All authors gave final approval of the version to be published, and agreed to be accountable for all aspects of the work, thereby ensuring that questions related to the accuracy or
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integrity of any part of the work are appropriately investigated and resolved.
Declaration of interest MBat and MM are the inventors of the flow-controlled syringe infusion pump. MW is co-inventor of the micro-volumetric infusion pump.
Funding Department of Anaesthesia, University Children’s Hospital, Zurich (research resources); Innosuisse support grant (18604.1 PFLS-LS to MBat).
Acknowledgements We thank the following local companies for providing the syringe pump assemblies to our institution without charge: Arcomed AG Medical Systems (Regensdorf, Switzerland), B. Braun Medical AG (Sempach, Switzerland), BD - CareFusion Switzerland (Rolle, Switzerland), CODAN Medical AG (Baar, Switzerland), Fresenius Kabi (Schweiz) AG (Oberdorf, Switzerland), and Theramed AG (Adligenswil, Switzerland).
Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.bja.2019.10.007.
References 1. Rooke GA, Bowdle TA. Syringe pumps for infusion of vasoactive drugs: mechanical idiosyncrasies and recommended operating procedures. Anesth Analg 1994; 78: 150e6 2. Lo€nnquist PA, Lofquist B. Design flaw can convert commercially available continuous syringe pumps to intermittent bolus injectors. Intensive Care Med 1997; 23: 998e1001 3. Weiss M, Baenziger O, Neff T, Fanconi S. Influence of infusion line compliance on drug delivery rate during acute line loop formation. Intensive Care Med 2000; 26: 776e9 4. Kim DW, Steward DJ. The effect of syringe size on the performance of an infusion pump. Paediatr Anaesth 1999; 9: 335e57 5. Kern H, Kuring A, Redlich U, et al. Downward movement of syringe pumps reduces syringe output. Br J Anaesth 2001; 86: 828e31 6. Weiss M, Hug MI, Neff T, Fischer J. Syringe size and flow rate affect drug delivery from syringe pumps. Can J Anaesth 2000; 47: 1031e5 7. Weiss M, Fischer J, Neff T, Baenziger O. The effects of syringe plunger design on drug delivery during vertical displacement of syringe pumps. Anaesthesia 2000; 55: 1094e8 8. Weiss M, Neff T, Gerber AC, Fischer J. Impact of infusion line compliance on syringe pump performance. Paediatr Anaesth 2000; 10: 595e9 9. Neff TA, Fischer JE, Schulz G, Baenziger O, Weiss M. Infusion pump performance with vertical displacement: effect of syringe pump and assembly type. Intensive Care Med 2001; 27: 287e91
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10. Neff T, Fischer J, Fehr S, Baenziger O, Weiss M. Start-up delays of infusion syringe pumps. Paediatr Anaesth 2001; 11: 561e5 11. Neff SB, Neff TA, Gerber S, Weiss M. Flow rate, syringe size and architecture are critical to start-up performance of syringe pumps. Eur J Anaesthesiol 2007; 24: 602e8 12. Oualha M, Urien S, Spreux-Varoquaux O, et al. Pharmacokinetics, hemodynamic and metabolic effects of epinephrine to prevent post-operative low cardiac output syndrome in children. Crit Care 2014; 18: R23 13. Snjider R, Egberts T, Lucas P, et al. Dosing errors in preterm neonates due to flow rate variability in multiinfusion syringe pump setups: an in vitro spectrophotometry study. Eur J Pharm Sci 2016; 93: 56e63 € nnqvist PA. How continuous are continuous drug in14. Lo fusions? Intensive Care Med 2000; 26: 660e1 15. Cook RI. Syringe pump assemblies and the natural history of clinical technology. Can J Anaesth 2000; 47: 929e35 16. U.S. Food and Drug Administration. Syringe pump problems with fluid flow continuity at low infusion rates can result in serious clinical consequences: FDA safety communication 2010. Available from: https://www.fdanews.com/ext/resources/ files/2016/08/08-25-16-pumpsafetynotice.pdf?1480880246. [Accessed 16 May 2019] 17. Achuff BJ, Achuff JC, Park HH, et al. Epinephrine syringe exchange events in a paediatric cardiovascular ICU: analysing the storm. Cardiol Young 2018; 28: 409e15
net T, et al. Benefits of smart pumps 18. Cour M, Hernu R, Be for automated changeovers of vasoactive drug infusion pumps: a quasi-experimental study. Br J Anaesth 2013; 111: 818e24 19. Mahieu LM, De Dooy JJ, Lenaerts AE, Ieven MM, De Muynck AO. Catheter manipulations and the risk of catheter-associated bloodstream infection in neonatal intensive care unit patients. J Hosp Infect 2001; 48: 20e6 20. Weiss M, Gerber S, Fu¨chslin RM, Neff TA. Accurate continuous drug delivery at low infusion rate with a novel micro-volumetric infusion pump (MVIP): pump design, evaluation and comparison to the current standard. Anaesthesia 2004; 59: 1133e7 21. Parker M, Lovich M, Tsao A, et al. Novel pump control technology accelerates drug delivery onset in a model of paediatric drug infusion. Anaesth Analg 2017; 124: 1129e34 22. Brotschi B, Grass B, Weiss M, Doell C, Bernet V. In-line filter included into the syringe infusion pump assembly reduces flow irregularities. Intensive Care Med 2012; 38: 518e22 23. Weiss M, Fischer J, Neff T, Schulz G, Baenziger O. Do antisiphon valves reduce flow irregularities during vertical displacement of infusion pump systems? Anaesth Intensive Care 2000; 28: 680e3 caudin B, Dewulf S, Lannoy D, et al. Impact of multi24. De access infusion devices on in vitro drug delivery during multi-infusion therapy. Anesth Analg 2009; 109: 1147e55 Handling editor: Tony Absalom
LABORATORY INVESTIGATION
Performance of modern syringe infusion pump assemblies at low infusion rates in the perioperative setting Martina Baeckert1,y, Martin Batliner2,y, Beate Grass3, Philipp K. Buehler1, Marianne Schmid Daners2, Mirko Meboldt2 and Markus Weiss1,* 1
Department of Anaesthesia, University Children’s Hospital Zurich, Zurich, Switzerland, 2Product Development Group
Zurich, ETH Zurich, Zurich, Switzerland and 3Department of Paediatric Intensive Care and Neonatology, University Children’s Hospital Zurich, Zurich, Switzerland *Corresponding author. E-mail: [email protected] y
These authors contributed equally to this article.
Abstract Background: Syringe infusion pumps are used for the precise continuous administration of intravenous drugs. Their compliance and mechanical deficiencies have been found to cause considerable start-up delays, flow irregularities during vertical displacement, as well extensive delays of occlusion alarms at low infusion rates. The aim of this study was to evaluate the performance of several modern syringe infusion pumps at low infusion rates and the impact on drug concentration. Methods: Seven currently marketed syringe infusion pump assemblies were assessed in an in vitro study during start-up, vertical displacement manoeuvres, and infusion line occlusion at a set flow rate of 1 ml h1. The measured data were used as input for a pharmacokinetic simulation modelling plasma concentration during a standard neonatal continuous epinephrine infusion. Results: The mean time from starting the infusion pump to steady-state flow varied from 89 to 1622 s. The zero-drug delivery time after lowering the pump ranged from 145 to 335 s. In all assemblies tested, occlusion alarm delays and measured flow irregularities during vertical displacement manoeuvres resulted in relevant deviations in plasma epinephrine concentration (>25%) as calculated by the pharmacokinetic simulation model. Conclusion: Problems with the performance of syringe infusion pump assemblies can have considerable impact on plasma drug concentration when highly concentrated short-acting cardiovascular drugs are administered at low flow rates. The problems, which affected all assemblies tested, are mainly related to the functional principle of syringe infusion pumps and will only partially be solved by incremental improvements of existing equipment. Keywords: continuous; infusion; infusion pump; low flow; paediatric anaesthesia; paediatric critical care; syringe
Editor’s key points When intravenous drugs are administered by a syringe driver infusion pump, performance accuracy depends on several factors. In small children, in whom low infusion rates are usually required, errors may result in significant differences in achieved plasma drug concentrations.
The authors studied the flow characteristics of several assemblies comprising commercially available syringe pumps, syringes, and administration sets at a set flow rate of 1 ml h1. At these flow rates, inaccuracies were noted on startup, after vertical displacement manoeuvres and on line occlusion.
Received: June 6, 2019; Accepted: 8 October 2019 © 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved. For Permissions, please email: [email protected]
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Syringe infusion pumps are used in critical care medicine and anaesthesia for the continuous intravenous administration of short-acting cardiovascular drugs. In the paediatric setting, highly concentrated drug solutions are administered at low infusion rates (1 ml h1) to prevent fluid overload, particularly in neonates and infants. Accordingly, precise and regular fluid delivery is essential to avoid haemodynamic disturbances. For almost 20 yr, the compliance and mechanical shortcomings of syringe infusion pump assemblies have been identified as causing considerable start-up delays, flow irregularities during vertical displacement, and delays in occlusion alarm times.1e11 However, these have so far only been investigated individually; a comprehensive assessment, including their impact on plasma drug concentration, is lacking. The aim of this study was to evaluate the performance of a large range of currently available modern syringe infusion pump assemblies during start-up, vertical displacement, and infusion line occlusion. Secondly, we aimed to investigate the effect of flow alterations of a standard neonatal epinephrine infusion on plasma drug concentration, using a numerical pharmacokinetic simulation model.
Methods In autumn of 2017, local distributors were asked to provide their currently marketed syringe infusion pump assemblies for use in paediatric critical care and anaesthesia. In total, seven different syringe infusion pump assemblies, including a 50 ml infusion syringe and a low-compliant, stiff 200 cm infusion line extension, from six different manufacturers were included (Table 1). One syringe infusion pump assembly was tested using an infusion line extension without (assembly BD) and with (assembly BD plus) a disc being inserted in the pressure transducer slot of the pump.
Experimental set-up 1 An in vitro set-up was used to evaluate start-up performance and flow characteristics during vertical pump displacement (Fig. 1a). The 50 ml syringe with corresponding infusion line extension filled with distilled water was connected to two serial flow sensors (SLS-1500 and SLI0430; Sensirion AG, Staefa, Switzerland). The output of the second sensor was connected to a fluid chamber filled with 13 cm of distilled water above the infusion syringe outlet level to simulate a central venous pressure of 10 mm Hg. No anti-siphon valves were used. Measured flow values (ml s1) from both sensors were simultaneously recorded on a personal computer 70 times per second using specific software provided by the manufacturer. Data obtained from the SLI-0430 flow sensor were used for flow analysis, and data from the SLS-1500, for measuring retrograde and anterograde infusion volumes.
Start-up experiments The 50 ml syringe was placed in the syringe pump and connected to the corresponding 200 cm infusion line. Thereafter, start-ups at 1 ml h1 were performed either with or without an initial priming bolus of 1 ml fluid from the syringe pump and with or without activating the FastStart mode of the syringe pump, if available, detachable, or both. FastStart mode has been developed and introduced to reduce drive gear slack of the syringe pump and gaps between the syringe barrel flanges and the pump housing. Its principle ranges from application of a fixed simple bolus to sophisticated interaction of plunger force and line pressure after starting the syringe infusion pump.10 The following parameters were measured. Time to first fluid delivery (T1) was defined as the time from activating the start button until the flow sensors registered a first continuous forward flow at 5% of steady-state fluid delivery.
Table 1 Infusion syringe pump assemblies included in the study. The tested assemblies included a syringe infusion pump, a 50 ml infusion syringe and a 200 cm non-compliant infusion line. Syringe pump
Infusion syringe
Infusion line
Assembly 1 (Arcomed)
Syramed mSP6000, Arcomed AG (Regensdorf, Switzerland)
Assembly 2 (BBraun)
Perfusor Space, B. Braun (Melsungen, Germany)
Assembly 3 (BD)
Alaris CC Plus Guardrails, CareFusion (Rolle, Switzerland)
Assembly 4 (BD Plus)
Alaris CC Plus Guardrails, CareFusion (Rolle, Switzerland)
Assembly 5 (Codan)
A616S InCare, Codan Argus AG (Baar, Switzerland)
Assembly 6 (Fresenius)
Agilia SP MC, Fresenius Kabi AG (Bad Homburg, Germany)
Assembly 7 (Theramed)
Terufusion Type SS TE-SS800, Terumo Europe N. V. (Leuven, Belgium)
Syramed 50 ml (60 ml), REF 8300026718, Henke-Sass, Wolf GmbH (Tuttlingen, Germany) Original Perfusor Syringe 50 ml, REF 8728852F-06, B. Braun (Melsungen, Germany) BD Plastipak 50 ml, REF 300865, Becton Dickinson and Company (Drogheda, Ireland) BD Plastipak 50 ml, REF 300865, Becton Dickinson and Company (Drogheda, Ireland) Codandsingle-use syringe; 50e60 ml LUER-LOCK, REF 62.8426 Codan Medical ApS (Rodby, Denmark) Injectomat Syringe 50 ml, REF 9000711, Fresenius Kabi AG (Bad Homburg, Germany) Terumo Syringe 50 ml, REF SSþ50L1, Terumo Europe N. V. (Leuven, Belgium)
Syramed Line, PE, 200 cm, REF APEF202, Fresenius Kabi AG (Bad Homburg, Germany) Original Perfusor Line, PE, 200 cm, REF 8723060, B. Braun (Melsungen, Germany) Extension Set, PE/PVC, 200cm, REF PB-G40720, Cair LGL (Lissieu, France) Extension Set with Pressure Disk, PE/PVC, 200 cm, REF G30302M, CareFusion (Rolle, Switzerland) Extension Set, 200 cm, REF 71.4002, Codan Medizinische € te GmbH & Co KG Gera (Lensahn, Germany) Syramed Line, PE, 200 cm, REF APEF202, Fresenius Kabi AG (Bad Homburg, Germany) Terex Extension Set, 200 cm, REF EXþ200TN1FL, RoweMed AG (Parchim, Germany)
Low flow performance of modern syringe pumps
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Fig 1. Schematic of experimental set-up: (a) in vitro set-up for start-up and vertical displacement manoeuvres, (b) in vitro set-up for infusion line occlusion and assembly compliance, and (c) for isolated syringe compliance. (1) Syringe infusion pump; (2) 50 ml infusion syringe; (3) 200 cm infusion line; (4) flow sensor SLS-1500; (5) flow sensor SLI-0430; (6) sampling glass; (7) PC; (8) three-way stopcock; (9) invasive blood pressure transducer; (10) anaesthesia monitor; (11) central venous catheter; (12) electronic balance; (13) infusion syringe holder; and (14) 5 ml injection syringe.
Time to steady-state fluid delivery (T2) was assessed as the time from activating the start button of the syringe pump until reaching 95% or, for the start-up bolus, 105% of steady-state fluid delivery.
subsequently elevated by 50 cm, whereupon the anterograde infusion volume (V2) delivered within 60 s was assessed.
Experimental set-up 2 Vertical syringe pump displacements After establishing steady-state flow at zero level, the syringe infusion pump assembly was lowered by 50 cm. The resulting retrograde aspiration volume (V1), the time from lowering the infusion pump until the first continuous forward movement of fluid (zero flow time; T3), and the time from lowering the infusion pump until the retrograde aspiration volume was reinfused (zero-drug delivery time; T4) were measured. Afterwards, the syringe infusion pump was placed back at zero level and, after steady-state flow had been re-established,
A second in vitro set-up was used to measure times until various pressure levels were reached with the distal infusion line occluded and the release bolus after re-opening the occlusion (Fig. 1b). Each of the seven syringe infusion pump assemblies were filled with 50 ml sterile water and connected by a stopcock to a central venous catheter (Seldiflex 4Fr - 11 cm; Prodimed, Le Plessis Boucard, France). A three-way stopcock with a blood pressure transducer (TruWave; Edwards Lifesciences, Irvine, CA, USA) was inserted between the infusion line and the catheter. The pressure transducer was connected to a vital sign monitor (S/5TM anaesthesia monitor; Datex-
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Ohmeda, Helsinki, Finland). After establishing steady-state conditions at 1 ml h1 flow rate, the three-way stopcock was set to occlude the syringe outflow. The times from steadystate flow until reaching a pressure of 20, 40, 60, 80, and 100 mm Hg (T5) were measured. At 100 mm Hg occlusion pressure, the three-way stopcock was re-opened. Assuming a specific density of 999.83 kg m3 for water at 22 C room temperature and 1 bar ambient pressure, the volume of fluid (V3) released through the catheter tip into the sampling glass was measured gravimetrically by using an electronic balance (sensitivity 0.0001 g; AT261 DeltaRange; Mettler Toledo, Schwerzenbach, Switzerland) and expressed in ml. The compliance of the syringe infusion pump assembly was calculated from the occlusion release bolus and occlusion pressure. Two identical syringe infusion pumps (A/B) were tested per assembly, and all experiments were performed with new infusion syringes and extension lines for each run. Measurements performed at a set flow rate of 1 ml h1 were repeated five times with both pumps (A/B) for all experiments and each assembly in randomised order.
used; this was translated into a one-compartment model, predicting the plasma epinephrine concentration as presented by Oualha and coworkers.12 The inputs to the simulation were measured flow raw data (no moving average), body weight, and drug concentration of the epinephrine infusion. The body weight was chosen to be 3 kg, and the chosen epinephrine concentration administered at a flow rate of 1 ml h1 corresponded to the continuous application of 0.1 mg kg1 min1. Output was the epinephrine plasma concentration. Data processing and simulation were carried out using a custom simulation model implemented through a numerical computing tool (MATLAB 2016a; The MathWorks Inc., Natick, MA, USA). Start-up time until reaching 95% of steady-state plasma epinephrine concentration (T6) and maximum decrease and increase of plasma epinephrine during vertical displacements were calculated for the two different syringe infusion pump assemblies. Furthermore, zero-drug delivery time until the plasma epinephrine concentration decreased by 25%, which is reported to cause haemodynamic disturbances, was calculated.13
Experimental set-up 3 For all assemblies studied (BD and BD plus have the same syringe, and thus were only evaluated once) the isolated infusion syringe compliance at 100 mm Hg occlusion pressure was measured by mounting the 50 ml infusion syringes into a selfmade syringe holder that prevented movement of plunger and syringe housing during pressure changes (Fig. 1c). The infusion syringes were pressurised to 100 mm Hg pressure by adding sterile water via a 5 ml syringe through a three-way stopcock. At 100 mm Hg the latter was opened to the balance system. The volume released (V4) through the catheter tip into the sampling glass was measured gravimetrically using an electronic balance to estimate infusion syringe compliance. Ten pieces of each infusion syringe brand were measured twice in randomised order (20 measurements per syringe brand).
Data analyses and calculations The high sampling rate of the flow sensors revealed the oscillations in the real-time flow signal. To determine the parameters from T1 to T4 accurately, the signal had to be further processed by using a trailing moving average filter with a window length of 10 s for all pumps except the Arcomed assembly. To account for the latter’s pronounced oscillations (forward movement every 56 s at 1 ml h1 flow rate), a 30 s window was necessary.
Statistical analyses The Wilcoxon rank sum test was used to compare start-up times T1 and T2 with and without an initial priming bolus, FastStart mode, or both, for each assembly, as selectable by the syringe pump. The non-parametric KruskaleWallis test was used to test the difference between the seven assemblies for T5 and V3 during occlusion pressure testing in each assembly. Furthermore, KruskaleWallis test was used to test for differences between the four settings in the Arcomed assembly for T3, T4, V1, and V2 during vertical displacement manoeuvres. Dunn’s test with Holm adjustment was used for pairwise comparisons. A linear mixed model was run to test independence of data for the two distinct pump models (A/B) used in each assembly and experiment. The Pearson correlation coefficient between measured parameters and calculated compliance was also computed. All analyses were performed with the R programming language (version 3.3.3; https://www. R-project.org/).
Results A total of 160 start-up runs, 70 vertical displacement manoeuvres, and 70 occlusion pressure time and pressure release tests were performed and included in the analyses. The null model indicated that most of the time the withinmodel variance (pumps A/B) was higher than the betweenmodel variance, which suggested independence of data.
Pharmacokinetic simulation To demonstrate the effect of continuous epinephrine administration on plasma concentration during start-up and vertical displacement manoeuvres, additional runs were conducted using the Codan and Fresenius assemblies (Table 1). Here, start-ups were performed after delivering a priming bolus of 1 ml, with FastStart activated if available, and at a flow rate of 1 ml h1. After >120 min, the syringe infusion pump assembly was physically lowered by 50 cm, then placed back at zero level and finally elevated by 50 cm. A simulation model based on the pharmacokinetic response of 39 children to an epinephrine infusion was
Start-up performance There were different patterns in start-up behaviour among the six syringe pump brands investigated (Table 2). The FastStart could be manually deactivated in only one syringe pump brand (Arcomed), in another brand the FastStart was automatically deactivated if a priming bolus was delivered (Fresenius), and in all other tested assemblies the FastStart was either unchangeably activated or not available. Overall, median start-up times (T1) ranged from 1.9 to 522.7 s, and median times to steady-state flow (T2) ranged from 88.1 to 1622.4 s (Table 2).
522.69 (5.19e692.44) 1622.35 (1355.78e2011.65) 2.06* (1.74e2.66) 88.07*** (64.89e112.22)
e
e
86.52 (8.09e456.27) 962.98** (611.12e1467.77) 3.62 (3.2e4.73) 106.07*** (77.69e163.24)
e
e
8.98 (5.2e12.48) 385.56 (324.26e660.04) 4.24** (3.41e5.22) 670.84 (308.46e715.16) e e
e e
e e
e
e
Theramed Fresenius Codan
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5
With FastStart activated, the priming bolus significantly improved T1 in the Theramed (P¼0.019) and Codan (P¼0.004) assemblies but not in others. Similarly, T2 was significantly reduced by a bolus in both BD assemblies (P<0.01 and P<0.05) and in the Theramed (P<0.001) and in the Codan (P<0.001) assemblies. In the Fresenius assembly, the combination priming bolus without FastStart (setting C) was superior to FastStart without priming bolus (setting D) for T1 (P¼0.007) but not for T2. T1 and T2 did not differ significantly among the four settings A, B, C, and D in the Arcomed assembly.
Vertical displacement manoeuvres Zero flow and zero drug delivery times (T3, T4), retrograde aspiration (V1), and anterograde infusion volumes (V2) during vertical displacement all differed significantly among the seven assemblies (P<0.001) (Fig. 2; Supplementary Appendix SI). The Codan assembly had the shortest and the Fresenius assembly the longest zero-drug delivery times (T4). V1 ranged from 0.01 ml up to 0.0415 ml, whereas V2 varied from 0.0978 to 0.1648 ml.
e
e
e
e
e
e
4.83 (3.66e6.22) 806.65 (461.09e1009.12) 5.75 (4.52e7.63) 396.78** (302.55e440.28)
e
1.88 (1.42e4.34) 306.32 (185.21e405.45) 2.84 (2.33e3.72) 151.98 (136.43e273.12)
7.97 (3.73e48.11) 1131.45 (806.6e1302.88) 7.31 (5.44e9.55) 323.52* (195.14e466.22)
e e
T2 (s)
T1 (s) (þB/þFS) D
(eB/þFS) C
B
T2 (s)
T2 (s)
T1 (s)
e T1 (s) (þB/eFS)
T2 (s)
e
20.30 (3.66e27.21) 482.89 (465.64e582.19) 5.96 (2.95e10.37) 466.82 (200.65e541.29) 4.43 (3.18e8.06) 352.02 (108.39e420.48) 4.68 (3.06e8.39) 381.35 (142.05e534.19) T1 (s) (eB/eFS) A
Parameter
Assembly
e
BD BBraun Arcomed
BD Disk
Infusion line occlusion
Setting
Table 2 Results of start-up performance tested in seven syringe infusion pump assemblies. Start-up delay times T1 (time to first fluid delivery) and T2 (time to steady-state flow) with (þB) and without (eB) an initial fluid bolus after placing the 50 ml infusion syringe into the syringe pump and with (þFS) and without (eFS) activated FastStart mode of the syringe pump, if available and selectable. Values are median (inter-quartile range) in seconds (*P<0.05; **P<0.01; ***P<0.001).
Low flow performance of modern syringe pumps
The time (T5) until an occlusion pressure of 100 mm Hg was reached, and occlusion release boluses (V3) and the calculated compliance of each assembly differed significantly between the seven assemblies (P<0.001) (Fig. 3 and Supplementary Appendix SII). The Codan assembly with the lowest compliance showed the shortest occlusion pressure times and smallest release volumes, whereas the Fresenius assembly, which had with the highest compliance, demonstrated the longest occlusion pressure times and largest boluses. There were strong positive correlations between assembly compliance and zero-drug delivery time and between compliance and anterograde infusion bolus (V2) (r¼0.807, P<2.2e16 and r¼0.732, P¼6.093e13). Including a pressure disc in the BD plus had no effect on calculated assembly compliance.
Isolated syringe compliance Similar to the whole syringe pump assembly, the isolated syringe compliance differed significantly between the six brands (P<0.001). Most of the isolated syringe compliances corresponded to the whole syringe infusion pump assembly, except in the BD infusion syringe (Fig. 3 and Supplementary Appendix SIII).
Pharmacokinetic simulation The calculated model of epinephrine plasma concentrations (0.1 mg kg1 min epinephrine delivery rate; 1 ml h1 flow rate) during start-up and vertical displacement manoeuvres is presented in Figure 4. A start-up time (T2) of 108 s in the Codan assembly resulted in duration of 665 s until 95% of the targeted plasma concentration was reached (T6). With the Fresenius assembly, a T2 of 291 s led to a T6 of 898 s. Lowering the syringe pump by 50 cm resulted in a 39.3% decrease in plasma epinephrine concentration in the Codan assembly and a 63% decrease in the Fresenius assembly. Elevating the pump by 50 cm caused a sudden, temporary increase of up to 145.1% and 183.9%, respectively, of steady-state epinephrine plasma concentration. The zero-drug delivery time at 1 ml h1 flow
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Fig 2. Results of fluid delivery during vertical displacement manoeuvres (50 cm below/50 cm above zero level) at 1 ml h1 flow rate set. Measured zero flow times (T3), zero-drug delivery times (T4), retrograde aspiration volumes (V1), and anterograde infusion volumes (V2) after vertical pump displacement manoeuvres for each of the seven syringe infusion pump assemblies tested at four different set-ups. Boxplot with median (red line), inter-quartile range (blue box), the range of adjacent values (whiskers), and outliers (þ).
rate until plasma epinephrine concentration decreases by 25% was calculated to be 55 s.
Discussion This comprehensive in vitro study investigated the performance of seven modern syringe infusion pump assemblies during start-up, vertical displacement manoeuvres, and infusion line occlusion. We observed large differences between the tested assemblies and between different runs within the same assembly. Start-up delays for 50 ml infusion syringes at a set flow rate of 1 ml h1 with and without activated FastStart mode were considerable and in agreement with earlier published data.10,11 In all but the Arcomed assembly, delivery of an initial priming bolus (before starting the pump at regular flow rate) considerably improved start-up performance. This indicates that there are still mechanical and gear shortcomings. It may also explain the considerable variation in start-up times between individual runs within the same assembly and is also supported by the lacking correlation of compliance with startup behaviour. As an exception, the Arcomed assembly has, via
optimised design, shown improvement over an earlier version of the pump.10 All of the seven syringe infusion pump assemblies tested revealed a zero-drug delivery time >55 s, which leads to a decrease of more than 25% in the prior steady-state plasma drug concentration, thereby resulting in potentially significant haemodynamic disturbances.13 The finding that there was a strong positive correlation between calculated compliance and zero-drug delivery time and with the anterograde infusion bolus implies that the behaviour observed during vertical displacement is mainly caused by the compliance of the whole assembly. In addition, the plasma epinephrine concentration decreased by 39.3% even with a less compliant syringe (Codan assembly) compared with 63% with the more compliant infusion syringe (Fresenius assembly).7 Similarly, the plasma epinephrine concentration after an elevation was related to the compliance of the syringe infusion pump assembly. Besides flow interruption with a decrease in plasma drug concentration after lowering the infusion pump assembly, a further issue is the 20e40 ml of blood aspirated into a smallbore catheter lumen for 3e6 min, which raises the risk of intraluminal catheter thrombosis or even occlusion if not flushed out by other infusion fluids.
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Fig 3. Results of infusion line occlusion at 1 ml h1 flow rate set. Upper left: simple linear regression plots of times from steady-state flow until reaching occlusion pressures of 20, 40, 60, 80, and 100 mm Hg. Upper right: box plots of times from steady-state flow until occlusion pressures of 100 mm Hg were reached. Lower left: box plots of calculated compliances for each of the seven assemblies tested. Lower right: box plots of calculated compliances for each of the seven infusion syringes investigated. Box plots with median (red line), inter-quartile range (blue box), the range of adjacent values (whiskers), and outliers (þ).
The time to occlusion pressure of different levels varied considerably among the assemblies tested and can mainly be explained by the measured infusion assembly compliances, which is in agreement with earlier findings.7 Modern syringe infusion pumps feature occlusion pressure alarms that are either activated at a pre-set alarm level by an increase in driving pressure of typically 30 cm H2O, or can be set to a certain value above current driving pressure. However, in all pumps, the time of a pressure increase of 20 mm Hg measured at any occlusion pressure level exceeded 55 s zero-drug delivery times, leading to a clinically significant 25% decrease in plasma epinephrine concentration. The released occlusion volume might also cause harm, which would be most pronounced in the smallest patients. In the present study only stiff, low-compliant infusion lines were used in all assemblies. The infusion line compliance of stiff infusion lines has been studied and shown not to have a relevant impact on flow irregularities during vertical displacement and time duration to set off the occlusion alarm.3,8 Our results show that the isolated infusion syringe contributed about 25e60% to the whole assembly compliance, indicating that there are considerable
differences in compliance among the infusion pumps. Both significant differences among different brands of infusion syringes or syringe infusion pumps have been reported and discussed in the past, and found to relate to the design and construction of the equipment tested.7,9 The extensive differences among infusion syringes and syringe pumps should prompt industrial manufacturers to analyse and improve their equipment. Unfortunately, conventional testing of syringe pump performance does not allow the detection of these shortcomings. As a consequence, regulations related to syringe infusion pump testing should be adapted accordingly by official bodies, at least for low flow applications. In the past, on the basis of several scientific publications, some major design flaws in syringe infusion pumps were eliminated, the drive gear slack of the pumps was minimised, and FastStart options were added to newer syringe infusion pumps. However, this study reveals that the problems with start-up performance, flow irregularities and risks with vertical displacement of the assembly, and prolonged occlusion alarm time persist at low flow rates. From a technical standpoint, there have been no significant changes in syringe
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Fig 4. Measured flow rate and calculated epinephrine concentration during start-up and vertical displacement (50 cm below/50 cm above zero level) of the syringe infusion pump assembly set at 1 ml h1 flow rate corresponding to 0.1 mg kg1 min1 continuous epinephrine infusion in a neonate with a body weight of 3 kg. (a) Codan assembly; (b) Fresenius assembly; T2, time from starting the syringe infusion pump until reaching 95% steady-state flow; T4, zero-drug delivery time; T6, time from starting the syringe infusion pump until achieving 95% of the targeted plasma epinephrine concentration; V2, anterograde infusion volume.
infusion pump technology that might eliminate the problems identified, although syringe pump manufacturers were asked to improve their equipment.14,15 In clinical practice, it is crucial to raise awareness and to teach countermeasures to overcome these problems, such as the prevention of vertical syringe pump displacement and delivery of a priming bolus before starting the syringe infusion pump. Recently, a Food and Drug Administration (FDA) communication on syringe pump problems with flow
continuity at low infusion rates has addressed the serious clinical consequences.16 Among other things, the selection of smaller syringes is recommended to reduce the compliance of infusion.4,6,11 However, the use of smaller syringes, even of a 20 or 30 ml syringe, would impact clinical practice, as this would lead to more frequent changes of syringe with associated haemodynamically relevant interruptions of the infusion and increased risk for central venous catheter infections.17e19
Low flow performance of modern syringe pumps
Other approaches have been proposed in the literatures that address the compliance issue of syringe infusion pumps. The micro-volumetric pump reduces the syringe to a small, non-compliant 10-ml container leading to enhanced performance during start-up and vertical displacement.20 Another approach involving the use of two syringe pumps at different flow rates, whose respective outflows are joined at a vented manifold controlled by a computer-executed algorithm, has been proposed to achieve an accelerated start-up.21 However, clinical applicability remains moot. Another countermeasure is the use of an in-line filter, increasing driving pressure, which helps reduce the delays and flow irregularities described above at very low infusion rates.22 Finally, antisiphon valves have been tested to avoid retrograde fluid flow during the lowering of the syringe infusion pump assembly. Anti-siphon valves may prevent aspiration boluses after the lowering of the syringe pump, but they cause a considerable prolongation of zero-drug delivery times, because they need an additional opening pressure beyond the valve’s operating pressure. Moreover, with the reopening of the valve an infusion bolus is released, itself increasing the risk of flow irregularities.23 The in vitro experiment presented here has several limitations. The flow irregularities in a real patient also depend on fluctuations in central venous pressure, on other infusion pumps delivering drugs through the same catheter lumen, and on the viscosity of the infusate.24 These factors were not considered in our study. Furthermore, the pharmacokinetic response to an epinephrine infusion is subject to considerable inter-individual variabilities, which the numerical model does not account for, being obtained by approximating the data of 39 patients. When patient variability was taken into account, the deviations in plasma drug concentration observed far exceed the threshold of 25%, which is considered clinically significant; this, however, does not invalidate the general conclusion.13 Furthermore, the pharmacokinetics of the numerical model is governed mainly by the half-life time of the drug, which is comparable to the values found in the literature. In conclusion, this study revealed that problems with the performance of syringe infusion pump assemblies have remained almost unsolved and that they may have considerable impact on plasma drug concentrations when highly concentrated, short-acting cardiovascular drugs are administered at low flow rates. The considerable differences between infusion syringes and syringe pumps compliance from different manufacturers indicate that there is room for improvement. However, as the problems are mainly related to the functional principle of syringe infusion pumps affecting all tested assemblies, these problems will only partially be solved by incremental improvements in existing equipment.
Author’s contributions Conception and design: MBae, MBat, PKB, MW. Acquisition of data: MBae, MBat, PKB, MW. Analysis and interpretation of data: MBae, MBat, BG, MSD, MM, MW. Writing up of the first draft of the manuscript: MBae, MBat. Revising the manuscript: BG, PKB, MSD, MM. Drafting the final version of the manuscript: MW. All authors gave final approval of the version to be published, and agreed to be accountable for all aspects of the work, thereby ensuring that questions related to the accuracy or
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integrity of any part of the work are appropriately investigated and resolved.
Declaration of interest MBat and MM are the inventors of the flow-controlled syringe infusion pump. MW is co-inventor of the micro-volumetric infusion pump.
Funding Department of Anaesthesia, University Children’s Hospital, Zurich (research resources); Innosuisse support grant (18604.1 PFLS-LS to MBat).
Acknowledgements We thank the following local companies for providing the syringe pump assemblies to our institution without charge: Arcomed AG Medical Systems (Regensdorf, Switzerland), B. Braun Medical AG (Sempach, Switzerland), BD - CareFusion Switzerland (Rolle, Switzerland), CODAN Medical AG (Baar, Switzerland), Fresenius Kabi (Schweiz) AG (Oberdorf, Switzerland), and Theramed AG (Adligenswil, Switzerland).
Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.bja.2019.10.007.
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