Effects of infusion tubing line lengths and syringe sizes on infusion system compliance: an experimental study using a syringe-type infusion pump at low flow rate

Ideally, the flow delivery of an infusion system is proportional only to the rate of mechanical actuation of the syringe pump plunger. However, in the real world, overall infusion system compliance may be affected by components such as an extension of tubing lines, or different sizes of syringes. With higher compliance, there may be greater chances of flow irregularity. In this experimental study, we investigated the effects of lengths of infusion lines and syringe sizes on the compliance of syringe pumps with low flow rate (2 ml h−1). In the first experiment, infusion system compliance was measured in various settings by occlusion release. As the infusion tubing length and size of the syringe increased, the time to reach each pressure was delayed and the infusion system compliance increased. The contributions to system compliance from syringes were significantly greater compared to those of extended infusion lines. In the occlusion alarm experiment, the occlusion alarm could be delayed by 69.76 ± 3.98 min for the 50-ml syringe with a 560 cm infusion line set-up. In conclusion, the compliance of a syringe pump system increases as the loaded syringe size, or the length of the infusion tubing increases. The occlusion alarm may be much delayed and not useful in highly compliant systems with respect to the potential occlusion of the infusion system, so more attention is required when using a highly compliant infusion system.


Introduction
Continuous intravenous drug infusion is one of the principal methods for treating patients.Therefore, it is essential that an accurate dose of drug is delivered to the patient through the infusion system as desired by the attending clinician [1][2][3][4][5].Compliance, defined as the change in internal volume divided by the change in applied pressure of the system, plays an important role in the accuracy of drug infusion system.In an ideal state, the infusion system can be assumed as a noncompliant rigid system.In a syringe-type infusion pump, rotation of the motor pushes the plunger constantly and delivers the drug at a desired fixed rate.In the real world, when the syringe plunger is pushed by the pump system, the internal volume of the infusion system slightly expands, delaying and decreasing the initial outward flow.In a system with higher compliance, the desired flow is reached at a slower pace, which makes it more difficult to deliver the correct dose of the drug at initiation [6][7][8].Likewise, after pushing the stop button on the syringe pump, the plunger movement can stop immediately, but expandable volume determined by compliance can be released and maintains the fluid delivery for a period of time until zero delivery is obtained.Detection of any occlusion of the system can also be extremely delayed [9,10].
Recent studies have focused on the effects of external factors on the flow rate of low-flow infusion systems.Vertical displacement and vibration conditions with various types of syringe pumps have been explored [11][12][13][14].However, even excluding the effects of external factors in a stable environment, the performance of infusion systems, such as flow rate variability, start-up delay, and zero drug delivery time, could be affected by the internal factors components, like syringe sizes or wall thickness, the material of the plunger head, the length of the extension tubing line, and the viscosity of a drug [15][16][17][18][19][20][21].In some clinical scenarios such as treating a patient infected with a fatal and highly infectious virus, to minimize unnecessary contact and reduce the chance of infection, maintaining a physical distance is necessary along with wearing personal protection equipment to protect the caregivers from infection [22].An infusion system can be installed in such case outside the patient's room using a longer extension line so that the empty syringe can be easily replaced.Another option is to keep the infusion system near the patient using a larger syringe to reduce the number of syringe replacements.Compliance will increase in both cases even though it remains difficult to anticipate the exact compliance especially with a low flow rate.The proper length of the tubing line and size of the syringe remain in question.
In this in vitro experimental study, we aimed to investigate the effect of various lengths of infusion line and syringe sizes on the compliance and performance of the infusion system using a syringe-type infusion pump with a low flow rate.

Study design
This is an in vitro experimental study observing the effect of various lengths of infusion line and syringe sizes on the compliance and performance of the infusion system.The requirement for ethical approval was waived by the Institutional Research Ethics Committee due to the in vitro experimental nature of this study.The experimental design was based on the intravenous drug infusion doses at low flow rate settings.The infusion system for the experiment was composed of a syringe pump (Injectomat MC Agilia, Fresenius Kabi) loaded with a saline-filled syringe (Cong Ty Tnhh mtv Shincahng vina, Vietnam) and an infusion tubing line (polyvinyl chloride extension tubes, JMS Hankook Medical, Republic of Korea).To confirm the accuracy of the experiment, the steady state flow rate of the syringe pump at 2 ml h −1 was pre-checked with an infusion analyzer (IDA-4 plus, Fluke Biomedical), which is used to measure the actual flow rate delivered by the infusion pump within 2% of error range.The syringe pump and infusion tubing line were placed at the same height without kinking or coiling to prevent any influence of gravity and the loop effect.To measure the applied pressure, a pressure transducer (Tru-Wave; Edwards Lifesciences, Irvine, CA, USA) was assembled between the infusion tubing line and a 7-Fr central line catheter (3-lm Arrow Guard Blue, Teleflex Medical) using a three-way connector (Sungwon Medical, Republic of Korea).The tip of the central line catheter was dipped in a half-filled well on an analytical balance (FX-200i; A&D Company) (Fig. 1) [23].Visible air bubbles were removed by tapping and flushing.In this experimental system, infusion tubing lines and syringes were changeable components that affected the compliance.Various sizes of syringes (10-, 30-, or 50-ml sized) and multiple infusion lines (length for each setting: 140, 280, 420, or 560 cm) were prepared for the experiment.The error range for flow regularity was 2% for the pump on the syringe.The error ranges for the length, diameter, and thickness of the syringe were 0.3% to 5% for the infusion tubing line according to the manufacturer's manual.Infusion flow was fixed at 2 ml h −1 .Each set of experiments were repeated five times in an experimental laboratory at 22 °C room temperature.

100 mmHg experiment
Each experiment started after the flow reached a steady state to exclude the effect of start-up delay.The internal pressure at the stopcock was same as the pressure on the monitor since the space was filled with homogeneous fluid.To initiate the experiment, the three-way stopcock was rotated and the infusion system was occluded.Time was manually recorded with a stopwatch for every increment of 20 mmHg to a pressure of 100 mmHg.When the pressure reached 100 mmHg, the three-way stopcock was rotated to release occlusion, and the volume accumulated in the infusion system was measured with an electronic balance.

Occlusion alarm experiment
The occlusion pressure alarm is set to 900 mmHg by default factory setting, and the occlusion alarm turns on at 50 mmHg below the occlusion setting.The experiment was conducted in a similar manner to the 100 mmHg experiment, except that the final target pressure was changed from 100 to 850 mmHg at which the occlusion alarm sounds.The experiment was also started after reaching the steady flow state to avoid start-up delay.Then, the three-way stopcock valve was rotated and the infusion system was occluded to initiate the experiment.When the pressure reached 850 mmHg and the occlusion alarm sounded, the three-way stopcock was rotated back to release occlusion.Finally, the time to the occlusion pressure alarm and the accumulated fluid volume during system occlusion were measured for each syringe size and infusion tubing line length.

Statistical analysis
The mean and standard deviation were used for descriptive analysis.The normality of variables was evaluated using the Shapiro-Wilk test.Continuous variables were analyzed using one-way analysis of variance (ANOVA) followed by a post hoc two-sample t-test with Bonferroni correction for pairwise comparisons.A p-value less than 0.05 (or 0.016 for pairwise comparison with different syringe sizes or 0.008 for pairwise comparison with different line lengths) was considered statistically significant.Each experiment consisted of a total of 12 combinations of three sizes of syringes and four lengths of infusion lines.Each set of experiments was repeated 5 times.Therefore, a total of 60 runs for 12 combinations of compliance experiments and 60 measurements of occlusion experiments were performed and included in the analyses.Statistical analyses were performed with R version 4.0.2(R Foundation for Statistical Computing, Vienna, Austria).Graphs were presented using Graphpad Prism 8 (GraphPad Software Inc., CA, USA).

Compliance of the infusion system
The changes of the internal compliance for the infusion system according to the length of the infusion line and the loaded syringe size are presented in Fig. 2. The overall compliance of the system, which was directly calculated from the accumulated flushed volume after occlusion release when the system pressure reached 100 mmHg, exhibited a consistent tendency to increase as the loaded syringe size increased and the length of the infusion line increased (Table 1).There was a statistically significant difference in system compliance even after post hoc analysis among the syringe sizes and line lengths (p-value < 0.001).In addition, use of a long infusion line of 560 cm significantly increased the system compliance compared to the setting with the infusion line of 140 cm or 280 cm (p-value < 0.001).In the infusion system loaded with 10-ml, 30-ml, and 50-ml syringes, the increase in system compliance per 140 cm increase in infusion tubing length was 0.04 μl mmHg −1 , 0.07 μl mmHg −1 , and 0.10 μl mmHg −1 , respectively.The difference in overall system compliance was 0.46 μl mmHg −1 between the 10-and 30-ml syringe-loaded systems, and the compliance difference between 30-and 50-ml syringe loaded systems averaged 0.375 μl mmHg −1 .Both factors (increase of infusion tubing length and loaded syringe size) affected system compliance, but as shown in Fig. 2, the syringe size contributed more to the increase in infusion system compliance compared to the length of the infusion line; compliance increased by 371% on average when syringe size changes from 10 to 50 ml and 43% on average when tube length changes from 140 to 520 cm.

Occlusion alarm experiment
Consistent with the compliance experiment, the occlusion alarm experiment demonstrated that both the time to activation of the occlusion alarm and the accumulated bolus dose at the release of the occlusion increased as the length of the infusion line and the syringe size both increased (Fig. 3).Activation of the occlusion alarm was delayed from 5.20 ± 0.05 min with the 10-ml syringe and 140 cm infusion line to 69.76 ± 3.98 min with the 50-ml syringe and 560 cm infusion line setup, and the flushed fluid volume at the release of the occlusion increased in weight from 201.40 ± 2.15 mg to 2101.20 ± 110.48 mg.There were statistically significant differences according to infusion line length or syringe size (Table 2).

Discussion
In this experimental study, we evaluated the effects of the length of the infusion tubing line and the size of the loaded syringe on the overall compliance of the syringetype infusion pump system.We observed that increases in the loaded syringe size and the length of the infusion line both increased the overall compliance of the infusion system.When the loaded syringe size was constant, the system compliance increased slightly as the line length increased by 140 cm.However, the increase in syringe size had a greater effect on system compliance change compared to the increase in infusion tubing line length.
In the first experiment, as the infusion tubing length increased, the time to reach the target pressure was delayed and the infusion system compliance increased.However, the effect of tubing line length extension on the increase of the overall infusion system compliance was smaller than anticipated.Four times increase in infusion tubing line increased the overall infusion system compliance by approximately one-third from baseline when the loaded syringe size was constant: from 0.17 to 0.28 μl mmHg −1 (with a 10-ml loaded syringe), from 0.60 to 0.80 μl mmHg −1 (30-ml syringe), and from 0.94 to 1.24 μl mmHg −1 (50-ml syringe) (Table 1).However, since small-diameter tubing was used in the experiments, the effect of tubing line extension might have been enlarged when using different tubing lines with higher compliance or larger diameter.
The result of our study is consistent with previous studies on the relation between syringe size and system compliance [7,16,19].Neff and Schmidt demonstrated lower flow  [16].In the present study, because we directly measured the values of system compliance, it is possible to intuitively recognize the change in compliance according to the increase in syringe size or the length of the infusion tubing line.In addition, we simulated the possible line occlusion situation and observed the effect of the increased compliance on the occlusion alarm.With a 30-ml syringe, which is three times larger than a 10-ml syringe, compliance increased more than three times, and with a 50-ml syringe, it increased more than four times.Numerous previous studies have reported the increased risk of flow irregularities or the occurrence of inadvertent bolus doses when using syringe pumps loaded with large-sized syringes [13,14].In the syringe-type infusion pump system, the use of a smaller syringe would be ideal to minimize system compliance and flow irregularity.However, in real-world clinical practice, the use of small-volume syringes presents issues that inevitably accompany frequent syringe exchanges causing discontinuation of drugs with subsequent start-up delays, increasing the workload of the caregivers as well as the risks of contamination or human errors [24][25][26].For  this reason, syringe-type infusion pumps are frequently used with large-sized syringes.Large compliance by large-sized syringes and long infusion lines is associated with start-up delays and late recognition of any unexpected occlusion, as seen in our results [6,7,9,16,27].Therefore, comprehensive understanding and caution about possible inadvertent drug delivery situations are highly recommended for caregivers when using syringe-type infusion pumps loaded with a large-sized syringe.
The second experiment revealed the quantification of the accumulated fluid bolus to the patient after the accidental release of system occlusion.If the infusion light is on without any warning alarm activation, an increasing pressure gauge displayed on the corner of the screen should not be of concern.In clinical practice, clinicians are notified first by an occlusion alarm and respond accordingly to resolve the issue.If the pressure is not released and increases, the occlusion alarm turns on, and the syringe pump stops to prevent accidental bolus injection.A previous simulation study found many anesthesiologists in practice might cause problems by decompressing the occluded infusion system inappropriately and emphasized the training and improvement of syringe pumps [28].Even with education and simulation to prevent accidents, human error cannot be completely eliminated.Although the anti-bolus system affects up to a 0.2 ml bolus after occlusion release, a mechanical improvement is required for abrupt pressure release or sustained pressure increase below the occlusion pressure.
It is well-known that flow irregularity increases at a low flow rate [19,29,30].In all experiments in this study, the flow rate of the infusion system was fixed at 2 ml•h −1 , which is an acceptable range in clinical settings.Highly potent vasoactive drugs are often started or maintained with a low flow rate.The infusion of norepinephrine or epinephrine at a concentration of 40 μg ml −1 and rate of 0.02 μg kg −1 min −1 for a 60-kg adult is converted to a flow rate of 1.8 ml h −1 .Infusion of remifentanil at a concentration of 50 μg ml −1 at a rate of 0.03 μg −1 kg −1 min for a 60-kg adult is at a flow rate of 2.16 ml h −1 .A diluted drug can be a solution to a high-compliance system by increasing the absolute flow rate and lowering fluid viscosity, especially for patients requiring meticulous management.
Previously, many studies have investigated the effects of external factors on the performance of infusion pumps with the main focus on the effect of syringe size among internal components.The present study has the strengths of actual quantification of increased compliance of the infusion system according to the length of the infusion line, which was considered a natural concept.However, when using infusion tubing lines with a small lumen diameter, extending the length does not appear to significantly increase the overall system compliance compared to an increase in syringe volume capacity.With respect to the potential occlusion of the infusion system, the occlusion alarm might not be useful in highly compliant systems, and special caution should be taken to ensure that the accumulated bolus is not flushed into the patient.
This study has several limitations.First, single types of syringe pumps, syringes, and infusion tubing lines were used for the experiments.However, other syringe pumps might exhibit a similar phenomenon.Although the syringe type did not previously affect the time to occlusion alarm activation [27], the syringe and infusion line can make a slight difference depending on the material, thickness, and diameter, which directly affect the resistance and compliance of the system.The anti-reflux valves can contribute to limiting the changes of compliance by increasing the resistance of the system.The density and viscosity of different drugs also have an influence on compliance [15,21].Second, stopcock rotation and time measurement could not be automated and executed manually.All the experiments were performed by a single investigator to reduce measurement bias.Third, in the second experiment, the weight increased rapidly with 30 ml and 50 ml syringes.Thirty seconds might not be enough for the accumulated volume to flow out, and the measured weight might have been underestimated.
In conclusion, the compliance of the syringe-type infusion pump system is increased when the loaded syringe size or the length of the infusion tubing line increases.Ideally, using small syringes and short lines will minimize compliance and reduce flow rate variability.In real-world clinical practice, when treating patients using syringe-type infusion pumps loaded with large syringes with long infusion lines, clinicians should consider the increased compliance of the infusion system and subsequent start-up delays, delayed drug dose controls, and extremely delayed alarms for any occlusion within the system.

Fig. 1
Fig. 1 Experimental setup for measuring compliance

Fig. 2
Fig. 2 Result of infusion line occlusion at a 2 ml h −1 flow rate set.a Box plots of times from steady-state flow until occlusion pressures of 100 mmHg.b Box plots of calculated compliances for each of the 12

Fig. 3
Fig. 3 Result of infusion line occlusion at a 2 ml h −1 flow rate set.a Box plots of times from steady-state flow until the occlusion alarm was activated at pressure of 850 mmHg.b Box plots of measured

Table 1
Released weight (mg) at 100 mmHg and calculated compliance (μl mmHg−1 )for each size of syringe and length of line Values are mean ± standard deviation and p-values calculated by one-way ANOVA of released weight and compliance of line length of 140, 280, 420, and 560 cm are all < 0.001 *Statistical significance (p < 0.016) compared to released weight or compliance with 10-ml syringe and same line length by two-sample t test with Bonferroni correction † Statistical significance (p < 0.016) compared to released weight or compliance with 30-ml syringe and same line length by two-sample t test with Bonferroni correction ‡ Statistical significance (p < 0.008) compared to released weight or compliance with 140 cm line and same size of syringe by two-sample t test with Bonferroni correction § Significance (p < 0.008) compared to released weight or compliance with 280 cm line and same size of syringe by two-sample t test with Bonferroni correction ∥ Significance (p < 0.008) compared to released weight or compliance with 420 cm line and same size of syringe by two-sample t test with Bon-

Table 2
Time to alarm (minutes) and released weight after the pre-occlusion alarm (mg) for each size of syringe and length of line Values are mean ± standard deviation and p-values calculated by one-way ANOVA of released weight and compliance of line length of 140, 280, 420, and 560 cm are all < 0.001 Weight 1000.00 ± 18.25 * 1026.80 ± 16.22 * 1071.80 ± 24.36 * 1098.80 ± 42.48 * ‡ § < 0.001 50 ml Time 62.71 ± 2.73 * † 61.37 ± 2.73 * † 66.56 ± 1.34 * † § 69.76 ± 3.98 * † § 0.003 Weight 2062.60 ± 39.60 * † 1922.20 ± 56.80 * † 2073.40 ± 29.39 * † § 2101.20 ± 110.48 * † 0.007 *Statistical significance (p < 0.016) compared to pre-occlusion time or measured weight with 10-ml syringe and same line length by two-sample t test with Bonferroni correction † Statistical significance (p < 0.016) compared pre-occlusion time or measured weight with 30-ml syringe and same line length by two-sample t test with Bonferroni correction ‡ Statistical significance (p < 0.008) compared to pre-occlusion time or measured weight with 140 cm line and same size of syringe by two-sample t test with Bonferroni correction § Significance (p < 0.008) compared to pre-occlusion time or measured weight with 280 cm line and same size of syringe by two-sample t test with Bonferroni correction