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Syringe Pump Performance Maintained with IV Filter Use During Low Flow Rate Delivery for Pediatric Patients

Chau, Destiny F. MD; Vasilopoulos, Terrie PhD; Schoepf, Miriam MD; Zhang, Christina; Fahy, Brenda G. MD, MCCM

doi: 10.1213/ANE.0000000000001273
Pediatric Anesthesiology: Original Laboratory Research Report

BACKGROUND: Complex surgical and critically ill pediatric patients rely on syringe infusion pumps for precise delivery of IV medications. Low flow rates and in-line IV filter use may affect drug delivery. To determine the effects of an in-line filter to remove air and/or contaminants on syringe pump performance at low flow rates, we compared the measured rates with the programmed flow rates with and without in-line IV filters.

METHODS: Standardized IV infusion assemblies with and without IV filters (filter and control groups) attached to a 10-mL syringe were primed and then loaded onto a syringe pump and connected to a 16-gauge, 16-cm single-lumen catheter. The catheter was suspended in a normal saline fluid column to simulate the back pressure from central venous circulation. The delivered infusate was measured by gravimetric methods at predetermined time intervals, and flow rate was calculated. Experimental trials for initial programmed rates of 1.0, 0.8, 0.6, and 0.4 mL/h were performed in control and filter groups. For each trial, the flow rate was changed to double the initial flow rate and was then returned to the initial flow rate to analyze pump performance for titration of rates often required during medication administration. These conditions (initial rate, doubling of initial rate, and return to initial rate) were analyzed separately for steady-state flow rate and time to steady state, whereas their average was used for percent deviation analysis. Differences between control and filter groups were assessed using Student t tests with adjustment for multiplicity (using n = 3 replications per group).

RESULTS: Mean time from 0 to initial flow (startup delay) was <1 minute in both groups with no statistical difference between groups (P = 1.0). The average time to reach steady-state flow after infusion startup or rate changes was not statistically different between the groups (range, 0.8–5.5 minutes), for any flow rate or part of the trial (initial rate, doubling of initial rate, and return to initial rate), although the study was underpowered to detect small time differences. Overall, the mean steady-state flow rate for each trial was below the programmed flow rate with negative mean percent deviations for each trial. In the 1.0-mL/h initial rate trial, the steady-state flow rate attained was lower in the filter than the control group for the initial rate (P = 0.04) and doubling of initial rate (P = 0.04) with a trend during the return to initial rate (P = 0.06), although this same effect was not observed when doubling the initial rate trials of 0.8 or 0.6 mL/h or any other rate trials compared with the control group.

CONCLUSIONS: With low flow rates used in complex surgical and pediatric critically ill patients, the addition of IV filters did not confer statistically significant changes in startup delay, flow variability, or time to reach steady-state flow of medications administered by syringe infusion pumps. The overall flow rate was lower than programmed flow rate with or without a filter.

Published ahead of print April 12, 2016

From the *Division of Pediatric Anesthesiology, Department of Pediatrics, The Children’s Hospital of the King’s Daughters, Eastern Virginia Medical School, Norfolk, Virginia; Department of Anesthesiology, University of Florida, College of Medicine, Gainesville, Florida; and Department of Engineering, University of Kentucky, Lexington, Kentucky.

Accepted for publication February 11, 2016.

Published ahead of print April 12, 2016

Funding: None.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Brenda G. Fahy, MD, MCCM, Department Anesthesiology, University of Florida, College of Medicine, 1600 SW Archer Rd, PO Box 100254, Gainesville, FL 32608. Address e-mail to bfahy@anest.ufl.edu.

The care of complex surgical and critically ill pediatric patients often involves continuous IV therapy of medications. Patients with extremely low body weight require very low infusion flow rates for medication delivery to minimize nonnutritive fluid administration because cumulative volumes of all IV therapies can quickly exceed the patient’s total daily fluid limit. With these low flow rates, flow rate accuracy is vital to ensure the precise delivery of medications at the programmed rates, thereby maintaining the desired pharmacologic effects. Syringe infusion pumps are used in the pediatric critically ill patient population because they provide more accurate delivery of medications compared with other available devices.a All connectors, tubing, and parts of a complete fluid pathway to the patient comprise an IV infusion system,b and each part may impact the overall performance of the system. In-line filters are frequently connected to IV infusion systems in critically ill pediatric patients to filter air and particle contaminants; their impact on drug delivery has yet to be determined.

We sought to determine the impact of adding an in-line IV filter on syringe infusion pump performance with low flow rates compared with control groups without filters. Our primary hypothesis was that an in-line IV filter would increase the amount of time from zero flow to initial flow (startup delay) and the amount of time to reach steady-state flow. Our secondary hypothesis was that a filter would reduce flow variability, defined as the variance around the mean steady-state flow rate.

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METHODS

The University of Kentucky institutional review board approved this project as an exempt study. The gravimetric method used was adapted from the study by Schmidt et al.1

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Syringe Infusion Pump Delivery System Design

Figure 1

Figure 1

Medfusion 3500 infusion pumps (Medex, Duluth, GA) were connected to an IV infusion system (Figure 1A). This system involved a 10-mL syringe (model no. 309604; Becton Dickinson, Franklin Lakes, NJ) filled with 10 mL of normal saline (NS; Becton Dickinson) attached to a 3-way stopcock (model no. MX4311L; Smiths Medical, Dublin, OH). The stopcock was connected to 2 pieces of 3-ft, low-volume (1 mL), noncompliant tubing (model no. MX663; Smiths Medical). An additional NS-filled, 10-mL syringe was connected to the third port of the stopcock and was used only to remove air from the IV system. This IV infusion system was then attached to a 16-gauge, 16-cm single-lumen catheter (model no. AK04306; Arrow International, Reading, PA). A NS-filled glass cylinder received the infusate and was located inside a high-precision scale (Mettler-Toledo, Columbus, OH). For the experimental trials with a filter, a 0.2-μm in-line IV filter (model no. ELD96NT; Pall, Port Washington, NY) with a filter-housing volume of 2 mL was placed between the 3-way stopcock and the low-volume tubing without modifying the original design (Figure 1B).

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Preparatory Protocol for Experimental Trials

Four different syringe pumps with current maintenance and inspection were tested with 1.0-mL/h preparatory trials. Because the results obtained from a testing trial of each pump were comparable, 2 of these pumps were randomly chosen for the experiment.

The high-precision scale was calibrated daily using certified calibrated weights immediately before each experimental session. The IV infusion system was carefully primed to eliminate air bubbles before starting each experimental trial. For the experimental trials using filters, the manufacturer’s recommendations were followed (ie, to “hold filter in upright position with the printed arrow pointing up. Prime filter. Verify that no air bubbles are present on patient [ribbed] side of filter.”). The syringe filled with 10 mL NS was then loaded onto the syringe infusion pump. The distal end of the catheter was submerged into the cylinder to a final depth of 11 cm for simulating a central pressure of 8 mmHg (1 cm water ~0.74 mmHg), and the syringe pump was positioned. Following the manufacturer’s instructions, the pump was used to prime the system (“pump priming”) at the manufacturer’s preset rate of 300 mL/h while observing for fluid movement at the distal end of the single-lumen catheter. A 2-mL priming volume was used for each experimental trial. At this point, the scale was tared and the infusion, timer, and data collection started simultaneously. With the exception of the single-lumen catheter, all parts of the IV infusion system were replaced for every experimental trial. All items were kept at room temperature, and all experimental trials were conducted in a laboratory setting.

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Assessment of Appropriate Priming Protocol

Preliminary data demonstrated that a combination of manual priming followed by the 2-mL pump priming was sufficient to minimize the startup delay component attributable to the mechanical features of the syringe pumps used in this experiment (Appendix 1).

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Experimental Design

Figure 2

Figure 2

Two groups were compared: the filter group with in-line IV filters and the control group without in-line IV filters; Figure 2 illustrates the experimental design. Experimental trials for initial programmed flow rates of 1.0, 0.8, 0.6, and 0.4 mL/h were performed in control and filter groups. For each trial, the flow rate was changed to double the initial flow rate and was then returned to the initial flow rate. All flow rates exceeded the manufacturer’s recommended minimum syringe pump flow rate of 0.33 mL/h using a 10-mL syringe. Each new rate had to achieve steady-state flow before the pump was programmed for the next flow rate. There were 3 replications in both the control and filter groups of each trial.

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Data Collection and Calculations

The syringe pump delivered the infusate to the cylinder, which was measured by the additional weight and then converted to a volume measurement (Appendix 1). For the 2 minutes after the initiation of the infusion and each rate change, the weight was measured every 30 seconds and subsequently measured every 2 minutes until steady-state flow was achieved. The flow rates delivered by the syringe pump were calculated by dividing the measured volume by the time and were graphically plotted against time.

For each experimental trial, the steady-state flow rate, time to reach steady-state flow, and percent deviation of the steady-state flow rates from the programmed flow rates were calculated and reported as mean ± SD. Data for the multiple repetitions with each flow rate were combined. The steady-state flow rate was defined as the mean of the measured flow rates obtained from the start of the steady state flow (as defined in Table 1) until the flow rate changed or the trial was completed. The steady-state flow rate was also used to calculate the percent deviation from the programmed flow rate (Table 1). For all analyses, the sample size was n = 3 replications per group (control vs filter). Each replication included the 3 flow rate conditions (initial rate, doubling of initial rate, and return to initial rate) described earlier. These flow rate conditions were analyzed separately to compare differences between controls and filter groups for steady-state flow rate and time to reach steady-state flow. Separate t tests (12 total) compared differences between control and filter groups during the initial flow rate period, doubling of initial rate period, and return to initial rate period within each programmed flow rate (1.0, 0.8, 0.6, and 0.4 mL/h). For percent deviation of the steady-state flow rates, percent deviation was calculated for each of the 3 flow rate conditions (initial rate, doubling of initial rate, and return to initial rate) and then averaged within replication; thus, there was only 1 estimate of percent deviation for each replication for each group (control vs filter). There was a single measurement of startup delay for each replication.

Table 1

Table 1

Power analysis determined, with 3 repetitions at each flow rate (n = 3) to compare the control and filter groups, that this study could detect a 0.06-mL/h mean difference in flow rate (assuming SD = 0.02) at 80% power with α = 0.05. With the same sample size, this study could detect a mean difference of 3.3 minutes between the filter and control groups for time to startup flow (assuming SD = 1.3) at 80% power with α = 0.05.

Differences between the filter and control groups were assessed using Student t test. F-ratio tests were used to test differences in variances (ie, the square of the SD) between groups. Data were analyzed using JMP Pro 11.0.0 (SAS Institute 2013, Cary, NC). P < 0.05 was considered statistically significant with the false discovery rate method used to adjust individual P values for multiple comparisons.

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RESULTS

Figure 3

Figure 3

Figure 3 depicts all data points that were recorded during the experimental protocol at the initial flow rates of 1.0 (Figure 3A), 0.8 (Figure 3B), 0.6 (Figure 3C), and 0.4 mL/h (Figure 3D).

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Startup Delay

Table 2

Table 2

Across all experimental trials, the startup delay at the initiation of the infusion was <1 minute in the filter and control groups (Table 2), which was not statistically different between the groups. Backflow is defined as fluid traveling in the reverse direction from programmed flow, from the tip of the catheter toward the syringe pump, and is expressed as a negative flow rate. Backflow occurred (Figure A1 in Appendix 1) during startup delay and did so more frequently in experimental trials with lower programmed flow rates, including all the flow rate trials at 0.4 mL/h (Figure 3D) and in one 0.6-mL/h trial (Figure 3C). Backflow was not observed in any of the trials at flow rates of 0.8 or 1.0 mL/h.

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Steady-State Flow Rates

Table 3

Table 3

Figure 4

Figure 4

The steady-state flow rates were normally distributed; thus, t tests were used to analyze steady-state flow rate data. The time intervals for steady-state flow rates ranged from 4 to 18 minutes. Overall, the steady-state flow rate for each trial in both groups was below the pump programmed flow rate. Figure 4 depicts the mean percent deviation from the programmed flow. This deviation was below 0 for each programmed flow rate (maximum deviation = −17.3% ± 5.8%), indicating that all flow rates were lower than the corresponding programmed flow rate. Table 3 depicts the mean steady-state flow rates for each trial. For the highest initial flow rate (1.0 mL/h), the steady-state flow rate attained was lower in the filter group than the control group for the initial rate (P = 0.04) and doubling of initial rate (P = 0.04) with a trend during the return to initial rate (P = 0.06). This effect was not observed when doubling the initial rate trials of 0.8 or 0.6 mL/h compared with the control group. There were no statistically significant differences in the steady-state flow rate between either group for any of the other flow rates (0.4, 0.6, or 0.8 mL/h), although the width for the 95% confidence intervals for these differences ranged from 0.08 to 0.73.

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Flow Rate Variability

When the variance (the square of the SD) for the steady-state flow rate was compared between the filter and control groups, the only difference in rate variability (Table 1) was observed for the doubling of the flow rate to 1.2 mL/h (after initial flow rate of 0.6 mL/h) for that rate trial. This difference was not observed in any other trial (Table 3).

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Time to Reach Steady-State Flow

Table 4

Table 4

Student t tests were used to analyze these data. The average time to reach steady-state flow from start of the infusion ranged from 1.3 to 3.8 minutes (Table 4) and did not differ statistically between the control and filter groups. In addition, the average time to reach steady-state flow after a flow rate change ranged from 0.8 to 5.5 minutes and also did not differ between the control and filter groups. The 95% confidence intervals for these differences were wide between both groups (see “Study Limitations”).

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DISCUSSION

This study found that an in-line IV filter did not statistically significantly increase the amount of time from zero flow to initial flow (startup delay) and did not statistically significantly increase the amount of time to reach steady-state flow. Also, in-line IV filters did not have an effect on flow variability.

Our study revealed that, even with adherence to the syringe pump manufacturer’s recommendations, the steady-state flow rates for all experimental trials were lower than the syringe pump programmed flow rates (Table 3; Figure 4). Only for the initial flow rate of 1.0 mL/h were the steady-state flow rates lower in the filter group compared with the controls with statistical significance only present with the initial flow rate and doubling of initial flow rate and not maintained with the return to initial rate (initial rate, P = 0.04; doubling of initial rate, P = 0.04; and return to initial rate, P = 0.06). This same effect was not observed at the initial rate trials of 0.8 or 0.6 mL/h when doubling to rates >1.0 mL/h compared with the control groups. Also, there were no differences in the experimental trials with initial flow rates of 0.4, 0.6, and 0.8 mL/h. Therefore, the aforementioned observed effect may not be a sustained finding with further investigation.

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Startup Delay

Our results demonstrate that in-line IV filters did not affect startup delay under our study conditions with a mean startup delay of <1 minute across all trials. The preparatory trials (Appendix 1) determined that 2 mL of fluid delivered immediately before starting any experimental trials minimized startup delay because of mechanical factors of the syringe pump. All experimental trials were performed immediately after this 2 mL of fluid delivery from the syringe pump. Bartels et al.2 tested the same syringe pump as our study (Medfusion 3500) and illustrated the importance of immediately starting the syringe pump infusion after pump priming; their study revealed that a longer time interval between pump priming and the subsequent start of the infusion created a longer startup delay. The backflow observed during startup delay was also noted by Schmidt et al.1 In that study, the authors described transient decreases in weight measurements using gravimetric methods when a 50-mL syringe was used with a syringe infusion pump.

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Time to Reach Steady-State Flow

In our study, the use of in-line IV filters did not significantly affect the time to reach steady-state flow with our time measurements ranging from 1.3 to 3.8 minutes, although the confidence limits for differences between filter and control groups were wide. After a rate change, the time to reach steady-state flow ranged from 0.8 to 5.5 minutes at all flow rates. Neff et al.3 found that infusate delivery was significantly influenced by the syringe size and the programmed flow rate; lower pump programmed flow rates and larger syringe sizes used for delivery from the syringe pump significantly prolonged the time to reach steady-state flow. In another study, the programmed flow rate of 1.0 mL/h was not achieved before 60 minutes when a 50-mL syringe connected to the syringe pump was used for delivery.1

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Steady-State Flow Rates Compared with Pump Programmed Flow Rates

Delivered steady-state flow rates were lower compared with programmed flow rates whether a filter was present or not. Although syringe infusion pumps represent the most accurate device for delivery at low flow rates, pump performance may be compromised4,5 when operational limits are approached (eg, with very low flow rates). Some of these operational limitations involve the pumps’ components and can lead to startup delays and a longer time to reach steady-state flow.1,3,6–10

To evaluate the effect of filters on syringe pump performance, Jonckers et al.11 compared the effect of in-line IV filters (0.2-μm size) with controls without a filter on the in-line pressures. When in-line pressures exceed a preset limit, this would cause the syringe pump to alert the user to a possible occluded syringe pump delivery system. A filter added to the system was associated with higher in-line pressures11 that Jonckers’ group hypothesized was because of increased resistance from the clogging of filter pores. Under our study conditions, steady-state flow rates were maintained after the addition of a filter, although at the highest flow rate of 1.0 mL/h, the steady-state flow rate attained was lower in the filter than the control group for the initial rate (P = 0.04) and doubling of initial rate (P = 0.04) with a trend during the return to initial rate (P = 0.06). Because this effect was not observed when doubling the initial rate trials of 0.8 or 0.6 mL/h compared with the control group, it brings into question the validity of these findings.

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Flow Rate Variability

Flow rate variability was similar in the filter and control groups in all conditions except for the doubling of the flow rate to 1.2 mL/h (after initial flow rate of 0.6 mL/h), which showed decreased variability (Table 3). These results were not sustained across the entire trial and raise questions about their reliability.

Transient and random flow rate alterations were observed during some of the trials (Figure 3, A and C). Each measurement was graphically displayed in real time after input into the database, allowing the study investigators to search for contributing factors present during the experimental trials. No factors were noted that could explain the rate alterations seen (eg, sudden changes in laboratory environment). Further investigation would be required to examine other internal or external factors that might influence the syringe infusion pump system delivery profile. These yet-to-be-determined factors may be present in patient care areas that use syringe infusion pumps.

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Clinical Impact of IV In-Line Filters

Filters may lead to decreased complication rates, lengths of stay, and organ dysfunction in pediatric intensive care unit patients12,13 and may significantly reduce overall complication rates in sick newborns.14 A 2015 Cochrane analysis involving 704 preterm infants and neonates15 revealed a nonsignificant reduction in individual complications (eg, sepsis) and may have been underpowered to detect low incidence complications. The 2015 Cochrane analysis15 concluded that there was “insufficient evidence to recommend the use of IV in-line filters to prevent mortality and morbidity in neonates.”

The American Society for Parenteral and Enteral Nutrition, the British Pharmaceutical Nutrition Group Working Party, and the U.S. Food and Drug Administration recommend IV filter use for parenteral nutrition to avoid the potential hazards of precipitation, particulate matter, air, and micro-organisms.16,17 The 0.2-μm size filter is recommended for nonlipid-containing admixtures, whereas the 1.2-μm size filter is recommended for lipid-containing solutions.

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Study Limitations

In our study, the following factors were controlled to minimize confounding variables: (1) a 10-mL syringe was used for all experimental trials to minimize effects related to syringe size differences; (2) the IV infusion system was standardized; (3) new IV infusion system parts and filters were used for each experimental trial with the exception of the single-lumen central line; (4) assembly and priming methods of the IV infusion system, and all experimental techniques, were standardized; (5) the syringe pump was positioned at the same height as the distal tip of the single-lumen catheter; and (6) environmental conditions were consistently maintained (eg, evaporation was negligible). Limitations of our study include analyzing only 1 syringe infusion pump brand and 1 size (0.2 μm) filter. In addition, this study may have been underpowered to detect smaller differences in time to reach steady state.

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Syringe Pump Infusion System Performance

Strategies to optimize pump performance have been described.7 Improving recognition of the limitations, safety issues, and other factors that impact syringe pump performances are a key strategy in the U.S. Food and Drug Administration’s Infusion Pump Improvement Initiative.c Syringe infusion pumps and in-line IV filters are 2 parts of the continuous IV drug delivery system for complex surgical and critically ill pediatric patients. Infusion system dynamics are complex with the potential for greater clinical impact in these very ill and low-body-weight pediatric patients. For instance, the very low body weight of the patient may result in limited IV access and restricted total daily fluid. Lovich et al.18–25 have extensively investigated drug delivery kinetics and the dynamics of continuous infusion therapy. Relevant factors influencing continuous drug delivery include the specific architecture of the connectors, the manifold design for multiple infusions, the selection of the infusion connecting port, the dead volume of the system, the presence of a carrier fluid, alterations in the infusate and carrier flow rates, and coinfusion interactions.18–25 Health care providers should be educated regarding syringe pump devices and limitations within their own patient care areas to enable the best clinical decisions for delivery of medications to complex surgical and critically ill pediatric patients.

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CONCLUSIONS

The results of this study demonstrate that IV filters do not have statistically significant effects on syringe pump performance in the delivery of infusate at the low flow rates that are commonly used in the pediatric intensive care unit or in the operating room for a complex pediatric surgical patient as it relates to startup delay, time to steady-state flow, and flow rate variability. The overall flow rate was lower than the programmed flow rate with or without a filter.

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APPENDIX 1

PREPARATORY TRIALS

Methods

Before full implementation of the experimental trial protocol involving the control and the filter groups, a series of separate preparatory trials were performed to establish the steps required to assure optimal syringe pump performance under reproducible conditions. These preparatory trials were designed to minimize the startup delay component attributable to the mechanical properties of the syringe pump (eg, engaging of the gears in the mechanical drive of the specific syringe pumps) used in this study. Filters were not used during any of these preparatory trials. Startup delay was defined as the time after initiation of the infusion from zero flow to initial fluid flow at the distal tip of the catheter (see the graphical representation in Figure A1). By using a flow rate of 1.0 mL/h, 6 preparatory trials were performed. Three of these experimental trials, “trials without pump priming,” involved manually priming the IV infusion system with NS and the syringe pump only used for infusion delivery at 1.0 mL/h per preparatory trial protocol. In the other 3 experimental trials, “trials with pump priming,” the IV infusion system was manually primed with NS followed by the additional step of “pump priming” before starting the infusion delivery at 1.0 mL/h. Pump priming followed the manufacturer’s instructions of using the syringe pump at a preset rate of 300 mL/h while observing for fluid movement at the distal end of the single-lumen catheter. A pump priming volume of 2 mL was used for each experimental trial. For all 6 experimental trials, the infusion was started at a programmed flow rate of 1.0 mL/h until steady-state flow was reached.

Figure A1

Figure A1

Weight measurements were obtained at the start of the 1.0-mL/h infusion flow rate and then every 2 minutes thereafter. For each time interval, the increase in the measured weight was converted to volume by multiplying by 1 g/mL (the density of NS at 22°C is 1.0046 g/mL, which was rounded to 1 g/mL). The flow rate was then calculated by dividing the volume by the time for each interval. These flow rates were graphed against the time elapsed in real time.

Data were collected every 2 minutes with a graph generated in real time that plotted the delivered flow rate of fluid per unit time. Steady-state flow was defined as being achieved when 4 consecutive graphical data points 2 minutes apart stabilized around a flow rate value with at least 1 data point above and 1 below this value. The first of these 4 data points was used to identify the start of the steady-state flow (Figure A1).

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RESULTS

We examined differences between preparatory experimental trials comparing trials “without pump priming” and trials “with pump priming” (Figure A2). Startup delay was significantly greater in the trials “without pump priming” (4.7 ± 1.2 minutes) compared with the trials “with pump priming” (0 ± 0 minute; P = 0.02). The preparatory trials “with pump priming” did not have any startup delay (0 ± 0 min), whereas every trial “without pump priming” had a startup delay with concomitant backflow (mean backflow = −0.11 g/mL ± 0.05).

Figure A2

Figure A2

The mean time to steady-state flow was lower in the group “with pump priming” (3.3 ± 1.2 minutes), achieving steady-state flow within 5 minutes after the start of the infusion. In contrast, the trials “without pump priming” had longer mean times to steady-state flow (12.7 ± 3.1 minutes; P = 0.02), requiring up to 15 minutes to achieve steady-state flow.

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DISCLOSURES

Name: Destiny F. Chau, MD.

Contribution: This author helped design the study, conduct the study, and write the manuscript.

Name: Terrie Vasilopoulos, PhD.

Contribution: This author helped statistical analysis, comparison of the data, and write the manuscript.

Name: Miriam Schoepf, MD.

Contribution: This author helped to analyze the data and write the manuscript.

Name: Christina Zhang.

Contribution: This author helped conduct the study and write the manuscript.

Name: Brenda G. Fahy, MD, MCCM.

Contribution: This author helped design the study, analyze the data, and write the manuscript.

This manuscript was handled by: James A. DiNardo, MD.

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FOOTNOTES

a The Medicines and Healthcare products Regulatory Agency. Infusion systems. Available at: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/403420/Infusion_systems.pdf. Accessed October 6, 2015.
Cited Here...

b U.S. Department of Health and Human Services, Food and Drug Administration. Infusion Pumps Total Product Life Cycle-Guidance for Industry and FDA Staff. Available at: http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM209337.pdf. Accessed October 6, 2015.
Cited Here...

c U.S. Department of Health and Human Services, Food and Drug Administration. Infusion Pump Improvement Initiative. Available at: http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/GeneralHospitalDevicesandSupplies/InfusionPumps/ucm202501.htm. Accessed October 6, 2015.
Cited Here...

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        21. Ma H, Lovich MA, Peterfreund RA. Quantitative analysis of continuous intravenous infusions in pediatric anesthesia: safety implications of dead volume, flow rates, and fluid delivery. Paediatr Anaesth 2011;21:78–86.
        22. Moss DR, Bartels K, Peterfreund GL, Lovich MA, Sims NM, Peterfreund RA. An in vitro analysis of central venous drug delivery by continuous infusion: the effect of manifold design and port selection. Anesth Analg 2009;109:1524–9.
        23. Lovich MA, Kinnealley ME, Sims NM, Peterfreund RA. The delivery of drugs to patients by continuous intravenous infusion: modeling predicts potential dose fluctuations depending on flow rates and infusion system dead volume. Anesth Analg 2006;102:1147–53.
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