Pediatric patients of all ages commonly require infusions of sedative, analgesic, vasoactive, antidysrhythmic, or inotropic drugs via central venous catheters (CVCs) in the neonatal intensive care unit (NICU)/pediatric intensive care unit or in the operating room. Compared with adults, the smaller body weight of infants and neonates often limits the total combined infusion rates of concurrent medications, fluids, and IV alimentation to very small volumes. Thus for a 3-kg infant in the NICU, the total hourly maintenance fluid delivery might be approximately 12 mL/h. Patient-specific considerations such as congenital heart disease, renal dysfunction, or elevated intracranial pressure may require a more restrictive fluid management strategy.
Currently available pediatric CVCs typically provide only one or two lumens. Sometimes only one lumen is available for the simultaneous administration of multiple drugs, necessitating the use of a carrier fluid that maintains patency of the lumen and facilitates changes in drug dosing. Especially in critical care settings, it is essential for drug delivery by continuous infusion to be both highly predictable and rapidly titratable. For example, the administration of concentrated dopamine via syringe pumps at low flow rates has been associated with clinically significant arterial blood pressure fluctuations in neonates.1 Such fluctuations in response to vasopressors were attributed to significant delays in fluid delivery by syringe pumps secondary to free play between the syringe plunger and the propulsive part of the pump at the initiation of an infusion. In addition, syringe size, device design, and drug flow rate impact the onset of an infusion.2,3 Drug delivery changes have been observed with lowering the infusion line or changing the height of the infusion pump.4 These findings suggest that multiple factors may influence the delivery of drugs by continuous IV infusion in a complex, potentially unpredictable fashion.
Previous work focusing on CVCs commonly used in the adult clinical environment demonstrated that drug delivery kinetics depend on both carrier fluid flow rate and the dead volume of the conduit system (the volume from the point of drug entry into the fluid path in the tubing set through to the tip of the intravascular catheter).5,6 The specific implications for drug delivery kinetics of the carrier flow rate, the total fluid flow rate, and the infusion system characteristics commonly encountered in the pediatric setting have not been studied.
In this study, we evaluated drug delivery through a commonly used pediatric CVC at flow rates representative of those encountered in pediatric intensive care unit or NICU settings. The main goal was to determine how the typical pediatric flow rates combine with the dead volume of a standard pediatric catheter to influence both the onset and offset delivery profile of drugs administered by continuous infusion. We compared conditions mimicking new infusions and the resumption of a stopped infusion at two different total flow rates. In addition, we tested for a contribution of the start-up characteristics of the infusion pump system to the overall profile of model drug delivery in this system.
We evaluated a pediatric 8-cm, 4F double-lumen catheter (#AK-15402, Arrow, Reading, PA), which is a commonly used device in both the pediatric and neonatal patient populations. Two 60-mL syringes (#309653, Becton-Dickinson, Franklin Lakes, NJ) were connected to pressure tubing (AMS-464, Churchill Medical Systems, Horsham, PA) and loaded into a dual-channel syringe pump (Harvard Clinical 2 pump, #003366, Harvard Clinical Technology, South Natick, MA). One syringe delivered 0.9% normal saline (NS) as the carrier fluid, whereas the other syringe delivered methylene blue (MB, 0.1 mg/mL), (American Reagent, Shirley, NY) as the model drug at a rate of 0.5 mL/h. The carrier flow was adjusted upon initiation and discontinuation of model drug flow to maintain a constant total fluid delivery rate. The total flow rate was set at 12 mL/h for the high flow experiments and at 2 mL/h for the low flow experiments.
The drug and carrier infusions were joined via a standard Y-piece adaptor (MX612H, Medex, Dublin, OH) that was attached at the inlet of the 22-gauge port of the CVC (mark D in Fig. 1). For the initial onset experiments, the connecting Y-piece was flushed only with NS, which was defined as “unprimed.” The priming volume was 0.14 mL (B to C in Fig. 1). The remaining dead volume was 0.34 mL (C to E in Fig. 1). The onset experiments were then repeated using a Y-piece whose drug limb had been primed with MB, which was defined as “primed.” Priming was accomplished by connecting the MB line to the Y-piece and filling the Y-piece with MB. The drug limb was then clamped at its most distal point (mark C in Fig. 1). NS was infused via the carrier fluid line to clear the common limb of the Y-piece before attaching it to the CVC. To simulate the cessation of drug delivery, we conducted offset experiments for which the drug limb of the Y-piece was clamped after achieving a steady state of drug delivery, and the carrier fluid was adjusted to maintain a constant total flow rate.
The collection interval for each sample was 1 min. The eluant from the distal tip of the CVC was collected using a fraction collector (FRAC-100, Pharmacia Fine Chemicals, Stockholm, Sweden). Each sample was diluted with NS to a volume of 250 μL. Aliquots of 200 μL from each fraction collector sample were subsequently transferred to a 96-well plate (#353075, Becton Dickinson) and absorption at 668 nm was measured using a spectrophotometer (Spectra MAX 340PC, Molecular Devices, Sunnyvale, CA). After deriving the MB concentration in the collected samples from an independent, simultaneously generated, standard curve, the drug delivery (μg/min) was calculated from the known flow rates.
Before initiating experiments, the pump and infusion tubing were primed by running the syringe pumps at a rate of 12 mL/h until flowing fluid was visualized at the end of the tubing. The pump for carrier fluid (NS) was then set to the predefined flow rate. After running the pump for the model drug at 0.5 mL/h for an additional 10 min, it was stopped just before connecting it to the Y-piece of the CVC. This process was defined as the purge maneuver. The purge maneuver for the drug pump was performed to minimize lag time until forward flow from the syringe was established.
The component of drug delivery onset delays attributable to the start-up performance of the drug infusion pump system (comprised by the pump itself and the 60 mL syringe)1–3 was assessed by measuring the volume of MB solution delivered by the syringe after activation of the pump. The 60-mL syringe was connected directly to a 25-gauge needle. The purge maneuver described above was completed and then the pump was stopped. The needletip was immersed into a 0.5-mL vial filled with 50 μg of olive oil, which prevented evaporation of the collected aqueous fluid. Two conditions were compared. In one condition, the pump was shut off for an interval of 1 min before being restarted. In the second condition, the pump was shut off for 10 min and then restarted. These two shut-off intervals bracket the conditions typical of the drug delivery experiments. The collection interval for each sample after pump restart was 1 min. Samples were collected sequentially for at least 10 min. Delivery was quantified by weighing the collection tube before and after sample collection using a high precision scale (Mettler AE163). The weight difference was converted to volume delivery assuming a conversion of 1 g of aqueous solution equaling 1 mL. To maintain consistency, only one syringe pump was used for dye delivery experiments through catheters. Start-up performance of this pump was compared with another manufacturer’s device (Medfusion 3500, Medex, Carlsbad, CA) to ensure that the observed behavior is a general property of syringe pump systems.
Experimental infusions for each condition were repeated at least three times. Results were graphically displayed and the half time to achieve a new steady state for drug delivery (t50) was determined. Data are reported as the mean ± sd of the multiple trials. Results were compared using analysis of variance followed by a Bonferroni correction for the onset experiments and by unpaired, two-tailed t-test for the offset and pump start-up experiments (Prism 2.0, GraphPad Software, San Diego, CA).
Onset of Drug Delivery by Continuous Infusion
We evaluated the kinetics of drug delivery onset via the Y-piece and CVC lumen under several conditions. To simulate the initiation of a new drug infusion at a low total flow rate (model infusion of MB = 0.5 mL/h, carrier = 1.5 mL/h), we started the MB infusion with only NS filling the drug limb of the Y-piece (“unprimed”). There was a substantial lag in the appearance of the marker dye at the tip of the CVC (mark E, Fig. 1). Measurable amounts of the marker MB were not detected until more than 15 min had passed. The time to achieve half of the steady-state delivery (t50) was 23.5 ± 2.1 min and the predicted steady-state delivery rate was not achieved for more than 40 min (Figs. 2 and 4).
Simulating the resumption of a drug infusion that had been halted for some time while continuing to administer carrier fluid, we primed the drug limb of the Y-piece with MB (“primed”). Under low total flow conditions, the t50 with MB priming was reduced to 12.7 ± 0.6 min and steady-state delivery was achieved in about 20 min (Figs. 2 and 4, Table 1).
Based on our previous work, we predicted that increasing carrier flow and thus total system flow would hasten the onset of drug delivery. This prediction was tested by initiating the MB infusion (0.5 mL/h) into a carrier stream flowing at 11.5 mL/h. With the drug limb of the Y-piece filled only with NS (“unprimed”), the t50 for onset was 15.7 ± 2.9 min, significantly faster than the delivery at the low total flow rate with the unprimed drug limb. With priming of the Y-piece drug limb, delivery of the MB was further accelerated, resulting in a t50 of 5.2 ± 0.8 min (Figs. 2 and 4, Table 1).
Offset of Drug Delivery
To simulate the cessation of drug delivery via a CVC infusion (offset), we ran an infusion of the model drug MB until steady-state levels were reached. The MB infusion was then terminated. The carrier flow rate was adjusted to preserve the same total flow through the system. At low total system flows (2 mL/h), the offset t50 was 11.6 ± 0.8 min. At the high total system flows (12 mL/h), delivery offset was substantially faster. The measured t50 was 3 ± 0.5 min (Figs. 3 and 4, Table 2).
Assessment of Pump System Start-Up Characteristics
To determine whether pump system start-up characteristics contributed to the drug delivery profile during infusion onset experiments, we measured fluid output from a syringe attached to a needle as a function of time after a purge maneuver with a subsequent halt of the pump. When restarting the pump 1 min after completing the purge maneuver, the time to reach one half of the set output of the pump and syringe (t50) was 1.3 ± 0.2 min. If the pump was restarted 10 min after completing the purge maneuver, the t50 was 4.8 ± 1.4 min (Fig. 5, Table 3). Under identical test conditions, start-up performance of a syringe pump from a second manufacturer was similar (data not shown).
Previous work modeling infusion systems encountered in adult clinical care demonstrated that carrier infusion rates have a substantial impact on drug delivery kinetics. Catheter design (the dead volume) and the choice of infusion tubing also contribute.4,5 This study specifically aimed to describe the impact on drug delivery of an infusion system (CVC and connector) and total system flow rates typically encountered in the pediatric environment.
A main finding of this study is the long lag time to achieve targeted steady-state delivery after the onset of an infusion. A second finding is the long delay before drug delivery terminates through the distal tip of the intravascular catheter after stoppage of the drug pump. Third, the data suggest that pump system start-up performance can significantly contribute to the delay encountered when a drug infusion is initiated. These findings have not been previously described in quantitative fashion for a pediatric infusion system.
Our data reveal that the time to achieve a new steady-state drug delivery rate after initiating or resuming an infusion varied from approximately 9 to >40 min (Fig. 2). The onset half time (t50) for steady-state drug delivery ranged from a minimum of 5.2 min to a maximum of 23.5 min (Figs. 2 and 4) under the conditions of this study. When resuming an infusion, the drug limb of the Y-piece is already primed with medication. Priming enhances onset of drug delivery substantially by eliminating the lag time for the drug to be admitted into the CVC. Applying this principle, onset rates for new infusions might be accelerated by priming the device (e.g., Y-piece or manifold) used for connection before attaching it to the CVC. Our data show that meticulous priming, as recommended by Rooke and Bowdle,7 decreased the onset t50 by 10 min (Fig. 4, Table 1). A higher total flow rate shortened t50 by an additional 8 min both for onset and offset experiments.
In contrast to the situation of initiating a new infusion, offset half times are not affected by priming the drug limb of the Y-connector. However, total system flow rates will impact offset times. At the low total system flow rate (2 mL/h), the t50 for offset was >11 min. At the faster carrier flow (12 mL/h), the offset of drug delivery occurred more rapidly, with a measured t50 of 3 min. An abrupt increase in carrier flow rate intended to accelerate drug clearance from the system obligates a bolus delivery of the drug mass residing in the dead volume.8 This could lead to undesirable clinical effects. Consequently, clinicians will generally have to accept a gradual tapering of drug delivery when stopping a drug infusion or reducing a dose. This study demonstrates the likelihood of lengthy offset lag times in pediatric clinical settings.
Based on previous work,6 the response time to achieve a new targeted rate of drug delivery after a change in pump settings can be estimated using the time constant τ (tau), where
and V = dead volume, QD = drug flow, QC = carrier flow.6
We have previously described how an infusion system can exhibit the characteristics of the “plug-flow” model. In this case, it would require only one time constant to clear the dead volume and reach a new steady state. At the other extreme, a system might behave according to the predictions of the “well-mixed” model, requiring three time constants to reach 95%, or 4.6 time constants to reach 99%, of the steady state.6 Assuming that there are no contributions from factors such as pump system start-up behavior or priming technique to the kinetics of drug delivery, we would expect that after a change an infusion system would reach a new steady state somewhere between the predictions of the “plug-flow” and “well-mixed” models.
For devices used in this study, the calculated time constant for the primed low flow setting is 0.34 mL/2 mL/h = 10.2 min. The target drug delivery in our experiments was reached after approximately 25 min during the primed low-flow onset experiments and after approximately 20 min during the offset experiments. The calculated time constant for the primed high flow setting is 0.34 mL/12 mL/h = 1.7 min. The target drug delivery in our experiments was reached after approximately 9 min during the primed high-flow onset experiments and after approximately 5 min during offset experiments (Figs. 2 and 3).
The delay to achieve the target drug delivery was longer for onset than for offset experiments. Because dead volumes and total flow rates were equal, we chose to examine further possible delay factors. A likely contributor to onset times that are longer than the respective offset times is the time for the pump and syringe to achieve the set delivery rate. An extensive evaluation of pump system start-up behavior is beyond the scope of this work but has been pursued by other investigators.2,3 To explore the contribution of pump start-up in our studies, after completing the purge maneuver, we measured the time profile for fluid volume delivered directly from the syringe after start-up of the pump. Purging a pump and the attached infusion system components aligns the mechanical elements of the pump with the syringe, overcomes compliance inherent in the components (E. Flachbart, personal communication), and expels air to achieve immediate fluid delivery after activating the pump for its infusion. After the purge maneuver, we compared starting the pump after 1 min or 10 min rest intervals.
Under the specified conditions, our findings suggest that start-up of the pump system can contribute approximately 1.3 min to the drug delivery onset t50 when the interval between the purge maneuver and restart of the pump is 1 min. After a 10-min rest, pump system start-up accounted for 4.8 min of the drug delivery onset t50 (Fig. 5, Table 3). Corresponding experiments using a pump from a different manufacturer demonstrated similar start-up delays, consistent with findings reported by Neff et al.2,3 We conclude that the start-up behavior of the pump system (mechanical pump plus 60-mL syringe) impacts the overall drug delivery profile for onset experiments and accounts for the observed differences between the t50 values for drug delivery onset and offset. The impact of pump performance will be relatively small when the time constant is large. However, when the time constant is small, the impact of pump start-up behavior might be substantial.
Minimizing the pause after the purge maneuver before starting an infusion appears to attenuate the impact of the pump start-up behavior. A key safety issue is that during the purge process the syringe and any associated tubing must be disconnected from the fluid path entering the patient to avoid unintended bolus drug delivery.
In summary, our data reveal delays in achieving the onset and offset of drug delivery to the pediatric patient at the targeted dose depending on the carrier flow rate and dead volume of the system. Clinicians need to consider the consequences of delayed onset and offset of particular drugs when selecting total infusion rates. Highly potent drugs require much tighter control of drug administration. To minimize delays, we suggest using higher carrier flow rates whenever large fluctuations in drug dose are anticipated and clinical considerations do not mandate more restrictive fluid delivery strategies. In addition, complete priming of the drug limb of the manifold or connector piece before its attachment to the intravascular catheter hastens onset of a de novo infusion. Prolonged inactivity of the drug infusion pump after a purge maneuver can significantly contribute to delivery delays. This effect can be decreased by minimizing the interval between the purge maneuver for the pump system and starting the infusion.
Our findings demonstrate that simple modifications in drug delivery technique can substantially impact drug delivery kinetics. The underlying mechanisms are multifactorial and probably underappreciated. An understanding of the principles defined in this study and in other reports1–3,8 and familiarity with the particular features of the pump, syringe, tubing, manifolds, and catheters in an individual clinical setting will facilitate controlled and predictable drug delivery. To precisely control drug delivery to small children, useful strategies are 1) to prime the drug infusion line up to the point where it joins the carrier flow, 2) minimize the dead volume between the junction where the drug infusion joins the carrier and the blood stream, 3) use the highest carrier flows possible in the clinical setting, and 4) reduce the lag time from syringe pump start-up. These considerations might be particularly relevant when a critically ill or anesthetized child receives multiple simultaneous infusions, when clinical needs require rapid titration of infusion rates, and when care of a child is transferred between clinical environments, such as from the operating room to the intensive care unit.
The authors thank Drs. Charles Coté, Jeevendra Martyn, Natan Noviski, Klaus Bartels, and Phoebe Yeager for advice on early versions of this manuscript.
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© 2009 International Anesthesia Research Society
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