title: Drug infusion system manifold dead-volume impacts the delivery response time to changes in infused medication doses in vitro and also in vivo in anesthetized swine.
abstract: BACKGROUND
  IV infusion systems can be configured with manifolds connecting multiple drug infusion lines to transcutaneous catheters. Prior in vitro studies suggest that there may be significant lag times for drug delivery to reflect changes in infusion rates set at the pump, especially with low drug and carrier flows and larger infusion system dead-volumes. Drug manifolds allow multiple infusions to connect to a single catheter port but add dead-volume. We hypothesized that the time course of physiological responses to drug infusion in vivo reflects the impact of dead-volume on drug delivery.
  
  
  METHODS
  The kinetic response to starting and stopping epinephrine infusion ([3 mL/h] with constant carrier flow [10 mL/h]) was compared for high- and low-dead-volume manifolds in vitro and in vivo. A manifold consisting of 4 sequential stopcocks with drug entering at the most upstream port was contrasted with a novel design comprising a tube with separate coaxial channels meeting at the downstream connector to the catheter, which virtually eliminates the manifold contribution to the dead-volume. The time to 50% (T50) and 90% (T90) increase or decrease in drug delivery in vitro or contractile response in a swine model in vivo were calculated for initiation and cessation of drug infusion.
  
  
  RESULTS
  The time to steady state after initiation and cessation of drug infusion both in vitro and in vivo was much less with the coaxial low-dead-volume manifold than with the high-volume design. Drug delivery after initiation in vitro reached 50% and 90% of steady state in 1.4 ± 0.12 and 2.2 ± 0.42 minutes with the low-dead-volume manifold and in 7.1 ± 0.58 and 9.8 ± 1.6 minutes with the high-dead-volume manifold, respectively. The contractility in vivo reached 50% and 90% of the full response after drug initiation in 4.3 ± 1.3 and 9.9 ± 3.9 minutes with the low-dead-volume manifold and 11 ± 1.2 and 17 ± 2.6 minutes with the high-dead-volume manifold, respectively. Drug delivery in vitro decreased by 50% and 90% after drug cessation in 1.9 ± 0.17 and 3.5 ± 0.61 minutes with the low-dead-volume manifold and 10.0 ± 1.0 and 17.0 ± 2.8 minutes with the high-dead-volume manifold, respectively. The contractility in vivo decreased by 50% and 90% with drug cessation in 4.1 ± 1.1 and 14 ± 5.2 with the low-dead-volume manifold and 12 ± 2.7 and 23 ± 5.6 minutes with the high-dead-volume manifold, respectively.
  
  
  CONCLUSIONS
  The architecture of the manifold impacts the in vivo biologic response, and the drug delivery rate, to changes in drug infusion rate set at the pump.
authors.affiliation: From the *Department of Anesthesiology, Critical Care and Pain Medicine, Steward St. Elizabeth's Medical Center; †Harvard Medical School, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Beth Israel Deaconess Medical Center; ‡Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Steward St. Elizabeth's Medical Center; and §Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Lovich
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Wakim
authors.forename: Abraham
authors.initials: A
authors.lastname: Wei
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Parker
authors.forename: Mikhail Y
authors.initials: MY
authors.lastname: Maslov
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Pezone
authors.forename: Hisashi
authors.initials: H
authors.lastname: Tsukada
authors.forename: Robert A
authors.initials: RA
authors.lastname: Peterfreund
mesh_terms: D000322:Adrenergic Agonists / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000758:Anesthesia; D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects; D057785:Catheters; D004334:Drug Administration Schedule; D016503:Drug Delivery Systems / Q000295:instrumentation; D004837:Epinephrine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004867:Equipment Design; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D007262:Infusions, Intravenous; D023421:Models, Animal; D009200:Myocardial Contraction / Q000187:drug effects; D013552:Swine; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects*; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: D000322:Adrenergic Agonists; D004837:Epinephrine