title: Necessity and risks of arterial blood sampling in healthy volunteer studies.
abstract: Arterial blood sampling is necessary when drugs such as the fast-acting opioid analgesic remifentanil exhibit relevant differences between arterial and venous blood concentrations. Arterial cannulation is generally considered to be clinically safe and has thus become a standard procedure in pharmacokinetic-pharmacodynamic assessments. However, rare cases of arterial occlusions have to be considered in risk-benefit assessments of arterial sampling in pharmacokinetic studies, especially when including healthy volunteers. In an actual case, arterial occlusion requiring surgical repair was caused by a factor V Leiden thrombophilia associated genetic variant F5 1691G>A (rs6025) and aggravated by a hypoplastic radial artery. Neither risk factor had been identified prior to enrolment by routine laboratory tests such as the prothrombin time (international normalized ratio), partial thromboplastin time and the clinical Allen's test of arterial function. Re-assessment of the necessity of arterial sampling showed that none of the potential alternatives, target concentrations of computerized infusions or venous concentrations during non-steady-state and steady-state conditions could provide the arterial concentrations. Relying on venous concentrations may result in erroneous pharmacodynamic parameters. Accurate pharmacokinetic-pharmacodynamic studies relying on precisely measured blood concentrations require serial sampling techniques during both steady-state and non-steady-state conditions. However, as illustrated by the presented case, incidents involving the generally safe procedure of arterial sampling are possible, although rare. To further minimize the risks, screening of subjects for prothrombotic risks and careful assessment of the suitability of the artery should be considered in pharmacokinetic studies requiring arterial cannulation.
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, J. W. Goethe-University Hospital, Frankfurt, Germany.
authors.forename: Bruno Georg
authors.initials: BG
authors.lastname: Oertel
authors.forename: Johannes
authors.initials: J
authors.lastname: Vermehren
authors.forename: Michael
authors.initials: M
authors.lastname: Zimmermann
authors.forename: Thomas Tao
authors.initials: TT
authors.lastname: Huynh
authors.forename: Alexandra
authors.initials: A
authors.lastname: Doehring
authors.forename: Nerea
authors.initials: N
authors.lastname: Ferreiros
authors.forename: Stephan
authors.initials: S
authors.lastname: Senzel
authors.forename: Thomas
authors.initials: T
authors.lastname: Schmitz-Rixen
authors.forename: Matthias
authors.initials: M
authors.lastname: Erbe
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.forename: Sebastian
authors.initials: S
authors.lastname: Harder
authors.forename: Martin S
authors.initials: MS
authors.lastname: Angst
authors.forename: Jörn
authors.initials: J
authors.lastname: Lötsch
mesh_terms: D000328:Adult; D000701:Analgesics, Opioid / Q000097:blood / Q000493:pharmacokinetics; D001800:Blood Specimen Collection / Q000009:adverse effects* / Q000379:methods; D002406:Catheterization, Peripheral / Q000009:adverse effects* / Q000379:methods; D064368:Healthy Volunteers; D006801:Humans; D007261:Infusions, Intra-Arterial; D008297:Male; D010880:Piperidines / Q000097:blood / Q000493:pharmacokinetics; D017534:Radial Artery / Q000000981:diagnostic imaging / Q000378:metabolism*; D000077208:Remifentanil; D018570:Risk Assessment; D012307:Risk Factors; D017131:Thrombectomy; D013927:Thrombosis / Q000097:blood / Q000000981:diagnostic imaging / Q000209:etiology* / Q000601:surgery; D014463:Ultrasonography
chemical_list: D000701:Analgesics, Opioid; D010880:Piperidines; D000077208:Remifentanil