title: Effects of vasopressinergic receptor agonists on sublingual microcirculation in norepinephrine-dependent septic shock.
abstract: BACKGROUND
  The present study was designed to determine the effects of continuously infused norepinephrine (NE) plus (1) terlipressin (TP) or (2) arginine vasopressin (AVP) or (3) placebo on sublingual microcirculation in septic shock patients. The primary study end point was a difference of ≥ 20% in the microvascular flow index of small vessels among groups.
  
  
  METHODS
  The design of the study was a prospective, randomized, double-blind clinical trial. NE was titrated to maintain mean arterial pressure (MAP) between 65 and 75 mmHg after establishment of normovolemia in 60 septic shock patients. Thereafter patients (n = 20 per group) were randomized to receive continuous infusions of either TP (1 μg/kg/hour), AVP (0.04 U/minute) or placebo (isotonic saline). In all groups, open-label NE was adjusted to maintain MAP within threshold values if needed. The sublingual microcirculatory blood flow of small vessels was assessed by sidestream dark-field imaging. All measurements, including data from right heart catheterization and norepinephrine requirements, were obtained at baseline and 6 hours after randomization.
  
  
  RESULTS
  TP and AVP decreased NE requirements at the end of the 6-hour study period. The data are medians (25th and 75th interquartile ranges (IQRs)): 0.57 μg/kg/minute (0.29 to 1.04) vs. 0.16 μg/kg/minute (0.03 to 0.37) for TP and 0.40 μg/kg/minute (0.20 to 1.05) vs. 0.23 μg/kg/minute (0.03 to 0.77) for AVP, with statistical significance of P < 0.05 vs. baseline and vs. placebo. There were no differences in sublingual microcirculatory variables, systemic hemodynamics, oxygen transport and acid-base homeostasis among the three study groups during the entire observation period. The proportions of perfused vessels increased in relation to baseline within all study groups, and there were no significant differences between groups. The specific data were as follows (median (IQR)): 9.7% (2.6 to 19.8) for TP, 8.9% (0.0 to 17.8) for AVP, and 6.9% (3.5 to 10.1) for placebo (P < 0.05 vs. baseline for each comparison), as well as perfused vessel density 18.6% (8.6 to 36.9) for TP, 20.2% (-3.0 to 37.2) for AVP, and 11.4% (-3.0 to 19.4) for placebo (P < 0.05 vs. baseline for each comparison).
  
  
  CONCLUSIONS
  The present study suggests that to achieve a MAP of 65 to 75 mmHg in septic patients treated with NE, the addition of continuously infused low-dose TP or AVP does not affect sublingual microcirculatory blood flow. In addition, our results suggest that microcirculatory flow abnormalities are mainly related to other factors (for example, volume status, timing, hemodynamics and progression of the disease) rather than to the vasopressor per se.
  
  
  BACKGROUND
  ClinicalTrial.gov NCT00995839.
authors.affiliation: Department of Anesthesiology and Intensive Care, University of Rome, La Sapienza, Viale del Policlinico 155, Rome I-00161, Italy. andrea.morelli@uniroma1.it
authors.forename: Andrea
authors.initials: A
authors.lastname: Morelli
authors.forename: Abele
authors.initials: A
authors.lastname: Donati
authors.forename: Christian
authors.initials: C
authors.lastname: Ertmer
authors.forename: Sebastian
authors.initials: S
authors.lastname: Rehberg
authors.forename: Tim
authors.initials: T
authors.lastname: Kampmeier
authors.forename: Alessandra
authors.initials: A
authors.lastname: Orecchioni
authors.forename: Alessandro
authors.initials: A
authors.lastname: Di Russo
authors.forename: Annalia
authors.initials: A
authors.lastname: D'Egidio
authors.forename: Giovanni
authors.initials: G
authors.lastname: Landoni
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Lombrano
authors.forename: Laura
authors.initials: L
authors.lastname: Botticelli
authors.forename: Agnese
authors.initials: A
authors.lastname: Valentini
authors.forename: Alberto
authors.initials: A
authors.lastname: Zangrillo
authors.forename: Paolo
authors.initials: P
authors.lastname: Pietropaoli
authors.forename: Martin
authors.initials: M
authors.lastname: Westphal
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000368:Aged; D001127:Arginine Vasopressin / Q000008:administration & dosage / Q000494:pharmacology*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008236:Lypressin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D008875:Middle Aged; D009060:Mouth Floor / Q000098:blood supply*; D009638:Norepinephrine / Q000008:administration & dosage / Q000494:pharmacology*; D011446:Prospective Studies; D017483:Receptors, Vasopressin / Q000819:agonists*; D012772:Shock, Septic / Q000188:drug therapy*; D000077585:Terlipressin
chemical_list: D000316:Adrenergic alpha-Agonists; D017483:Receptors, Vasopressin; D001127:Arginine Vasopressin; D008236:Lypressin; D000077585:Terlipressin; D009638:Norepinephrine