Effects of nitroglycerin on sublingual microcirculatory blood flow in patients with severe sepsis/septic shock after a strict resuscitation protocol: a double-blind randomized placebo controlled trial.
OBJECTIVE
Microcirculatory alterations have been associated with morbidity and mortality in human sepsis. Such alterations occur despite pressure-guided resuscitation. Earlier data suggested that impaired microcirculatory blood flow could be corrected with intravenous nitroglycerin in these patients. We tested this concept after fulfillment of preset systemic hemodynamic resuscitation end points in the early phase of sepsis.


METHODS
Prospective, single center, randomized, placebo-controlled, double-blind clinical trial.


METHODS
Closed-format 22-bed mixed intensive care unit in a tertiary teaching hospital.


METHODS
Patients > or =18 yrs with sepsis, according to international criteria, and at least one early sign of organ dysfunction, as the principal reason for intensive care unit admission, were eligible for enrollment.


METHODS
Patients were randomly assigned to receive nitroglycerin (n = 35) or placebo (n = 35) after fulfillment of protocol-driven resuscitation end points. This trial is registered with ClinicalTrials.gov as NCT00493415.


RESULTS
Primary outcome was sublingual microcirculatory blood flow of small vessels, as assessed by side-stream dark field imaging. After protocolized resuscitation, we observed recruitment of sublingual microcirculation in both groups, as indicated by a significant improvement in the microcirculatory flow index after 24 hrs, in comparison to baseline. However, no difference in the sublingual microvascular flow index was observed between groups. The median microvascular flow index in sublingual small-sized vessels was 2.71 (1.85-3) in the nitroglycerin group and 2.71 (1.27-3), p = .80, in the placebo group. In medium-sized vessels, the respective values were 3 (2.75-3) vs. 2.86 (2.19-3), p = .21, and in large-sized vessels, 3 (3-3) vs. 3 (2.89-3), p = .06. In-hospital mortality, as a secondary outcome, was 34.3% in the nitroglycerin group and 14.2% in the placebo group, p = .09.


CONCLUSIONS
In the context of a strict resuscitation protocol, based upon fulfillment of systemic hemodynamic end points in patients with early-phase severe sepsis or septic shock, we conclude that intravenous nitroglycerin does not promote sublingual microcirculatory blood flow.
Boerma
E Christiaan
EC
Department of Translational Physiology (ECB, CI), Academic Medical Centre, Amsterdam, The Netherlands. e.boerma@chello.nl
Koopmans
Matty
M
Konijn
Arjan
A
Kaiferova
Katerina
K
Bakker
Andries J
AJ
van Roon
Eric N
EN
Buter
Hanneke
H
Bruins
Nienke
N
Egbers
Peter H
PH
Gerritsen
Rik T
RT
Koetsier
Peter M
PM
Kingma
W Peter
WP
Kuiper
Michael A
MA
Ince
Can
C
D000286:Administration, Sublingual; D000328:Adult; D000368:Aged; D001783:Blood Flow Velocity / Q000187:drug effects; D002423:Cause of Death; D003422:Critical Care / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D017052:Hospital Mortality / Q000639:trends*; D006784:Hospitals, Teaching; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D008875:Middle Aged; D009060:Mouth Floor / Q000098:blood supply; D005996:Nitroglycerin / Q000008:administration & dosage*; D011336:Probability; D012016:Reference Values; D012151:Resuscitation / Q000379:methods*; D018570:Risk Assessment; D018805:Sepsis / Q000175:diagnosis / Q000188:drug therapy / Q000401:mortality / Q000628:therapy; D012772:Shock, Septic / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality* / Q000628:therapy; D016019:Survival Analysis; D016896:Treatment Outcome
D005996:Nitroglycerin