Resuscitating the microcirculation in sepsis: the central role of nitric oxide, emerging concepts for novel therapies, and challenges for clinical trials.
Microcirculatory dysfunction is a critical element of the pathogenesis of severe sepsis and septic shock. In this Bench-to-Bedside review, we present: 1) the central role of the microcirculation in the pathophysiology of sepsis; 2) new translational research techniques of in vivo video microscopy for assessment of microcirculatory flow in human subjects; 3) clinical investigations that reported associations between microcirculatory dysfunction and outcome in septic patients; 4) the potential role of novel agents to "rescue" the microcirculation in sepsis; 5) current challenges facing this emerging field of clinical investigation; and 6) a framework for the design of future clinical trials aimed to determine the impact of novel agents on microcirculatory flow and organ failure in patients with sepsis. We specifically focus this review on the central role and vital importance of the nitric oxide (NO) molecule in maintaining microcirculatory homeostasis and patency, especially when the microcirculation sustains an insult (as with sepsis). We also present the scientific rationale for clinical trials of exogenous NO administration to treat microcirculatory dysfunction and augment microcirculatory blood flow in early sepsis therapy.
Trzeciak
Stephen
S
Department of Emergency Medicine, Division of Critical Care Medicine, University of Medicine and Dentistry of New Jersey (UMDNJ)-Robert Wood Johnson Medical School at Camden, Cooper University Hospital, Camden, NJ, USA. trzeciak-stephen@cooperhealth.edu
Cinel
Ismail
I
Phillip Dellinger
R
R
Shapiro
Nathan I
NI
Arnold
Ryan C
RC
Parrillo
Joseph E
JE
Hollenberg
Steven M
SM
D002302:Cardiac Output / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008833:Microcirculation / Q000187:drug effects*; D009569:Nitric Oxide / Q000502:physiology / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D012151:Resuscitation / Q000379:methods*; D018805:Sepsis / Q000188:drug therapy* / Q000503:physiopathology
D009569:Nitric Oxide