The effect of increasing doses of norepinephrine on tissue oxygenation and microvascular flow in patients with septic shock* Shaman Jhanji, MRCP, FRCA; Sarah Stirling, MRCP, FRCA; Nakul Patel, MBBS; Charles J. Hinds, FRCP, FRCA; Rupert M. Pearse, FRCA, MD S epsis is characterized by a complex combination of car- diovascular derangements, in- cluding vasodilatation, hypo- volemia, myocardial depression, and altered microvascular flow (1– 4). In se- vere cases, arterial hypotension may per- sist despite aggressive intravenous fluid resuscitation, a condition termed septic shock (5). In health, constant organ blood flow is maintained by autoregula- tion over a range of mean arterial pres- sures (MAPs) between 60 and 100 mm Hg; when MAP falls below this range, organ blood flow also decreases in a lin- ear fashion (6). Consequently, in septic shock, vasopressor therapy is recom- mended to maintain tissue perfusion and oxygenation (7), although sepsis-related changes in vascular reactivity may alter the normal autoregulatory range (8), and the optimal arterial pressure end point for vasopressor therapy remains uncer- tain (9). Indeed, the current recommen- dation to maintain MAP at 65 mm Hg is supported by only limited evidence (10, 11), and some have advocated routine use of higher arterial pressure targets, or al- ternatively the restoration of MAP to pre- morbid values. Because the consequences of both inadequate and excessive vasopres- sor therapy can be serious (12), it is impor- tant to clarify the optimal end points to which these potent agents should be ti- trated and to investigate the effects of alter- native vasopressor agents (13). Sepsis results in a variety of deleteri- ous microvascular changes that are asso- ciated with organ failure and death (14). These derangements include increased endothelial permeability, endothelial leu- kocyte adhesion (15), and a characteristic heterogeneity of blood flow that is asso- ciated with tissue hypoxia (4, 16, 17). The causes of heterogeneous microvascular flow are not fully understood but reduced vascular tone because of impaired endo- thelial signal transduction may be one explanation (18). It is possible, therefore, that vasopressors might correct the ab- normalities of microvascular flow and the tissue oxygenation associated with septic shock. The dose-related effects of vasopressor therapy on microvascular flow and tissue oxygenation in sepsis have not been pre- viously fully investigated. The aim of this investigation was to evaluate, in more detail, the effects of increasing doses of norepinephrine, targeted to achieve suc- cessively greater MAPs, on microvascular flow and tissue oxygenation in patients with septic shock. *See also p. 2120. From the Barts and The London School of Medicine and Dentistry, Queen Mary’s University of London, London, United Kingdom. Supported, in part, by a research grant from the Barts and The London Charity. Dr. Pearse has received an unrestricted research grant from LiDCO Ltd. The remaining authors have not disclosed any potential conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.ccmjournal.org). For information regarding this article, E-mail: rupert.pearse@bartsandthelondon.nhs.uk Copyright © 2009 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0b013e3181a00a1c Objective: To investigate the effect of escalating doses of norepinephrine, aimed at achieving incremental increases in mean arterial pressure (MAP), on microvascular flow and tissue oxygenation in patients with septic shock. Design: Single-center interventional study. Setting: University hospital intensive care unit. Patients: Sixteen patients with established septic shock. Interventions: The norepinephrine dose was escalated to achieve incremental increases in the MAP from 60 to 70, 80, and 90 mm Hg. Measurements and Main Results: In addition to routine clinical measurements, cardiac output was determined using lithium di- lution and arterial waveform analysis, cutaneous tissue PtO 2 was measured using a Clark electrode, cutaneous red blood cell flux was assessed using laser Doppler flowmetry, and sublingual microvascular flow was evaluated using sidestream darkfield imaging. The mean (SD) norepinephrine dose increased from 0.18 (0.18) gkg 1 min 1 at 60 mm Hg to 0.41 (0.26) gkg 1 min 1 at 90 mm Hg (p < 0.0001). During this period, global oxygen delivery increased from 487 (418 – 642) to 662 (498 – 829) mLmin 1 m 2 (p < 0.01), cutaneous PtO 2 increased from 44 (11) to 54 (13) mm Hg (p < 0.0001) and cutaneous microvascular red blood cell flux increased from 26.1 (16.2– 41.9) to 33.3 (20.3– 46.7) perfusion units (p < 0.05). No changes in sublingual microvas- cular flow index, vessel density, the proportion of perfused ves- sels, perfused vessel density, or heterogeneity index were iden- tified by sidestream darkfield imaging. Conclusions: In patients with septic shock, targeting higher MAP by increasing the dose of norepinephrine resulted in an increase in global oxygen delivery, cutaneous microvascular flow, and tissue oxygenation. There were no changes in preexisting abnormalities of sublingual microvascular flow. Further research is required to clarify the optimal end points for vasopressor therapy in patients with septic shock. (Crit Care Med 2009; 37: 1961–1966) KEY WORDS: septic shock; norepinephrine; microcirculation; tis- sue oxygenation; global oxygen delivery 1961 Crit Care Med 2009 Vol. 37, No. 6