There's More to Sepsis Than Macrocirculatory Derangements

Dear Editor,

I felt obligated to write a quick commentary after reading your journal's recently published article, "Don't Go Chasing Waterfalls: Excessive Fluid Resuscitation in Severe Sepsis and Septic Shock", by Chen et al. First, I would like to commend the authors on writing their concise yet extremely comprehensive review of current management strategies for sepsis. I certainly believe that this publication adds invaluable knowledge to the ever-evolving sepsis arena by elucidating the evidence-based treatment goals in sepsis. In addition to the important topics raised by Chen et al, I felt compelled to expand on their article with some additional sepsis information that I believe to be pertinent. First, as alluded to in their article, sepsis is indeed a complex pathophysiological state and its downstream complications result from an intense host response to infection that release proinflammatory cytokines, reactive oxygen species, nitric acid (NO), arachidonic acid metabolites, and adhesion molecules.1,2 Thus far, resuscitative therapies for sepsis have focused on early antibiotic administration and infection control, while optimizing organ perfusion by correcting macrocirculatory parameters such as blood pressure.3 Another prominent and often underappreciated mechanism of sepsis-induced organ injury that remains a hotbed of research, however, is locoregional microcirculatory dysfunction causing tissue hypoxia.4 The pathophysiology of this mechanism results in an oxygen extraction deficit, as oxygen transport is shunted to venous compartments past collapsed and disrupted microcirculatory units.4 The microcirculation and its importance in sepsis and septic shock could explain why resuscitative strategies focused on upstream hemodynamic variables do not correct downstream indicators of dysoxia such as hyperlactemia.4,5 Hence, any drug or therapy that fails to address the microcircula-tory derangements of sepsis is likely to be imper-fect and suboptimal.4,5

The microcirculation is the critical junction where oxygen exchanges take place at the organ level.6 A prominent feature of sepsis is an impaired ability of the tissues to extract oxygen such that anaerobic metabolism and lactic acidosis occur at oxygen deliveries that would be normally sufficient to meet aerobic demand.7-9 Furthermore, numerous inflammatory mediators, such as NO and platelet activating factor, are released that increase capillary permeability and decrease vascular tone, resulting in microcircula-tory dysfunction, locoregional oxygen supply-demand mismatch, and anaerobic glycolysis with lactic acidosis.9-12 Regardless of whether systemic hemodynamics are within targets, microcircula-tory derangements are frequently observed in sepsis and septic shock.6,12 Alterations in micro-circulatory competency contribute to oxygen extraction abnormalities in sepsis and explain why signs of tissue hypoperfusion such as hyperlactemia can be observed even when venous oxygen saturation and systemic hemodynamics are normalized.6 This means that the achievement of normal/high cardiac output and the normalization of blood pressure with fluids, vasopressors, and inotropic agents may not prevent the occurrence or persistence of hypoperfusion.6,9,12,13

The clinical significance of an intact micro-circulation in sepsis has been repeatedly validated.6,12,14 A 252-patient study showed mortality and organ dysfunction from sepsis to be directly related to microvascular incompetency.6 Likewise, Hernandez et al13 demonstrated microvascular dysfunction to be significantly associated with organ dysfunction and mortality in septic shock and that the presence of hyper-lactemia and vasopressor requirements was indicators of microcirculatory pathology. Moreover, other trials have shown improvements in microvascular perfusion to be associated with improved survival and organ function.14 Finally, additional trials have shown the duration of microvascular alterations to differ between survivors and nonsurvivors of sepsis, with nonsurvivors having a longer duration of microvascular dysfunction.14

Unfortunately, since the microcirculatory effects of sepsis are independent from the changes at the macrocirculatory system, difficulty exists in identifying patients with microcircula-tory failure due to a lack of specific techniques that measure the microcirculation.6,12 Therefore, clinically speaking, it is difficult to identify those patients with septic shock who are more likely to have microcirculatory dysfunction and thus constitute better patients both for microvascular assessment and for potential treatments.13 To date, only prolonged hyperlactemia and norepine-phrine requirements have been shown to increase the odds of finding severe microcirculatory disturbances in septic patients.13 To compound this problem, adequate resuscitation goals for the optimization of the microcirculation are unclear.12 Similarly, the treatments for sepsis-induced macro- and microcirculatory dysfunction differ and can sometimes counteract each other.6,10 More specifically, correction of hypotension is a critical clinical target, but the use of vasopressor agents and fluids could be detrimental to septic patients' microcirculation and overall clinical status.4 For example, fluid boluses improve only microvas-cular perfusion in early but not late sepsis, independent from systemic hemodynamics.14 Pranskunas et al14 showed "responders" to fluid boluses to be patients with significant micro-circulatory dysfunction whereas "nonresponders" had minimal dysfunction. Like fluid responsive-ness, many have also shown marked variability regarding vasopressor-induced microcirculatory changes.12 Thus, innovative clinical techniques are needed to monitor the microcirculation since there is a fine line between maintaining critical global hemodynamic targets and promoting microcirculatory flow.4

Vasodilation of the microcirculation can enhance flow, improve regional perfusion, and improve the function of end-organ cells.4,15 Thus, vasodilating agents, which have the ability to increase NO, endothelium-derived relaxing factor, and cGMP synthesis, inhibit platelet aggregation, dilate microcirculation, and improve tissue oxygenation, could be beneficial in septic patients with microcirculatory derangements.5,12 However, despite their theoretical benefit, there are no vasodilating agents that are recommended in current sepsis guidelines.4,10,12

Thus, the purpose of my letter is merely to highlight an important point, which is that the treatment of sepsis has traditionally focused on early antibiotic administration and infection control, while optimizing organ perfusion by correcting global hemodynamic parameters. In addition to the macrocirculatory effects, however, significant microcirculatory disturbances occur in sepsis, which lead to inadequate oxygen delivery at the end-organ level. Further studies and clinical trials are warranted that specifically investigate interventions that improve the microcirculation and survival in septic patients with significant microcirculatory derangements.

-Jason Chertoff, MD, MPH

University of Florida

College of Medicine

Gainesville

([email protected])

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