Annual Update in Intensive Care and Emergency Medicine 2011

largely absent in sepsis, suggesting a metabolic rather than ischemic etiology [12].
These data have prompted interest in a field of research referred to as ‘metabolic
therapies’ that collectively were the subject of a roundtable conference at the
International Symposium on Intensive Care and Emergency Medicine in 2007.
This broadly-defined field encompasses basic nutritional support including small
nutrients and pharmaconutrition; function and manipulation of the endocrine
system including glucose metabolism; and cellular and mitochondrial dysfunction.
Due to the widespread, heterogeneous changes that characterize microcirculatory
dysfunction after macrocirculatory optimization, metabolic therapies represent
promising novel adjuvant treatments not only for sepsis-induced multiorgan
dysfunction syndrome, but also as specific therapies for microcirculatory
failure.
Insulin as a Metabolic Therapy
Mitochondrial Function in Septic Shock 357
The role of insulin in critical illness has been the subject of significant research
interest in the past decade. Because of the known deleterious effects of both
hyper- and hypoglycemia, multiple studies have now addressed the issue of tight
glucose control in the setting of critical illness, with sometimes conflicting results
[13]. There remains the possibility, however, that the results of these studies and
the effects of insulin relate less to regulation of glucose and more to other properties
of insulin itself. Like other components of the endocrine system, insulin has
numerous and far-reaching effects in the body apart from its role in glucose
homeostasis, including anti-inflammatory properties and cardiovascular actions.
Sepsis provokes a pro-inflammatory condition that overwhelms compensatory
anti-inflammatory mechanisms. The presence, magnitude, and duration of this
pro-inflammatory state are major determinates of organ dysfunction, organ failure,
and death [14]. Insulin has potent anti-inflammatory properties and in many
conditions, including sepsis, has been shown to suppress nuclear factor-kappa B
(NF-κB) expression [15], as well as interleukin (IL)-1, IL-6, and tumor necrosis
factor (TNF)-α expression and serum levels [16]. Insulin also promotes the
expression and increased serum levels of anti-inflammatory cytokines, such as
IL-2, IL-4, and IL-10 [16]. Combined, these actions of insulin serve to promote a
more homeostatic inflammatory state in the host. These aforementioned effects
appear to be direct anti-inflammatory mechanisms of insulin and are independent
of modulation of glucose oxidation or membrane polarization [16].
Insulin also has considerable direct cardiovascular effects. In supraphysiologic
doses, insulin functions as a potent inotrope, even in conditions refractory to
conventional treatments [17]. The microcirculation is also sensitive to insulin’s
effects, as overall capillary recruitment improves in animal models and healthy
subjects under hyperinsulinemic-euglycemic clamp, perhaps as a feed-forward
mechanism that insulin utilizes to stimulate its own access to hypoperfused tissue
[18]. In critically ill patients, improvements in forearm blood flow have been
demonstrated in those receiving intensive insulin treatment [19]. These effects of
insulin on inflammation and the microcirculation, combined with the familiarity
of clinicians with insulin infusions for tight glucose control, make insulin an
attractive therapeutic agent in targeting the microcirculation in sepsis.
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