What is Metabolic Resuscitation?
Resuscitation in sepsis has been focused on administration of fluids, pressors, and antibiotics, and not without justification. Over the past two decades we’ve observed the mortality rates decrease for severe sepsis/septic shock. Always looking forward, where does the next advancement lie?
The aim of metabolic resuscitation/HAT therapy is to go a step beyond the restoration of oxygen delivery and to restore the ability of the mitochondria to carry out aerobic metabolism. In critical illness and sepsis, hypovitaminosis and corticosteroid insufficiency can occur leaving patients deficient in numerous essential compounds with some that the body is unable to manufacture for itself. A few examples pertinent to both septic patients and this blog are Hydrocortisone, Vitamin C (ascorbic acid), and Vitamin B1 (thiamine).
Hydrocortisone aka cortisol, is a corticosteroid and has been shown to augment hemodynamics in sepsis. It does so by preventing the induction of nitric oxide synthase–an enzyme located in the endothelium that is involved in the regulation of vasodilation–and thereby improves the vasoactive response to catecholamines.
Ascorbic acid is a known co-factor for endogenous catecholamine production. Many of us will recall the trivial anecdote of the role of Vitamin C in treating scurvy. Yet, surprisingly many of us don’t realize that without Vitamin C we cannot synthesize endogenous dopamine, norepinephrine, or epinephrine. Additionally, Vitamin C can act as free radical scavenger and improve micro- and macrovascular permeability.
Thiamine is a key co-factor for mitochondrial function among many other metabolic pathways. In regards to mitochondria, deficiency in thiamine prevents pyruvate from entering the Kreb’s Cycle resulting in conversion of pyruvate to lactate. Bypassing the Kreb’s Cycle leads to a significant reduction in ATP and potentially a rising serum lactate. Furthermore, thiamine is thought to be renal-protective by preventing the conversion of glyoxylate to oxalate via glyoxylate aminotransferase.
What’s the Data Say?
-Josh Farkas of PulmCrit analyzed the most recent studies at the time of his writing, and there appeared to be a point of clinical equipoise. Most studies were small, retrospective, and single-center. Additionally, in regards to experimental design, quite a few had delays in initiation of metabolic resuscitation. In summary, as we are accustomed to hearing with newer/controversial interventions, more studies of higher-level evidence were needed.
-ACTS Trial published in JAMA this past month, did not show a statistically significant improvement in SOFA score. This was a multicenter randomized controlled trial with early initiation of metabolic resuscitation/HAT therapy.
-In light of the ACTS Trial, there may be a turning of the ship towards finding no benefit from HAT therapy. However, the components of HAT therapy are inexpensive, readily available, and contain a relatively large safety profile. Furthermore, the replacement of vital endogenous substances seems reasonable considering the roles of the compounds, which are supported by basic science.
Contemplative Conclusion:
In the absence of “definitive answer” is metabolic resuscitation something that Critical Care Transport Teams would be uniquely situated to implement during transport?
While research has not yet been able to detect measurable impacts on clinical outcomes, there is logic in the supplementation of deficiciences, and research supporting the safety in doing so with these compounds.
Whether you agree or disagree, keeping our attention focused on new developments/interventions whose window of implementation extends into the realm of Critical Care Transport providers, it will nonetheless serve to drive our practice forward and eventually improve the clinical trajectory of the patients we meet.
References:
Annane D, Pastores SM, Arlt W, et al. Critical Illness-Related Corticosteroid Insufficiency (CIRCI): A Narrative Review from a Multispecialty Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM). Critical Care Medicine. 2017; 45(12):2089-2098. doi: 10.1097/CCM.0000000000002724
Moskowitz A, Huang DT, Hou PC, et al. Effect of Ascorbic Acid, Corticosteroids, and Thiamine on Organ Injury in Septic Shock: The ACTS Randomized Clinical Trial. JAMA. 2020; 324(7):642–650. doi:10.1001/jama.2020.11946
Rudd KE, Johnson SC, Agesa KM, et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet (London, England). 2020; 395(10219):200–211. doi.org/10.1016/S0140-6736(19)32989-7