Ekbal, NJ; (2015) NADH monitoring in shock states. Doctoral thesis , UCL (University College London).

Abstract

Shock is defined as inadequate delivery or utilization of oxygen by the body tissues. Currently measured cardiorespiratory variables however, indicate decompensation only when patients become (near) shocked. Belated intervention often fails to reverse injury, leading to organ dysfunction and failure. Precise monitoring of the adequacy of tissue perfusion thus represents a major deficiency in clinical practice, particularly in the critically ill. As mitochondria utilize >90% of the oxygen consumed by the body, predominantly for ATP production, there is an obvious logic in targeting this organelle for monitoring the adequacy of tissue perfusion. Within mitochondria, NADH transfers electrons from the Krebs’ cycle to Complex I of the electron transport chain. In doing so, NADH is oxidized to NAD+. A rise in NADH:NAD+ ratio (redox state) will occur with a downstream block in the chain, e.g. due to lack of oxygen. As NADH (but not NAD+) fluoresces in response to UV light excitation (340nm), with an intensity relating to its concentration, and as most of the NADH signal represents changes in mitochondrial NADH, this property may be utilized for non-invasive assessment of tissue hypoperfusion. I validated the technique in vitro, and investigated its utility in rat shock models. During graded or abrupt decreases in the constituent parts of tissue oxygen delivery (cardiac output, haemoglobin and oxyhaemoglobin saturation), as well as during resuscitation, I assessed the relationship between skeletal muscle NADH fluorescence intensity, organ perfusion and oxygenation. I compared these against measures of global haemodynamics and tissue perfusion routinely measured in critically ill patients. With each graded insult, NADH fluorescence demonstrated increases reflecting severity of the insult, with improvements upon resuscitation. A persisting rise in NADH fluorescence >50% above baseline foretold death within the following 30-45 minutes, in advance of the other monitored variables. My results indicate that NADH fluorescence may be used for monitoring tissue hypoperfusion in shock states, and as a guide to the timing and adequacy of therapeutic interventions.

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