The Effects of Sedating Medications on the levels of Physiological Stress in Critically Unwell Patients

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The survival of an organism in the face of internal and external events requires a measured and appropriate stress response. It has been hypothesised that an abnormal stress response is linked to the likelihood of the development and severity of critical illness and multi-organ failure. The stress response is coordinated by the primitive brain structures of the diencephalon and brainstem in response to somatosensory inputs and comprises a broad range of neuro-hormonal and immune effects. We hypothesise that the use of sedating medications confuses the normal generation of a stress response. If this is confirmed, this may be a fundamental underlying cause for the abnormal haemodynamics, metabolic disturbances and organ dysfunction observed in critical illness. The large multi-centre randomised-controlled SPICE-III study offers the opportunity to study two similar groups of patients who may have differing levels of physiological stress as a result of an Early Goal-Directed Sedation (EGDS) strategy as compared to standard care. We aim to conduct a substudy to determine whether a strategy of EGDS and the resultant reduced sedation level results in a differing physiological stress response in critically unwell patients as measured by a panel of blood-borne markers. We hypothesise that the application of an early goal directed sedation protocol and the resultant reduced sedation level in the first 5 days of critical illness will result in a differing pattern of stress as measured by metabolic, sympathetic, hormonal and inflammatory responses. All-SPICE will be a prospective parallel-group multi-centre observational sub-study of the the SPICE-III study. The SPICE-III study is a prospective, un-blinded, randomised controlled trial of Early Goal-Directed Sedation compared with Standard care. The SPICE-III study will recruit patients who are intubated and ventilated in a participating ICU, are expected to remain intubated the day after enrolment and need immediate and ongoing sedation. Due to the immediate need to choose a sedative regimen for ongoing patient safety and comfort, it is proposed that study enrolment will occur using deferred consent. A total of 100 patients from approximately 4 ICUs will be enrolled in All-SPICE. Immediately following randomisation on day 1, patients will have blood samples taken, which will be repeated on days 2, 4 and 6. These samples will be assessed for various blood-borne markers which are considered to be potentially affected by the coordination of the stress response.