Sleep Intervention During Acute Lung Injury

Critically ill patients with acute lung injury and acute respiratory distress syndrome
(ALI/ARDS) who receive mechanical ventilation can suffer from severe sleep disruption despite
continuous sedative infusions. Sleep disruption, in turn, may activate the sympathetic
nervous system and cause elevation of circulating inflammatory cytokines, which, in turn, may
play a causative role in delirium and post-traumatic stress disorder through consolidation of
unpleasant memories during awakenings from sleep. Currently, there is very little
understanding of the inter-relationship between critical illness, sleep, and
neuropsychological well-being, due to the lack of intervention-based trials that improve
sleep during critical illness. The central purpose of this proposal is to study the
short-term effects of sedation with sympatholysis (central α2 adrenergic agent) on sleep and
inflammation in critically ill patients with ALI/ARDS. Sedation with sympatholysis will be
achieved by a novel sleep-promoting agent with central α2 adrenergic properties. This FDA
approved novel sedative agent, dexmedetomidine, has been shown to decrease delirium (an
independent predictor of mortality) and decrease duration of mechanical ventilation and ICU
stay in critically ill patients receiving mechanical ventilation (Riker et al, JAMA
2009;301:542-44 and Pandharipande et al, JAMA 2007;298:2644-53). We will undertake sleep
studies and measure circulating inflammatory cytokines that modulate sleep in patients with
ALI/ARDS randomized to receive two different sedation strategies: central α2 adrenergic
sedative-analgesic (dexmedetomidine) versus a conventional sedation strategy (midazolam and
fentanyl) in a randomized, double blind, cross-over study. Specific Aim 1: To assess the
short-term effect of an α2 adrenergic agent on sleep quality in critically ill patients with
ALI/ARDS. Specific Aim 2: To assess the short-term effect of an α2 adrenergic agent on
sleep-modulating inflammatory cytokines in critically ill patients with ALI/ARDS. Specific
aim 3: To determine the effect of α2 adrenergic agent on the in-vitro production of
sleep-modulating inflammatory cytokines by peripheral blood mononuclear cells of patients
with ALI/ARDS. Collectively, our study will identify whether sleep disruption in such
patients can be minimized. In the long-term, this program of research will identify sedation
practices that are least associated with adverse short- and long-term consequences of
critical illness, and thereby ultimately help improve quality of life of patients surviving
critical illness

Inclusion Criteria:

- Age range 18-85 (inclusive)

- Potential subjects receiving mechanical ventilation

- Potential subjects must have:

1. Acute hypoxemia with a PaO2/FiO2 < 300 mm Hg (for ALI) OR < 200 mm Hg (for ARDS),

2. Bilateral infiltrates (including very mild infiltrates)

3. No clinical evidence of left atrial hypertension, or a pulmonary artery wedge
pressure < 18 mm Hg.

- Potential subjects will be recruited after intubation and following a (systolic BP >
90 mm Hg on 2 or less continuous infusion of pressors) and ventilatory parameters
(requiring < 60% fractional inspired O2 concentration [FiO2] and PEEP < 8 cm H2O).

Exclusion Criteria:

- Acute myocardial infarction or unstable angina or active myocardial ischemia

- Potential subjects who are considered too unstable to undergo this investigation by
their primary physician.

1. Symptomatic bradycardia (ventricular rate < 50 accompanied by hypotension
[Systolic blood pressure < 90 mm Hg] or atrio-ventricular block [second degree
type II or greater]).

2. Known inability to tolerate beta-blockers or dexmedetomidine.

3. Systolic blood pressure < 90 mmHg despite continuous infusions of 2 vasopressors
before the start of study drug infusion.

- Potential subjects who are comatose or suffering from severe debilitating neurological
disease (Intracerebral hemorrhage).

- History of severe dementia (derived from medical records or family sources).

- Active seizures

- Alcohol abuse by history

- Clinical evidence for decompensated congestive heart failure (elevated jugular venous
distension, dependent edema) with echocardiographic evidence for significant systolic
heart failure- left ventricular ejection fraction <30%.

- Renal failure (on renal dialysis); Hepatocellular failure (Child-Pugh class C).

- Metastatic or terminal cancer and patients with do-not-resuscitate orders

- Pregnancy

- Potential subjects who are expected to be extubated within 48 hours