Randomized Trial of Inhaled Nitric Oxide to Augment Tissue Perfusion in Sepsis

Sepsis is a common and devastating disease that is responsible for 215,000 deaths annually
in the United States and is the leading cause of death in critically ill patients. Sepsis is
now recognized as a time-sensitive emergency, as patients stand the best chance for survival
when effective therapeutic interventions are delivered as early as possible. Early
goal-directed therapy (EGDT), a protocol-directed resuscitation strategy targeting early
optimization of global hemodynamic parameters, can save lives. Use of an EGDT protocol has
been associated with the largest mortality benefit demonstrated in sepsis randomized
controlled trials to date; however, sepsis still carries an extremely high mortality rate
(~30%), even with effective EGDT. As tissue perfusion in sepsis can remain markedly impaired
despite normalization of global hemodynamics, targeting macrocirculatory goals of
resuscitation (e.g. blood pressure, cardiac output) alone may not be sufficient.

Microcirculatory dysfunction is a pivotal element in the pathogenesis of sepsis.
Microcirculatory dysfunction causes impairment of tissue perfusion independent of global
hemodynamics, and is hypothesized to be a critical factor in the development of
sepsis-induced organ dysfunction, especially in the earliest phase of sepsis therapy.
Orthogonal polarization spectral (OPS) videomicroscopy is a technique that permits
non-invasive assessment of the microcirculation in human subjects. Using the OPS technique,
increasing severity of early microcirculatory derangements in sepsis patients have been
associated with acute multi-organ failure and mortality. We recently demonstrated that early
derangements of microcirculatory flow in sepsis patients were more severe in non-survivors
compared to survivors, even with the application of EGDT. Early recognition of
microcirculatory dysfunction and its reversal may lead to improved outcome. Currently,
however, there are no therapies to specifically target the microcirculation in sepsis. Novel
strategies that go beyond optimization of global hemodynamics and aim to improve
microcirculatory blood flow could be a new frontier for sepsis resuscitation. Since the
early resuscitation phase of therapy represents the greatest opportunity for impact on
clinical outcome in sepsis, it also appears to be the most promising window of opportunity
to demonstrate a benefit when investigating novel therapies.

Nitric oxide (NO) is an endogenous molecule that is essential for maintaining
microcirculatory homeostasis. Nitric oxide becomes especially critical for protecting
microcirculatory patency, integrity, and function when the microcirculation sustains a
severe insult (e.g. sepsis). Although NO production is globally upregulated in sepsis, the
production of NO is heterogeneous between and within organ systems at the microcirculatory
level. We believe that exogenous NO administration may preserve microcirculatory flow in
sepsis, and we hypothesize that this will be an effective therapy to augment tissue
perfusion. Inhaled nitric oxide (iNO) can deliver NO effectively to the distal
microcirculation and "open" low-flow microcirculatory units via modulation of microvascular
tone as well as anti-adhesive effects on the microvascular endothelium. Because iNO would
not be expected to induce or exacerbate arterial hypotension in sepsis patients, iNO
administration is an ideal method to test hypotheses about the effects of exogenous NO on
the microcirculation in sepsis.

We hypothesize that iNO will augment microcirculatory perfusion in sepsis resuscitation, and
this increase in microcirculatory flow will be associated with improved lactate clearance
(an important marker of resuscitation effectiveness) and decreased organ failure (a critical
patient-oriented outcome measure). To test our hypothesis, we generated two inter-related
specific aims:

Specific Aim 1: To determine whether iNO can augment tissue perfusion in sepsis
resuscitation. In a randomized double-blind placebo-controlled trial, we will evaluate the
effect of iNO compared to placebo on microcirculatory perfusion indices in sepsis patients
who exhibit persistent microcirculatory flow impairment after achievement of global
hemodynamic endpoints of resuscitation during EGDT.

Specific Aim 2: To determine whether iNO-mediated improvement in microcirculatory perfusion
in sepsis leads to more effective resuscitation and a reduction in organ failure. In a
randomized double-blind placebo-controlled trial, we will evaluate the effect of iNO on
clinical outcomes of sepsis patients: [(a) increase in lactate clearance from 0-2 hours, and
(b) decrease in the Sequential Organ Failure Assessment (SOFA) score from 0 to 24 hours].

Inclusion Criteria:

1. Confirmed or suspected infection (acute)

PLUS:

2. One or both of the following criteria for potential tissue hypoperfusion:

(2a) systolic blood pressure <90 mmHg despite 30cc/kg intravenous crystalloid challenge,
OR (2b) serum lactate >4 mmol/L.

Exclusion Criteria:

1. age < 14 years

2. pregnancy

3. "Do Not Resuscitate" status (prior to enrollment)

4. active clinically significant bleeding of any etiology

5. status-post cardiac arrest

6. need for immediate surgery

7. inability to place a sublingual videomicroscopy probe under the tongue (e.g.
inability to open the mouth or patient requirement of a high-flow face mask for
supplemental oxygen [although videomicroscopy can be performed in patients with an
endotracheal tube or nasal cannula])

8. >24 hours elapsed since first documented evidence of meeting criteria for potential
tissue hypoperfusion (2a or 2b above).

9. inability to obtain written informed consent