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

• Sponsor: National Institute of General Medical Sciences (NIGMS) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00608322
• Collaborator: (none)
• Enrollment: 49
• Location: 1
• Arms: 2
• Duration (Months): 44
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether inhaled nitric oxide is an effective treatment for microcirculatory dysfunction and acute organ system failure in the early stage of sepsis therapy.

Condition or Disease	Intervention/Treatment	Phase
Sepsis	Drug: Inhaled nitric oxide; Other: Sham inhaled nitric oxide	Phase 3

Detailed Description

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].

Study Design

• Study Type: Interventional
• Actual Enrollment: 49 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Randomized Double-blind Placebo-controlled Trial of Inhaled Nitric Oxide for the Treatment of Microcirculatory Dysfunction and Organ Failure in Sepsis
• Study Start Date: Aug 1, 2009
• Actual Primary Completion Date: Apr 1, 2013
• Actual Study Completion Date: Apr 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Subjects receive inhaled nitric oxide (40 parts per million) for six hours.	Drug: Inhaled nitric oxide; Inhaled nitric oxide, 40 parts per million, for six hours.; Other Names: INOmax
Sham Comparator: 2 Subjects receive sham inhaled nitric oxide for six hours.	Other: Sham inhaled nitric oxide; Sham inhaled nitric oxide administration, 0 parts per million, for six hours.

Outcome Measures

Primary Outcome Measures

1. Change in the Sequential Organ Failure Assessment (SOFA) Score [0-24 hours from protocol initiation]

2. Change in Sublingual Microcirculatory Flow Index (MFI) [0-2 hours of study drug administration]

   The MFI is a continuous scale from 0-3, with 3.0 being better outcome and 0.0 being worse outcome.

Secondary Outcome Measures

1. Lactate Clearance (Blood) [0-2 hours of study drug administration]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 14 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Confirmed or suspected infection (acute)

PLUS:

1. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cooper University Hospital	Camden	New Jersey	United States	08103

Sponsors and Collaborators

• National Institute of General Medical Sciences (NIGMS)

Investigators

• Principal Investigator: Stephen Trzeciak, MD, MPH, UMDNJ-Robert Wood Johnson Medical School at Camden, Cooper University Hospital, Camden, New Jersey

Study Documents (Full-Text)

None provided.

More Information

Publications

• Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M; Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001 Nov 8;345(19):1368-77.
• Sakr Y, Dubois MJ, De Backer D, Creteur J, Vincent JL. Persistent microcirculatory alterations are associated with organ failure and death in patients with septic shock. Crit Care Med. 2004 Sep;32(9):1825-31.
• Trzeciak S, Dellinger RP, Parrillo JE, Guglielmi M, Bajaj J, Abate NL, Arnold RC, Colilla S, Zanotti S, Hollenberg SM; Microcirculatory Alterations in Resuscitation and Shock Investigators. Early microcirculatory perfusion derangements in patients with severe sepsis and septic shock: relationship to hemodynamics, oxygen transport, and survival. Ann Emerg Med. 2007 Jan;49(1):88-98, 98.e1-2. Epub 2006 Nov 7.

• Responsible Party: Dr. Trzeciak, PI, The Cooper Health System
• ClinicalTrials.gov Identifier: NCT00608322
• Other Study ID Numbers: K23GM083211; 1K23GM083211-01
• First Posted: Feb 6, 2008
• Last Update Posted: Jul 11, 2013
• Last Verified: Jun 1, 2013

• Keywords provided by Dr. Trzeciak, PI, The Cooper Health System: Sepsis; Severe sepsis; Septic shock
• Additional relevant MeSH terms: Sepsis; Toxemia; Nitric Oxide

Study Results

Participant Flow

Recruitment Details	We enrolled septic patients in the Emergency Department and Intensive Care Unit

Arm/Group Title	Inhaled Nitric Oxide	Sham (Comparator)
Arm/Group Description	Subjects receive inhaled nitric oxide (40 parts per million) for six hours.	Subjects receive sham inhaled nitric oxide for six hours.
Period Title: Overall Study
STARTED	26	23
COMPLETED	24	22
NOT COMPLETED	2	1

Baseline Characteristics

Arm/Group Title	Inhaled Nitric Oxide	Sham (Comparator)	Total
Arm/Group Description	Subjects receive inhaled nitric oxide (40 parts per million) for six hours.	Subjects receive sham inhaled nitric oxide for six hours.	Total of all reporting groups
Overall Participants	26	23	49
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	17 65.4%	14 60.9%	31 63.3%
>=65 years	9 34.6%	9 39.1%	18 36.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59 (15)	58 (20)	58 (17)
Sex: Female, Male (Count of Participants)
Female	15 57.7%	10 43.5%	25 51%
Male	11 42.3%	13 56.5%	24 49%
Region of Enrollment (participants) [Number]
United States	26 100%	23 100%	49 100%

Outcome Measures

1. Primary Outcome

Title	Change in the Sequential Organ Failure Assessment (SOFA) Score
Time Frame	0-24 hours from protocol initiation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

2. Primary Outcome

Title	Change in Sublingual Microcirculatory Flow Index (MFI)
Description	The MFI is a continuous scale from 0-3, with 3.0 being better outcome and 0.0 being worse outcome.
Time Frame	0-2 hours of study drug administration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhaled Nitric Oxide	Sham (Comparator)
Arm/Group Description	Subjects receive inhaled nitric oxide (40 parts per million) for six hours.	Subjects receive sham inhaled nitric oxide for six hours.
Measure Participants	24	22
Median (Inter-Quartile Range) [units on a scale]	-0.06	-0.03

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inhaled Nitric Oxide, Sham (Comparator)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.37
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	0.03
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Lactate Clearance (Blood)
Time Frame	0-2 hours of study drug administration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Participants were followed for the duration of hospital stay, an average of 5 weeks.
Arm/Group Title	Inhaled Nitric Oxide		Sham (Comparator)
Arm/Group Description	Subjects receive inhaled nitric oxide (40 parts per million) for six hours.		Subjects receive sham inhaled nitric oxide for six hours.
All Cause Mortality
	Inhaled Nitric Oxide		Sham (Comparator)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Inhaled Nitric Oxide		Sham (Comparator)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/26 (34.6%)		6/23 (26.1%)
General disorders
Death	9/26 (34.6%)		6/23 (26.1%)
Other (Not Including Serious) Adverse Events
	Inhaled Nitric Oxide		Sham (Comparator)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/26 (34.6%)		6/23 (26.1%)
General disorders
Death	9/26 (34.6%)		6/23 (26.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.