Studies of Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome

NCT00159510 | Terminated Phase 1

• 3 other identifiers: 4001.721.132Helse Nord (Norway), projectnumber 4001.721.132
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 1

Brief Summary

Nitric oxide (NO) plays a pivotal role in maintenance of normal vascular tone. However, in sepsis the excessive production of NO results in myocardial depression, vasoplegia, and cytotoxic effects, thus promoting shock and multiple organ dysfunction. A recently completed study from our group showed advantageous cardiovascular effects of continuously infused methylene blue (MB), an inhibitor of NO pathway, in human septic shock. In another investigation, we have found that the combination of inhaled NO and continuously infused MB attenuates endotoxin-induced acute lung injury (ALI) in sheep. Our intention is, in a new study, to test the hypothesis that the combination of MB and NO (MB+NO) improves both cardiovascular and pulmonary functions as well as clinical outcome in patients with septic shock and ALI. Forty mechanically ventilated patients diagnosed with hyperdynamic septic shock and ALI, will be randomized to groups receiving

1. 1.Conventional treatment (control group)(n =10);
2. 2.MB infusion in addition to conventional treatment (n=10);
3. 3.Inhaled NO in addition to conventional treatment (n=10);
4. 4.MB infusion combined with inhaled NO (MB+NO) in addition to conventional treatment (n=10).

Conditions

Sepsis

Keywords

sepsis, methylene blue, nitric oxide, acute lung injury

Outcome Measures

Primary Outcomes (1)

• Mortality

  Mortality rate by Day 28

  28

Secondary Outcomes (2)

• Duration of inotropic and vasopressor support

  7 Days

• Severity of organ dysfunction

  7 Days

Study Arms (4)

Control

NO INTERVENTION

The control group with neither nitric oxide nor methylene blue used

MB alone

ACTIVE COMPARATOR

Single methylene blue used

Drug: Methylene blue

NO alone

ACTIVE COMPARATOR

Nitric oxide alone used

Drug: Nitric oxide

MB+NO

ACTIVE COMPARATOR

Both nitric oxide and methylene blue used

Drug: Methylene blue & nitric oxide

Interventions

Methylene blue DRUG

Injection bolus of 2 mg/kg PBW and infusion of 0.2 mg/kg/hr

MB alone

Nitric oxide DRUG

An inhalation of NO via ETT at 10 ppm, partially weaned by 72 hrs of therapy

Also known as: Not actual

NO alone

Methylene blue & nitric oxide DRUG

See the dosage in the previous arms

Also known as: Not actual

MB+NO

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Informed written consent from the patient, or a written consent from a relative together with a the doctor responsible for the treatment of the patient
• Aged 18 years or above.
• Severe sepsis diagnosed less than 72 h prior to randomization.
• Septic shock defined as a syndrome characterized by severe sepsis in association with either:
• a MAP \<70 mm Hg for at least 30 consecutive minutes despite fluid resuscitation or,
• a requirement for vasopressor support with a constant dose rate of either epinephrine \>0,05 mcg/kg/min and/or norepinephrine \>0.05 mcg/kg/min and/or dopamine \>5 mcg/kg/min and/or phenylephrine \>0.5 mcg/kg/min for at least 30 consecutive minutes to maintain a MAP \>90 mm Hg
• Cardiac index (CI) must be \>3.5 l/min/m2, pulmonary artery occlusion pressure (PAOP) must be between 8 and 18 mm Hg, and in the opinion of the investigator the patient must be adequately fluid resuscitated
• A 4 French Pulsiocath thermodilution catheter (Pulsion Medical Systems, München, Germany) in place in one of the femoral arteries and a 7 French thermistor-tipped balloon floatation catheter (Swan Ganz) in the pulmonary artery for determination of hemodynamics, including extravascular lung water index (EVLWI).
• A dedicated intravenous line for infusion of MB
• A respirator with a device for delivery of gaseous NO to the inspiration gas and equipped with analysis tools for lung mechanics
• The patients will be treated in intensive care units with the possibility to provide full life support for the whole duration of the study

You may not qualify if:

• \) Patients who have received vasopressor infusion therapy as described in the definition of septic shock either intermittently or continuously for a period of more than 24 h prior to randomization 2) The use of any vasoactive drug infusion other than epinephrine, norepinephrine, dopamine, phenylephrine and dobutamine, at the time of study entry 3) Patients in whom either vasodilators or dobutamine are contraindicated 4) Patients who cannot have their MAP managed safely within the range of 70-90 mm Hg (e.g. patients with raised intracranial pressure) 5) Shock due to any cause other than severe sepsis (e.g. drug reaction or drug overdose, adrenal insufficiency, pulmonary embolus, burn injury etc.) 6) Patients that are immunocompromised due to any of the following:
• known corticosteroid therapy either greater than or equal to a total daily dose equivalent to 1 mg/kg or greater than 70 mg/day of oral prednisolone for at least 7 consecutive days within one month prior to study entry,
• clinically suspected or known to have Acquired Immunodeficiency Syndrome (AIDS),
• granulocyte count less than 1000/mm3 due to a cause other than severe sepsis (e.g. metastatic or hematological malignancies or chemotherapy),
• immunosuppressant therapy (e.g. due to an organ or bone marrow transplant), 7) Underlying disease, exclusive of septic shock, which is expected to cause death within 1 month from study entry 8) Within 30 days prior to this study, the patient should not have been included in any other randomized therapeutic study of an agent not licensed, or administration of any other investigational agent for the treatment of sepsis and/or septic shock. Patients must not participate in such studies for at least 30 days after enrolment into this study.
• \) Pregnant women, pregnancy test required of any fertile women.

Sponsors & Collaborators

• Northern State Medical University: lead
• Helse Nord: collaborator

Study Sites (1)

University Hospital #1

Arkhangelsk, Russia, 163000, Russia

Location

MeSH Terms

Conditions

Sepsis; Acute Lung Injury

Interventions

Methylene Blue; Nitric Oxide

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Lung Injury; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Phenothiazines; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Reactive Nitrogen Species; Free Radicals; Inorganic Chemicals; Nitrogen Oxides; Nitrogen Compounds; Oxides; Oxygen Compounds

Study Officials

• Mikhail Y Kirov, MD, PhD

  Northern State Medical University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof.

Study Record Dates

• First Submitted: September 8, 2005
• First Posted: September 12, 2005
• Study Start: April 1, 2004
• Primary Completion: September 1, 2014
• Study Completion: September 1, 2014
• Last Updated: October 6, 2015

Record last verified: 2015-10

Locations

RU (1)