HEAL: Hemodynamics and Extravascular Lung Water in Acute Lung Injury

• Sponsor: Oregon Health and Science University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00624650
• Collaborator: Pulsion Medical Systems (Industry), Oregon Clinical and Translational Research Institute (Other)
• Enrollment: 33
• Locations: 3
• Arms: 2
• Duration (Months): 35
• Patients Per Site: 11
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this study is to test a treatment that tries to reduce the amount of fluid in the lungs of subjects with acute lung injury to see if this is helpful.

Condition or Disease	Intervention/Treatment	Phase
Acute Lung Injury	Drug: Diuresis (furosemide) part I; Other: Fluid Bolus (crystalloid or albumin); Other: Fluid Bolus (crystalloid or albumin); Drug: Vasopressors (Norepinephrine, Vasopressin, Phenylephrine, Epinephrine); Drug: Vasopressors (Norepinephrine, Vasopressin, Phenylephrine, Epinephrine); Drug: Dobutamine; Drug: Dobutamine; Other: Concentrate all drips and nutrition; Drug: Diuresis (furosemide) part II; Procedure: Dialysis	Phase 2

Detailed Description

The objective of this study is to conduct a randomized, controlled trial of a goal directed therapy designed to improve outcome in patients with acute lung injury (ALI). The investigators are comparing two algorithmic approaches in managing patients with ALI - one, the control arm, attempts to reduce the amount of fluid in the lung in patients with ALI by diuresis based on central venous pressure and urine output, the other the treatment arm attempting to reduce lung water by directing therapy to measured lung water and using more sensitive indicators of preload status than CVP. The protocol uses measured extravascular lung water (EVLW) to direct diuresis and appropriate fluid restriction in a goal directed fashion in order to lower EVLW towards the normal range.

Study Design

• Study Type: Interventional
• Actual Enrollment: 33 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Primary Purpose: Treatment
• Official Title: Hemodynamics and Extravascular Lung Water in Acute Lung Injury: A Prospective Randomized Controlled Multicentered Trial of Goal Directed Treatment of EVLW Versus Standard Management for the Treatment of Acute Lung Injury
• Study Start Date: Feb 1, 2008
• Actual Primary Completion Date: Jan 1, 2011
• Actual Study Completion Date: Jan 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Modified FACTT (control) The investigators control arm consists of a simplified algorithm for conservative management of fluids in patients with ALI, as to be published by the ARDSnet group, based on the protocol used in the FACTT trial. The protocol calls for strict adherence to ARDSnet ventilation, our weaning protocol and use of only select vasoactive, beta-adrenergic drugs as it is felt that variation in these treatments could seriously confound our results. Albuterol administration will not be permitted in the either arm except for life threatening bronchospasm not responsive to ipratropium. Ipratropium may be administered at the treating physician's discretion for bronchospasm. PiCCO's will be placed in each control patient and data recorded twice daily. The treating physician's will be blinded to this data.	Drug: Diuresis (furosemide) part I; Goal: Overall I/O net negative 50ml/hour Initiation: Continuous IV furosemide at 3mg/hour or last known protocol specified dose Titrate up or down by 3mg/hour increments every hour as needed to establish diuresis goal Do not exceed 30mg/hour Furosemide Bolus: If unable to establish adequate diuresis at maximum dose may attempt furosemide bolusing as follows By intravenous bolus give 30, then 60, then 80, and 120 mg - one bolus dose every hour until urine output results in 1 ml/kg PBW/hr net negative fluid balance per hour Bolusing trials may be done at will but total furosemide dose may not exceed 800mg/24hour period; Other: Fluid Bolus (crystalloid or albumin); 15 ml/kg PBW crystalloid (round to nearest 250 ml) or 25 grams albumin as rapidly as possible. Used for patients with a measured CVP<8 or measured PaOP <12mmHg in addition to concurrent urine output of <0.5 ml/kg/hr; Drug: Vasopressors (Norepinephrine, Vasopressin, Phenylephrine, Epinephrine); (may use any alone or in combination) Norepinephrine - 0.05mcg/kg/min - increase for effect not to exceed (NTE) 1mcg/kg/min. Vasopressin - 0.04 international units/hour Phenylephrine - 7mcg/min - may increase to for effect not to exceed 500mcg/min. Epinephrine - 1 mcg/min - may increase for effect not to exceed 20mcg/min. Weaning: When MAP ≥ 60 mm/Hg on stable dose of vasopressor begin reduction of vasopressor by greater than or equal to 25% stabilizing dose at intervals ≤ 4 hours to maintain MAP ≥ 60 mm/Hg.; Drug: Dobutamine; Begin at 5mcg/kg/min and increase by 3 mcg/kg/min increments at 15 minute intervals until C.I. ≥ 2.5 or maximum dose of 20mcg/kg/min has been reached. Begin weaning 4 hours after low CI is reversed. Wean by ≥ 25% of the stabilizing dose at intervals of ≤ 4 hours to maintain hemodynamic algorithm goals. If patient is on dobutamine as a result of an earlier cell assignment, dobutamine should be ignored for the purpose of subsequent assignment, but should be continued to be weaned per protocol.; Drug: Diuresis (furosemide) part II; Withhold furosemide if: Significant hypokalemia (K+ <= 2.5 meq/L), or hypernatremia (Na+ >= 155 meq/L) occurs within last 12 hours may then be restarted if the prevailing condition no longer exists Dialysis dependence Oliguria (less than 0.5ml/kg/hour) with either creatinine > 3, or clinical suspicion of rapidly evolving ARF More than 800mg has been given in less then 24 hours Creatinine increases > 1.5 mg/dl in any 24 hour period; Procedure: Dialysis; Need for CVVHD or intermittent hemodialysis to be determined by treating clinicians. CVC arm: If fluid management to be accomplished with dialysis then fluid balance goals to be determined per clinicians. EVLW arm: Fluid balance as per algorithm When using intermittent HD it is recommended that no more than 2 liters net negative fluid is removed per dialysis session. Total fluid removal per run to be estimated by the clinicians to attain CVP or GEDI goals per algorithm.
Experimental: EVLW When EVLW exceeds 9 ml/kg PBW the algorithmic treatment is begun and continued until EVLW ≤9 ml/kg PBW or extubation whichever comes first as tolerated (see figure 6). Furosemide and volume contraction are initiated when sufficient volumetric preload (GEDI) is available to enact volume contraction as a means to decrease measured EVLW without causing concomitant hypoperfusion. Fluid administration is also guided by changes in EVLW. An increase in EVLW > 2ml/kg PBW as a result of fluid administration curtails any further fluid administration until the next scheduled measurement. Our ultimate treatment goal is to maximally lower EVLW towards the normal range - thus improving lung mechanics and gas exchange - without causing concomitant hemodynamic compromise and end-organ injury. By doing so we feel this algorithmic, goal directed, therapeutic approach should improve outcome.	Drug: Diuresis (furosemide) part I; Goal: Overall I/O net negative 50ml/hour Initiation: Continuous IV furosemide at 3mg/hour or last known protocol specified dose Titrate up or down by 3mg/hour increments every hour as needed to establish diuresis goal Do not exceed 30mg/hour Furosemide Bolus: If unable to establish adequate diuresis at maximum dose may attempt furosemide bolusing as follows By intravenous bolus give 30, then 60, then 80, and 120 mg - one bolus dose every hour until urine output results in 1 ml/kg PBW/hr net negative fluid balance per hour Bolusing trials may be done at will but total furosemide dose may not exceed 800mg/24hour period; Other: Fluid Bolus (crystalloid or albumin); 10 ml/kg PBW crystalloid (round to nearest 70ml) or 25 grams albumin as rapidly as possible. Perform thermodilution immediately before and after and 60 minutes after each bolus. If EVLW increases > 2ml/kg PBW within 60 minutes after a bolus do not give any further boluses until next regularly scheduled measurement. This therapy is available for patients with a map < 60 or who are on vasopressors that also have a measured GEDI less than goal; Drug: Vasopressors (Norepinephrine, Vasopressin, Phenylephrine, Epinephrine); (may use alone or in combination) Norepinephrine - 0.05mcg/kg/min - increase for effect not to exceed (NTE) 1mcg/kg/min. Vasopressin - 0.04 international units/hour Phenylephrine - 7mcg/min - may increase to for effect not to exceed 500mcg/min. Epinephrine - 1 mcg/min - may increase for effect not to exceed 20mcg/min. Weaning: When MAP ≥ 60 mm/Hg on stable dose of vasopressor begin reduction of vasopressor by greater than or equal to 25% stabilizing dose at intervals ≤ 4 hours to maintain MAP ≥ 60 mm/Hg. In the experimental arm vasopressors are a treatment option in patients with a Mean Arterial Pressure of < 60; Drug: Dobutamine; Begin at 5mcg/kg/min and increase by 3 mcg/kg/min increments at 15 minute intervals until C.I. ≥ 2.5 or maximum dose of 20mcg/kg/min has been reached. Begin weaning 4 hours after low CI is reversed. Wean by ≥ 25% of the stabilizing dose at intervals of ≤ 4 hours to maintain hemodynamic algorithm goals. If patient is on dobutamine as a result of an earlier cell assignment, dobutamine should be ignored for the purpose of subsequent assignment, but should be continued to be weaned per protocol. Used in patients with a measured cardiac index < 2.5; Other: Concentrate all drips and nutrition; Concentrate all drips and nutrition in order to minimize fluid volume as much as possible. Intravenous fluid to be run at keep vein open rate. EVLW arm: Patients with a MAP > 60 and off vasopressors for >12 hours, as well as patients with a measured cardiac index >2.5 that also have a measured GEDI > goal.; Drug: Diuresis (furosemide) part II; Withhold furosemide if: Significant hypokalemia (K+ <= 2.5 meq/L), or hypernatremia (Na+ >= 155 meq/L) occurs within last 12 hours may then be restarted if the prevailing condition no longer exists Dialysis dependence Oliguria (less than 0.5ml/kg/hour) with either creatinine > 3, or clinical suspicion of rapidly evolving ARF More than 800mg has been given in less then 24 hours Creatinine increases > 1.5 mg/dl in any 24 hour period; Procedure: Dialysis; Need for CVVHD or intermittent hemodialysis to be determined by treating clinicians. CVC arm: If fluid management to be accomplished with dialysis then fluid balance goals to be determined per clinicians. EVLW arm: Fluid balance as per algorithm When using intermittent HD it is recommended that no more than 2 liters net negative fluid is removed per dialysis session. Total fluid removal per run to be estimated by the clinicians to attain CVP or GEDI goals per algorithm.

Outcome Measures

Primary Outcome Measures

1. The Primary Efficacy Variable Will be the Total Reduction in Measured Lung Water [The first seven days of treatment]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Acute onset of:

1. PaO2/FiO2 less than or equal to 300.

2. Bilateral infiltrates consistent with pulmonary edema on the frontal chest radiograph.

3. Requirement for positive pressure ventilation through an endotracheal tube or tracheostomy.

4. No clinical evidence of left atrial hypertension that would explain the pulmonary infiltrates. If measured, pulmonary arterial wedge pressure less than or equal to 18 mmHg.

Exclusion Criteria:

1. Age younger than 18 years old.

2. Greater than 24 hours since all inclusion criteria first met.

3. Neuromuscular disease that impairs ability to ventilate without assistance, such as C5 or higher spinal cord injury, amyotrophic lateral sclerosis, Guillain-Barré syndrome, myasthenia gravis, or kyphoscoliosis (see Appendix I.A).

4. Pregnancy (negative pregnancy test required for women of child-bearing potential).

5. Severe chronic respiratory disease (see Appendix I.C).

6. Severe Chronic Liver Disease (Child-Pugh 11 - 15, see Appendix I.E)

7. Weight > 160 kg.

8. Burns greater than 70% total body surface area.

9. Malignancy or other irreversible disease or conditions for which 6-month mortality is estimated to be greater than 50 % (see Appendix I.A).

10. Known cardiac or vascular aneurysm.

11. Contraindications to femoral arterial puncture - platelets < 30, bilateral femoral arterial grafts, INR > 3.0.

12. Not committed to full support.

13. Participation in other experimental medication trial within 30 days.

14. Allergy to intravenous lasix or any components of its carrier.

15. History of severe CHF - NYHA class ≥ III, previously documented EF < 30%.

16. Diffuse alveolar hemorrhage.

17. Presence of reactive airway disease (active will be defined based on recent frequency and amounts of MDI's use and steroids to control the disease).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Kaiser Permanente Sunnyside	Clackamas	Oregon	United States	97015
2	Legacy Good Samaritan	Portland	Oregon	United States	97210
3	Oregon Health and Science University	Portland	Oregon	United States	97219

Sponsors and Collaborators

• Oregon Health and Science University
• Pulsion Medical Systems
• Oregon Clinical and Translational Research Institute

Investigators

• Principal Investigator: Charles Phillips, M.D., Oregon Health and Science University

Study Documents (Full-Text)

None provided.

More Information

Publications

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• Responsible Party: Oregon Health and Science University
• ClinicalTrials.gov Identifier: NCT00624650
• Other Study ID Numbers: IRB00003491; IRB #e2978
• First Posted: Feb 27, 2008
• Last Update Posted: Sep 10, 2019
• Last Verified: Aug 1, 2019

• Keywords provided by Oregon Health and Science University: Acute Lung Injury; Extravascular Lung Water; Acute Respiratory Distress Syndrome
• Additional relevant MeSH terms: Lung Injury; Acute Lung Injury; Wounds and Injuries; Phenylephrine; Dobutamine; Furosemide; Vasopressins; Arginine Vasopressin; Epinephrine; Racepinephrine; Oxymetazoline; Norepinephrine; Vasoconstrictor Agents; Epinephryl borate

Study Results

Participant Flow

Arm/Group Title	Modified FACTT (Control)	EVLW
Arm/Group Description
Period Title: Overall Study
STARTED	17	16
COMPLETED	16	15
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	Modified FACTT (Control)	EVLW	Total
Arm/Group Description	Total of all reporting groups
Overall Participants	17	16	33
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	15 88.2%	14 87.5%	29 87.9%
>=65 years	2 11.8%	2 12.5%	4 12.1%
Sex: Female, Male (Count of Participants)
Female	13 76.5%	6 37.5%	19 57.6%
Male	4 23.5%	10 62.5%	14 42.4%
Region of Enrollment (participants) [Number]
United States	17 100%	16 100%	33 100%

Outcome Measures

1. Primary Outcome

Title	The Primary Efficacy Variable Will be the Total Reduction in Measured Lung Water
Time Frame	The first seven days of treatment

Outcome Measure Data

Analysis Population Description

The study's Principal Investigator departed the institution before analyses were conducted. OHSU will never have analyses complete for this study. The study device is no longer manufactured.

Arm/Group Title	Modified FACTT (Control)	EVLW
Arm/Group Description
Measure Participants	0	0

Adverse Events

Arm/Group Title	Modified FACTT (Control)		EVLW
Arm/Group Description
All Cause Mortality
	Modified FACTT (Control)		EVLW
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/17 (11.8%)		5/16 (31.3%)
Serious Adverse Events
	Modified FACTT (Control)		EVLW
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/17 (11.8%)		5/16 (31.3%)
Cardiac disorders
Death	2/17 (11.8%)		5/16 (31.3%)
Other (Not Including Serious) Adverse Events
	Modified FACTT (Control)		EVLW
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/17 (5.9%)		2/16 (12.5%)
Renal and urinary disorders
Hypernatremia	1/17 (5.9%)		2/16 (12.5%)

Limitations/Caveats

Principal Investigator departed the institution before Primary Outcome Measure analyses were conducted.

More Information

Certain Agreements

Principal Investigators are NOT 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.