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Hemodynamics and Extravascular Lung Water in Acute Lung Injury (HEAL)

This study has been completed.
Sponsor:
Collaborators:
Pulsion Medical Systems
Oregon Clinical and Translational Research Institute
Information provided by:
Oregon Health and Science University
ClinicalTrials.gov Identifier:
NCT00624650
First received: February 19, 2008
Last updated: May 27, 2011
Last verified: July 2010
  Purpose

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

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Subject)
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

Resource links provided by NLM:


Further study details as provided by Oregon Health and Science University:

Primary Outcome Measures:
  • The primary efficacy variable will be the total reduction in measured lung water [ Time Frame: The first seven days of treatment ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • The number of ventilator-free days (VFDs [ Time Frame: number of days after initiating unassisted breathing to day 28 after randomization, assuming a patient survives for at least 2 consecutive days after initiating unassisted breathing and remains free of assisted breathing. ] [ Designated as safety issue: No ]
  • The physiologic severity of clinical lung injury as measured by the 4-point acute lung injury scoring system. [ Time Frame: Day 1-28 ] [ Designated as safety issue: No ]
  • Number of ICU-free days [ Time Frame: From randomization to day 28 ] [ Designated as safety issue: No ]
  • Number of Organ Failure Free Days [ Time Frame: Randomization to day 28 ] [ Designated as safety issue: No ]
  • Percentage of patients alive at day 28 in patients with ALI [ Time Frame: Day 28 ] [ Designated as safety issue: No ]
  • Percentage of patients discharged alive from hospital within 60 days [ Time Frame: Day 60 ] [ Designated as safety issue: No ]
  • Mortality and VFDs in patients with pre- randomization PaO2/FiO2 less than or equal to 200 [ Time Frame: Day 60 ] [ Designated as safety issue: No ]
  • Mortality prior to hospital discharge to day 60 in patients who receive norepinephrine, dobutamine, or vasopressin at any point during the treatment period [ Time Frame: Day 60 ] [ Designated as safety issue: No ]
  • number of VFDs to day 28 in patients who receive the following intravenous vasoactive agonists (norepinephrine, dobutamine, and vasopressin) at any point during the treatment period [ Time Frame: Day 28 ] [ Designated as safety issue: No ]
  • Mortality prior to hospital discharge to day 60 in patients with shock (defined in 2.3.6 in the HEAL protocol) at the time of randomization [ Time Frame: Day 60 ] [ Designated as safety issue: No ]
  • number of VFDs to day 28 in patients with shock (defined in 2.3.6 in the HEAL protocol) at the time of randomization [ Time Frame: Day 28 ] [ Designated as safety issue: No ]
  • Mortality prior to hospital discharge to day 60 in patients with severe sepsis (defined in 2.3.8 in the HEAL protocol) at the time of randomization. [ Time Frame: Day 60 ] [ Designated as safety issue: No ]
  • number of ventilator-free days to day 28 in patients with severe sepsis (defined in 2.3.8) at the time of randomization. [ Time Frame: Day 28 ] [ Designated as safety issue: No ]
  • Changes in quasistatic total respiratory system compliance [ Time Frame: Randomization to day 28 ] [ Designated as safety issue: No ]
  • Need for vasoactive medication - dose, duration and total amounts of all vasoactive medications. [ Time Frame: Randomization to day 28 ] [ Designated as safety issue: No ]
  • Changes in the plasma levels of interleukin-1b, 6 and 8, and TNF-α. [ Time Frame: 60 days ] [ Designated as safety issue: No ]
  • Changes in the airspace (bronchoalveolar lavage: BAL) levels of interleukin-1b, 6 and 8, and TNF-α. Changes in BAL cell count and differential. [ Time Frame: 60 days ] [ Designated as safety issue: No ]

Estimated Enrollment: 72
Study Start Date: February 2008
Study Completion Date: January 2011
Primary Completion Date: January 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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:

  1. Continuous IV furosemide at 3mg/hour or last known protocol specified dose
  2. Titrate up or down by 3mg/hour increments every hour as needed to establish diuresis goal
  3. Do not exceed 30mg/hour

Furosemide Bolus:

  1. If unable to establish adequate diuresis at maximum dose may attempt furosemide bolusing as follows
  2. 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
  3. 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)

  1. Norepinephrine - 0.05mcg/kg/min - increase for effect not to exceed (NTE) 1mcg/kg/min.
  2. Vasopressin - 0.04 international units/hour
  3. Phenylephrine - 7mcg/min - may increase to for effect not to exceed 500mcg/min.
  4. 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
  1. 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.
  2. 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.
  3. 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:

  1. 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
  2. Dialysis dependence
  3. Oliguria (less than 0.5ml/kg/hour) with either creatinine > 3, or clinical suspicion of rapidly evolving ARF
  4. More than 800mg has been given in less then 24 hours
  5. Creatinine increases > 1.5 mg/dl in any 24 hour period
Procedure: Dialysis
  1. Need for CVVHD or intermittent hemodialysis to be determined by treating clinicians.
  2. CVC arm: If fluid management to be accomplished with dialysis then fluid balance goals to be determined per clinicians.
  3. EVLW arm: Fluid balance as per algorithm
  4. 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:

  1. Continuous IV furosemide at 3mg/hour or last known protocol specified dose
  2. Titrate up or down by 3mg/hour increments every hour as needed to establish diuresis goal
  3. Do not exceed 30mg/hour

Furosemide Bolus:

  1. If unable to establish adequate diuresis at maximum dose may attempt furosemide bolusing as follows
  2. 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
  3. 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)

  1. Norepinephrine - 0.05mcg/kg/min - increase for effect not to exceed (NTE) 1mcg/kg/min.
  2. Vasopressin - 0.04 international units/hour
  3. Phenylephrine - 7mcg/min - may increase to for effect not to exceed 500mcg/min.
  4. 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
  1. 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.
  2. 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.
  3. 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:

  1. 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
  2. Dialysis dependence
  3. Oliguria (less than 0.5ml/kg/hour) with either creatinine > 3, or clinical suspicion of rapidly evolving ARF
  4. More than 800mg has been given in less then 24 hours
  5. Creatinine increases > 1.5 mg/dl in any 24 hour period
Procedure: Dialysis
  1. Need for CVVHD or intermittent hemodialysis to be determined by treating clinicians.
  2. CVC arm: If fluid management to be accomplished with dialysis then fluid balance goals to be determined per clinicians.
  3. EVLW arm: Fluid balance as per algorithm
  4. 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.

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00624650

Locations
United States, Oregon
Kaiser Permanente Sunnyside
Clackamas, Oregon, United States, 97015
Legacy Good Samaritan
Portland, Oregon, United States, 97210
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
  More Information

Publications:
Ware, L.B. and M.A. Matthay, The acute respiratory distress syndrome. N Engl J Med, 2000. 342(18): p. 1334-49.
Rubenfeld, G.D., et al., Incidence and outcomes of acute lung injury. N Engl J Med, 2005. 353(16): p. 1685-93.

Responsible Party: Charles Phillips, M.D., Associate Professor of Medicine, Oregon Health and Science University
ClinicalTrials.gov Identifier: NCT00624650     History of Changes
Other Study ID Numbers: IRB00003491, IRB #e2978
Study First Received: February 19, 2008
Last Updated: May 27, 2011
Health Authority: United States: Institutional Review Board

Keywords provided by Oregon Health and Science University:
Acute Lung Injury
Extravascular Lung Water
Acute Respiratory Distress Syndrome

Additional relevant MeSH terms:
Acute Lung Injury
Lung Injury
Respiratory Distress Syndrome, Adult
Lung Diseases
Respiration Disorders
Respiratory Tract Diseases
Thoracic Injuries
Wounds and Injuries
Arginine Vasopressin
Dobutamine
Epinephrine
Epinephryl borate
Furosemide
Norepinephrine
Oxymetazoline
Phenylephrine
Racepinephrine
Vasoconstrictor Agents
Vasopressins
Adrenergic Agents
Adrenergic Agonists
Adrenergic alpha-1 Receptor Agonists
Adrenergic alpha-Agonists
Adrenergic beta-1 Receptor Agonists
Adrenergic beta-Agonists
Anti-Asthmatic Agents
Antidiuretic Agents
Autonomic Agents
Bronchodilator Agents
Cardiotonic Agents

ClinicalTrials.gov processed this record on November 25, 2014