Pulmonary Vascular Effects of Respiratory Rate & Carbon Dioxide

The Pulmonary Vascular Consequences of Divergent Strategies for Low Tidal Volume Ventilation: Hypercapnia or High Respiratory Rate?

The purpose of this protocol is to perform serial physiological measurements and blood testing on mechanically ventilated patients comparing conditions of eucapnia and hypercapnia in the same patient. We will be testing two hypotheses: (1) while administering inspired carbon dioxide (CO2), eucapnia achieved by high respiratory rate (EHR) significantly decreases pulmonary artery pressures compared to hypercapnia with a lower respiratory rate (HLR), and (2) that EHR decreases myocardial strain compared to HLR.

Study Overview

• Status: Withdrawn
• Conditions: Acute Respiratory Distress Syndrome; Low Tidal Volume Ventilation
• Intervention / Treatment: Other: HLR; Other: EHR

Detailed Description

The purpose of this protocol is to perform serial physiological measurements and blood testing on mechanically ventilated patients comparing conditions of eucapnia (maintaining alveolar ventilation to target carbon dioxide partial pressure (pCO2) 35-40 mm Hg) and hypercapnia (providing inspired CO2 to target pCO2 55-60 mm Hg) in the same patient. This prospective clinical study will enroll consenting adult patients scheduled for elective cardiac surgery and who require postoperative mechanical ventilation, pulmonary artery (Swan-Ganz) catheter monitoring, and arterial catheterization as part of routine standard care during the immediate postoperative period. The study will perform measurements using available ventilator monitors, ventilator in-line pneumotachograph and capnograph, measurements from the indwelling pulmonary artery catheter, transesophageal echocardiography, and other measurements available as part of routine care. The entire experimental protocol will be performed in one day over 2-4 hours, and the protocol will not interfere with routine postoperative care, nor prolong the need for mechanical ventilation, pulmonary artery catheterization, arterial catheterization, or intensive care unit length of stay.

Ventilation with low tidal volumes has been shown definitively to improve mortality from acute respiratory distress syndrome (ARDS)1 and may provide benefit even in patients without ARDS.2 During low tidal volume ventilation, practice varies on whether to allow some degree of alveolar hypoventilation with incidental hypercapnic acidosis (termed "permissive hypercapnia"),3 or to increase respiratory rate to maintain alveolar ventilation and target eucapnia, often requiring respiratory rates > 30/min.4 The physiological consequences of these divergent strategies remain to be fully elucidated. We propose the following study to distinguish the effects of a eucapnic high respiratory rate (EHR) strategy from a hypercapnic low respiratory rate (HLR) strategy on pulmonary hemodynamics during low tidal volume ventilation.

Specific Aim: To test the hypothesis that, while administering inspired CO2, eucapnia achieved by high respiratory rate (EHR) significantly decreases pulmonary artery pressures compared to hypercapnia with a lower respiratory rate (HLR).

Specific Aim: To test the hypothesis that EHR decreases myocardial strain compared to HLR.

• Study Type: Interventional
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02122
      • Beth Israel Deaconess Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 95 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age ≥ 18 years old.
• Able to consent pre-operatively prior to scheduled cardiac surgery.
• Intubation on mechanical ventilation post-operatively.
• Presence of a pulmonary artery catheter and/or central venous catheter as part of usual care post-operatively.
• Presence of a radial, brachial, or femoral arterial catheter as part of usual care post-operatively.

Exclusion Criteria:

• Significant intra-operative or immediate post-operative complications, such as uncontrolled bleeding or persistent hemodynamic instability.
• Intra-cardiac or intrapulmonary shunt.
• Persistent post-operative moderate or severe hypoxemia, defined as PaO2/FiO2 < 200 mmHg.
• Moderate or severe lung disease, including moderate or severe chronic obstructive pulmonary disease (COPD) or asthma.
• Recently treated for bleeding varices, stricture, or hematemesis, esophageal trauma, recent esophageal surgery, or other contraindication to transesophageal echocardiography.
• Severe coagulopathy (platelet count < 10,000 or international normalized ratio [INR] > 4).
• History of lung, heart, or liver transplant.

• Elevated intracranial pressure or conditions where hypercapnia-induced elevations in intracranial pressure should be avoided, including:

  • Intracranial hemorrhage
  • Cerebral contusion
  • Cerebral edema
  • Mass effect (midline shift on head CT)
  • Flat EEG for > 2 hours
• Evidence of active air leak from the lung, such as broncho-pleural fistula or ongoing air leak from an existing chest tube.
• Treating physician refusal.
• Inability to obtain informed consent directly from the subject prior to surgery.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: HLR-first; Patients in this arm will have the "hypercapnia with low respiratory rate" (HLR) strategy first. Once hypercapnia is achieved via inspired carbon dioxide, no additional changes will be made to the ventilator. Once steady-state is achieved, physiological measurements will be taken. The patient will be returned to baseline settings for a 15-minute "rest period" before starting the EHR strategy per the cross-over design.	Other: HLR; Other Names: hypercapnia with low respiratory rate; Other: EHR; Other Names: eucapnia with high respiratory rate
Experimental: EHR-first; Patients in this arm will have the "eucapnia with high respiratory rate" (EHR) strategy first. Once hypercapnia is achieved via inspired carbon dioxide, respiratory rate will be increased until PetCO2 returns to baseline or up to 35 breaths per minute, as limited by the National Heart Lung and Blood Institute (NHLBI) ARDS Network protocol. fraction of inspired oxygen inspired oxygen fraction and set tidal volume will be maintained. Once steady-state is achieved, physiological measurements will be taken. The patient will be returned to baseline settings for a 15-minute "rest period" before starting the HLR strategy per the cross-over design.	Other: HLR; Other Names: hypercapnia with low respiratory rate; Other: EHR; Other Names: eucapnia with high respiratory rate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
mean pulmonary artery pressure (mPAP)	Pulmonary artery pressure will be measured directly by transducing the pulmonary artery catheter, and will include systolic (PASP) and diastolic (PADP) Ppa. The mean pulmonary artery pressure (mPAP) will be calculated according to the formula: mPAP = 1/3 PASP + 2/3 PADP	4 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Right ventricular systolic function	Right ventricular systolic function will be assessed using strain echocardiography or peak tricuspid annular systolic velocity.	4 hours

Collaborators and Investigators

• Sponsor: Beth Israel Deaconess Medical Center
• Investigators: Principal Investigator: Daniel Talmor, MD MPH, Beth Israel Deaconess Medical Center

Publications and helpful links

General Publications

• Acute Respiratory Distress Syndrome Network, Brower RG, Matthay MA, Morris A, Schoenfeld D, Thompson BT, Wheeler A. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000 May 4;342(18):1301-8. doi: 10.1056/NEJM200005043421801.
• Amato MB, Barbas CS, Medeiros DM, Magaldi RB, Schettino GP, Lorenzi-Filho G, Kairalla RA, Deheinzelin D, Munoz C, Oliveira R, Takagaki TY, Carvalho CR. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med. 1998 Feb 5;338(6):347-54. doi: 10.1056/NEJM199802053380602.
• Rubenfeld GD, Caldwell E, Peabody E, Weaver J, Martin DP, Neff M, Stern EJ, Hudson LD. Incidence and outcomes of acute lung injury. N Engl J Med. 2005 Oct 20;353(16):1685-93. doi: 10.1056/NEJMoa050333.
• Serpa Neto A, Cardoso SO, Manetta JA, Pereira VG, Esposito DC, Pasqualucci Mde O, Damasceno MC, Schultz MJ. Association between use of lung-protective ventilation with lower tidal volumes and clinical outcomes among patients without acute respiratory distress syndrome: a meta-analysis. JAMA. 2012 Oct 24;308(16):1651-9. doi: 10.1001/jama.2012.13730.
• Malhotra A. Low-tidal-volume ventilation in the acute respiratory distress syndrome. N Engl J Med. 2007 Sep 13;357(11):1113-20. doi: 10.1056/NEJMct074213.

Study record dates

Study Major Dates

• Study Start: September 1, 2013
• Primary Completion (Actual): August 1, 2014
• Study Completion (Actual): August 1, 2014

Study Registration Dates

• First Submitted: August 20, 2013
• First Submitted That Met QC Criteria: August 20, 2013
• First Posted (Estimate): August 22, 2013

Study Record Updates

• Last Update Posted (Actual): February 27, 2017
• Last Update Submitted That Met QC Criteria: February 24, 2017
• Last Verified: August 1, 2014

More Information

Terms related to this study

• Keywords: ARDS; pulmonary artery pressure; alveolar hypoventilation; hypercapnic acidosis; permissive hypercapnia; myocardial strain
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury
• Other Study ID Numbers: 2013P000222

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No