Contrast Enhanced PA Pressure Measurements
Condition: Pulmonary Hypertension
MeSH terms: Hypertension, Pulmonary
Study type: Observational

Summary: 
      Pulmonary hypertension (PH) is an abnormal increase of the pressure inside the lung
      circulation. This condition can be caused by many different diseases. If PH persists for a
      long period of time, irreversible damage to the lung circulation and to the heart may ensue.
      A definitive diagnosis of PH requires direct measurement of the pressure within the lung
      circulation with a procedure called right heart catheterization (RHC). While overall safe,
      RHC is an invasive procedure and is associated with a small risk of complications (~1.1%)
      and, very rarely, death (0.055%), even when performed in experienced laboratories. Therefore,
      alternative diagnostic approaches are often employed such as an ultrasound technique called
      Doppler echocardiography which is non-invasive, relatively inexpensive and widely available
      technique. It is suitable not only as a screening tool but also for serial monitoring of
      disease progression in PH. However, the accuracy of Doppler echocardiography in measuring
      pressure in the lung circulation appears to be modest in patients with suspected PH. To
      improve the performance of Doppler echocardiography it is common practice to inject a small
      amount of agitated saline or an echocardiographic contrast medium (usually composed of
      microbubbles of fat containing a minuscule amount of a gas) into a vein. However, the
      accuracy of using agitated saline or a contrast agent in the measurement of pressures inside
      the lung circulation has not been established. The proposed study will assess the accuracy of
      Doppler echocardiographic measurements of pressures in the pulmonary circulation by
      simultaneously comparing the pressures collected during a RHC. The investigators will enroll
      100 consecutive patients undergoing RHC in the Catheterization Laboratory of Northwestern
      Memorial Hospital. The investigators will measure pulmonary pressures by RHC and by Doppler
      echocardiography at baseline and following the injection of agitated saline as well as
      Optison®, an FDA-approved contrast agent commonly used in the echo laboratory. The
      investigators will then determine the accuracy of the Doppler echocardiography measurement
      without and with the use of agitated saline or Optison® with the measurements obtained during
      the RHC which is the gold standard. The results of this study will allow determination
      whether the use of echo contrast improves the accuracy of Doppler echocardiography and
      whether contrast-enhanced Doppler measurements are a clinically useful alternative to RHC
      measurements.
    

Detailed description: 
      Background Pulmonary hypertension (PH), defined as a mean pulmonary arterial pressure ≥ 25
      mmHg at rest as assessed by right heart catheterization (RHC), is present in several clinical
      conditions1. While considered the gold standard for the measurement of pulmonary pressure,
      RHC is an invasive procedure and is associated with a small risk of morbidity (1.1%) and
      mortality (0.055%) even when performed at experienced centers2. Therefore, alternative
      diagnostic approaches are often employed. Doppler echocardiography is non-invasive,
      relatively inexpensive and widely available technique. It is potentially suitable not only as
      a screening tool for PH but also as a method for serial monitoring of disease progression.
      Among the echocardiographic methods introduced to indirectly measure pulmonary arterial
      pressure, the tricuspid valve regurgitant jet method and the pulmonary artery regurgitant jet
      method have been widely adopted3. By measuring with Doppler ultrasound the maximum velocity
      of the tricuspid regurgitant jet (v), the transtricuspid pressure gradient (Pg) can be
      calculated using the modified Bernoulli equation: Pg = 4v2. Right ventricular systolic
      pressure (RVSP) can then be estimated by adding the transtricuspid pressure gradient to the
      right atrial pressure (RAP), indirectly estimated by the diameter of the inferior vena cava
      (IVC) and the degree of its collapse during spontaneous respiration4. In the absence of
      pulmonary valve stenosis, the RVSP can be equated to the pulmonary arterial systolic pressure
      (PASP). Measurements of PASP by Doppler echocardiography show a very high correlation
      (r=0.93) with values obtained by RHC 5. However, the accuracy of Doppler echocardiography
      appears to be limited in the assessment of patients with suspected PH, in whom the difference
      in PASP determined by echo and by RHC may be overestimated or underestimated by greater than
      10 mmHg6. To improve the performance of Doppler echocardiography, particularly in the
      presence of an inadequate jet of tricuspid regurgitation, it is common practice to use
      maneuvers such as the injection of agitated saline and/or echo contrast media such as
      Optison® (Perflutren Protein-Type A Microspheres Injectable Suspension, USP) to augment the
      tricuspid regurgitant velocity profile4. However, whether these maneuvers increase the
      accuracy of Doppler echocardiography in the assessment of right ventricular and pulmonary
      arterial pressures compared to standard Doppler echocardiography has not been investigated.

      2. Research Methods Study Design Cross-sectional investigation to assess: 1) the correlations
      between right sided (right ventricular, pulmonary artery, and right atrial) pressures
      measured by RHC and by Doppler echocardiography in the absence of contrast and during the
      intravenous administration of agitated saline or Optison®; and 2) to compare such measures by
      assessment modality. The investigators hypothesize that the correlations between right sided
      pressures measured by Doppler echo during agitated saline or Optison® will be higher than
      those measured in the absence of a contrast agent, and that the correlations between right
      sided pressures measured by Doppler echo during Optison® will be higher than those measured
      during agitated saline.

      The main correlations explored in the study will be:

      Correlation between right atrial pressure measured by RHC and by Doppler echocardiography in
      the absence of a contrast agent.

      Correlation between right ventricular pressure measured by RHC and by Doppler
      echocardiography in the absence of a contrast agent and during the intravenous administration
      of agitated saline or Optison®.

      Correlation between PASP measured by RHC and by Doppler echocardiography in the absence of a
      contrast agent and during the intravenous administration of agitated saline or Optison®.

      The main comparisons performed in the study will be:

      Comparison between PASP measured by Doppler echocardiography in the absence of a contrast
      agent and the PASP measured during the intravenous administration of agitated saline or
      Optison®.

      Comparison between PASP measured by Doppler echocardiography during the intravenous
      administration of agitated saline and during the intravenous administration of Optison®.

      Study Population This study will include unselected consecutively patients 18 to 80 years old
      referred for RHC to the Cardiac Catheterization Laboratory of Northwestern Memorial Hospital.
      The informed consent for RHC will be obtained as part of the clinical assessment. A study
      physician will then approach patients and eligibility will be assessed. A separate informed
      consent will be obtained for the limited Doppler echocardiographic study to be performed
      simultaneously during the RHC in patients interested in participating in the protocol.
      Participants are expected to be in the study only for the time required to conduct the RHC
      and the Doppler echocardiographic study.

      Exclusion Criteria

      Exclusion criteria will include:

      Severe pulmonary hypertension that is O2-dependent History of allergy to Optison®
      Hypersensitivity to perflutren, blood, blood products or albumin History of patent foramen
      ovale (PFO) or atrial septal defect (ASD) Known or suspected right-to-left, bi-directional,
      or transient right-to-left cardiac shunts Pregnancy Breastfeeding Advanced liver disease

      Withdrawal Criteria

      Withdrawal criteria will include:

      Sustained ventricular arrhythmias at the time of the procedure Evidence of PFO or ASD at the
      time of the Doppler echocardiographic study Development of hypersensitivity or allergy to
      Optison®

      Right Heart Catheterization

      Invasive hemodynamic assessment by Swan-Ganz catheterization will be performed according to
      the standard protocol of the Cardiac Catheterization Laboratory. The following parameters
      will be recorded:

      Right atrial pressure Right ventricular pressure Pulmonary artery pressure (PAP) Pulmonary
      capillary wedge pressure (PCWP) Cardiac output by thermodilution method (CO)

      Pulmonary vascular resistance (PVR) will be calculated according to the following formula:

      PVR=80*(Mean PAP-Mean PCWP)/CO

      Blood Drawing During the right heart catheterization a total of 30 mL of blood will be drawn
      when the tip of the catheter is in the main pulmonary artery, in the right pulmonary artery,
      and in the wedged position. Blood will be collected in tubes, placed in ice and subsequently
      processed. Whole blood, serum and plasma will be frozen and stored for measurement of various
      biomarkers (e.g. osteoprotegerin and endothelin-1).

      Doppler Echocardiographic Study Echocardiographic image acquisition will be performed using
      routine transthoracic echocardiography standards. Right ventricular outflow tract
      velocity-time integral (RVOT

      VTI) will be measured. The tricuspid annular plane systolic excursion (TAPSE) will be
      assessed in the apical four chamber view with the M-mode cursor through the lateral tricuspid
      annulus. The peak velocity (v) of the tricuspid regurgitation jet will be measured by Doppler
      echocardiography in multiple projections, and the tricuspid pressure regurgitation gradient
      (P) will be calculated from the modified Bernoulli equation using the highest velocity
      obtained:

      P=4v^2

      The inferior vena cava will be visualized in the subcostal view throughout multiple
      respiratory cycles and IVC diameter will be measured at end expiration and end inspiration to
      assess right atrial pressure according to current criteria. The ratio of peak tricuspid
      regurgitation velocity (TRV) and RVOT VTI, which has been shown to correlate with PVR, will
      be calculated.

      Monitoring The investigators will perform monitoring after the Optison® injection according
      to the package insert.

      Statistical Analyses The primary analyses will aim to correlate noninvasive and invasive RAP
      or PASP measures. Secondary analyses will compare such measures by assessment modality. To
      address the first specific goal, Pearson's correlation coefficient will be estimated for RAP
      obtained noninvasively and by RHC. For the remaining three goals, the same approach will be
      utilized to correlate the outcome of interest measured noninvasively and by RHC. For example,
      in the second goal, Pearson's correlation coefficient will be estimated for PASP measured
      noninvasively by agitated saline solution administration and invasively via RHC. For each
      specific goal, measurements via the two modalities will be displayed graphically using
      scatterplots. To summarize the nature of this relationship, flexible regression methods,
      including smoothing splines regression, will be utilized in each specific goal. In secondary
      analyses, for each specific goal, comparisons of the two outcomes (RAP or PASP values)
      measured using the noninvasive and the invasive approaches will be made based on paired
      t-test, if the outcomes are normally distributed. Otherwise, Wilcoxon's signed rank test
      shall be employed. Detailed summaries of the RAP and PASP values obtained noninvasively or
      invasively will be presented for each specific goal. Summaries will include the mean, median,
      standard deviation, minimum and maximum values. Regression models will be explored to gain a
      better understanding of the underlying patterns in RAP or PASP values, while adjusting for
      important patient characteristics such as demographics. An overall type I error of 5% will be
      maintained. To ensure this, each of the aims will be allocated a 1.25% type I error. For each
      specific goal, a sample of 100 participants will yield statistical power in excess of 85% to
      detect a Pearson correlation level of ±0.35. To detect increased correlation levels of ±0.50
      or more extreme, power exceeds 99%. Consequently, based on a sample of size 75, this study is
      well equipped to detect realistic level of correlation between RAP or PASP values obtained by
      noninvasive and invasive methods. Statistical significance for each of the four primary
      analyses will be performed at 1.25% alpha level. Significance level in all secondary and
      additional exploratory analyses will be set at 5%.

      3. Anticipated Results The investigators expect to collect accurate estimates of the
      correlations between cardiac right-sided pressures assessed noninvasively by Doppler
      echocardiography and the gold standard RHC-measured pressures. Additionally, the
      investigators expect to demonstrate an improvement in the accuracy of Doppler
      echocardiography measurements with the use of an intravenous contrast agent. Finally, the
      investigators expect to find associations between biomarkers level and pressures measured
      during the right heart catheterization.

      4. Potential Pitfalls Insufficient enrollment of research participants. Technical difficulty
      with echo images.
    

Intervention name(s): Pulmonary artery pressure measurements
Intervention type(s): Other
Intervention description(s): The investigators will compare noninvasive measurements of right sided pressure measurements with invasive RHC performed in 3 steps:at rest, with agitated saline and with agitated echo contrast, Optison. This was not a clinical trial and there were no intervention arms per se. All patients received agitated saline and echocardiographic contrast.
Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Unselected consecutively patients 18 to 80 years old referred for RHC to the Cardiac
        Catheterization Laboratory of Northwestern Memorial Hospital.
      
Keywords: Echo; PA pressures; comparison; Right Heart Catheterization