Rebreathing of Inert Gas for Measurement of Cardiac Output and Validation of Intra-Cardiac Shunt

Number: 0714

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses rebreathing of inert gas for measurement of cardiac output and validation of intra-cardiac shunt.

1. Experimental and Investigational

   The following procedures are considered experimental and investigational because the effectiveness of these approaches has not been established:

   1. Rebreathing of inert gas for the measurement of cardiac output. 
   2. Rebreathing of inert gas for the prediction of survival in persons with pulmonary hypertension.
   3. Rebreathing of inert gas for the validation of intra-cardiac shunt. 

2. Related Policies

   • CPB 0472 - Electrical Bioimpedance for Cardiac Output Monitoring and Other Selected Indications

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
Re-breathing of inert gas for measurement of cardiac output:
No specific codes
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
I27.0, I27.20 - I27.29	Pulmonary hypertension
Q21.0 - Q21.9	Congenital malformations of cardiac septa [intra cardiac shunt]

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Background

Measurement of cardiac output (CO) is an essential part of cardiovascular monitoring for critically ill patients as well as patients with cardiovascular diseases.  The thermodilution technique, which requires catheterization of the pulmonary artery, has long been considered the standard method for measuring CO.  Non-invasive approaches are increasingly being advocated because of several purported advantages -- avoidance of technical challenges and risks associated with catheterization as well as allowance of early and extended duration of assessment.  Non-invasive methods for CO measurements used in clinical practice or under development include lithium dilution technique, trans-esophageal Doppler ultrasonography, trans-pulmonary dilution/pulse contour techniques, thoracic electrical bioimpedance and inert gas re-breathing.

Inert gas re-breathing, also known as foreign gas re-breathing, has been investigated for use in measuring CO during cardiac stress test for patients with heart diseases.  Foreign gases used in the re-breathing method are physiologically inert, blood soluble gases such as acetylene, carbon dioxide and nitrous oxide.  This technique entails the use of a closed re-breathing system where a very small amount of an inert gas is inhaled from a re-breathing bag.  Patients breathe through a mouth piece with the nasal passages closed by a nose clip.  An instrument (e.g., respiratory mass spectrometer or infrared photo-acoustic gas analyzer) measures the concentration curve of the inert gas and calculates the wash-out rate, which is proportional to CO. Devices to measure CO non-invasively through inert gas re-breathing have been cleared by the U.S. Food and Drug Administration based upon 510(k) premarket notification.

Initial clinical trials have evaluated the agreement between inert gas re-breathing and other techniques such as thermodilution.  However, these clinical trials were small and mainly focused on specific patient groups.  Changing patterns of ventilation may have an unpredictable influence on measurements using inert gas re-breathing techniques. 

Warburton et al (1999) evaluated the reliability and validity of various non-invasive techniques for CO measurements during incremental to maximal aerobic exercise.  These researchers stated that Doppler echocardiography and the modified acetylene re-breathing method hold promise for the assessment of CO during maximal exercise.  Damgaard and Norsk (2005) noted that measurement of CO using inert gas re-breathing is based on the assumption that there is no re-breathing gas in the alveoli prior to the start of re-breathing; otherwise CO will be under-estimated.  They note, in this regard, that inert gas re-breathing may produce faulty results in patients with abnormal alveolar gaseous exchange.  These authors concluded that the use of inert gas re-breathing for measuring CO in patients with pulmonary diseases needs further investigation.

Evaluation of CO is also an important element in the management of patients with pulmonary hypertension.  Hoeper et al (1999) examined the accuracy of the thermodilution technique and the acetylene re-breathing technique in patients with low CO or severe tricuspid regurgitation.  The investigators compared 105 CO measurements simultaneously obtained by the Fick method, the thermodilution technique, and the acetylene re-breathing technique in 35 patients with pulmonary hypertension.  These investigators found that neither the mean agreement nor the 95 % limits of agreement of both thermodilution and acetylene re-breathing with the Fick method was affected by the presence of low CO or severe tricuspid regurgitation.  They concluded that thermodilution is a useful tool for assessing CO in patients with pulmonary hypertension, even in the presence of low CO or severe tricuspid regurgitation.  They also noted that acetylene re-breathing may be useful, but certainly can not fully replace thermodilution because other variables obtained during catheter testing (e.g., right atrial pressure, pulmonary artery pressure, pulmonary wedge pressure and blood gases) are needed for a comprehensive evaluation.  These researchers stated that acetylene re-breathing has potential to serve as a complementary diagnostic tool that could be particularly useful for non-invasive follow-up evaluations of patients with pulmonary hypertension and assessment of alterations in CO following commencement of a new therapy.

Gabrielsen and colleagues (2002) reported that a foreign gas re-breathing method using an infrared photo-acoustic gas analyzer is a promising non-invasive technique for measuring CO in patients with heart failure.  They stated, however, that clinical experience with the re-breathing method is modest and further evaluation is needed.  This is in agreement with the findings of Christensen and co-workers (2000) who compared measurements of the effective pulmonary blood flow by the inert gas re-breathing method and the thermodilution technique in critically ill patients.  These investigators concluded that inert gas re-breathing is a promising method for simultaneous non-invasive estimation of effective pulmonary blood flow as well as functional residual capacity in mechanically ventilated patients.  However, they stated that more studies are needed to assess potential problems of this approach before it can be adopted for clinical purposes. 

In a comment on lithium dilution for measurement of CO, Vincent and De Backer (2002) stated that “a non-invasive approach is, of course, desirable when possible, practical, and profitable, but we should not be tempted to swing too far for the sake of following a trend.  Indeed, although a reliable, non-invasive measure of cardiac output is great in principal, it is of little use if we are unable to interpret the values obtained without inserting a central venous catheter to provide us with a measure of oxygen saturation in the superior vena cava, or better still, a pulmonary artery catheter to be sure we have an accurate mixed venous oxygen saturation.  After all, the complications associated with pulmonary artery catheterization are probably limited … Although we are all in favor of non-invasiveness where appropriate, in terms of cardiac output measurement, the least invasive method may not always be the best”.

Botero and associates (2004) compared the agreement among a non-invasive continuous CO (NICO) system, bolus and continuous thermodilution, with aortic transit-time flowmetry by means of ultrasound before and after cardiopulmonary bypass (n = 68).  The NICO system used a ratio of the change in the end-tidal carbon dioxide partial pressure and carbon dioxide elimination in response to a brief period of partial re-breathing to measure CO.  These researchers concluded that before initiation of cardiopulmonary bypass, the accuracy for all three techniques was similar.  Following cardiopulmonary bypass, the tendency was for NICO to under-estimate CO and for bolus and continuous thermodilution to over-estimate it.  It is interesting to note that Bein et al (2004) stated that the NICO monitor appears to be inappropriate for determination of CO during xenon-based anesthesia.

In a prospective observational study (n = 37), Levy et al (2004) performed CO measurements determined by thermodilution or partial carbon dioxide re-breathing in children less than 12 years of age who had undergone cardiac catheterization.  Differences between partial re-breathing measurements and thermodilution measurements were largest in children with a body surface area of less than or equal to 0.6 m2 ventilated with tidal volumes of less than 300 ml.  Based on these findings, the authors concluded that non-invasive CO measurement using partial carbon dioxide re-breathing may be clinically acceptable in children with body surface area over 0.6 m2 and tidal volume greater than 300 ml.  However, Hoffman and co-workers (2005) noted that aside from limitations related to incorrect assumptions, carbon dioxide re-breathing techniques become significantly error prone with smaller tidal volume and carbon dioxide production rates and unfeasible in patients weighing less than 15 kg.

In an editorial on new techniques for measuring CO, Rhodes and Ground (2005) noted that the use of pulmonary artery catheterization (PAC) for monitoring CO in critically ill patients is an accepted clinical practice.  In deed, many clinicians consider PAC a gold standard for measurements of CO.  Regarding the new tools for measuring CO such as lithium dilution, transpulmonary dilution, trans-esophageal Doppler ultrasonography and carbon dioxide re-breathing, these researchers stated that the accuracy, precision and reproducibility of these new technologies must be at a level that is clinically relevant and that clinicians are able to use the information obtained from these devices with clearly defined protocols that have been demonstrated to lower morbidity, mortality and/or cost-effectiveness for the patients being treated.  These authors further stated that “there is no point replacing one monitor, the PAC, with another that simply gives us the same or perhaps less information.  We must insist that the manufacturers sponsor not just accuracy studies of these new tools, but also clinical effectiveness studies that demonstrate to us that if used in the right way, benefits will accrue”.

Guidelines on diagnosis and treatment of pulmonary arterial hypertension produced by the Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology (Galie et al, 2004) as well as guidelines on the diagnosis and treatment of acute heart failure furnished by the Task Force on Acute Heart Failure of the European Society of Cardiology (Nieminen et al, 2005) do not mention inert gas (foreign gas) re-breathing among established methods of measuring CO.

Jakovljevic and associates (2008) compared CO determined by different re-breathing methods at rest and at peak exercise.  These investigators compared values for resting Q (T) produced by the equilibrium-CO(2), exponential-CO(2) and inert gas-N(2)O re-breathing methods; evaluated the reproducibility of these 3 methods at rest; and assessed the agreement between estimates of peak exercise Q (T) derived from the exponential and inert gas re-breathing methods.  A total of 18 healthy subjects were included in this study.  Repeated measures of Q (T), measured in a seated position, were separated by a 5-min rest period.  Twelve participants performed an incremental exercise test to determine peak oxygen consumption.  Two more exercise tests were used to measure Q (T) at peak exercise using the exponential and inert gas re-breathing methods.  The exponential method produced significantly higher estimates at rest (averaging 10.9 L/min) compared with the equilibrium method (averaging 6.6 L/min) and the inert gas re-breathing method (averaging 5.1 L/min; p < 0.01).  All methods were highly reproducible with the exponential method having the largest coefficient of variation (5.3 %).  At peak exercise, there were non-significant differences between the exponential and inert gas re-breathing methods (p = 0.14).  The limits of agreement were -0.49 to 0.79 L/min).  Due to the ability to evaluate the degree of gas mixing and to estimate intra-pulmonary shunt, the authors believed that the inert gas re-breathing method has the potential to measure Q (T) more precisely than either of the CO(2) re-breathing methods used in this study.  At peak exercise, the exponential and inert gas re-breathing methods both showed acceptable limits of agreement.  Also, Saur et al (2009a) stated that inert gas re-breathing and continuous wave Doppler ultrasound are among the most promising newer techniques aiming at a non-invasive, point of care measurement of CO.

Saur and colleagues (2009b) prospectively evaluated the accuracy and reproducibility of CO measurements obtained by inert gas re-breathing (IGR) in 305 consecutive patients as compared to the non-invasive gold standard, cardiovascular magnetic resonance (CMR) imaging.  Bland-Altman analysis showed a good correspondence of the two methods for CO measurement with an average deviation of 0.2 +/- 1.0 L/min (mean +/- SD) and a good reproducibility with a mean bias of 0.2 +/- 0.5 L/min.  The accuracy of the present measurements at rest was significantly better in the physiological range than in higher or lower CO ranges.  The error levels set forth by current recommendations were exceeded.  The authors concluded that the data show that IGR measurements are easy to perform and show good agreement with CMR; however, the technique appears to be less accurate in extreme CO ranges at rest.  Moreover, they stated that the clinical importance of the IGR method remains to be proven by further studies.

A statement from the American Heart Association Council on Cardiovascular Disease in the Young, Committee on Atherosclerosis, Hypertension, and Obesity in Youth (Paridon et al, 2006) found little clinical utility of measurement of inert gas rebreating in the pediatric population.  The statement noted that "[v]arious techniques have been used for noninvasive evaluation of cardiac output during exercise.  Historically, the 3 most common techniques have included the CO2 rebreathing method, acetylene rebreathing method, and use of continuous-wave Doppler echocardiography.  All 3 techniques have their shortcomings and thus have largely been limited to use in the research setting.  Recent software developments allow for a single-breath maneuver to be performed during exercise that may allow for assessment of cardiac output near peak exercise.  The technique requires inhalation of an inert gas (acetylene) that is soluble in tissue and blood.  The rate of alveolar absorption is proportional to the pulmonary capillary blood flow.  The rate of absorption is determined by repeated measurements of the exhaled concentration of the gas obtained from a controlled single exhalation maneuver.  The maneuvers required for both the single breath and rebreathing methods are often difficult for small children, especially at higher minute ventilation.  This can often limit the usefulness of these techniques in the pediatric population".

An UpToDate review on “Pulmonary artery catheterization: Indications, contraindications, and complications in adults” (Weinhouse, 2016) states that “Several less invasive approaches to assessing hemodynamic data in critically ill patients have been proposed. These include dynamic indices and transesophageal echocardiography, as well as electrical bioimpedance, lithium dilution, and inert gas rebreathing systems”.

Hassan and colleagues (2017) validated CO measurement using the IGR method against other non-invasive and invasive methods of CO quantification in a cohort of patients with heart failure (HF; n = 97; age of 42 ± 15.5 years) and reduced ejection fraction (EF); 64 patients (65.9 %) had idiopathic dilated cardiomyopathy and 21 patients (21.6 %) had ischemic heart disease.  Median left ventricle EF (LVEF) was 24 % (10 % to 36 %).  Patients with atrial fibrillation were excluded; CO was measured using 4 methods (IGR, cardiac magnetic resonance imaging (MRI), cardiac catheterization, and echocardiography) and indexed to body surface area (cardiac index [CI]).  All studies were performed within 48 hours.  Median CI measured by IGR was 1.75, by cardiac MRI was 1.82, by cardiac catheterization was 1.65, and by echo was 1.7 L·min-1·m-2.  There were significant modest linear correlations between IGR-derived CI and cardiac MRI-derived CI (r = 0.7; p < 0.001), as well as cardiac catheterization-derived CI (r = 0.6; p < 0.001).  Using Bland-Altman analysis, the agreement between the IGR method and the other methods was as good as the agreement between any 2 other methods with each other.  The authors concluded that the IGR method is a simple, accurate, and reproducible non-invasive method for quantification of CO in patients with advanced HF.  Moreover, they state that the prognostic value of this simple measurement needs to be studied prospectively.

Middlemiss and colleagues (2019) examined an inert gas rebreathing method (Innocor) for measurement of CO and related hemodynamic variables and provided robust normative data describing the influence of age, gender and body size on these variables.  A total of 4 separate studies were conducted: measurement repeatability (study 1, n = 45); postural change (study 2, n = 40); response to submaximal cycling exercise (study 3, n = 20); and the influence of age, gender and body size (study 4, n = 1,400).  Repeated measurements of CO, stroke volume (SV) and heart rate (HR) were similar, with low mean (± SD) differences (0.26 ± 0.53 L/min, 0 ± 11 ml and 2 ± 6 beats/min, respectively).  In addition, CO and SV both declined progressively from supine to seated and standing positions (p < 0.001 for both) and there was a step-wise increase in both parameters moving from rest to submaximal exercise (p < 0.001 for both).  In study 4, there was a significant age-related decline in CO and SV in men and women, which remained significant after adjusting for body surface area (BSA, p < 0.001 for all comparisons).  Both parameters were also significantly higher in those with high body mass index (BMI; p < 0.01 versus those with normal BMI for all comparisons), although indexing CO and SV to BSA reversed these trends.  The authors concluded that inert gas rebreathing using the Innocor device provided repeatable measurements of CO and related indices, which were sensitive to the effects of acute physiological maneuvers.  Moreover, these researchers noted that inert gas rebreathing is a suitable technique for examining chronic influences such as age, gender and body size on key hemodynamic components of the arterial blood pressure (BP).

The authors stated that a potential limitation of the inert gas rebreathing method was the need for subjects to actively engage with the rebreathing maneuver, which might present difficulties in very elderly or frail individuals.  Therefore, clear and precise operator instructions are needed.  Moreover, the presence of pulmonary disease leading to uneven ventilation or the presence of any significant intra-pulmonary shunt may result in erroneous determinations of pulmonary blood flow, and thus CO.  In addition, these findings were based on cross-sectional observations and longitudinal data would better inform the extent to which aging influenced hemodynamic variables.  It was also beyond the scope of the present study to examine detailed measurements of ventricular volume, metabolic rate or body composition; however, inclusion of such data may have provided valuable mechanistic insights concerning the trends observed in this study.  Nevertheless, these investigators had demonstrated that inert gas rebreathing with the Innocor device provided repeatable measurements of CO, which were sensitive to acute physiological perturbations and chronic influences of age, gender and body size.  These researchers stated that further studies examining the contribution of CO and other hemodynamic variables to age-related changes in BP are needed.

Stach and associates (2019) stated that in postural stress, an increased pre-load volume would lead to higher SV according to the Frank-Starling law of the heart.  These investigators examined the hemodynamic response to postural stress using non-invasive (IGR in patients with normal as well as impaired LV function.  Hemodynamic measurements were performed in 91 patients undergoing CMR.  Mean CO and SV determined by IGR were 4.4 ± 1.3 l/min and 60 ± 19 ml in the up-right position, which increased significantly to 5.0 ± 1.2 l/min and 75 ± 23 ml in the supine position (p < 0.01).  Left ventricular systolic function was normal [LVEF greater than or equal to 55 %] in 42 patients as determined by CMR.  In 21 patients, LVEF was mildly abnormal (45 to 54 %), in 16 patients moderately abnormal (30 to 44 %) and in 12 patients severely abnormal (less than 30 %).  An overall trend for a lower percentage change in SV (%ΔSV) was indicated with increasing impairment of EF.  In patients with abnormal EF in comparison to those with normal EF, the %ΔSV was significantly lower (13 % versus 22 %; p = 0.03).  The authors concluded that non-invasive measurement of cardiac function using IGR during postural changes may be feasible and detected significant difference in %ΔSV in patients with normal and impaired EF according to the Frank-Starling law of the heart.  Several clinical scenarios including cases of heart rhythm disturbances or pulmonary or congenital heart disease are worthy of further prospective investigations.

The authors stated that although the present cohort included a sufficient number of patients, there were drawbacks to be considered.  First, there was no standardization of orthostatic testing of only single measurements.  Second, the assertions were restricted to systolic heart failure while heart failure with preserved left ventricular ejection fraction may be of special interest due to a reduced ventricular distensibility, this should be studied further due to unique/different cardiac characteristics.  Nevertheless, non-invasive measurement of cardiac function during postural changes using IGR is feasible, easy to perform and associated with low costs.  The maneuver may also be performed by trained nursing staff and medical technical assistants.  Thus, It may be useful in the evaluation of patients presenting with syncope, and during the treatment of heart failure and arterial hypertension.

Robertson et al (2022) stated that CO is a strong indicator of right ventricular function and disease severity in pulmonary hypertension (PH) and a consistent prognostic predictor.  Traditional methods of CO measurement include invasive techniques using either Fick or thermo-dilution (TD).  Limitations with right heart catheterization (RHC)-based procedures include expense, require specialist infra-structure to be carried out well and are resource-intensive; and additionally, there can be a small but significant risk of complications.  Thus, the ability to measure CO non-invasively is attractive.  Although there are various techniques, none has been adopted for widespread use.  IGR is a simple, non-invasive technique that can determine CO using a portable photo-acoustic gas analyzer.  Despite the fact IGR measurements have been validated against invasive CO measurements by a number of investigations in PH patients, they have not made it into widespread use.  These investigators presented single-center data that validated the IGR technique in patients with PH and, for the 1st time, demonstrated that IGR has long-term prognostic value comparable to invasive CO measurements.  These researchers stated that the Innocor system could be an additional tool for monitoring PH in the outpatient or in the community setting; however, it requires validation in a multi-center study using serial measurements.

The authors stated that drawbacks of this trial included not comparing IGR to the gold standard direct Fick method.  The direct Fick method due to its impracticality is rarely the standard method of use to measure CO in PH and therefore these investigators believed their studies were more relevant to real-world practice.  However, the primary methods of CO measurement that the authors employed had some important limitations.  The TD method could be inaccurate due to a variety of factors notably demonstrated to be less reliable in patients with tricuspid regurgitation and low CO.  The indirect Fick method relies on estimates of total body oxygen consumption that could be inaccurate in disease.  The IGR method may be less accurate in lung disease because of incomplete alveolar gas mixing and intra-pulmonary shunting of blood flow causing under-estimation of pulmonary blood flow.  However, IGR accuracy has not always been shown to be impacted by lung disease.  This was not likely to affect the findings of this study as very few of the patients presented with significant lung disease.  Additional limitations of this study included being a single-center study with potential for selection bias as patients enrolled onto this investigation were based on those who had a planned RHC; the study was sequential and prospective and therefore no additional filtering of populations was carried out.  The predominant chronic thrombo-embolic PH (CTEPH) cohort may therefore reduce the applicability of these findings to all PH cohorts, and due to the small sized PH cohorts, these researchers were unable to examine differences in prognostic value of IGR between different PH groups and this requires future investigation.  As the Innocor system has the potential to monitor PH in the outpatient or in the community setting, future investigations need to clarify the value of serial IGR measures in relation to clinical worsening of other clinical predictors.

Inert Gas Rebreathing for Validation of Intra-Cardiac Shunt

Filaire and colleagues (2019) noted that intra-thoracic shunt quantification is a major factor for appropriate clinical management of heart and pulmonary diseases.  Intra-cardiac shunts quantified by pulmonary to systemic output ratio (Qp/Qs) are generally assessed by Doppler echocardiography, MRI or catheterization.  Recently, some investigators suggested the concomitant use of thoracic bioimpedance (TB) and IGR techniques for shunt quantification.  These researchers attempt to validate the use of this approach under conditions where shunt fraction is directly quantified such as in patients with isolated atrial septal defect (ASD).  This trial is a prospective, observational single-center, non-blinded study of adults observed for percutaneous closure of ASD; Qp/Qs ratio will be directly measured by Doppler echocardiography and direct Fick; IGR and TB will be used simultaneously to measure the CO before and after closure: the ratio of outputs measured by IGR and TB reflecting the shunt fraction.  The primary outcome will be the comparison of shunt values measured by TB-IGR and Doppler echocardiography.  The authors stated that this study has been approved by an independent Research Ethics Committee (2017-A03149-44 Fr) and registered as an official clinical trial.  The results will be published in a peer-reviewed journal.

Inert Gas Rebreathing for Prediction of Survival in Persons with Pulmonary Hypertension

Stadler and colleagues (2019) noted that CO is a prognostic marker in patients with pulmonary hypertension.  Pulmonary blood flow as a surrogate for CO can be measured non-invasively by IGR.  These researchers hypothesized that pulmonary blood flow could predict outcome in patients with pulmonary hypertension.  From January 2009 to January 2012, these investigators measured pulmonary blood flow by IGR in out-patients with pulmonary hypertension.  Patients with pulmonary hypertension confirmed by right heart catheterization and a valid IGR maneuver were followed until January 2016.  The investigated outcome was all-cause mortality.  These researchers included 259 patients (mean age of 65 ± 13 years, 53 % women) with pulmonary hypertension and classified into groups 1 (n = 103), 2 (n = 26), 3 (n = 80), and 4 (n = 50) according to the current pulmonary hypertension classification system.  The median time between pulmonary hypertension diagnosis and IGR was 9 (IQR 0; 36) months.  During a median follow-up time of 51 (inter-quartile range [IQR] 20; 68) months, 109 patients (42 %) died.  Parameters significantly associated with survival (in order of decreasing statistical strength) were diffusion capacity of the lung for carbon monoxide (DLCO), 6-minute walk distance (6MWD), age, natriuretic peptides (NTpro-BNP), World Health Organization functional class (WHO-FC), group 3 pulmonary hypertension, and tricuspid annular plane systolic excursion (TAPSE), while baseline hemodynamics and pulmonary blood flow were not.  In multi-variable Cox regression analysis, DLCO, age, 6MWD, and TAPSE remained significant and independent predictors of the outcome.  DLCO as the strongest parameter also significantly predicted survival in etiological subgroups except for group 4.  The authors concluded that DLCO was a strong and independent predictor for survival in patients with pulmonary hypertension of different etiologies; however, pulmonary blood flow measured by IGR was not.

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References