Aetna considers re-breathing of inert gas for the measurement of cardiac output experimental and investigational because the clinical value of this type of measurement has not been established.

See also CPB 0472 - Thoracic Electrical Bioimpedance for Cardiac Output Monitoring.

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".