Non-Invasive Cardiac Output Measurement Using Inert Gas Rebreathing Method during Cardiopulmonary Exercise Testing—A Systematic Review

Background: The use of inert gas rebreathing for the non-invasive cardiac output measurement has produced measurements comparable to those obtained by various other methods. However, there are no guidelines for the inert gas rebreathing method during a cardiopulmonary exercise test (CPET). In addition, there is also a lack of specific standards for assessing the non-invasive measurement of cardiac output during CPET, both for healthy patients and those suffering from diseases and conditions. Aim: This systematic review aims to describe the use of IGR for a non-invasive assessment of cardiac output during cardiopulmonary exercise testing and, based on the information extracted, to identify a proposed CPET report that includes an assessment of the cardiac output using the IGR method. Methods: This systematic review was conducted by PRISMA (Preferred Reporting Items for Systematic Reviews and Meta Analyses) guidelines. PubMed, Web of Science, Scopus, and Cochrane Library databases were searched from inception until 29 December 2022. The primary search returned 261 articles, of which 47 studies met the inclusion criteria for this review. Results and Conclusions: This systematic review provides a comprehensive description of protocols, indications, technical details, and proposed reporting standards for a non-invasive cardiac output assessment using IGR during CPET. It highlights the need for standardized approaches to CPET and identifies gaps in the literature. The review critically analyzes the strengths and limitations of the studies included and offers recommendations for future research by proposing a combined report from CPET-IGR along with its clinical application.


Introduction
Cardiopulmonary exercise testing (CPET) offers the investigator the unique opportunity to study cellular, cardiovascular, and ventilatory system responses under controlled conditions of metabolic stress [1].
Cardiopulmonary exercise testing (CPET) is a versatile and comprehensive diagnostic tool that has gained popularity and is now utilized across various demographics and patient groups [2].Previously, CPET was primarily performed on healthy individuals or those with specific cardiovascular conditions.However, its application has broadened significantly, and it is now employed in diverse populations.CPET is routinely conducted on both men and women, allowing for a gender-specific assessment of exercise capacity and functional limitations.It provides valuable insights into the physiological responses of different genders during exercise and helps identify any gender-specific exercise limitations [3].Furthermore, CPET is not limited to specific age groups; it is now employed for children [4,5] and the elderly [6].This allows for the evaluation of exercise performance and the identification of any age-related limitations.
In addition to studying healthy individuals and those with specific conditions, CPET is now applied to assess exercise capacity in both athletic and frail populations [7,8].By comparing the performance of highly trained athletes with individuals who are frail or have reduced functional capacity, CPET helps determine the impact of physical fitness on exercise performance and identifies the limitations faced by the frail population during physical activity.
CPET has evolved beyond examining exercise performance and peak oxygen uptake alone.It now aims to answer broader questions about the underlying causes of exercise limitations.By analyzing various parameters during CPET, such as heart rate, blood pressure, gas exchange, and ventilatory responses, medical professionals can identify which organ or bodily function is responsible for the exercise limitation [9,10].This information aids in the diagnosis and treatment of various conditions impacting exercise capacity.Moreover, CPET plays a crucial role in determining the prognosis of patients, being the strong and independent marker of risk for cardiovascular and all-cause mortality [11][12][13][14][15].By assessing exercise performance and physiological responses, healthcare providers can predict a patient's condition's potential outcome, helping to make informed decisions regarding their treatment plans and interventions.What is more, CPET is considered an ideal pre-operative assessment tool, as it provides an objective measure of fitness or functional capacity [16].It assesses the comprehensive function of the cardiac, circulatory, respiratory, and muscle metabolic systems during physiological stress.Further, it can pinpoint the underlying cause of exercise intolerance.The anaerobic threshold (AT) measured through CPET testing strongly predicts mortality resulting from cardiopulmonary causes during the postoperative period.By conducting preoperative screening with CPET testing, high-risk patients can be identified, enabling the selection of appropriate perioperative management strategies [17].The current guidelines from the American Heart Association, American College of Cardiology [18], and the European Society of Cardiology [19] suggest that assessing exercise capacity, when feasible, can provide valuable insights in the evaluation of noncardiac surgery for high-risk patients with an unknown functional capacity.
Nevertheless, the European Society of Cardiology stated, "The full potential of CPET in the clinical and research setting remains underused" [10].Despite its intrinsic advantages, CPET also has limitations due to how it assesses cardiac and pulmonary function, i.e., in the case of the heart, it only provides an indirect assessment of cardiac function as a pump.In contrast, in the case of the lungs, it gives intermediate AT values unless the method is extended to include arterial blood gasometry during the test.This review considers the use of the already-known IGR (Inert Gas Rebreathing) method to assess the direct cardiac function during CPET.This is presented in detail in this paper.
The inert gas rebreathing method is a non-invasive technique used to assess cardiac output (CO) and pulmonary blood flow (PBF) during exercise.It involves the rebreathing of a gas mixture containing inert gases, which are soluble and enter the bloodstream via pulmonary diffusion without binding to hemoglobin [20].
This method allows for the measurement of respiratory gas exchange and airflow, providing additional information on oxygen utilization and ventilation [21].
The inert gas rebreathing method has been shown to be a safe and reliable alternative to invasive and expensive techniques for measuring CO, such as thermodilution [22].It has been used in numerous studies to assess cardiac function in patients with heart failure [22] and to evaluate the accuracy and precision of different rebreathing techniques [20,22,23].The results of these studies have demonstrated that the inert gas rebreathing method can provide reasonable estimates of CO and pulmonary blood flow, with some variations in accuracy and precision depending on the specific gases used and the exercise intensity [20,23].
The use of CPET and IGR provides us with an even broader understanding of the clinical state of the patient under examination through lots of symptom-limited, incremental exercise, commonly in combination with the comprehensive breath-by-breath monitoring of cardiopulmonary variables (e.g., peak oxygen consumption/maximal oxygen consumption (peak VO 2 /VO 2 max), pulmonary CO 2 output (VCO 2 ), minute ventilation (VE), heart rate (HR), cardiac output (CO), stroke volume (SV), and subjective responses (e.g., dyspnea and leg pain)) and, as needed, measurements such as exercise-related arterial oxygen desaturation and dynamic hyperinflation [3].

Cardiac Output Measurement
It is useful to add the measurement of CO, which is considered the best indicator of cardiac function during exercise, to the values described above [24].The measurement of CO represents an added value to a standard CPET.
CO is defined as the volume of blood pumped by the heart per minute.It is an important parameter that reflects the ability of the heart to supply blood to the body's tissues.CO is calculated as the product of the heart rate (HR) and stroke volume (SV), which is the volume of blood pumped by the heart with each beat.
CO can be expressed mathematically as CO = HR × SV.CO is a crucial determinant of oxygen delivery to the body's tissues, and it can be affected by several factors, including heart rate, contractility, preload, and afterload [25].Measuring CO is important for diagnosing and managing heart and circulatory conditions [26][27][28] and monitoring the response to therapy [29][30][31].

Inert Gas Rebreathing
IGR is a non-invasive technique used to measure CO and PBF.The use of IGR has been shown to produce pulmonary blood flow measurements that are comparable to those obtained by various other methods such as thermodilution, direct Fick, and modified Fick methods during rest as well as graded exercise [46][47][48][49].Furthermore, this method offers high reproducibility for CO measurements during rest and exercise for both healthy individuals and those with cardiac indications [50,51].
The IGR method may use different neutral gases, i.e., nitrogen, helium, acetylene, carbon dioxide, and sulfur hexafluoride [52].Nitrogen is an inert gas that is relatively insoluble in blood and tissue, making it an ideal tracer for measuring blood flow.Xenon gas is also used in inert gas rebreathing, as it has low solubility in blood and a high tissueto-blood partition coefficient, which makes it a useful tracer for measuring pulmonary blood flow [53].Due to its low solubility in blood, helium is often used as a diluent in the rebreathing mixture to increase the tracer gas concentration and improve measurement accuracy [53].
Acetylene is an inert gas used as a tracer gas in some IGR methods.However, compared to other commonly used tracer gases, acetylene is more soluble in blood and tissue and, therefore, is less ideal for measuring blood flow [54].
Another commonly used gas is carbon dioxide, as it is readily metabolized by the body and can provide information about gas exchange in the lungs [55].
Finally, sulfur hexafluoride (SF 6 ) is also used as a tracer gas in IGR, which has a high molecular weight and is even less soluble in blood than nitrogen, making it an effective tracer for measuring CO [56].

IGR with the Use of SF 6
The IGR technique involves a machine inflating a bag with an oxygen-enriched mixture of an inert soluble gas (0.5% nitrous oxide) and an inert insoluble gas (0.1% sulfur hexafluoride-SF 6 ), which is an inert gas that does not alter the body's metabolism [45,[57][58][59][60][61].Patients breathe into a respiratory valve via a mouthpiece and a bacterial filter with a nose clip, and at the end of expiration, the valve automatically activates so that patients rebreathe from the prefilled bag for 10 to 20 s.The CO measurement is taken by a photoacoustic analyzer over a three to five breath interval.The lung volume is determined by sulfur hexafluoride, while the nitrous oxide concentration decreases during rebreathing with a rate proportional to the PBF [45,57].CO equals the PBF only if SpO 2 is above 98% on the pulse oximeter, indicating no pulmonary shunt flow.If SpO 2 is below 98%, CO equals the PBF plus the shunt flow [57].
This method can be successfully performed both at rest and during CPET [45,51].
A standard IGR report typically includes resting measurements such as CO, CI (Cardiac Index), VO 2 /kg (Oxygen consumption per kilogram of body weight), VO 2 /min (Absolute oxygen consumption per minute), SV (Stroke Volume), (a-v)O 2 difference (Oxygen content difference between arterial and venous blood), and shunt (%).The report may also feature graphs showing the normalization curves of the gases used for measurement.
If the IGR test is performed during an exercise protocol, the report includes additional results from the breath-by-breath exercise assessment.These results may consist of a maximum load (highest workload achieved), maximum heart rate, respiratory rate, VCO 2 (Ventilatory Carbon Dioxide Output), VO 2 (Oxygen Consumption), RQ (Respiratory Quotient), VE/VCO 2 (Ratio of minute ventilation to carbon dioxide output), saturation levels, and other typical outcomes.
The process of performing an IGR during CPET is presented in Figure 1.
Finally, sulfur hexafluoride (SF6) is also used as a tracer gas in IGR, which has a high molecular weight and is even less soluble in blood than nitrogen, making it an effective tracer for measuring CO [56].

IGR with the Use of SF6
The IGR technique involves a machine inflating a bag with an oxygen-enriched mixture of an inert soluble gas (0.5% nitrous oxide) and an inert insoluble gas (0.1% sulfur hexafluoride-SF6), which is an inert gas that does not alter the body's metabolism [45,[57][58][59][60][61].Patients breathe into a respiratory valve via a mouthpiece and a bacterial filter with a nose clip, and at the end of expiration, the valve automatically activates so that patients rebreathe from the prefilled bag for 10 to 20 s.The CO measurement is taken by a photoacoustic analyzer over a three to five breath interval.The lung volume is determined by sulfur hexafluoride, while the nitrous oxide concentration decreases during rebreathing with a rate proportional to the PBF [45,57].CO equals the PBF only if SpO2 is above 98% on the pulse oximeter, indicating no pulmonary shunt flow.If SpO2 is below 98%, CO equals the PBF plus the shunt flow [57].
This method can be successfully performed both at rest and during CPET [45,51].
A standard IGR report typically includes resting measurements such as CO, CI (Cardiac Index), VO2/kg (Oxygen consumption per kilogram of body weight), VO2/min (Absolute oxygen consumption per minute), SV (Stroke Volume), (a-v)O2 difference (Oxygen content difference between arterial and venous blood), and shunt (%).The report may also feature graphs showing the normalization curves of the gases used for measurement.
If the IGR test is performed during an exercise protocol, the report includes additional results from the breath-by-breath exercise assessment.These results may consist of a maximum load (highest workload achieved), maximum heart rate, respiratory rate, VCO2 (Ventilatory Carbon Dioxide Output), VO2 (Oxygen Consumption), RQ (Respiratory Quotient), VE/VCO2 (Ratio of minute ventilation to carbon dioxide output), saturation levels, and other typical outcomes.
The process of performing an IGR during CPET is presented in Figure 1.The contents of the standard IGR report are shown in Figure 2. The contents of the standard IGR report are shown in Figure 2. The SF6 concentration measurement is repeated several times during the exercise challenge and the CO is calculated using a specialized computer software (Innocor™, Innovision, Odense, Denmark, ver.8.10).
CO can be derived from the change in the SF6 concentration in the exhaled air, which reflects the amount of SF6 that has diffused into the blood and been transferred to the lungs.This method provides a continuous and relatively accurate measurement of CO [49,62,63] during CPET and can be used to monitor changes in CO over time.Currently, available IGR measurement systems using SF6 (i.e., Innocor ® CO-Cardiac Output-COS-MED) do not include a rhythmic assessment of the exercise ECG, which limits the possibility of monitoring patient safety during CPET-IGR.Of course, this difficulty can be overcome by performing simultaneous ECG recordings with an external system.
However, there are no guidelines for the inert gas rebreathing method during a cardiopulmonary exercise test (CPET).In addition, there is also a lack of specific standards for assessing the non-invasive measurement of CO during CPET, both for healthy patients and those suffering from diseases and conditions.Hence, there is the need to write a systematic review to bring together the available up-to-date knowledge on using IGR during CPET.
The purpose of this systematic review is to systematically describe the use of IGR for the non-invasive assessment of CO during cardiopulmonary exercise testing, present the extracted data, if applicable, and, based on the information extracted, to identify a proposed CPET report that includes the assessment of CO using the IGR method.

Literature Search
This systematic review was performed in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement [64].The PICO (Patients, Interventions, Comparisons, and Outcomes) approach was not used, as this systematic review was not to evaluate intervention effects.The following predetermined strategy was used to identify eligible articles.We searched PubMed, Web of Science, Scopus, and Cochrane.

Evidence Acquisition
On 29 December 2022, the targeted online databases were searched.The search query was constructed with the use of MeSH structures: (("inert gas rebreathing") AND ("exercise test" OR "walk test" OR "ergometry" OR "stress test" OR "treadmill test" OR "bicycle The SF 6 concentration measurement is repeated several times during the exercise challenge and the CO is calculated using a specialized computer software (Innocor™, Innovision, Odense, Denmark, ver.8.10).
CO can be derived from the change in the SF 6 concentration in the exhaled air, which reflects the amount of SF 6 that has diffused into the blood and been transferred to the lungs.This method provides a continuous and relatively accurate measurement of CO [49,62,63] during CPET and can be used to monitor changes in CO over time.Currently, available IGR measurement systems using SF 6 (i.e., Innocor ® CO-Cardiac Output-COSMED) do not include a rhythmic assessment of the exercise ECG, which limits the possibility of monitoring patient safety during CPET-IGR.Of course, this difficulty can be overcome by performing simultaneous ECG recordings with an external system.
However, there are no guidelines for the inert gas rebreathing method during a cardiopulmonary exercise test (CPET).In addition, there is also a lack of specific standards for assessing the non-invasive measurement of CO during CPET, both for healthy patients and those suffering from diseases and conditions.Hence, there is the need to write a systematic review to bring together the available up-to-date knowledge on using IGR during CPET.
The purpose of this systematic review is to systematically describe the use of IGR for the non-invasive assessment of CO during cardiopulmonary exercise testing, present the extracted data, if applicable, and, based on the information extracted, to identify a proposed CPET report that includes the assessment of CO using the IGR method.

Literature Search
This systematic review was performed in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement [64].The PICO (Patients, Interventions, Comparisons, and Outcomes) approach was not used, as this systematic review was not to evaluate intervention effects.The following predetermined strategy was used to identify eligible articles.We searched PubMed, Web of Science, Scopus, and Cochrane.

Evidence Acquisition
On 29 December 2022, the targeted online databases were searched.The search query was constructed with the use of MeSH structures: (("inert gas rebreathing") AND ("exercise test" OR "walk test" OR "ergometry" OR "stress test" OR "treadmill test" OR "bicycle ergometry test" OR "fitness testing" OR "cardiopulmonary exercise testing" OR "CPET")).No search filters were applied.The search was completed with a manual search of references from key papers.The primary search returned 261 articles.The number of articles after duplicate removal was narrowed to 186.The initial screening process involved two researchers (AC, ŁM), independently reviewing the titles and abstracts of all the records.Any inconsistencies were discussed until a consensus was reached.Then, the researchers independently screened the full-text articles for inclusion.The data were collected using an Excel spreadsheet.In case of any disagreement, they discussed and reached a consensus on whether to include or exclude the article.The complete protocol is depicted in a PRISMA flowchart (Figure 3).ergometry test" OR "fitness testing" OR "cardiopulmonary exercise testing" OR "CPET")).No search filters were applied.The search was completed with a manual search of references from key papers.The primary search returned 261 articles.The number of articles after duplicate removal was narrowed to 186.The initial screening process involved two researchers (AC, ŁM), independently reviewing the titles and abstracts of all the records.Any inconsistencies were discussed until a consensus was reached.Then, the researchers independently screened the full-text articles for inclusion.The data were collected using an Excel spreadsheet.In case of any disagreement, they discussed and reached a consensus on whether to include or exclude the article.The complete protocol is depicted in a PRISMA flowchart (Figure 3).

Inclusion and Exclusion Criteria
Studies were included in the current systematic review if they conformed with the following criteria: (1) a cardiopulmonary exercise test (CPET) had been performed, (2) the inert gas rebreathing method was used in the CO assessment, (3) it included an adult population, and (4) the CPET protocol was described in a precise and explicit manner, allowing the study to be reconstructed.If articles met the predefined criteria, they were included and categorized as eligible.The exclusion criteria included: (1) review articles, (2) studies including a pediatric population, (3) studies including patients with congenital heart diseases, or (4) the entire text was unavailable in English.

Evidence Synthesis and Quality Assessment
Given the experimental nature of the studies and the fact that, in most cases, the IGR method was not the focus of the research, it was not possible to use widely recognized tools for a quality assessment.Therefore, the quality assessment was performed manually by referring to a model study written by Agostoni et al. [57], the only author with defined reference values.The manual evaluation of the quality of the included studies consisted of assessing whether the study description contained an accurately described study protocol, allowing for reproduction.In addition, each study was evaluated against the inclusion criteria (described in Section 2.3) by two independent authors of the systematic review, and any disagreement was resolved by a third author.Reference data presented in the article by Agostoni and co-authors, titled: "Reference values for peak exercise cardiac output in healthy individuals" [57], are presented in Table 1.The study involved 500 normal subjects of varying ages and genders.They underwent a maximal cardiopulmonary

Inclusion and Exclusion Criteria
Studies were included in the current systematic review if they conformed with the following criteria: (1) a cardiopulmonary exercise test (CPET) had been performed, (2) the inert gas rebreathing method was used in the CO assessment, (3) it included an adult population, and (4) the CPET protocol was described in a precise and explicit manner, allowing the study to be reconstructed.If articles met the predefined criteria, they were included and categorized as eligible.The exclusion criteria included: (1) review articles, (2) studies including a pediatric population, (3) studies including patients with congenital heart diseases, or (4) the entire text was unavailable in English.

Evidence Synthesis and Quality Assessment
Given the experimental nature of the studies and the fact that, in most cases, the IGR method was not the focus of the research, it was not possible to use widely recognized tools for a quality assessment.Therefore, the quality assessment was performed manually by referring to a model study written by Agostoni et al. [57], the only author with defined reference values.The manual evaluation of the quality of the included studies consisted of assessing whether the study description contained an accurately described study protocol, allowing for reproduction.In addition, each study was evaluated against the inclusion criteria (described in Section 2.3) by two independent authors of the systematic review, and any disagreement was resolved by a third author.Reference data presented in the article by Agostoni and co-authors, titled: "Reference values for peak exercise cardiac output in healthy individuals" [57], are presented in Table 1.The study involved 500 normal subjects of varying ages and genders.They underwent a maximal cardiopulmonary exercise test with a peak CO measurement using a specific method.The results showed that peak CO was higher in males compared to females.Both peak CO and peak VO 2 decreased with age.Moreover, the study provided the formula to predict peak CO from peak VO 2 values.The equation shows that, in the general population, peak CO = 4.4 × peak VO 2 + 4.3, while peak CO in males = 4.3 × peak VO 2 + 4.5 and peak CO in females = 4.9 × peak VO 2 + 3.6.The data reported in Agostoni's study are clear, and the study model allows for the reproduction of protocol.Given the lack of established tools for assessing the quality, this approach seemed appropriate for the current systematic review.However, it is important to acknowledge the limitations of this method and the potential for bias in the quality assessment process.Therefore, the results of the quality assessment should be interpreted with caution.

Study Registration
This systematic review has been registered with PROSPERO (International Prospective Register of Systematic Reviews) under registration number CRD42023456820.A detailed protocol for this systematic review is available in PROSPERO, where it can be accessed and evaluated.

Availability of Data
The data, code, and other materials used in this systematic review are available upon request from the corresponding author.We are committed to promoting transparency and reproducibility in research, and we encourage interested parties to reach out for access to the data and materials used in this study.

Study Selection and Description
The search flowchart is presented in Figure 3.In Table 2, all included studies were considered, and raw data related to measurements conducted using IGR were extracted wherever feasible (Table 3).The studies included in the systematic review where the extraction of raw data was unattainable are marked with "*" in Table 2.The reasons for the inability to obtain the raw data were data presented solely in graphical form, data presented as value differences, or data presented in units different from those sought in this systematic review.This comprehensive approach ensured a thorough assessment of the available data.Table 2, presented herein, provides the most critical information, e.g., the protocols used, patients' characteristics, the study design, and the primary and secondary points.Where feasible, there are comments and conclusions listed.This table serves to streamline and highlight key findings and relevant data points from the studies included, offering a succinct overview of the essential aspects of the research synthesized in this review.This is the first systematic review to address the topic of a non-invasive CO assessment using IGR during CPET.And as such, we believe it is necessary to provide a comprehensive description of the protocols, indications for cardiopulmonary exercise testing with IGR (CPET-IGR), technical details of the testing, and proposed reporting standards.Due to the lack of a standardized approach to CPET-IGR, the inclusion criteria for this review were broad to capture as many relevant studies as possible.

Participants of the Studies Included
This systematic review resulted in the extraction of 48 articles that matched the search criteria.The total number of patients from all studies is 4465.The average age of the participants ranges from 21 to 72 years old.The populations are diverse in terms of health comorbidities (Section 3.4 and Table 4).For an accurate description of the population of each study, see Table 2.

Protocols Used in CPET-IGR Studies
A cardiopulmonary exercise test typically requires a cycloergometer or a treadmill.The type of exercise equipment used depends on the patient's preference, physical capabilities, and the test's purpose.In the studies included in this systematic review, the authors used both cycle ergometers [58,86,88,90] and treadmills [84,87,89,91].
The standard CPET protocol involves the following steps.(1) Pre-test procedures: Before the test, the subject's height, weight, age, and medical history are recorded.The subject is also instructed on using exercise equipment and wearing an interface for measuring respiratory gases.(2) Baseline measurements: the subject rests quietly for several minutes while measurements of their resting heart rate, blood pressure, and oxygen saturation are taken.(3) Incremental or constant load exercise: The subject begins exercising on a cycle ergometer or treadmill at a low intensity, gradually increasing every minute until exhaustion or a pre-determined endpoint is reached.The exercise protocol can vary based on the individual being tested and the test's purpose.(4) Respiratory gas measurements: During exercise, the subject wears a mask connected to a metabolic cart that measures the volume of oxygen and carbon dioxide consumed and produced, respectively.These data allow for the various physiological parameters, such as the anaerobic threshold, peak oxygen uptake, and respiratory exchange ratio.(5) ECG monitoring: the subject's heart rhythm is continuously monitored during exercise using an electrocardiogram (ECG) to detect any abnormalities or changes in the heart rate.(6) Termination of the test: the test is usually stopped when the subject reaches a pre-determined endpoint, such as the maximum heart rate, symptom limitation, or a predetermined workload.(7) Recovery: The subject rests for several minutes while their heart rate, blood pressure, and oxygen saturation measurements are taken.The subject may also be monitored for any post-exercise symptoms or complications.The protocol for CPET-IGR may vary depending on the patient's specific medical history and condition, and may be adjusted accordingly by the healthcare provider performing the test (Table 1).
The authors of the papers discussed do not strictly state how the measuring system is connected to the patient (mouthpiece or full-face mask).It should also be noted that there are no studies validating the different interfaces of CPET-IGR.

Health Conditions as Indication for IGR Study
As there are no separate recommendations available for the indications for CPET-IGR, general indications for CPET were used by the authors of the cited papers to perform CPET-IGR.
According to the American Thoracic Society and American College of Cardiology, there are several common indications for CPET: the diagnosis and assessment of an exercise intolerance in patients with cardiovascular or pulmonary diseases, such as heart failure, chronic obstructive pulmonary disease (COPD), or pulmonary hypertension; the assessment of preoperative risk in patients undergoing major surgery; the determination of exercise-induced bronchoconstriction in patients with suspected exercise-induced asthma; the evaluation of the fitness and training status in athletes or individuals participating in endurance sports; an unexplained dyspnea diagnosis; or the assessment of interstitial lung diseases [103].
Among the studies included in this systematic review, the predominant indications for CPET in patients were HF (53% of included articles) and a physical capacity assessment in healthy individuals or athletes (28%).Only 19% of the included articles concerned other patient populations.For instance, only two articles (4% of included articles) focused on COPD patients (Table 4).

Other
The IGR method has high repeatability, reproducibility, and its reliability is not compromised by atrial fibrillation or pulmonary diseases [45,51,55,56,63,76,84].The IGR method is, therefore, ideally suitable for determining CO in LVAD (Left Ventricular Assist Device) patients at rest and during exercise.It allows the evaluation of the physical fitness of a particular population of patients.Since the method is non-invasive, it can be performed any number of times, allowing the long-term documentation of hemodynamics [104].

Proposed IGR Report Style
The proposed CPET-IGR report is presented in Table 5.

Discussion
The systematic review conducted on the topic of a non-invasive CO measurement using the IGR method during cardiopulmonary exercise testing (CPET) has revealed important insights into the current state of research in this field.While the application of IGR holds promise for assessing cardiac function in a non-invasive manner, the synthesis of findings across numerous studies has highlighted several key challenges that need to be addressed for this method to reach its full potential.

The Validation and Utility of CPET-IGR
This systematic review encompasses a diverse array of studies exploring the potential of IGR as a valuable tool for assessing CO during CPET.By synthesizing findings from studies across various clinical contexts, the discussion sheds light on the evolving landscape of CO measurement, with an emphasis on the insights provided by the IGR method.
A particularly important study conducted by Middlemiss et al. [56] reveals the potential of CPET-IGR.Normative data highlight age-related declines in CO and SV, particularly in males.Body size, assessed through BMI (Body Mass Index), significantly impacts CO and SV, especially in younger individuals.IGR proves sensitive to physiological changes, highlighting posture-induced CO shifts.Although limitations exist, this study paves the way for understanding age, body size, and posture effects on CO, offering insights for future investigations and clinical applications.
Several studies acknowledge the variability, validation, and limitations inherent in different CO assessment methods [56,59,70,81,86,91,93,94]. Articles compare the CO measurement methods during CPET, obtained by Innocor (IGR) and other methods including the Fick method, Physioflow (impedance cardiography), Nexfin (pulse contour analysis), finger photoplethysmography, cardiac magnetic resonance and bioreactance.The conclusions from the above studies suggest that the IGR method offers a straightforward, precise, and consistently replicable non-invasive approach for quantifying CO during CPET [56,59,70,91].However, as stated by Siebenmann et al. [94] and Okwose et al. [70], the four extensively employed and valid techniques for assessing CO during exercise yield notably divergent measurements.Consequently, the choice of method significantly impacts the determination of CO during exercise, and those methods cannot be used interchangeably.
The systematic review includes, among others, studies focused on patients with heart failure (CHF), a population characterized by complex hemodynamic responses during exercise.The studies demonstrate the potential of IGR to provide valuable insights into the management of HF.A study conducted by Halbirk et al. [31] examines the effects of a 48 h infusion of glucagon-like peptide-1 in patients with compensated chronic heart failure and highlights the potential of IGR to elucidate cardiovascular and metabolic effects in this context.What is more, there are several articles investigating the management of patients with left ventricular assist devices (LVADs) [69,71,76,77,83,87].Researchers highlight the usefulness of IGR in assessing CO changes and optimizing device settings.This application underscores the role of IGR as a non-invasive tool in the evolving landscape of LVAD care and optimization.Another notable theme in the discussion is the exploration of the predictive power of CO measurements, particularly in relation to exercise capacity and prognosis.Among the studies included in this systematic review, only a few articles addressing the predictive value of the IGR were identified [58,82,83,88,90].In the Pastormerlo et al. [90] study, IGR was among other methods used in stratifying the risk of HF progression.Goda et al. [58] stated that CO at 25 W, measured non-invasively during submaximal exercise, may have potential value as a predictor of outcomes in patients with CHF.Additionally, Lang et al. [82] describe peak cardiac power, measured non-invasively, as an independent predictor of an outcome that can enhance the prognostic power of peak VO 2 in the evaluation of patients with HF.However, Y. Shen et al. [88] concluded that peak CPO is not a predictor of cardiac death in Chinese CHF patients.
According to Jakovljevic et al. [83], powerful exercise-derived prognostic indicators, including peak VO 2 , AT, circulatory power, and the ventilatory efficiency slope, demonstrate limited capacity to reflect the cardiac organ function in patients treated with LVADs.
Hence, further research should focus on investigating the predictive value of the IGR method during CPET.The above-described studies on the prognostic and predictive value mainly focus on HF patients.Data are needed to provide the reliability, reproducibility, and predictive value of the IGR method in patients with conditions other than HF.Special attention should be given to patients suffering from lung diseases.

Lack of Uniform Result Presentation
One of the foremost observations arising from the systematic review is the lack of standardized results presentations across studies utilizing the IGR method.The absence of a consistent reporting format hampers the comparability of results, making it challenging to draw meaningful conclusions from the accumulated data.This inconsistency impedes one's ability to discern trends, potential variations, or establish normative values for CO measurements.

Diverse Study Protocols
Another noteworthy finding is the substantial heterogeneity in the study protocols employed in investigations utilizing IGR for CO measurement.The diversity in experimental designs, including variations in the use of masks or mouthpieces, as well as interruptions in CPET for the transition between measurement devices, introduces confounding factors that could influence study outcomes.In particular, the practice of switching from a CPET mask to an IGR mouthpiece during peak exercise phases may introduce variability in the peak values, thereby impacting the reliability of the results obtained.

Inadequate Methodology Reporting
The systematic review also highlights the inconsistency in reporting the methodology of IGR measurements.Often, authors fail to detail whether a mask or a mouthpiece was used for IGR, which undermines the transparency and reproducibility of the studies.This lack of transparency poses challenges in interpreting the results and prevents the establishment of standardized best practices for IGR utilization.

Points for Clinical Practice
Considering these challenges, it is evident that there is an urgent need for the development of guidelines and standardized protocols for non-invasive CO measurement using the IGR method during CPET.By establishing clear guidelines on the instrumentation, experimental setup, and result reporting, researchers can enhance the consistency and reliability of their findings.This will enable more meaningful comparisons across studies, facilitating the accumulation of robust evidence for clinical applications.

Establishing Normative Ranges
Moreover, the systematic review underscores the necessity of generating comprehensive normative ranges for CO measurements using the IGR method.These normative values will serve as a valuable reference point, aiding in the interpretation of results obtained from different populations and under various conditions.Developing a wide range of normative values will contribute to the broader clinical utility of CPET-IGR.In conclusion, while the non-invasive measurement of CO using the IGR method during CPET holds significant potential, the systematic review illuminates the current challenges and limitations.Addressing the issues of result presentation, diverse study protocols, inadequate reporting, and the need for guidelines and normative ranges is imperative for the method's advancement.By collaboratively addressing these challenges, researchers can unlock the true clinical and research potential of non-invasive CO assessment using IGR during CPET.

Limitations
The presented systematic review includes several limitations.Firstly, some of the studies included in this review were based on small patient groups [31,51,59,66,76,79], and most of the studies focused on patients with either healthy conditions or heart failure.There were few studies available that focused on other disease entities [85,89,[95][96][97][98][99].Additionally, not all the required values could be obtained from the studies because they were not described.In addition, in most studies, a non-invasive CO assessment using the IGR method was not the main subject under investigation and was only one of many measures used in the study.These limitations should be considered when interpreting the results of this systematic review.Further studies with larger and more diverse patient populations are needed to provide more comprehensive information on the topic.

Conclusions
Given that the investigators conducting the studies included in this systematic review identified heart failure or a physical capacity assessment in healthy patients as the main indications for CPET and a non-invasive CO assessment, it is reasonable to conclude that the IGR technique is not used in a wide range of patients.Therefore, there is a need to validate and expand research on the IGR technique in patients with various conditions.
In conclusion, this systematic review provides a comprehensive overview of the use of IGR for a non-invasive assessment of CO during CPET.The evidence supports the reliability and validity of IGR as a method for measuring CO during exercise.However, there is a need for standardized protocols, guidelines, and reporting standards to ensure the consistent and accurate use of IGR in CPET assessments.Future research should focus on establishing normative values, and validating quality assessment tools specific to IGR studies.By addressing these gaps, we can enhance the clinical utility of IGR and its contribution to our understanding of cardiovascular function during exercise.

Figure 1 .
Figure 1.Cardiac output measurement with the use of IGR method during CPET.

Figure 1 .
Figure 1.Cardiac output measurement with the use of IGR method during CPET.

Figure 2 .
Figure 2. Contents of standard IGR report.

Figure 2 .
Figure 2. Contents of standard IGR report.

Table 2 .
Results of the systematic review.

Table 4 .
Indications for CPET-IGR in included articles.

Table 5 .
Proposed CPET-IGR report.Indication for CPET + IGR: Provide a summary of the patient's medical condition or reason for conducting the CPET.This may include a suspected cardiovascular or pulmonary disease, exercise intolerance, preoperative evaluation, or any other relevant clinical indication.Protocol: Describe the specific CPET protocol employed during the test.Include details such as the type of ergometer (treadmill or cycle ergometer), ramp or incremental protocol, exercise duration, and any specific adjustments made based on the patient's condition or limitations.Medication taken: [List all medications the patient took before the CPET, including the dosage and frequency.Highlight any medications that may affect cardiovascular or respiratory parameters.]Hb:[the hemoglobin level at the time of the CPET measured in g/dL or other appropriate units; the level of Hb impacts the a-vO 2 diff] Include a graph that depicts the relationship between CO and VO 2 max.Plot the CO values on the y-axis and the VO 2 max values on the x-axis.Each data point represents an individual patient's result.Additionally, you may consider highlighting the patient's specific data point on the graph for easier interpretation.Interpretation: Provide a detailed interpretation of the CPET and non-invasive CO measurement results, considering the patient's demographics, indication for the test, medications taken, and reference values when available.Discuss any abnormalities or significant findings in the context of the patient's clinical presentation.Consider integrating the relevant literature or guidelines to support your interpretation.
Conclusions: Summarize the key findings of the CPET and non-invasive CO measurement, highlighting any notable results or abnormalities.Provide recommendations for further evaluation or management if applicable.