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Validation of a Novel Method for Noninvasive Mixed Venous Oxygen Saturation Monitoring in Anesthetized Children.

Svedmyr A, Steiner K, Andersson A, Sjöberg G, Hallbäck M, Wallin M, Lönnqvist PA, Karlsson J.Anesth Analg. 2024 Oct 1;139(4):781-788. Doi: 10.1213/ANE.0000000000007083. Epub 2024 Aug 2.PMID: 39093817

Commentary by:

Martina Barbic, MD¹ and Vy A. Tran, MD²

¹ Pediatric Anesthesiology Fellow

² Assistant Professor, Pediatric Cardiac Anesthesiologist 

Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas at Houston

Take-home Points:

1. Pulmonary artery catheters (PAC) are the gold standard for mixed venous oxygen saturation (SvO₂₎ monitoring, but it is not frequently used in the pediatric population due to its inherent risks. Alternatively, existing non-invasive monitors such as near-infrared spectroscopy (NIRS) is commonly used to monitor the adequacy of oxygen delivery in the postoperative pediatric cardiac population but is limited in some instances.
2. Non-invasive capnodynamic SvO₂ monitoring is a novel method that has been applied in animal models and can potentially be used to continuously measure SvO₂ in pediatric patients undergoing general anesthesia. 
3. The study compared continuous capnodynamic SvO₂ (Capno-SvO₂), derived from breath-to-breath variability in end-tidal CO₂ data using a differential Fick’s principle, against gold standard CO-oximetry obtained by a PAC. It represents the first clinical application of a novel noninvasive monitoring concept without the need for a PAC.
4. Capnodynamic non-invasive estimation of SvO₂ generated absolute values and trending capacity that is in close agreement with the gold standard reference method of PAC CO-oximetry. Based on the findings in this study, Capno-SvO₂ could eventually serve as a useful tool in the assessment and management of tissue oxygenation and perfusion in children undergoing anesthesia or in the intensive care unit.

Background

To further understand the theory and application of capnodynamics, some details from several previous non-clinical studies by the same authors need to be summarized. This theory was first developed and trialed in a porcine model in 2014 on the premise of monitoring changes in end-tidal carbon dioxide (CO₂) after inducing small changes in the respiratory pattern in intubated patients (Figure 1).¹

Figure 1: A schematic pattern of time-based capnography demonstrating the capnodynamic breathing cycle with 6 breaths with I:E ratio of 1:2 followed by 3 breaths with an expiratory pause. The variations in alveolar and end-tidal CO₂ provides the data used in the capnodynamic calculations. 

Although an oversimplification, the two determinants of Capno-SvO₂ are continuous breath-by-breath calculations of effective pulmonary blood flow (i.e. the amount of deoxygenated blood that participates in gas exchange, EPBF) and oxygen consumption (VO₂). 

The authors previously validated capnodynamic CO_EPBF in children and piglets in a 2018 publication using a differential Fick’s principle. ² A mathematical model calculated the EPBF from respiratory variations as described above. Here, EPBF was used as a surrogate for cardiac output in the absence of major pulmonary shunts (CO_EPBF ).^1,3 

Next, VO₂ is calculated from VCO₂ (CO₂ production) and the respiratory quotient (RQ). VCO₂ is also computed from breath-by-breath CO₂ elimination from the changes in respiratory patterns as depicted in Figure 1.

Then, using the Classic Fick’s equation, the oxygen content in mixed venous blood (CvO2) can be derived. 

Here, the pulmonary end capillary oxygen content (CcO₂) is assumed to be saturated and in equilibrium with PO₂ in alveolar gas, which is calculated from the alveolar gas equation. The above equation is rearranged for CvO₂.

Finally, CvO₂ is then used to calculate SvO₂ with formulas previously described.⁴

Summary of Study
Mixed venous oxygen saturation (SvO₂) is used as an important surrogate for tissue oxygenation and perfusion.^5,6 The use of pulmonary artery catheters (PAC) represents a gold standard method for continuous SvO₂ and cardiac output (CO) measurement. However, PACs are typically not used in small children and can be unreliable with pre-existing intracardiac shunts. Although it is a percutaneous method, it is still considered invasive and is associated with risks such as bleeding, cardiac perforation, thromboembolism, and infection.^7,8 

Previous experimental studies have shown promising results correlating non-invasive cardiac output and SvO₂ monitoring based on capnodynamic assessment of effective pulmonary blood flow (EPBF) with established gold standard references.^4,9 The authors of the article compared continuous noninvasive capnodynamic SvO₂ (Capno-SvO₂) with CO-oximetry results obtained by PAC to validate the accuracy of Capno-SvO₂ in intubated and anesthetized children. 

This was a prospective observational study involving 25 procedures from 23 patients (11 males and 12 females) aged 3 months to 16 years (mean of 7.2 years) presenting for cardiac catheterization under general anesthesia. The study protocol included 10 ASD closures, 8 post heart transplant heart biopsies (2 of which were included twice), 3 PDA closures, 2 pulmonary artery dilations, and 2 diagnostic heart catheterizations. Continuous Capno- SvO₂ method based on Fick’s principle was used, according to description in the previous studies.^4,9 The method combines the continuous estimation of EPBF and oxygen consumption (VO₂) within a modified Fick’s equation. ⁴

Capno-SvO₂ was assessed under baseline conditions, followed by exposure to hemodynamic challenges (increase in PEEP from 3 to 8 cmH₂O and vice versa, increase in FiO₂ from 0.3 to 0.8 and vice versa), generating 150 paired data points of CO-oximetry SvO₂ and Capno-SvO₂. Absolute SvO₂ values collected through both methods and the paired differences between them were checked for normal distribution using the D’Agostino and Pearson test in addition to visual inspection of corresponding histograms.
Study results indicated that absolute values obtained by capnodynamic non-invasive breath-by-breath estimation of SvO₂ were in close agreement with the gold standard reference method PAC CO-oximetry. Furthermore, Capno-SvO₂ showed a 92% concordance in detecting changes in SvO₂ in comparison with PAC CO-oximetry, demonstrating an accurate trending ability. The novel concept of Capno-SvO₂ could thus be potentially utilized in the assessment of the whole-body oxygen supply and demand in children with structurally normal hearts, undergoing general anesthesia or intensive care, when used in adjunction to standard monitoring.

Capnodynamics: Theoretically useful, but is it practical?
The use of advanced hemodynamic monitoring in the pediatric population is limited. For children under general anesthesia, various parameters such as heart rate and blood pressure alone might be less reliable as markers of global oxygen supply and demand balance.⁷ Assessment of SvO₂ is a critical indicator of tissue oxygenation and perfusion.^5,6 PAC, a gold standard for SvO₂ monitoring is infrequently used in the pediatric population due to associated risks, particularly in infants and small children. Near-infrared spectroscopy (NIRS), although a popular non-invasive monitor commonly used in the pediatric cardiac surgery realm, has shown limitations regarding reliability in certain instances.¹⁰ Alternatively, the authors developed a novel, noninvasive method for SvO₂ measurement (Capno-SvO₂) that can accurately estimate SvO₂ and its trends when compared with gold standard PAC measurements, under normal physiological conditions.

This current study demonstrated that capnodynamic noninvasive breath-to-breath estimation of SvO₂ indeed correlated closely with measurements obtained by a PAC, when both were compared to fiberoptic SvO₂ monitoring. In addition, it detected changes in SvO₂ with a 92% concordance when compared with CO-oximetry. Based on study findings, Capno- SvO₂ demonstrated sufficient accuracy to assess SvO₂ and detect its changes in anesthetized children.

However, the study only evaluated moderate hemodynamic variations applied over a short period, and within physiologic SvO₂ range. For ethical reasons, effects of variations on hemoglobin, major cardiac output shifts, or hypoxia were not investigated. In addition, all measurements in the study were made on structurally normal hearts without residual shunts. Patients with congenital heart disease (i.e. single ventricle physiology), those with remaining intra and extra cardiac shunts (pulmonary shunts), and ongoing extracorporeal membrane oxygenation (ECMO) were excluded from the study.

The authors also recognize the small sample size, as there were only 25 participants. As such, they were unable to stratify based on age and weight to assess any correlation between the reference method and tested method. Additionally, only 2 baseline measurements were obtained to limit excessive blood loss.

Furthermore, the current Capno-SvO₂ model was investigated on intubated patients with controlled mechanical ventilation necessitating a specialized breathing pattern. There was a lack of assessment with other ventilation settings such as pressure support mode. The protocol required an intubated patient without a leak around the endotracheal tube. Therefore, it is unclear if the current study algorithm can be replicated when using other ventilation modes or a laryngeal mask airway. Since the method is based on changes in I:E ratio, the use of this method is limited in neonates less than 3.5kg and those requiring a faster respiratory rate and currently requires additional software for the ventilator pattern. 

Interestingly, the derivation of capno-SvO₂ relies on the respiratory quotient RQ (Ratio of CO₂ production to O₂ consumption). A standard RQ of 0.81 was used based on what is estimated for fasting children undergoing general anesthesia. While this is adequate for healthy patients, this may not be applicable to a critically ill or septic patient.
Despite the above limitations, this study represents the first clinical application of a novel concept for noninvasive SvO₂ monitoring in the pediatric population. As the authors appropriately identified, further studies are required to include a wider participant sample that is more applicable in the acute setting. Nevertheless, initial results provide a proof of concept that Capno-SvO₂ method provides absolute values and trending capacity that is comparable to the gold standard reference method. Capno-SvO₂ may be a promising novel method for noninvasive assessment of SvO₂ in children under general anesthesia and the critical care unit. There are ongoing clinical studies trialing this method on children with congenital heart disease with the aim for use in the realm of adult and pediatric cardiac anesthesia.³ We await how the challenge of shunts and single ventricle physiology can be circumvented to allow for the use of non-invasive, continuous SvO₂ monitoring in our unique patient population.

References

1. Karlsson J, Lönnqvist PA. Capnodynamics – noninvasive cardiac output and mixed venous oxygen saturation monitoring in children. Front Pediatr. 2023;11:1111270.

2. Karlsson J, Winberg P, Scarr B, et al. Validation of capnodynamic determination of cardiac output by measuring effective pulmonary blood flow: a study in anaesthetised children and piglets. Br J Anaesth. 2018;121(3):550-558.

3. Sander CH, Hallbäck M, Wallin M, Emtell P, Oldner A, Björne H. Novel continuous capnodynamic method for cardiac output assessment during mechanical ventilation. Br J Anaesth. 2014;112(5):824-831.

4. Karlsson J, Lönnqvist PA, Wallin M, Hallbäck M. A Continuous Noninvasive Method to Assess Mixed Venous Oxygen Saturation: A Proof-of-Concept Study in Pigs. Anesthesia Analg. 2021;132(6):1768-1776.

5. Holm J, Håkanson E, Vánky F, Svedjeholm R. Mixed venous oxygen saturation predicts short- and long-term outcome after coronary artery bypass grafting surgery: a retrospective cohort analysis. Br J Anaesth. 2011;107(3):344-350.

6. Bootsma IT, Boerma EC, Scheeren TWL, Lange F de. The contemporary pulmonary artery catheter. Part 2: measurements, limitations, and clinical applications. J Clin Monit Comput. 2022;36(1):17-31.

7. Hadian M, Pinsky MR. Evidence-based review of the use of the pulmonary artery catheter: impact data and complications. Crit Care. 2006;10(Suppl 3):S8.

8. Karlsson J, Lönnqvist P. Blood pressure and flow in pediatric anesthesia: An educational review. Pediatr Anesthesia. 2022;32(1):10-16.

9. Svedmyr A, Konrad M, Wallin M, Hallbäck M, Lönnqvist PA, Karlsson J. Non-invasive capnodynamic mixed venous oxygen saturation during major changes in oxygen delivery. J Clin Monit Comput. 2022;36(5):1315-1324.10. Soehle M, Langer J, Schindler E, Manekeller S, Coburn M, Thudium M. Effect of Extracerebral Contamination on Near-infrared Spectroscopy as Revealed during Organ Donation: A Prospective Observational Study in Brain-dead Organ Donors. Anesthesiology. 2024;140(2):231-239.