Mechanisms of limitation of oxygen delivery during veno-venous extracorporal membrane oxygenation

Ensuring adequate tissue oxygenation is a cornerstone of intensive care medicine. We here present a new integration of mechanisms of tissue oxygenation during veno-venous (V-V) extracorporal membrane oxygenation (ECMO) into a holistic physiologic model.

An integrated physiological model of tissue oxygenation describes oxygen delivery (DO₂) as process of multiple steps: diffusion of the oxygen from the alveolus to the pulmonary capillary, convective transport via perfusion with oxygen mostly bound to hemoglobin (Hb), diffusion from capillary through tissue to the mitochondrium. As all steps occur in sequence, a limitation can occur on each of these steps (1-6).

We will first describe the integration of oxygen transport during convection and diffusion according to this model.

The global convective DO₂ can be described as: DO₂ = Q × CaO₂ [Q: cardiac output (CO); CaO₂: arterial oxygen content]. The main determinants of CaO₂ are Hb concentration and arterial oxygen saturation (SaO₂).

The oxygen consumption (VO₂) according to the Fick principle can be described as: VO₂ = Q × (CaO₂ − CvO₂) (CvO₂: venous oxygen content).

The DO₂ from the capillary to the mitochondrium with a certain diffusion capacity D can be described as: VO₂ = D × (PcapO₂ − PmitO₂) (PcapO₂: oxygen partial pressure in the capillaries; PmitO₂: oxygen partial pressure at the mitochondrium).

If the partial pressure of oxygen at the mitochondrium can be neglected and the partial pressure of oxygen in the terminal capillaries is proportional to venous partial pressure of oxygen with a constant factor k, this can be described as: VO₂ = D × k × PvO₂ (PvO₂: venous oxygen partial pressure).

If the dissolved oxygen is in equilibrium with the oxygen bound to Hb following the sigmoid oxygen dissociation curve, the connective and diffusive DO₂ can be plotted on the same graph where VO₂ is the ordinate and PvO₂ is the abscissa. This model is consistent with the current understanding of the physiology of DO₂ (5).

Patients with severe respiratory failure may experience a total loss of lung function. In these cases, V-V ECMO may provide the entire oxygen supply for the patients. If the Hb is considered constant, the CaO₂ is determined by the maximal ECMO flow, because we consider the ECMO oxygenator to be capable of fully oxygenating all blood passing through the oxygenator.

In a subset of patients, a high CO that is significantly higher than the maximal achievable effective ECMO flow, will lead to a significant addition of deoxygenated venous blood, thus lowering the SaO₂. There is controversy, if the addition of beta-blockers with the intention of lowering the CO and thus increasing the SaO₂ is beneficial, because the total amount of oxygen delivered by ECMO is not changed (7).

To introduce our integrated model of tissue oxygenation during V-V ECMO in cases of total lung failure, we analyze two situations (Situation A and Situation B). We consider these situations to be completely equal regarding ECMO flow and all physiologic parameters and to differ only in regard to CO and SaO₂

We make some simplifying assumptions:

• Situation A: high CO (QA), low CaO₂ (CaO₂A), DO₂A = QA × CaO₂A; Situation B: low CO (QB), higher CaO₂ (CaO₂B), DO₂B = QB × CaO₂B
• Under the conditions of a CO that is significantly higher than the ECMO flow, a properly functioning oxygenator and minimal recirculation we consider DO₂A = DO₂B
• VO₂ remains constant and equal in both situations VO₂A = VO₂B = QA × (CaO₂A − CvO₂A) = QB × (CaO₂B − CvO₂B).

If we put these assumptions together, we get the following relationship: QA/QB = CaO₂B/CaO₂A = (CaO₂B − CvO₂B)/(CaO₂A − CvO₂A) = CvO₂B/CvO₂A.

That implies, that in Situation A with higher Q and lower CaO₂, the absolute difference between CaO₂ and CvO₂ will be lower than in the low output situation, but the absolute value for CvO₂ will still be lower in Situation A than in Situation B.

With these underlying assumptions we can generate a Wagner diagram depicting Situation A and Situation B (Figure 1). The intersections of the diffusion line with the curves of the convective transport are the values for maximal VO₂ (VO₂max).

Figure 1 Wagner diagram of convective transport in Situation A (blue line) and Situation B (red line). Dotted vertical lines: PvO₂ at a given VO₂ represented by the broken line. Dotted horizontal lines: VO₂max in Situation A and Situation B. PvO₂, venous oxygen partial pressure; VO₂, oxygen consumption; VO₂max, maximal VO₂.

As it can be seen on the diagram, we consider the convective maximal DO₂ to be identical in both situations. For any given VO₂ (broken line in Figure 1) the PvO₂ in Situation A will be lower than the PvO₂ in Situation B, because the oxygen content in any given volume of blood will be higher in Situation B.

If we now introduce the diffusion capacity in our model, we see that the VO₂max on the diffusion step is higher in Situation B, because the concentration gradient of O₂ between the capillary and the mitochondrium is higher.

Since a limitation on the diffusion step has been described in past research (8,9), we consider it to be an important component of a holistic concept of DO₂ into the tissues.

While values for arterial oxygen partial pressure (PaO₂) around 60 mmHg have been considered safe in past clinical trials (HOT-ICU, ICU-ROX), the LOCO₂ trial with a target of 55–70 mmHg in the conservative oxygen group was stopped early because of an increased number in mesenterial ischemia (10-12).

Our hypothesis is, that in PaO₂ values below the lower threshold in the past trials, a diffusion limitation might lead to tissue hypoxia in patients with low CaO₂ values despite an identical convective DO₂. Diffusion limitation as the limiting factor of DO₂ has previously been described (8,13,14). We therefore suggest, that the use of medications to decrease the CO in situations of total lung failure and ECMO support might decrease the risk of tissue hypoxia by accounting for the risk of a limitation on the diffusion step. The use of a short acting medication like esmolol is preferable in this situation in cases where adverse events are observed.

If there is some lung function left, this concept does not apply, since the potential influence of changes in CO on the ventilation/perfusion mismatch have to be taken into account (15). Furthermore, especially in the context of a femoro-jugular cannulation, recirculation might increase with a decrease in CO (16). In this situation the use of beta-blockers to reduce CO may be hazardous. Our concept therefore only applies to a situation where minimal recirculation can be achieved as with a bi-caval dual lumen cannula. In this case recirculation may be negligible (17). If the effect of the admixture of deoxygenated blood is also taken into account, the PvO₂ of the venous blood will also be higher in Situation B as we calculated above.

While a previously discussed mathematical model suggests, that the convective DO₂ is improved in the situation of increased CO and reduced SaO₂, this does not take into account the following steps of tissue oxygenation (7). Furthermore, a decrease in CO might worsen perfusion on the microvascular level. To our knowledge, there is currently no established cut-off for CO and CaO₂ to decide when lowering CO and thus increasing diffusion is beneficial.

There are multiple possible options to solve this question, including data mining of hemodynamic and blood gas data from patients treated with V-V ECMO, mathematical modelling of tissue perfusion and diffusion or models using animal tissue for direct testing.

Further data is needed to evaluate whether the effects predicted by this model have a clinically meaningful effect.

Acknowledgments

Funding: None.

Footnote

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-800/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-800/coif). D.R. receives an authors’ salary from Springer Verlag for having published a medical textbook. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. No human or animal experiments have been performed for this work.

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