Commentary: Intermittent Hypoxia Severity in Animal Models of Sleep Apnea.

Obstructive sleep apnea (OSA) is a common disorder that leads to problems including intermittent hypoxia (IH) and arousals from sleep. To simulate consequences of OSA, some studies expose rodents to IH with the intention of simulating the oxygen profile experienced by OSA patients. Some IH experiments induce hemoglobin oxygen saturation (SaO2) to fall to 50–70% during the nadir phase. In a recent review, we stated that this degree of hypoxemia is more severe than that experienced by typical OSA patients (Chopra et al., 2015). Farre et al. challenged this statement (Farré et al., 2018), pointing out that small mammals such as rodents have a right-shifted oxyhemoglobin dissociation curve (ODC) compared to humans (Schmidt-Nielsen, 1970). They argue that the higher arterial partial oxygen pressure (PaO2) for a given SaO2 confers mice with “better oxygen reserve.” To achieve PaO2 nadir values similar to those experienced by severe OSA patients they contend, “SaO2 in mice should be much lower than the SaO2 observed in patients.” We disagree with this statement, which relies on PaO2 as an indicator of tissue oxygenation. Arterial O2 content (CaO2) is determined by classic formula:

Systemic O2 delivery (DO2) is the product of blood flow (Q) and CaO2. From these equations, it is apparent that PaO2 as it determines the amount of dissolved O2 gas, itself has a negligible contribution to CaO2 or DO2. As oxygenated blood reaches target tissues, O2 dissociates from hemoglobin to maintain a favorable capillary-to-tissue PO2 driving gradient. When O2 diffuses into tissues, systemic capillary PaO2 falls, and is replenished by upstream oxygenated hemoglobin. Aerobic metabolic processes then consume cell O2. The balance between O2 supply and demand determines the cellular PO2. Therefore, cellular PO2–the parameter that truly determines oxygen adequacy - depends upon DO2, capillary density, and rates of O2 utilization. A right-shifted ODC means that O2 is unloaded from hemoglobin more rapidly, but this does not increase the total amount of O2 delivered.

To propose that mice should have their SaO2 lowered in order to achieve a PaO2 equal to that of humans is tantamount to suggesting that one should load a truck to only half its capacity, because it unloads boxes twice as quickly. If we invoke this logic, and use the figure provided by Farre et al., mouse SaO2 would have to be decreased to ~75% to match a normoxic human PaO2 at ~65 mm Hg. Mice exposed to hypoxemia of this magnitude exhibit robust erythrocytosis (Fagan, 2001) and activate anaerobic metabolic pathways (Jun et al., 2012, 2014) indicating that mice are effectively hypoxic at a higher PaO2 than humans. Their higher PaO2 may be necessary to maintain adequate tissue PO2 (as opposed to having “better oxygen reserve”), as mice have dramatically higher mass-specific metabolic rates than humans. Therefore, we should be targeting equivalent drops in SaO2 between humans and rodents if the goal is to reduce distal O2 delivery to the same extent.

Implicit in the argument by Farre et al. is that a right-shifted ODC is advantageous in mitigating effects of low SaO2. There is no evidence that we could find to support this argument. A right-shifted ODC is advantageous in states such as shock or hemorrhage ensuring O2 is maximally transferred to ischemic tissues (Agostoni et al., 1975; da Luz et al., 1975; Cornum et al., 1998; Morgan, 1999). Conversely, transfusion of blood depleted of 2,3 diphosphoglycerate to left-shift the ODC (Riggs et al., 1973) decreases tissue oxygen supply. These examples pertain to conditions when hemoglobin is fully O2 saturated (i.e., SaO2 is constant). What is the effect of shifting the ODC during hypoxemia (e.g., high altitude, OSA)? Here, effects of hemoglobin O2 affinity are not straightforward. Left shifting the ODC increases O2 uptake in the pulmonary capillaries, but compromises peripheral tissue O2 unloading. At high altitude, this trade-off is advantageous for survival; the “tipping point” occurs when O2 uptake becomes diffusion limited (Storz and Moriyama, 2008). Indeed, rats exposed to severe hypoxia survived longer with a left-shifted ODC (Eaton et al., 1974). The rightward ODC curve of rodents may actually be counter-productive in the setting of ambient hypoxia.

In conclusion, we should not “titrate” SaO2 in different species to match their PaO2, based on different hemoglobin O2 affinities. We stand by our statement that IH experiments that lower the SaO2 of mice to nadirs of 50–70% are severe. Our intent was not to dismiss the importance or validity of these IH models. We merely object to the claim that SaO2 needs to be lowered more in mice than humans to simulate consequences of OSA.

Author Contributions

JJ and ES collaboratively wrote the manuscript.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.