Worth the risk? Effects of prolonged hypoxia and hypercapnia on ventilatory responses in patients with bilateral resection of the carotid bodies

Augmented sympathetic tone is an established hallmark of congestive heart failure (CHF), recent investigations have shown that this increase can be a result of overactive peripheral chemoreceptors (Niewinski et al. 2013, 2017). It has been proposed that the ablation of carotid bodies (CB), the primary peripheral chemoreceptors, can be a therapeutic target for sympathetic hyperactivity syndromes such as CHF. Previous studies performed by Niewenski et al. (2017) showed that surgical resection of carotid bodies (CBR) in CHF patients, both unilateral (uCBR) and bilateral (bCBR), was associated with both decreased muscle sympathetic nerve activity (MSNA) and peripheral chemosensitivity 1-month post-surgery. Due to the CB being the primary response mechanism to acute hypoxaemia, understanding the effects of hypoxia on bCBR patients is important for identifying its clinical practice in the HF population. To date, no study has documented the dynamics of blood-oxygen saturation levels (SpO2 ) in bCBR patients as a result of both sustained hypoxia and hypoxic/ hypercapnic mixtures. Therefore, understanding the interplay between ventilation, haemodynamics, and oxygenation patterns due to prolonged hypoxia will be critical in identifying the surgeries clinical usage. In a recent article in The Journal of Physiology, Niewinski et al. (2021) investigated the effects of administering various gas mixtures on three different groups: (1) CHF patients with CBR performed 5 years prior (bCBR group), (2) CHF controls and (3) healthy controls, with all groups having a sample size of n = 4. The subjects received the following interventions: transient hypoxia (brief N2 administration lasting between 10–30 s, repeated 4–11 times on each individual), mild hypoxia (15% O2), moderate hypoxia (12% O2), combined hypoxia and hypercapnia (12% O2/5% CO2) and hyperoxic hypercapnia (95% O2/5% CO2), with the latter four gas mixtures lasting a time period of 5–10 min each. These experiments were designed to identify the changes in ventilatory, haemodynamic and oxygen saturation patterns relative to baseline and between groups. Furthermore, whereas transient and prolonged exposures to hypoxia alone were used to assess peripheral chemoreceptors, the combination of O2 and CO2 mixtures allowed for a preferential assessment of central chemoreceptors. It was observed that 5 years post bCBR surgery, in response to transient hypoxia, hypoxic ventilatory response (HVR) remained eliminated, heart rate (HR) was maintained, and blood pressure (BP) was reduced. Moreover, prolonged bouts of hypoxia (both mild and moderate) led to (1) approximately 10% lower minimal values of SpO2 in the bCBR group compared to controls and (2) three-fold greater short-term SpO2 variability in the bCBR group during mild hypoxia relative to controls. In comparison, the combination of hypoxia and hypercapnia (5% CO2 /12% O2) led to similar changes in both minimal SpO2 values and short-term SpO2 variability between all studied groups, which suggests a preservation of central chemoreceptors in the bCBR group. The novelty of the study by Niewinski et al. (2021) is that it used an innovative short-term SpO2 variability measure to examine the oxygenation pattens of CHF patients who had their carotid bodies removed 5 years prior. In previous studies, this group had successfully completed CBR surgeries on CHF patients and showed that the bilateral procedure may carry a risk due to reduced oxygenation at night (Niewinski et al. 2017). Consequently, completing the present study was necessary to further evaluate the clinical implications of such a surgery. A highlight of the present paper which can be commended is the thoughtful protocol, with regards to subject selection, interventions chosen, and parameters measured. Firstly, a thorough measurement of cardiovascular and respiratory parameters was completed at baseline, as well as both 5 and 10 min post-gas administration. This was critical in identifying the haemodynamic and ventilatory changes that accompanied the hypoxic and hypercapnic exposures. Secondly, having two control groups (i.e. CHF controls and healthy controls) allowed the experimenters to control for (1) pathophysiological changes in response to HF, (2) medical pharmacological treatments of CHF and (3) normal physiological changes in response to hypoxia and hypercapnia. As such, this allowed the group to preferentially isolate the impact of hypoxia and hypercapnia on CBR. Together, this provides an excellent model for future studies that look to control for both physiological and pathophysiological variables. It should be noted that the group used the novel procedure of short-term SpO2 variability measurements to assess fluctuations in oxygen saturation. Amoving window approach was specifically designed to measure short-term variability changes in SpO2 during 15% and 12% O2 exposure. As such, combining the traditional use of a pulse oximeter to measure SpO2 with this novel methodology represents a comprehensive protocol for eliciting oxygenation patterns. Together, these two tests demonstrated that the bCBR group were more susceptible to the effects of hypoxia relative to controls. Since previous studies have conceptualized the therapeutic benefits of reducing afferent signals from the CB in CHF patients (Niewinski et al. 2017), continuing to measure oxygenation patterns using short-term variability analysis seems both logical and necessary in the future. The study of Niewinski et al. (2021) is not without its limitations, but it is clear that the authors are aware of its pitfalls. As the authors discussed, the use of a small sample size (i.e. n = 4) decreases the power of the data significantly. As they stated, the paper should be considered