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 () 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 in the bCBR group compared to controls and (2) three-fold greater short-term 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 values and short-term 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 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 variability measurements to assess fluctuations in oxygen saturation. A moving window approach was specifically designed to measure short-term variability changes in during 15% and 12% O2 exposure. As such, combining the traditional use of a pulse oximeter to measure 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 an observational study with a focus on individual data. The lack of participants is understandable, as it is rare to find patients who have undergone such a procedure. Moreover, they mention that their subjects combat their congestive heart disease using prescribed medications such as beta-blockers, angiotensin-converting enzyme inhibitors/blockers, and diuretics. As this study investigated several cardiovascular parameters (i.e. cardiac output and HR), the use of these drugs would greatly affect these values. Therefore, it should be noted that the parameters seen in the paper reflect a practical setting and not an experimental one. The study of Niewinski et al. (2021) opens the door for future studies to incorporate cardiovascular measures such as baroreflex sensitivity (BRS) and MSNA into their model, both of which this group has had experience investigating in the past. In previous studies, Niewinski et al. (2013) studied a single 56-year-old male patient with CHF who underwent uCBR by measuring the parameters BRS via sequence methods and MSNA via microneurography. Niewinski et al. (2021) stated that direct measures of sympathetic outflow via microneurography would have provided greater insight into sympathetic vasoconstriction seen with hypercapnia. As this paper addresses the influence of the residual chemoreflex 5 years after CBR, we believe that future studies should incorporate the measure of MSNA during each introduction of gas to provide an additional insight into autonomic control. Moreover, it has been shown that in CHF patients who have reduced ejection fraction (<35%), a blunted BRS accompanied with augmented sympathetic output is commonly observed (Seravalle et al. 2019). This augmentation would undoubtedly add to the increases in sympathetic outflow seen with hypercapnia, and thus further understanding of the changes in BRS is required. Consequently, we believe that future studies should address these cardiovascular parameters to better understand differences among the three studied groups. Another interesting concept to explore is the influence of the aortic bodies on the residual peripheral chemoreflex. Although it is well established that the CB have a greater influence on the autonomic system relative to the aortic bodies, there is limited data on their activity. Since aortic bodies stimulation has been shown to increase heart contractility (Cooper et al. 2005), it is within reason to assume that they have an influence on sympathetic outflow. Considering that attenuating peripheral chemoreceptor afferent discharge may be a useful intervention for CHF patients, understanding the consequences of bCBR surgeries on patients is of clinical significance. The present study showed that when exposed to prolonged mild hypoxia, bCBR patients had a 10% lower minimal value of when compared to CHF subjects with intact CB (Niewinski et al. 2021). They also stated that mild hypoxia (15% O2) is comparable to travelling 2700 m above sea level, equivalent to a transatlantic flight. As this paper shows the struggle of bCBR patients regulating when exposed to sustained hypoxia (i.e. 5–10 min), chronic exposure to such levels may inevitably lead to poor outcomes. Also, as mentioned in Niewinski et al. (2021), bCBR patients may have difficulty breathing during times of sleep apnoea, which has been widely established as a common comorbidity to CHF. Although the direct relationship between CB and sleep apnoea remains unclear, the elimination of the HVR in bCBR patients, as demonstrated in the present study, may present patients with breathing complications during sleep. Understanding this, the present data introduce the potential for compulsory sleep tests and continuous positive airway procedures (CPAP) devices post-surgery. This may be beneficial in determining a future protocol for physicians to prescribe their patients who have undergone this procedure. In conclusion, Niewinski et al. (2021) have shown that investigating the blood oxygen dynamics of bCBR patients is relevant in identifying the clinical implications of CBR. This study demonstrated that prolonged hypoxia could lead to reduced levels of oxygen saturation in bCBR patients, whereas combined mixtures of O2 and CO2 (12% O2/5% CO2) are better tolerated. Therefore, the authors have recommended the need for future studies to address the complications of performing bCBR surgeries in CHF patients. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. None declared. Both authors have read and approved the final draft of the manuscript and agree to be accountable for all aspects of the work. None.

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.