Physiological and clinical impact in the carotid baroreceptor function following the surgical management of bilateral carotid body tumors

Introduction

Carotid Body Tumors (CBT) are rare neoplasms of neuroendocrine origin. These represent the most common type of head and neck parangliomas, and the bilateral presentation is rarely encountered and reported in the literature.^1–3 Due to the malignant potential, the surgical management of these masses is recommended and remains the mainstay management. Given the proximity to important neck vessels and the possibility for arterial reconstruction, vascular surgeons have been involved in the care of these patients in experienced centers.^1,2,4 The study of the clinical manifestations and the indications of surgical treatment are areas of particular research interest and controversies among researches, in order to better define risk and benefits, predictors, outcomes and prognosis; however, due to the relatively low incidence, definitive expert consensus and standardized managements are lacking.^1–5

Baroreflexes are responsible for maintaining blood pressure homeostasis by avoiding volatile hemodynamic changes, these are buffered by baroreceptors (BR) located in the aortic arch and the carotid bifurcation, ⁶ specifically in the sinus and carotid body. The carotid sinus (CS) is a dilated area at the base of the internal carotid artery, just superior to the bifurcation, and it contains the main vascular baroreceptors. This is composed of a set of stretch receptors located in the adventitia of the carotid bulb. The carotid body (CB) is located in the bifurcation of the common carotid artery, and it is composed by small cluster of chemoreceptors of cells type 1, or chief glomus cells, which are peripheral chemoreceptors, and type 2 sustentacular supportive cells. ⁷ The CB and CS are innervated by the carotid sinus nerve, also known as Hering’s nerve, branch of the glossopharyngeal nerve (CN IX), which sends information to the cervical sympathetic trunk, pharyngeal branches of the vagus, hypoglossal, and the superior laryngeal nerve. ⁸ Signals travel through these pathways to the nucleus tractus solitarius (NTS) in the dorsal medulla. ⁹ When stimulated, the CS has a sympathetic-inhibitory effect on the peripheral and myocardial vascular tissue. This reflex arc is a negative feedback loop that acts as a buffer for blood pressure and heart rate during postural changes, and during physical or emotional stress. In addition to its baroreceptor function, the CB has the ability to function as chemoreceptor, with sensitivity to changes in PaO₂, PaCO₂, pH, and blood flow. The CB is the main arterial chemoreceptor and when stimulated by hypoxia, hypercapnia or acidemia, produces hyperventilation, a peripheral vascular sympathetic effect, and parasympathetic effect on the myocardium. ¹⁰ BR were initially believed to be involved only in short-term BP control; however, an association with long-term control has recently been found.^11–13

The impact in BR functions of vascular surgery interventions such as carotid endarterectomies has been studied and described.^14–17 In our institution, the section of Vascular Surgery and Endovascular Therapy evaluates and treats routinely patients with Carotid Body Tumors.^1,2,12,18,19 The relatively high incidence of this pathology in the Metropolitan area of Mexico City, which is the largest and most populous in North America and located between 7200 and 12,894 feet above sea level, has led us to observe and document recurrence and the bilateral presentation in single patients. Nowadays, little is known how the surgical treatment might impact in the function of the BR following these procedures.^20,21 In the present study, we aim to describe the natural history of baroreflex failure in patients with previous history of bilateral CBT that underwent surgical management.

Methods

This is an observational study conducted with single and cross-sectional evaluation of data. Approval was obtained from the Institutional Review Board, and consent to participate was given by patients. We evaluated the baseline demographics and clinical characteristics and performed autonomic testing to quantify baroreceptor sensitivity in seven patients who underwent bilateral CBT resection at the National Institute of Medical Sciences and Nutrition Salvador Zubiran in Mexico City. Baroreflex sensitivity was assessed using a questionnaire related to BRF symptomatology or history of BP variability, and using the Composite Autonomic Severity Score (CASS) for a complete quantification of the cardiovagal and adrenergic autonomous functions, the sudomotor domain was excluded for not influencing in the baroreceptor function. Total score enabled us to classify it as mild, moderate, or severe, and sympathetic, parasympathetic, or mixed failure (Figure 1).OPEN IN VIEWER

Results

Seven patients that underwent bilateral carotid body tumor resection were identified. Demographic characteristics are described in Table 1, the mean age was 61 years [standard deviation (SD) ± 11], six (85%) were female, there was no family history of paragangliomas, and all were residents of high elevation areas in the Valley of Mexico. Only one (7%) of the 14 resected tumoral masses had malignant histopathological characteristics. None of the tumors were functional or secretory. Two patients had clinical manifestations of chronic hypoxemia associated to severe obstructive sleep apnea syndrome; one patient had a pituitary adenoma, one had antiphospholipid syndrome, one had essential tremors, and two patients did not have prior history of disease. The clinical presentations and reason for evaluation for our vascular surgery team were the presence of palpable cervical mass that impacted the quality of life in five cases (71%), and odynophagia in two (29%). None of the patients underwent preoperative embolization, and with respect the surgical resection technique, all CBTs were approached with the retrocarotid dissection technique, ¹ during which, the hypoglossal nerve is carefully dissected and isolated with vessel loop. In Figures 2 and 3, we present two different patients that underwent bilateral surgical treatment of CBT.

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Table 1.

Comparison of the clinical and tumor characteristics of the seven patients presented in this study.

Patient	Gender/age (years)	Comorbidities	Symptoms of BRF
			Headache	Palpitations	Syncope	Fatigue	Vertigo
1	F/51	No comorbidities	✔	—	✔	—	—
2	F/65	Pituitary adenoma	—	—	✔	—	✔
3	F/83	Antiphospholipid syndrome	—	✔	✔	—	✔
4	F/68	Essential tremor	—	—	—	✔	—
5	F/60	Obstructive sleep apnea, obesity	—	—	✔	✔	✔
6	M/44	Obstructive sleep apnea	—	✔	—	✔	—
7	F/58	No comorbidities	—	—	—	✔	✔

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Figure 2.

(a and b) Preoperative computed tomographic angiography (CTA) with three dimensional (3D) reconstructions (a and b) in a 52 year-old female patient with bilateral carotid body tumors.

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Figure 3.

(a and b) Intraoperative photograph of a Shamblin III carotid body tumor (CBT) resection. The hypoglossal nerve is encircled with vessel loop and facial vein has been ligated (a). CBT has been resected, and superior thyroid artery is preserved (b).

Discussion

Baroreceptor failure occurs when an afferent component of this baroreflex arc fails. ²² The disruption of the baroreflex arc can lead to autonomic instability, such as volatile changes in arterial blood pressure. Among the most frequent causes of BRF are extensive cervical surgery, trauma, and radiation.^23–25 Four forms of BRF have been described: (1) Hypertensive crisis is generally manifested as hypertension, severe tachycardia, and headache, systolic blood pressure usually above 250 mmHg, occurs in the immediate period after a BR lesion and is a medical emergency; (2) Labile blood pressure or volatile hypertension results from the gradual loss of BR function that presents days to weeks after damage of the baroreflex and is the most common presentation. The baseline BP can be normal or elevated, but the patients show spontaneous sympathetic activation resulting in BP peaks and tachycardia of varying duration of minutes or hours. During the episodes, the patients have dizziness, palpitations, headache, anxiety, and irritability, and they can be hypotensive while sleeping; (3) Orthostatic tachycardia with increases in heart rate >30 bpm when the subject changes from the supine position to sitting or standing; and (4) Vasovagal Response with hypotension and severe bradycardia with asystole, due to increased parasympathetic tone resulting in fatigue, dizziness, or syncope. ²⁶

BRF after carotid body tumor (CBT) resection is more frequently observed after bilateral CBT resection due to denervation of both carotid sinuses.^{20,21,27–29} Adaptation to chronic hypoxia requires respiratory and cardiovascular adjustments to ensure adequate tissue perfusion to critical organs. However, the sustained activation of these hypoxia-induced reflexes due to acclimatization to hypoxemia in high altitudes as in Mexico City, or in medical conditions, can give rise to these neoplasms. ³⁰ CBT are generally benign, slow-growing neoplasms arising from the chemoreceptor system; only approximately 10% of CBTs are bilateral.^31,32 It is generally accepted that surgery is the mainstay of management for CBTs with acceptable morbidity rates. ³³ BRF is not present in all bilateral CBT resections, or it may improve through time suggesting a compensation mechanism, possible by aortic arch baroreceptors or by other unclear processes. ³⁴ BRF is typically subclinical, reflecting abnormal responses to environmental triggers, rather than an altered set-point. ³⁵ Neterville et al. ⁷ reported 30 patients with CBTs, of the 16 patients with bilateral CBT, 10 underwent bilateral resection and 100% of those developed BRF, characterized by tachycardia and fluctuations in blood pressure. Metheetrairut et al. ³⁶ published an incidence of BRF of 16.49%. In a review of the literature, this series, consistent with these findings in the present manuscript, BRF in our experience was rare in unilateral surgery and occurs in all of the bilateral cases. Because most patients did not show BRF after the first CBT excision, bilateral denervation of baroreceptors may be responsible for postoperative symptoms. It is difficult to elucidate if the great variability in the reported incidence of BRF ³⁶ is due to the low incidence of bilateral CBT or to unawareness or low suspicion of this poorly known entity. Considering the low incidence of malignant histopathology in these patients (4.1% overall in the largest systematic review ³¹ and 15% of our bilateral CBT series ³ ), and the negative impact in quality of life of patients with BRF, it should be appropriate to establish precise selection criteria to approach and operated the contralateral CBT. Limitations of our study include the retrospective nature and relatively small sample; however, these findings contribute importantly to reduce the lack of knowledge still prevalent in this area.

Conclusions

Baroreceptor failure after the surgical management of bilateral carotid body tumor is an underestimated and underdiagnosed sequela. In our study, the most alarming symptoms were seen immediately after the second CBT resection and consisted in severe hypertensive crisis, bradycardia, or asystole in immediate postoperative period; while chronic disabling symptoms occurred several weeks after the surgery, particularly recurrent syncope, vertigo, and fatigue. Autonomic testing showed baroreflex failure in all the cases, with mixed, sympathetic, and parasympathetic dysfunction in most cases. The real incidence and severity of the CBT BRF remains unknown, and given the relatively infrequency of this important and complex pathology, an international registry, further studies and expert consensus are necessary to adequately select the most appropriate approach and treatment for bilateral carotid body tumors.