Sequential Use of Aminophylline and Theophylline for Temporizing Neck Cancer-Induced Carotid Sinus Syncope

Abstract

Carotid sinus syncope due to head and neck cancer is uncommon and the management is challenging. Permanent pacemaker implantation is generally considered but malnutrition with subsequent chemo-radiation increases the risk of device infection. This is a first case report of the sequential use of aminophylline and theophylline for pharmacological temporization. (Level of Difficulty: Advanced.)

Graphical abstract

Carotid sinus syncope due to head and neck cancer is uncommon and the management is challenging. Permanent pacemaker implantation is generally…

History of Presentation

A 65-year-old man presented following a 2-week history of frequent syncopal events. The episodes occurred at night when lying in bed and were provoked by rightward neck rotation. After he was found unresponsive on the bathroom floor without seizure or incontinence, he presented to our hospital. He also noted a gradually enlarging right neck mass in addition to new taste changes and right lower facial numbness. He denied orthostatic, exercise-induced, or daytime syncope. He did not take any medications. During this presentation, he had unintentional weight loss but denied fever, night sweats, exertional chest pain, or shortness of breath. His smoking history was significant for 3 packs/day for the last 40 years. His physical examination was notable for a right suprahyoid, firm, neck mass from the level of the right ear lobe to the middle neck. There was no concurrent skin change or lymphadenopathy noted. Heart and lung sounds were normal.

Learning Objectives

• •To understand the pathophysiology of CSS.
• •To understand the pharmacological mechanisms and available evidence of using xanthine derivatives (aminophylline and theophylline) in patients with bradycardia.
• •To understand the high-risk of device infection in oncology patients who develop malnutrition with subsequent CR in head and neck cancer.
• •To consider pharmacological temporization in head and neck cancer−induced CSS and recognize the limited experience in this condition.

Medical History

No previous medical and surgical histories.

Differential Diagnosis

The differential diagnoses were carotid sinus syncope (CSS) due to neck tumor, sick sinus syndrome (SSS), or atrioventricular block, electrolyte-induced arrhythmia, or autonomic dysfunction.

Investigations

His 12-lead electrocardiogram showed normal sinus rhythm and was otherwise unremarkable (Figure 1). His orthostatic blood pressure was normal. The initial blood tests did not show any electrolyte abnormalities, and serial troponin levels were not detectable. He was admitted to our cardiac intensive care unit for close observation.

Figure 1.

12-Lead Electrocardiogram on Admission

A normal sinus rhythm without concurrent arrhythmias or ischemic changes.

He subsequently had witnessed syncope and documented hypotension while supine, and the telemetry demonstrated subsequent sinus pauses (Figure 2). Transthoracic echocardiography showed normal left ventricular systolic function (55% to 60%) without left ventricular outflow tract obstruction or valvular disease. Computed tomography of the neck demonstrated a 4.7- × 4.1- × 7.9-cm vascular mass in the right suprahyoid neck that was adjacent to the carotid artery bifurcation (Figure 3). A fine-needle aspiration biopsy identified squamous cell carcinoma. His positron emission tomography computed tomography did not show metastatic lesions. Therefore, he was formally diagnosed with an advanced stage, right-suprahyoid squamous cell carcinoma (stage T_XN₃M₀). Surgical resection was not indicated due to the complicated vascular anatomy, and chemo-radiation (CR) was the decided therapy.

Figure 2.

Telemetry Electrocardiogram

It was found to correlate with symptomatic sinus pauses.

Figure 3.

Coronal Computed Tomography Neck

(A) A 4.7- × 4.1- × 7.9-cm vascular mass in the suprahyoid right neck (white arrows) adjacent to the carotid artery (white arrowheads). (B) The sagittal neck on computed tomography showed this neck tumor (white arrows) invaded the carotid artery bifurcation (black arrowhead).

Management

Based on these findings, the etiology of his syncopal episodes was consistent with carotid sinus hypersensitivity; a continuous isoproterenol infusion was initiated. Because of the potential for a reversible etiology of his CSS and the prospect of improvement once the tumor burden decreased, a pharmacological approach was decided instead of directly proceeding to permanent pacemaker (PPM) implantation. Isoproterenol was switched to a continuous aminophylline infusion (0.5 mg/kg/h) following an initial 250 mg intravenous bolus. The serial theophylline levels were repeated to maintain the therapeutic level (10 to 20 μg/ml). After initiating this approach, his heart rate was well maintained at approximately 60 to 80 beats/min, and he had no recurrent pauses. Three days later, the aminophylline was replaced with oral theophylline (immediate release) 600 mg daily, and he was discharged home with extended-release theophylline 600 mg daily.

Discussion

Recurrent CSS in patients with head and neck cancer is uncommon and most previously reported cases are due to metastatic squamous cell carcinoma (1). The suggested pathophysiology is an abnormally stimulated carotid sinus reflex due to mechanical compression of the carotid sinus baroreceptors and/or tumor-induced irritation of the glossopharyngeal nerve (1). Physiologically, the increased intraluminal pressure in the carotid bifurcation is sensed by the baroreceptors and the carotid sinus nerve, a branch of the glossopharyngeal nerve, and then afferent signals are transmitted to the brainstem hypothalamus. The vagal reflex results in bradycardia due to suppression of both sinus and atrioventricular nodal activities (1). In addition, carotid sinus stimulation can also inhibit noradrenergic vasoconstriction, which results in significant hypotension (1). Based on the pathophysiology, CSS is classified as a cardio-inhibitory type (asystole or marked bradycardia, with or without hypotension) and a vasodepressor type (profound hypotension without bradycardia) (1). Because of the sinus pauses provoked by rightward neck rotation, hemodynamically significant bradycardia, and hypotension, the authors diagnosed this case as predominantly cardio-inhibitory CSS.

Because isoproterenol infusion is not a practical regimen for outpatient management, a PPM implantation was initially considered. However, malnutrition in neck cancer patients is very common, especially with subsequent CR. Malnutrition increases the risk of PPM infection (odds ratio: 2.66; p < 0.001) (2). Surgical interruption of the glossopharyngeal nerve and/or carotid sinus could be considered as a palliative intervention because of the complicated vascular anatomy in many cases. There is no international consensus with regard to the pharmacological treatment.

The suggested pathophysiology of CSS is a peripheral activation of the adenosine chemoreceptor; xanthine derivatives are one of the promising medications (3). The activation of the endogenous adenosine receptor results in slowing the sinoatrial node activity (negative chronotropic effect) and blocking atrioventricular node conduction (negative dromotropic effect) (3). These adenosine effects can be antagonized competitively with xanthine derivatives such as aminophylline and theophylline (3). The xanthine derivatives can also suppress the adenosine-induced vasodepressor response by increasing the endogenous catecholamine concentrations (3). Theoretically, these medications can alleviate cardio-inhibitory and vasodepressor type of tumor-induced CSS. Nelson et al. (4) reported the clinical effectiveness of oral theophylline in patients with vasovagal syncope. The low-dose theophylline (6 to 12 mg/kg/day) may prevent vasovagal syncope in selected patients who can tolerate theophylline. Although the available evidence of using xanthine derivatives in patients with CSS is still limited, the authors considered the xanthine derivatives because they could regulate the underlying pathophysiology of CSS in this patient.

Hurtley et al. (5) summarized the previous clinical trials of aminophylline use for brady-asystolic cardiac arrest; most trials use an intravenous aminophylline dose of 250 mg as the loading dose. Therefore, the authors used the same dose and started the continuous infusion (0.5 mg/kg/h), which was the recommended maintenance dose for airflow obstruction with a therapeutic theophylline level (10 to 20 μg/ml). The clinical use of theophylline in patients with bradycardia has been suggested previously. The THEOPACE study, published in 1997, was a randomized clinical trial that evaluated the effectiveness of PPM and theophylline in patients with SSS. The resting heart rate was always higher in the theophylline group compared with the placebo (6). Based on this evidence, the authors decided to transition from aminophylline to oral theophylline for the pharmacological temporization.

There is only 1 case report of using oral theophylline for a similar neck cancer−induced CSS. Vallurupalli et al. (7) successfully temporized the symptomatic CSS with sustained-release theophylline (100 mg/day). However, the authors believe the preceding use of aminophylline is very important to confirm the clinical effectiveness of xanthine derivatives before transitioning to oral theophylline. There is only 1 case report of the sequential use of aminophylline and theophylline for atropine-resistant bradycardia after a spinal cord injury (8).

Follow-Up

The patient did not develop recurrent syncope or theophylline-related side effects during his outpatient follow-up. The neck tumor diminished with a 3-month course of CR, and the theophylline was successfully discontinued.

Conclusions

Carotid sinus hypersensitivity induced from neck cancer was effectively treated with xanthine derivatives that prevented the need for PPM while the tumor was treated. The initial use of intravenous aminophylline not only provided an immediate response but demonstrated the effectiveness of xanthine derivatives. Transition to oral theophylline was then made successfully before discharge. The sequential use of aminophylline and theophylline in patients with neck cancer−induced CSS avoided PPM implantation in this unique clinical scenario.