Case of Episodic and Positional Hypertension: Diagnosis and Treatment

Summary

A case of episodic hypertension related to changes in position with the biochemical diagnosis of pheochromocytoma confirmed on imaging. The positional hypertension due to pheochromocytoma was treated by right open adrenalectomy, but the episodic hypertension recurred after 1 year and remained unresolved.

Case Introduction:

A 59-year-old Caucasian man who worked as a carpenter was seen in September 2014 as an outpatient at the University of Alabama at Birmingham (UAB) Hypertension Clinic. The patient was self-referred for a 14-year history of episodic hypertension related to positional changes.

During the hypertensive episodes at home, the patient’s systolic blood pressure (SBP) was 140–275 mmHg, while his diastolic BP (DBP) was 75–160 mmHg. Between episodes, his mean SBP was usually 140–150 mmHg and his DBP was 75–80 mmHg. The episodes generally lasted 45–60 minutes and usually occurred at around 3:00 AM, waking him up from sleep. At that time, he occasionally found himself lying on his right side with a BP ≥ 250/160 mmHg. The patient attributed this episodic hypertension to attacks of chronic pain with other symptoms, including nausea, vomiting, and heart pounding despite a normal heart rate (HR). The patient also complained of a tingling sensation in the head and spine and cramping of the hands and feet. The increases in BP were also positional i.e. they occurred while he was bending or turned to the right. The patient worked as a carpenter, making furniture and musical instruments, and reported also having these episodes while working. Specifically, they occurred when he was bending or pushing wood parts or pieces together.

Co-morbidities:

Important comorbidities included type 2 diabetes, obstructive sleep apnea (OSA), dyslipidemia, gastroesophageal reflux disease, hiatus hernia, peripheral neuropathy, carpal tunnel syndrome, chronic pain syndrome, palpitations, and anxiety. The diabetes was managed with metformin, with a glycated hemoglobin of 7.1%. The OSA was treated with continuous positive airway pressure (CPAP) and the hyperlipidemia was controlled on diet and exercise. The gastroesophageal reflux disease was managed with proton pump inhibitors. The carpal tunnel syndrome was surgically treated, while the chronic pain syndrome was managed with hydrocodone/acetaminophen.

Social history

Alcohol: The patient was a former heavy drinker from age 17 years, but his intake had tapered down and he reported a current alcohol intake of around one to two drinks a week. Tobacco: The patient was a former smoker from age 17 years to 2012; he had quit smoking using nicotine patches 2 years before his initial visit to the UAB Hypertension Clinic. Illicit drugs: He reported using cocaine until 1986 for 4–5 years and reported last using marijuana in May 2014.

Personal history:

The patient was divorced and had two daughters.

Occupational history:

The patient was a self-employed carpenter who made furniture and musical instruments. He also was a musician.

Family history:

There was no family history of any similar episodes. His mother had hypertension, hyperlipidemia, and diabetes mellitus. His father had no medical problems. The patient had three siblings with no medical problems. The patient’s daughter had asthma.

Review of systems: Initial visit

Head, eyes, ears, nose and throat (HEENT): Earaches, ear drainage, and ringing in the ears. Cardiac: Palpitations, irregular heartbeat. Gastrointestinal: Heartburn, indigestion, belching, and constipation. Genitourinary: Erectile dysfunction, change in sexual desire. Respiratory: Snoring, apnea, and hypopnea episodes while asleep. Musculoskeletal: Back and joint pain, muscular pain, and leg cramps at night. Psychiatry: Difficulty focusing on specific issues, normal mood, no depression.

Physical examination: Initial visit

General: Vitals: BP taken in the supine position after a 5-minute rest was 180/110 mmHg on the right arm and 176/110 mmHg on the left arm. The patient was not in acute distress; he was alert and oriented. HEENT: The fundi were not examined, neck veins were less than 5 cm above the right atrium, carotid pulses were 2+ bilateral without bruit, and neck was supple without cervical or supraclavicular lymphadenopathy. The thyroid was normal in size and consistency. Lungs: Clear with no crackles or wheezes. Heart: Regular rate and rhythm with no murmurs, rubs, or gallops. Abdomen: Soft bowel sounds heard in four quadrants; no masses, tenderness, or bruits; no hepatosplenomegaly. Extremities: No cyanosis, clubbing, or peripheral edema. The radial and pedal pulses were 4/4 bilaterally. Skin: Warm and dry without rashes; no skin lesions. Neurological: The patient was oriented to place and time; strengthened sensations were grossly intact; no focal deficits. Musculoskeletal: Pain and tenderness in the back and in multiple joints.

Medication regime: Initial visit

The patient’s medications included doxazosin 2 mg twice daily, diltiazem ER 180 mg twice daily, nebivolol 1 mg once daily, metformin 500 mg in the morning and 1,000 mg in the afternoon, hydrocodone/acetaminophen 7.5/325 mg once daily, baclofen 5 mg twice daily, naproxen 500 mg as needed, acyclovir 200 mg as needed, and history of taking gabapentin and alprazolam.

Discussion: Differential diagnosis of episodic and positional hypertension

Dr. Carey: It is very unusual to have this kind of BP response to positional change. One of the things that can do this, especially since the pressure was so high, is increased sympathetic discharge, especially from a tumor such as a pheochromocytoma or a paraganglioma, in which positional change may alter the tumor’s secretory capacity and/or the degree of noradrenergic discharge from an expanded norepinephrine pool in sympathetic nerve terminals. I wanted to ask about BMI and weight patterns. Had there been any recent changes?

Dr. Siddiqui: His BMI was 30 kg/m² and his weight had not changed over the last couple of years.

Dr. Carey: What was the total duration of the pain and these episodes?

Dr. Dudenbostel: Fourteen or 15 years.

Dr. Carey: They have not changed in character at all during that period?

Dr. Siddiqui: This patient did not have insurance. The first time he came to our clinic was a month before he became eligible for insurance.

Dr. Carey: There were no episodes of hypotension accompanying or associated with these episodes?

Dr. Siddiqui: No, he did not report any hypotension.

Dr. Carey: One other cause of variability in BP is abnormal baroreceptor reflex activity. However, hypotension is usually mixed with hypertension. Therefore, this is a straightforward postural or positional increase in pressure.

Prof. Dominiczak: That is great. We have a differential diagnosis. I think now we will get the tests right.

Dr. Lombardi: I am a doctor, but as my mom would say, not one that would do anybody any good. I have a PhD. Anyway, we’ve worked with patients at Serenity Lane Treatment Center for the chemically dependent and had people who would drink up to 1 L of sherry a day for several years; this person also had several years of primary dependent alcoholism. We have seen that such consumption fries the baroreceptors. In addition, there is a significant issue with supine to standing measurements in which there are wild variations. I am certain something else is going on such as pheochromocytoma, but I just thought I would make that point. Thank you.

Dr. Bhalla: I am Vivek Bhalla from Stanford University. I will save the first question I have, a comment about etiology, for later. However, I have questions about the timing of when this started, as I think it would inform the differential diagnosis. Therefore, in 2000, he was 45 years old when this started. How sure are you that this actually started when he was 45 as opposed to somebody who had episodes from a young age that just simply were not detected due to a lack of medical care? You mentioned that he was a heavy smoker and heavy drinker for many years. Then, when he is around 45, when he stopped drinking, he received medical care. So, the first question has to do with whether there was an inflection point. Thus, when did this etiology of hypertension actually begin? Was the BP normal and were episodes lacking prior to the time it began? The second question is more of a pragmatic and simple one, which is that you mentioned a history of OSA and treatment with CPAP, but you also mentioned positional symptoms that were consistent with not being very well treated for OSA. So, how well do you know that he is actually receiving adequate treatment with the CPAP? Do you have a sleep study of the current fittings? Does the fit change when he turns to his side? The questions are related to the efficacy of treatment for that particular risk factor.

Dr. Dudenbostel: To answer question 1, he reported that he first had symptoms in 2000. We had to believe that. He reported that back then, he had palpitations, and that was the main symptom that concerned him, and he was 45. All the work up back then focused more on cardiac etiology. He had a holter monitor and I believe an echo or so, and everything came back negative. He was told “we cannot find anything” and since he did not have insurance and did not want to follow up, he was lost to follow up. In 2014, he came to our clinic in September 2014 when he turned 60 in October. He timed that, on purpose. Because he knew, he would then have insurance. Actually, we did not manage that because we wanted to get everything else done fairly quickly, and enrolled him in our charity program, so that we could do everything in September, before he actually turned 60. This was the first question. The second question regarding OSA. Actually, a friend of his supervises a sleep clinic and observed that he stopped breathing at night and said, “I think you may have OSA.” He underwent a sleep study and subsequently received a CPAP machine. When we asked about it, he said he actually felt like after he was wearing the CPAP, the nightly episodes decreased in frequency. Specifically, he had less cramping and fewer attacks. Then, for a while, he also said, “Maybe it’s not serious and I don’ t need to follow up on this” since he felt like everything was getting better. In retrospect, I feel like maybe because he was more in a supine position of the CPAP machine and not turning as much around as you do without, which may have been one reason for its benefits. He was on his back more overnight and for longer hours instead of turning left and right. However, we do not have an in progress CPAP sleep study to see how many hours he actually used the CPAP and if it still fit after several years and the pressures were still okay and everything.

Dr. Basile: Jan Basile from Charleston. Obviously, this is not a patient with just essential hypertension, and you have to think about secondary causes. I agree with Dr. Carey that I would be very concerned about a pheochromocytoma or paraganglioma. He had perspiration, pain, and headache. He has palpitations. In addition, he has paroxysms of hypertension, which may be more common than sustained hypertension in these patients. Although a 24-hour BP is not necessary for the diagnosis of hypertension in this patient, I would like to know what his pressures are when he is having positional hypertension and when he is in a different position. Other tumors that raise BP in the neck area would be very concerning to me. You have not told us his labs yet. What is the renal function, proteinuria, left ventricular hypertrophy (LVH) by electrocardiography or echo, and has he sustained any of the trophic effects of intermittent sympathetic output overdrive? So far, however, he seems very fortunate. The OSA definitely has to be addressed and testing should be repeated after a CPAP fitting to see if it is adequately controlled? In no way do I think that is going to be his major issue with his BP. However, his general health must be addressed and we must ensure that the palpitations are not from atrial fibrillation with OSA, for example.

Prof. Dominiczak: Okay. We grow increasingly warmer. Good.

Dr. Egan: Brent Egan, Greenville, South Carolina, and I agree with what my colleagues Dr. Carey and Dr. Basile have said. I just wanted to throw a couple of other potential considerations into the differential. Certainly, the vertebral basilar arteries, as they lie near the medulla in some very sensitive areas, can be positional and elicit a significant neurogenic hypertensive response. If this is due to an excess of catecholamines, it is interesting that you did not see an increase in HR, which suggests that this is not predominantly an epinephrine phenomenon but probably more of a norepinephrine phenomenon. You are not seeing an increase in HR; you can actually see a reduction in HR with pure norepinephrine tumors. I think that is one potential concern. The other thing that will drive BP crazy – and I am not going to link this to position, but certainly renal artery stenosis can give you very episodic and severe elevations of BP. This patient did not have heart failure symptoms that sometimes accompany it, but I would not entirely remove it from the differential. An autonomic instability can be triggered by certain events. I am thinking about whether he might have a thoracic outlet syndrome or something else that may be triggering this. For consideration in the differential, I would look for other things that could drive this other than just catecholamine-secreting tumors.

Dr. Dudenbostel: Thank you for these very good points.

Dr. Roush: George Roush from NYU. How much documentation do we actually have, apart from the office of the magnitude of these BP swings? I think this speaks to Dr. Basile’s point about 24-hour monitoring… Are these episodes occurring every night that he bends, or are other factors involved?

Dr. Dudenbostel: He reported experiencing them nightly at times but then sometimes just three times a year. Very inconsistent.

Dr. Roush: Very inconsistent, okay.

Dr. Dudenbostel: I am not sure we had to rely basically on the patient’s self-report. The audience just said that alcoholism may have played a role too. Regarding reporting and accuracy, and how the patient perceived it…

Dr. Roush: That is certainly very interesting that it occurred a few times in a year.

Dr. Dudenbostel: Regarding the 24-hour BP, we do not have 24-hour ambulatory BP monitoring; rather, the BP was self-reported.

Dr. Roush: I was previously a cancer epidemiologist and alcohol and cigarette smoking interact dramatically to contribute to esophageal and other tumors. I just wonder could we think about some unusual paraneoplastic syndromes in this patient?

Prof. Dominiczak: Okay, we are keeping this in mind, and we go to the last comment in this series.

Dr. Bursztyn: What is the nature of his chronic pain?

Dr. Siddiqui: He could not describe the exact nature of his chronic pain. He was referred to a pain clinic and tried several options, but maybe it was psychological, maybe it was chronic pain syndrome. We did review his chart in an effort to determine the nature of his pain, but we could not.

Dr. Dudenbostel: He had a kind of chronic pain syndrome possibly related to osteoarthritis.

Dr. Bursztyn: Yes, but chronic pain syndrome is not really clear. I mean that it is not helpful to try to understand what hurts them. Was it in the hands? In the feet? In the abdomen? The back? I understand that his vocation was physically demanding.

Dr. Siddiqui: Yes.

Dr. Bursztyn: Were the opiates helping him?

Dr. Siddiqui: Yes, they helped him by decreasing his pain and BP. He attributed his pain to the positional changes, and hydrocodone was the only medication that helped lower his BP.

Dr. Dudenbostel: We will come back to the chronic back pain later with a couple of slides.

Dr. Bursztyn: Autonomic instability and episodic chronic pain may hint at an atypical form of porphyria.

Dr. Dudenbostel: We will return to that.

Dr. Carey: This man has a history of cocaine abuse.

Dr. Dudenbostel: Yes.

Dr. Carey: He stated that he had stopped using it, but he might have actually continued it. Cocaine abuse is associated with abdominal pain, nausea, and hypertension in this range.

Prof. Dominiczak: Tachycardia and palpitations and all these things.

Dr. Carey: All of these things.

Prof. Dominiczak: Right, this is fantastic. We have a very broad differential diagnosis; we now need to perform some tests.

Differential diagnosis

The differential diagnoses for positional hypertension include dysautonomia, vascular adrenergic hypersensitivity, renal artery stenosis, aortitis, and pheochromocytoma.

The differential diagnosis of episodic hypertension is labile hypertension based on emotional stress, pseudopheochromocytoma, page syndrome with excessive dopamine secretion, pheochromocytoma, illicit drug use, and chronic pain episodes^1–4.

BP variability is defined as short-term variability, long-term variability, 24-hour variability, visit-to-visit variability, and seasonal variability. Short-term BP variability is associated with an increased risk of LVH, target organ damage, and cardiovascular events^5–7. Long-term BP variability is also associated with stroke, coronary heart disease, a poor cardiovascular prognosis, and an increased mortality risk^8–10.

Diagnostic tests

Cardiac workup:

To evaluate the symptoms of palpitations, Holter monitoring was performed, but it revealed no arrhythmias. Cardiac MRI revealed no cardiac abnormalities. Transthoracic echocardiography findings were normal. The stress test was negative.

Biochemical workup:

The comprehensive metabolic panel including electrolytes and kidney function was normal. The lipid profile showed elevated cholesterol (260 mg/dL) and triglycerides (235 mg/dL). The HbA1c was 7.1%. The thyroid stimulating hormone level was normal. The urine drug detection screen for illicit drugs was negative for amphetamines, barbiturates, benzodiazepines, cocaine, methadone, and opiates.

Serum aldosterone (4.4 mg/dL) and plasma renin activity (1.4 ng/mL/h) levels were normal. Plasma-free normetanephrine (16 nmol/L) and metanephrine (49 nmol/L) levels were elevated. 24-hour urinary dopamine (502 mcg), epinephrine (1750 mcg), norepinephrine (248 mcg), total catecholamines (1998 mcg), vanillylmandelic acid (53.8 mcg), metanephrines (45419 mcg), normetanephrines (5899 mcg), and total metanephrines (51318 mcg) levels were elevated, diagnostic of pheochromocytoma (Table 1).

Table 1.

Biochemical findings before and after surgery

	Before surgery	After surgery	Reference values
Plasma metanephrine (nmol/L)	49	<0.20	<0.5
Plasma normetanpehrine (nmol/L)	16	0.66	<0.9
Urinary dopamine (mcg)	502	259	65–400
Urinary epinephrine (mcg)	1750	2	<21
Urinary norepinephrine (mcg)	248	55	15–80
Urinary total catecholamines (mcg)	1998	55
Urinary vanillylmandelic acid (mcg)	53.8	3.7	<8
Urinary metanephrine (mcg)	45419	142	<400
Urinary normetanephrine (mcg)	5899	383	<900
Urinary total metanephrines (mcg)	51318	525	<1300

Imaging workup for pheochromocytoma:

The chest computed tomography (CT) scan was unremarkable and did not show evidence of intrathoracic metastases. The abdominal and pelvic CT scan showed a large (8.4 cm) heterogeneous mass with areas of central necrosis and calcification seen arising off the right adrenal gland with possible extension into the inferior aspect of the right hepatic lobe. These findings were consistent with pheochromocytoma with possible malignant transformation given the presence of a thrombus within the right adrenal vein (Figure 1A). The positron emission tomography (PET) scan showed a hypermetabolic right adrenal mass containing necrotic areas corresponding to pheochromocytoma with no additional suspicious hypermetabolic lesions elsewhere (Figure 1B).

Figure 1A:

Computed tomography findings of pheochromocytoma: A large 8.4-cm heterogenous mass with areas of central necrosis and calcification is seen arising from the right adrenal gland with possible extension into the inferior aspect of the right hepatic lobe. The findings are most consistent with pheochromocytoma with possible malignant transformation given the presence of the thrombus within the right adrenal vein.

Figure 1B:

Positron emission tomography findings of pheochromocytoma: The hypermetabolic right adrenal mass containing areas of necrosis corresponds with pheochromocytoma.

Effects of medication on pheochromocytoma

The patient reported that doxazosin (an α-blocker) helped decrease his symptoms and that a decrease in its dosage increased the severity of the episodes. In addition, β-blockers precipitated the episodes, a typical finding in pheochromocytoma. The patient also reported better BP control using hydrocodone/acetaminophen.

Management

Diagnosis:

Based on his clinical presentation and biochemical and imaging results, the patient was diagnosed with an 8.5-cm pheochromocytoma of the right adrenal gland.

Preoperative management:

Medication consisted of α-blockade with doxazosin 8 mg at night with titration in 2-mg increments according to orthostatic vitals and β-blockade with metoprolol. The patient was also instructed to take alprazolam 0.5 mg thrice daily, diltiazem 180 mg ER baclofen 5 mg twice daily, and hydrocodone/acetaminophen 7.5/325 mg as needed. The preoperative BP was 147/82 mmHg with an HR of 97 beats/minute.

Surgery:

A right open adrenalectomy was performed on November 5, 2014. A large mass in the retroperitoneum was identified as an extensive hypervascular tumor.

Pathology:

An 8.5 × 8.2 × 8.0 cm encapsulated mass was examined. Serial sectioning of the mass revealed a heterogeneous cut surface characterized by glistening soft solid tan-pink tissue and multiple large smooth lined cystic spaces filled with necrotic yellow debris. Prominent areas of hemorrhage were observed throughout the tumor (Figure 2A).

Figure 2A:

Gross pathology findings of pheochromocytoma: An 8.5 × 8.2 × 8.0 cm encapsulated mass. The external surface is inked black. Serial sectioning of the mass revealed a heterogeneous cut surface characterized by glistening soft solid tan-pink tissue and multiple large smooth lined cystic spaces filled with necrotic yellow debris. Prominent areas of hemorrhage were observed throughout the tumor. Diagnosis: Pheochromocytoma.

Microscopic pathology:

The cells were arranged in nests surrounded by delicate fibrous bands. Each nest consists of cells with versicolor nuclei and abundant amphophilic cytoplasm. A subpopulation of small hyperchromatic cells (denoted by arrows) known as sustentacular cells was present at the periphery of the individual nests. Numerous capillaries filled with red cells were also observed.

Postoperative events:

The postoperative BP was 140/78 mmHg with a HR of 95 beats/minute. The patient had episodes of atrial fibrillation with a rapid ventricular rate and intermittent premature atrial contraction with a maximum HR of 160 beats/minute that were managed by an amiodarone drip. The patient also had BP fluctuations with hypotensive episodic BP of 80/50 mmHg. He required vasopressors (epinephrine and norepinephrine), which were closely monitored and successfully discontinued. After resolution of the BP fluctuations, the patient had non-ST elevation myocardial infarction with a troponin level of 0.85 that was managed by a β-blocker (metoprolol 25 mg twice daily) for rate control and anticoagulation with warfarin and a heparin bridge.

Postoperative discharge medications:

The postoperative medications included diltiazem ER 180 mg twice daily, metoprolol 50 mg twice daily, metformin 500 mg in the morning and 1,000 mg in the afternoon, aspirin 81 mg, warfarin 5 mg, baclofen 5 mg twice daily, and hydrocodone/acetaminophen 7.5/325 mg daily.

Postoperative vitals:

The patient’s BP did not fluctuate widely but remained uncontrolled.

Follow-up

After 1 year, the patient returned to the UAB Hypertension Clinic complaining of episodic BP fluctuations related to pain episodes but not position. The SBP was 120–170 mmHg and DBP was 70–110 mmHg. Further, the patient reported that he had discontinued all his medications after surgery. Figure 3 shows the BP and HR trajectories before and after surgery, demonstrating fluctuations in BP before surgery with a period of stabilization after surgery and a postoperative onset of BP fluctuations after 1 year.

Figure 3:

Blood pressure and heart rate before versus after surgery

Follow-up test:

A repeat 24-hour urine collection showed normal levels of catecholamines and fractionated metanephrines, and repeat urine drug screening results were negative.

Follow-up management:

BP management at the UAB Hypertension Clinic consisted of diltiazem ER 180 mg twice daily and chlorthalidone 25 mg once daily. Chronic pain management in the pain clinic consisted of hydrocodone/acetaminophen 7.5/325 mg daily and tramadol. The patient did not regularly attend follow-up at the UAB Hypertension Clinic and his episodic hypertensive episodes remained unresolved. The staff at the UAB Hypertension Clinic was notified in 2017 by a family member that he had passed away at home unexpectedly.

Discussion:

Dr. Carey: This large, slow-growing, ugly tumor that was removed was at the root of the problem. Although pathological examination did not identify a malignant pheochromocytoma, one cannot judge malignancy by simply observing the histology. It is possible that a malignant pheochromocytoma had recurred in the adrenal bed that was from the adrenal that was removed or a more distant site, increasing catecholamine and metanephrine levels and repeating the previous process. The other thing that I hope was done, although there was no family history of pheochromocytoma, paraganglioma, or any secondary hypertension, was a genetic analysis, not necessarily for the patient, but for his immediate relatives. Once an abnormal genetic pattern is identified, all direct relationships should be screened. This should be continued for generations because the risk is often much higher than it is in cases of sporadic pheochromocytoma.

Prof. Dominiczak: Right, absolutely, and we discussed this just before the session that genetic testing is now an obligation. It is necessary to perform genetic tests because certain mutations feature much more malignant changes and histology is completely unhelpful for this differentiation.

Dr. Basile: I would refer everyone to the New England Journal of Medicine review article by Neumann et al. that just came out on paraganglioma and pheochromocytoma because it talks extensively about the importance of a genetic workup³. Did you perform an autopsy on the patient?

Dr. Dudenbostel: No, we did not.

Dr. Basile: Interestingly. I might think about an extra-adrenal paraganglioma, but with the catecholamine level normal, I feel comfortable that this was not the case. With his chronic pain and his presentation, when you first described his case, he had what sounded like trigger points and a number of other things. Could he actually have a pseudo-pheochromocytoma after the pheochromocytoma removal? I have followed patients with pseudo-pheochromocytoma. Nobody wants to manage them. They should not be on narcotics. They need understanding and reassurance, but they often have panic attacks and hyper-anxiousness. I would have loved to have seen a 24-hour ambulatory BP monitor before he passed because these patients tend to have intermittent spikes of hypertension when they get anxious and you can reassure them of this. This is my best guess, but unconfirmed without an autopsy, which is unfortunate. I would be concerned that he actually behaved as if he had a pseudo-pheochromocytoma presentation after removal of the pheochromocytoma. But this certainly would not account for his death.

Prof. Dominiczak: Okay, this is very interesting.

Dr. Luther: I agree with Dr. Carey and many of Dr. Basile’s comments. I wonder about drug contributions to his hypertension. This did not resolve, and there was clear biochemical resolution. I was wondering before pheochromocytoma, if baclofen could have contributed to the BP liability. The fact that he used opioids and maybe avoided baclofen at times when his BP was controlled may support that. There is certainly hypertension if baclofen pump malfunction at high doses occurs. I wonder if baclofen or other drugs could have contributed to it.

Prof. Dominiczak: Okay, let’s hear the next comment, and then you will deal with them all together.

Dr. D’Costa: This was a very interesting case. I was just wondering, in this diabetic patient, I know he had a normal creatinine in 2014, but I did not see any urine tests, to see if he had any glomerular disease, urine protein analysis just to make sure he did not have any hematuria or proteinuria that could have contributed to the degree or quality of the hypertension.

Dr. Siddiqui: He did not have proteinuria; this was part of the 24-hour urine test, which was not on the presentation slides.

Dr. Young: Okay. I noticed in the urine toxicity that there were no opioids despite hydrocodone being on his medication list. After the pheochromocytoma resection, he was still hypertensive but not as severely. I wonder if opioid-induced hyperalgesia complicated his postoperative course, causing the more moderate elevations in BP with the once-daily dose of hydrocodone, which maybe he was not even taking every day based on the urine test results.

Dr. Elijovich: This is a rhetorical question but there is something that has not been answered in this case, unless somebody asked the surgeon. I have seen about 15 to 20 patients with pheochromocytomas over the years. However, this patient had a unique symptom that cannot be neglected. I am referring to the fact that he had paroxysms in certain positions only. This suggests that an anatomical structure put pressure on the tumor. This is analogous to the paroxysms that can be provoked by the hand of an examiner or by manipulation by the surgeon during the procedure. I suggest that perhaps some anatomical structure compressed the tumor when the patient was in a certain position. Did the surgeon have any idea of what it could have been?

Dr. Dudenbostel: The surgeon Dr. Heslin was aware of it because we discussed it preoperatively and hypothesized that it explained the labs we saw. These levels of 50,000 mcg of total metanephrines resulted from the patient bending to the right when he had the blood work done. The patient wanted to make sure that his labs were very high on the biochemical diagnostic testing. He told me later that he squeezed a little bit to the right.

Dr. Elijovich: This is very interesting because in secondary hypertension there may be compression of a tumor, or of the renal artery by the mesenteric ligament. Similarly, Dr Egan mentioned that a vertebral artery can be compressed in patients with obvious cervical spine osteoarthritis and cause positional hypertension.

Dr. Dudenbostel: Yes, and the patient knew about it and was helping us a little bit by bending during the blood draw.

Prof. Touyz: An important question, this patient had a chronic history and this episodic event with very severe hypertension; however, he had no evidence of any target organ damage. Is that correct?

Dr. Dudenbostel: This is correct. The echocardiogram obtained before surgery showed no LVH or signs of target organ damage.

Prof. Dominiczak: This is amazing.

Dr. Dudenbostel: Yes, it is.

Prof. Dominiczak: The patient’s demise, presumably due to cardiac complications, we assume sudden cardiac death due to arrhythmia without any structural changes in the heart. Fabulous case, we thank you for sharing it. I think in the paper we might want to discuss perioperative management. I worried that there would be a huge BP increase because of this huge tumor the moment the surgeon touched it. Was he alpha blocked sufficiently? In my experience with a few such huge pheochromocytomas, we tended to alpha block until the patient could not stand because we worried so much about unstable BP intraoperatively. I just wonder if it is possible to know whether that contributed to his complications.

Dr. Carey: Just a quick comment, I was equally concerned about using doxazosin alone in a patient like this. We would use phenoxybenzamine, a general α-blocker, combined with metryosine to block catecholamine secretion. This kind of double blockade would be predicted to reduce perioperative complications.

Dr. Siddiqui: Thank you for this comment.

Prof. Dominiczak: Fantastic case.

Figure 2B:

Histology of pheochromocytoma: The cells were arranged in nests surrounded by delicate fibrous bands. Each nest is composed of cells with vesicular nuclei and abundant amphophilic cytoplasm. A subpopulation of small hyperchromatic cells (denoted by the arrow) known as sustentacular cells is present at the periphery of the individual nests. Numerous capillaries filled with red cells are visible. Diagnosis: Pheochromocytoma.