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available concerning management of patients who have Samuel J. Mann, MD New York Presbyterian Hospital-Weill/Cornell Medical School, a pheochromocytoma, fewer than two dozen papers deal 450 East 69th Street, New York, NY 10021, USA. with the 98% who do not. Doctors and researchers simply do not know how to manage these patients. Current Hypertension Reports 2008, 10:12–18
This article presents a new understanding of the origin, Current Medicine Group LLC ISSN 1522-6417 diagnosis, and successful treatment of otherwise unexplained Copyright 2008 by Current Medicine Group LLC paroxysmal hypertension, or pseudopheochromocytoma. Paroxysmal hypertension always engenders a search for a catecholamine-secreting pheochromocytoma. Yet 98% The clinical presentation of pseudopheochromocytoma of people with paroxysmal hypertension do not have this has been reported [3,4••]. It is more common among tumor. The cause and management of paroxysmal hyper- women. The frequency of paroxysms ranges from daily to tension remain a mystery, and the subject of remarkably less than one per month, with paroxysms lasting from less few papers. This review presents an approach to under- than 10 minutes to a few days. Blood pressure levels can standing and successfully treating this disorder. Patients exceed 240/140 mm Hg. Hypertensive surges are typically experience symptomatic blood pressure surges likely accompanied by physical symptoms such as chest pain, linked to sympathetic nervous system stimulation. A light-headedness, headache, diaphoresis, nausea, palpita- specific personality profile associated with this disorder tions, dyspnea, and weakness. Most patients with severe suggests a psychological basis, attributable to repressed paroxysmal hypertension are hospitalized at some point emotion related to prior emotional trauma or a repressive and have some degree of impaired functioning [4••].
(nonemotional) coping style. Based on this understand- The fear of recurrent attacks, which typically occur ing, three forms of intervention, alone or in combination, without warning, leads many patients to restrict their appear successful: antihypertensive therapy with agents activity and even leave their job. Thus, the disorder has a directed at the sympathetically mediated blood pressure considerable clinical and financial impact. elevation (eg, combined α- and β-blockade or central α-agonists such as clonidine); psychopharmacologic interventions including anxiolytic and/or antidepres- sant agents; and psychological intervention, particularly Many think of pseudopheochromocytoma as a diagnosis reassurance and increased psychological awareness. An by default after a pheochromocytoma has been excluded. appropriately selected intervention can reduce or elimi- Yet its specific characteristics (Table 1) enable the diag- nosis to be made with considerable confidence. It is a disorder that is not found in just anyone. The following characteristics define the disorder.
IntroductionParoxysmal hypertension is the textbook symptom for a 1. Hypertensive paroxysms characterized by sudden pheochromocytoma, but fewer than 2% of patients with onset. Patients typically describe paroxysms as this symptom actually have this tumor [1]. This is not having an abrupt onset unassociated with any surprising, given the rarity of pheochromocytomas [2]. Typically, diagnostic evaluation reaches a dead end, leav- 2. Blood pressure elevation is associated with very ing patients with an unexplained, difficult-to-treat, and distressful physical symptoms. Blood pressure elevation is not asymptomatic. Physical symptoms The literature provides little guidance regarding resemble pheochromocytomas, and include light- clinical management. Although hundreds of papers are headedness, headache, diaphoresis, nausea, chest Severe Paroxysmal Hypertension Mann 13 encountered with pheochromocytoma. Although these Table 1. Clinical features characteristic of
pseudopheochromocytoma
high levels deserve attention, they do not merit an unend-ing search for a pheochromocytoma and rarely lead to a 1. Hypertensive paroxysms characterized by sudden onset diagnosis of this tumor. If plasma norepinephrine is in the 2. Blood pressure elevation is associated with physical range of 1000 to 2000 pg/mL, a clonidine suppression symptoms (eg, headache, flushing, fatigue, dizziness) test can be helpful, with a fall in norepinephrine level to 3. Episodes are not triggered by emotional distress or panic the normal range suggesting that a pheochromocytoma is 4. Biochemical tests have been performed and do not support the diagnosis of pheochromocytoma Plasma metanephrine and normetanephrine levels 5. In nearly all cases, inquiry into psychosocial factors have recently been reported to have high sensitivity and reveals either a history of unusually severe abuse or specificity in testing for a pheochromocytoma [7••]. trauma, or a defensive, very even-keeled personality style Their plasma half-lives, which are much longer than those of catecholamines, may explain the greater sensi- pain, palpitations, flushing, shortness of breath, tivity. However, clinical experience indicates that mild and weakness [4••,5]. Many patients feel like they elevations are common, perhaps related to sympathetic nervous system (SNS) stimulation in patients with parox- 3. Episodes are not triggered by emotional distress ysmal hypertension, and should not provoke an endless or panic. Unlike panic attacks, hypertensive paroxysms are not heralded by panic. Instead, It is often difficult for physicians to accept that a patients typically insist that paroxysms occur “out patient with paroxysmal hypertension does not have a of the blue.” However, once an episode has begun, pheochromocytoma, even if catecholamine levels are the severe physical symptoms typically provoke a normal. Rarely, catecholamine studies can be normal in fear of dying, a classic symptom of the disorder. a patient with a pheochromocytoma, but such cases rep-resent a very uncommon presentation of an uncommon 4. Biochemical tests do not support the diagnosis of disorder. The likelihood of pseudopheochromocytoma is a pheochromocytoma. Because of the similarities much greater. The presence of the classic psychological characteristics of pseudopheochromocytoma offers fur- chromocytoma and because of the harm done if a curable pheochromocytoma is missed, the possibility of a pheochromocytoma must be considered. This Other common conditions
requires biochemical testing of blood or urine levels The most common conditions resembling pseudopheo- of catecholamines or catecholamine metabolites, chromocytoma, and which need to be differentiated from it, are panic disorder, labile hypertension, and posttrau- 5. In nearly all cases of severe paroxysmal hyperten- sion, inquiry into psychosocial factors reveals either a history of unusually severe abuse or trauma, or a defensive, very even-keeled personality style. A Both panic disorder and pseudopheochromocytoma distinct psychological profile is characteristic, and is are characterized by sudden episodes of severely dis- evident in nearly all patients with severe paroxysmal tressing physical symptoms (eg, headache, dyspnea, hypertension, as discussed below. This distinct dizziness, weakness, and diaphoresis). The two differ profile provides an important diagnostic clue and in that attacks are dominated by the emotional mani- enables a confident diagnosis of pseudopheochromo- festation of panic in patients with panic disorder, but cytoma, rather than a diagnosis by default.
not in those with pseudopheochromocytoma. In panic disorder, blood pressure elevation is usually milder (on average 20 mm Hg or less [9]), although some patients experience considerable blood pressure elevation. In Pheochromocytoma
contrast, pseudopheochromocytoma is dominated by Excluding pheochromocytoma is the first order of busi- the autonomic manifestation of a blood pressure surge ness. If catecholamine studies are abnormal, radiologic (40–100 mm Hg or more [4••]), without panic. To a studies are needed. Radiologic imaging usually is not fair extent, the prominence of autonomic versus emo-indicated when catecholamine studies are normal, tional manifestations is reciprocally related in these particularly if plasma catecholamines were measured two disorders (Fig. 1). during, or urine catecholamines immediately following, Hypertensive paroxysms can be viewed as the auto- nomic equivalent of panic attacks, or panic attacks Many patients have mildly elevated catecholamine without panic. This perspective led to consideration of levels rather than the extremely high levels usually antidepressants as treatment. 14 Pathogenesis of Hypertension: Genetic and Environmental Factors Labile hypertensionBlood pressure lability is common and should not be mis-construed as pseudopheochromocytoma, unless it has the Panic attack
Hypertensive
characteristics defined previously. In some patients, it is paroxysm
asymptomatic, although others experience physical symp-toms such as hypertensive or tension headaches. Blood pressure increases can be associated with anxiety or hyperventilation [10]. Unlike patients with pseudopheo-chromocytoma, most patients with labile essential hypertension readily attribute blood pressure fluctuation to stress and emotional distress. Like pseudopheochromocytoma, posttraumatic stress dis- order is associated with prior trauma. It is also associated with elevated plasma norepinephrine levels [11]. However, Figure 1. The reciprocal relationship between emotional and
in contrast to pseudopheochromocytoma, severe blood autonomic manifestations in pseudopheochromocytoma and in pressure elevation is not characteristic. Also, patients are Current Hypertension Reports HR 10-1-1-01 fig. 1 very aware of the trauma and its impact. Hypertensive paroxysms are often characterized by Other medical conditions
one of two hemodynamic patterns. In some patients, par- Many medical conditions, both common and rare, can oxysms are consistently characterized by palpitations and also cause paroxysmal hypertension, but seldom provide an increased heart rate. In others, the heart rate may be a diagnosis [4••]. Symptomatic hypertensive encepha- unaffected, or even slowed, during paroxysms. lopathy can usually be distinguished by a previous The increased heart rate and plasma epinephrine level history of sustained severe hypertension. Paroxysmal found in some patients with pseudopheochromocytoma hypertension can be a manifestation of other common resembles the syndrome of hyperdynamic circulatory state and uncommon conditions, such as a brain tumor, vari- described by Frohlich et al. [15], and the primary hyper- ous endocrine conditions, or coronary insufficiency, but epinephrinemia described by Streeten et al. [16]. Neither usually other signs or symptoms typical of those disor- group of investigators identified a cause for the increases ders are evident; paroxysmal hypertension is unlikely to in heart rate and epinephrine level.
be the sole manifestation.
The previously reported data of two patients Illicit drugs (eg, cocaine or amphetamines) must be illustrate these patterns and reveal an important considered, although patients with pseudopheochro- underlying hormonal difference [3]. In one case, the mocytoma are so symptomatic and frightened that they blood pressure increased to 228/130 mm Hg during are unlikely to continue using, or to deny using, these a paroxysm, accompanied by cold extremities, reflex drugs. Ingestion of sympathomimetic agents, monoamine bradycardia, and a sixfold increase in plasma norepi-oxidase inhibitors, and tyramine or withdrawal from nephrine, with no increase in epinephrine level. In the clonidine should be evident from the history. Baroreceptor other case, the heart rate increased to 96 bpm with a failure is extremely unlikely without a predisposing con- ninefold increase in epinephrine level, and no change in dition, such as prior neck surgery or irradiation [12,13]. norepinephrine level. In addition, the abnormal blood pressure lability that it The explanation for these differing hemodynamic patterns can be found in differences in the pattern of SNS stimulation. The SNS is composed of two limbs, the adrenal and the neural. Stimulation of the adrenal limb results in secretion of epinephrine by the adrenal Sudden symptomatic blood pressure surges typical of gland, and an increased heart rate and cardiac output. pseudopheochromocytoma are more likely to be medi- Stimulation of the neural limb results in increased neural ated by the SNS, which is responsible for instantaneous release of norepinephrine from sympathetic nerve end-changes in blood pressure, than by volume or the renin- ings in vascular smooth muscle, and increased peripheral angiotensin system. Evidence of increased catecholamine resistance, without an increase in heart rate. levels during paroxysms support this notion [3]. Kuchel Different stressors can stimulate one limb of the SNS et al. [14] also reported evidence of SNS activation in more than the other. For example, anxiety stimulates patients with paroxysmal hypertension, but were unable mainly the adrenal limb. The observed hemodynamic to identify the cause.
patterns of pseudopheochromocytoma suggest that in Severe Paroxysmal Hypertension Mann 15 different patients, for reasons that remain unclear, one style. Two patterns of emotional unawareness appear to limb or the other can dominate. be associated with pseudopheochromocytoma. The first pattern, seen in about two thirds of patients, consists of a history of severe trauma that most patients claim they have put behind them, strikingly insisting they suffer no The possibility that pseudopheochromocytoma’s origin and its underlying SNS activation are related to psycho- logical factors is largely overlooked. This disregard is understandable because paroxysms are dominated by A 33-year-old Hispanic man suffered from hemodynamic changes and physical symptoms rather than hypertensive paroxysms with blood pressure eleva- by emotional distress, panic, or stressful circumstances. tion as high as 220/140 mm Hg. He reported a A breakthrough in understanding occurred with the childhood history of severe physical abuse by his observation that most patients acknowledged a history of father. He insisted that he loved his father and bore unusually severe abuse or trauma, often from as long ago as no anger toward him. Treatment with alprazolam childhood [3]. Remarkably, most patients claimed they were and amitriptyline eliminated hypertensive attacks.
free of lingering psychological effects, suggesting that they had repressed trauma-related emotions too overwhelming A 35-year-old foreign-born woman who was to be borne without adverse psychological consequences. a physician experienced debilitating hypertensive Patients had vivid memories of the trauma without the paroxysms. She initially reported no prior history powerful and painful emotions related to them. of trauma. However, further questioning revealed This observation suggested that the psychological origin that, as a college student, she had been detained as of pseudopheochromocytoma might involve emotions kept a political prisoner for 30 days. She had been blind- from awareness by defenses such as repression. Contrary to folded, her life had been repeatedly threatened, typical psychosomatic approaches, the absence rather than and she had witnessed the death of several friends. the presence of understandable emotional distress suggests After she was freed, she moved on with her life. She insisted there were no emotional aftereffects, had Many trauma survivors experience severe emotion early, not sought psychotherapy, and had discussed her but eventually manage to repress trauma-related emotion experiences with no one. Treatment with an anti- and move forward. However, the repressed emotion has not depressant eliminated the paroxysms.
It has been widely demonstrated that our emotions In trauma survivors, it is important to recognize affect blood pressure. Because we repress emotions that repression as a successful psychological defense rather can be far more overwhelming, it is plausible to suggest than as psychopathology. In handling overwhelming their role in otherwise unexplained SNS arousal and par- emotion, the alternative to repression is long-term psy- chological suffering and dysfunction. Many patients with Repression is crucial to emotional health and explains pseudopheochromocytoma have dealt with major trauma why some victims of severe trauma can survive without through repression, and have led lives marked by consid-apparent adverse psychological effects. They do not report erable achievement. Their resilience can be attributed to emotional distress, and usually do not even mention old their successful use of repression. trauma to a physician. The relationship between old The second pattern of emotional unawareness, seen in trauma and unexplained autonomic surges decades later about one third of patients, is the lifelong tendency to cope would never occur to either patient or doctor. Even psy- unemotionally with the stresses of life [4]. Such patients chosocially conscious physicians do not ask about previous report never having experienced depression regardless of abuse or trauma, and instead focus on the patient’s report circumstances. They are doers, not reactors, and tend to of current stress and emotional distress. be very even-keeled. Because they report little emotional Unfortunately, the concept of repressed emotion is for- distress, physicians rarely consider their condition as eign to many. Therefore, most physicians and researchers linked to psychological factors.
do not consider these concepts and their corollary treatment approaches, even though standard treatments have failed Clinical examplesand no other approaches have emerged. A 66-year-old man suffered from hourlong epi- Two patterns of emotional repression
sodes of blood pressure elevation to 190/110 mm Hg, We cannot measure emotions that patients cannot report, with diaphoresis and facial reddening. He did not but the prominent use of repression can be surmised by have a history of past trauma, but described himself paying attention to a patient’s life story and personality as very independent, never needing or seeking emo- 16 Pathogenesis of Hypertension: Genetic and Environmental Factors tional support, and having a very even temperament Table 2. Treatment options for paroxysmal
(the classic description of a repressor). He reported hypertension*
having shed no tears 7 years earlier when his only son was left permanently paraplegic after a car acci- 1. Antihypertensive drug therapy
dent. Treatment with atenolol, terazosin, lorazepam, a. Acute management of hypertensive paroxysms i. IV labetalol or nitroprussideii. Clonidine A 52-year-old pampered, well-to-do woman experienced daily hypertensive attacks for 4 months. She insisted she had no stress or distress, and that she was very happy. However, after further discus- 2. Psychopharmacologic treatment
sion, she acknowledged to herself, for the first time, a. Acute management of hypertensive paroxysms that she was miserable and ashamed because she had no job or purpose and felt useless. Her attacks ceased quickly as she became depressed for the first time in her life. However, the awareness enabled her i. Antidepressant agent (SSRI or tricyclic) to initiate changes in her life. Her paroxysms ceased 3. Psychological interventions
In people with this pattern of not feeling, the absence of emotion is usually a pattern developed in childhood. They are not buffeted by emotions, and the experience of depression or anxiety may be foreign to them. *Interventions can be given alone or in combination. IV—intravenous; SSRI—selective serotonin reuptake inhibitor.
Approach to TreatmentThe treatment of paroxysmal hypertension has been a (see below), given alone or in combination with an anti-major dilemma. Diuretics, angiotensin-converting enzyme hypertensive agent such as clonidine.
inhibitors (ACEIs), and adrenergic receptor blockers (ARBs) do not prevent SNS-driven hypertensive surges, Preventive managementnor would they be expected to. The normal blood pressure As mentioned earlier, ACEIs, ARBs, and diuretics would between episodes precludes an aggressive antihypertensive not be expected to prevent paroxysms. Also, neither β-regimen. Although no controlled treatment trials have been blocker monotherapy nor α-blocker monotherapy reduces conducted, treatment approaches are needed. Based on the SNS-mediated blood pressure reactivity [18••]. However, understanding of pseudopheochromocytoma presented combined α- and β-blockade does, and offers a well-toler-in this review, certain approaches—whose validity is sug- ated, logical approach [18••]. Clinical experience indicates gested by their effectiveness in clinical practice—merit this approach can reduce peak blood pressure elevation. reporting (Table 2). Alone or in combination, they can Labetalol and carvedilol both provide combined α- and eliminate paroxysms in most patients and enable them to β-blockade, but both suffer from unpredictable bioavail-resume a normal life.
ability [17,19]. Therefore, an α-blocker (eg, doxazosin or terazosin) combined with a β-blocker would seem pref- Antihypertensive drug therapy
erable. A central α-agonist such as clonidine is another Acute management of hypertensive paroxysms alternative, although its extended use is limited by side The sudden and severe elevation of blood pressure dur- ing paroxysms would seem to put patients at risk of an If severe hypertensive paroxysms recur despite treat- acute cerebrovascular or cardiovascular event. Fortu- ment, dosage can be guided by the heart rate during nately, such events seem rare, although more outcome paroxysms: if rapid, the β-blocker dose should be increased. data are needed. If not rapid, it would be logical to instead increase the dose Extreme blood pressure elevation can be treated with of the α-blocker. When given in combination with a β- rapid-acting intravenous agents, such as labetalol or blocker, α-blockers such as doxazosin need not be titrated nitroprusside. With less severe elevation, an oral sympa- higher than the 2- to 4-mg range for maximal effect [20].
tholytic agent, such as clonidine, can be given either in
an emergency department or at home. Oral labetalol may Psychopharmacologic intervention
be unreliable because of unpredictable bioavailability due Acute management of hypertensive paroxysms
to first-pass hepatic metabolism [17]. Milder paroxysms A rapid-acting benzodiazepine such as alprazolam can
can be managed in some patients with an anxiolytic agent quickly abort attacks in some patients. It can be used
Severe Paroxysmal Hypertension Mann 17 instead of, or in combination with, an antihypertensive Unfortunately, this shift in awareness usually is not agent such as clonidine. The recently released orally achieved because most patients who are repressing over-disintegrating formulation of alprazolam can reduce whelming emotion related to unspeakable trauma need response time to a few minutes, allowing administration to continue repressing, and will defend against aware-of a second dose within 10 minutes in nonresponders. ness. They are unlikely to be interested in, or to benefit from, psychotherapy aimed at awareness, and should not be coerced into it. Psychotherapy could even do harm if The use of antidepressant and anxiolytic agents to treat previously blocked overwhelming emotions are brought pseudopheochromocytoma was suggested by its similarity to awareness. The dictum that it is always best to deal to panic disorder. Antidepressant agents, including selective with the past is not inherently true. Patients who do not serotonin reuptake inhibitors and tricyclic antidepressants have a history of trauma but who have a lifelong tendency (TCAs), appear to prevent recurrence of paroxysms in to repress are also very resistant to psychotherapy.
most patients at dosages recommended for treating panic The wisest course would be to offer an explanation disorder [3,4]. Improvement is evident within 2 weeks of for the disorder, and reassure the patient that the disorder instituting the effective dose. TCAs are associated with can be successfully managed and normal life resumed. If more side effects; however, agents such as desipramine are the patient comprehends and wishes to pursue psycho-better tolerated than older TCAs. therapy, this course can be encouraged. If the patient Antidepressant agents are effective even in patients cannot see the connection of the disorder with trauma or who are unwilling to consider psychological factors. In repressed emotion, or prefers not to pursue psychother-such patients, it is important to emphasize the successful apy, psychological discussion and psychotherapy should track record of these drugs. Although an antidepressant can prevent attacks, many patients are reluctant to commit to long-term treatment with a psychotropic agent. A reasonable approach would be Obstacles to Successful Treatmentto start an antidepressant in patients with extremely severe Barriers are encountered with all three treatment hypertensive paroxysms (eg, > 220/120 mm Hg) or in those approaches. Barriers to treatment with antihypertensive with compromised ability to function. In others, acute agents include the ineffectiveness of ACEIs, ARBs, and management with alprazolam or clonidine, and/or mainte- diuretics, and normal blood pressure levels between par- nance therapy with combined α- and β-blockade, can be oxysms limiting the aggressiveness of antihypertensive tried first. Delaying initiation of antidepressant treatment therapy. In addition, antihypertensive agents are unlikely also allows for a trial of psychological intervention. An antidepressant can be given in combination with Barriers to treatment with antidepressants include α- and β-blockade. If paroxysms have ceased, and the patients’ refusal to try them and, in some cases, multiple patient is otherwise normotensive, the α- and β-blocker drug intolerance that prevents using an effective dose. can be tapered and stopped, with careful follow-up. Many patients refuse to try an antidepressant no matter how severely symptomatic they are because its use implies Psychological interventions
a psychological cause. Some eventually agree to try one because they are severely symptomatic and no other treat- Extremely symptomatic hypertensive paroxysms can ment has helped.
be terrifying to patients. The fear of dying during an Finally, there are major barriers to psychological attack can come to dominate their life. A physician’s intervention. Because pseudopheochromocytoma’s man-confident reassurance that the disorder can be treated, ifestations are physical rather than psychological and and that a catastrophic event or death during a par- are not triggered by obvious current stressors, patients oxysm is very unlikely can help reduce the terror and and doctors usually do not suspect its emotional basis. possibly the number and severity of attacks. Unfortu- Many patients are extremely resistant to the concept nately, most physicians—lacking understanding of the that emotions related to events from decades ago might disorder and experience treating it—cannot provide still be affecting them, particularly if they are not that reassurance. experiencing distress. In addition, many patients are unknowingly battling to avoid psychological discus- sion or awareness. Furthermore, for many patients, the When the disorder’s origin in repressed emotion is barrier against conscious awareness of overwhelming explored with patients, some will grasp it at an emotional emotions must be maintained. level. With this awareness, some quickly experience Sometimes, merely mentioning the emotional com- a reduction or elimination of paroxysms without any ponent is so threatening at an unconscious level that the psychotherapy. Psychotherapy can then be helpful in pro- patient might not return for follow-up care. Therefore, the psychological origin must be broached very sensitively, 18 Pathogenesis of Hypertension: Genetic and Environmental Factors and it is sometimes best to quickly abandon the topic if a 4.•• Mann SJ: Severe paroxysmal hypertension (pseudopheo-
chromocytoma): understanding its cause and treatment.
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