Clinical Endocrinology

Phaeochromocytoma crisis

Authors


Summary

Phaeochromocytoma crisis is an endocrine emergency associated with significant mortality. There is little published guidance on the management of phaeochromocytoma crisis. This clinical practice update summarizes the relevant published literature, including a detailed review of cases published in the past 5 years, and a proposed classification system. We review the recommended management of phaeochromocytoma crisis including the use of alpha-blockade, which is strongly associated with survival of a crisis. Mechanical circulatory supportive therapy (including intra-aortic balloon pump or extra-corporeal membrane oxygenation) is strongly recommended for patients with sustained hypotension. Surgical intervention should be deferred until medical stabilization is achieved.

Introduction

Phaeochromocytoma crisis (PCC) is an endocrine emergency associated with significant mortality. There have been two consensus guidelines published on the management of phaeochromocytoma, but they do not include the management of PCC.[1-3] An expert review from the National Institute of Health was published in 2006 describing the clinical spectrum of PCC and offering guidance on management.[4] Since then, the published literature consists of case reports, with a small number of retrospective series. This clinical practice update summarizes the relevant published literature, including a detailed review of cases published in the past 5 years, to review the management of phaeochromocytoma crisis. In addition, we have described a potential classification system for PCC, which was lacking in the literature.

Phaeochromocytomas are catecholamine-secreting tumours arising from chromaffin cells in the adrenal medulla. The clinical presentation is variable: some are silent, some present with characteristic signs and symptoms such as hypertension, sweating, palpitations and headache, which are often paroxysmal, whilst others present with local tumour symptoms such as abdominal pain.

Phaeochromocytoma crisis (PCC) has been defined as the acute severe presentation of catecholamine-induced haemodynamic instability causing end-organ damage or dysfunction.[5] It can occur after a variable period of preceding symptoms, during which time the diagnosis of phaeochromocytoma may have been previously suspected or confirmed, or may be the first clinical manifestation of the underlying tumour. A retrospective series of patients identified from a histopathological database after surgery for phaeochromocytoma reported the incidence of PCC to be 18% (25 of 137),[6] whilst another similar single-centre series reported a rate of 7% (6 of 81).[7]

Paragangliomas are extra-adrenal chromaffin tumours that may also secrete catecholamines and be associated with crisis syndromes indistinguishable from phaeochromocytoma crisis. Analysis of a case series of patients presenting with PCC showed that crises are approximately ten times more frequently related to phaeochromocytomas compared with paragangliomas.[6] For the purpose of this review, we refer to phaeochromocytoma crisis throughout, and unless stated, the comments apply equally to paraganglioma crisis.

Types of phaeochromocytoma crisis

Phaeochromocytoma crisis (PCC), by definition, causes haemodynamic instability and end-organ damage or dysfunction,[5] which is often reversible with appropriate treatment, or if the crisis recedes. The severity of presentation can vary with regard to both haemodynamic stability and extent of organ dysfunction. There is therefore a clinical spectrum, but currently no accepted classification system for PCC. Newell et al. reported three cases of severe phaeochromocytoma crisis, which included four components: multi-organ system failure, severe hypertension and/or hypotension, high fever and encephalopathy.[5] Newell termed this ‘phaeochromocytoma multisystem crisis’ to define a severe subgroup of PCC.[5] This term has persisted in the PCC literature.[8] We agree that it is appropriate to subclassify severe crises, but suggest that the most appropriate criteria should be the presence of shock, sustained hypotension and multi-organ dysfunction caused by the effects of catecholamine excess. High fever and encephalopathy may be associated with a severe crisis, but are not mandatory features. We propose that the term ‘type A crisis’ is used to describe a more limited crisis without sustained hypotension, whereas ‘type B crisis’ is used to describe a severe presentation with sustained hypotension, shock and multi-organ dysfunction (See Fig. 1). A patient could potentially progress from type A to type B in the course of a crisis. Analysis of a recently published single-centre series showed that when using such classification system, type A crisis is four times more common than type B crisis (20 cases vs 5 cases).[6] Since 2008, 106 cases (73 as case reports and 33 as part of a series) (details summarized in supplementary data Table S1) of PCC have been published in the literature. We found that cases of type B crisis were reported nearly as often as type A (40 cases vs 66 cases), which is likely to represent a publication bias.

Figure 1.

Types of clinical presentation of pheochromocytoma.

The most common presentations of PCC are hypertensive crisis or catecholamine cardiomyopathy. The spectrum of potential organ manifestations is summarized in Table 1. For a more detailed review, see Brouwers et al. 2003.[9]

Table 1. Clinical spectrum of organ dysfunction in PCC
Cardiac[10]

Cardiomyopathy (classically takotsubo or inverted takotsubo)[11]

Myocardial infarction

Arrhythmia

Cardiogenic shock[12]

Respiratory

Pulmonary oedema

Acute respiratory distress syndrome (ARDS)

Massive haemoptysis[13]

Neurological

Encephalopathy[5]

Ischaemic or haemorrhagic stroke[14]

Vertebral artery dissection[15]

Posterior reversible encephalopathy (PRES)[16]

RenalAcute kidney injury[17]
HepaticAcute liver injury
GastrointestinalIleus,[18] bowel ischaemia, perforation[19]
Metabolic

Lactic acidosis,[20] ketoacidosis

hypoglycaemia,[21] hyperglycaemia[17]

MusculoskeletalRhabdomyolysis[22]
Vascular

Thrombosis[23]

Adrenal haemorrhage[24]

Furthermore, phaeochromocytoma crisis can mimic other common conditions and so is initially misdiagnosed frequently[25] (see Table 2) or is identified as an unexpected finding on imaging performed for an alternative diagnosis; for example, computed tomography of the aorta for presumed aortic dissection reveals an adrenal mass consistent with a pheochromoyctoma.

Table 2. Common diagnoses mimicked by PCC with associated misleading clinical features
Acute coronary syndrome/myocardial infarction[11]Chest pain, shortness of breath, ischaemic changes on ECG, raised troponin, acute left ventricular failure
Cardiomyopathy and cardiogenic shock[26, 27]Raised troponin, acute left ventricular failure, low cardiac index
Septic shock[28] (note sepsis can coexist[29])Fever and multi-organ failure
Pre-eclampsia[30] or amniotic fluid embolismHypertensive crisis in pregnancy

Pathogenesis

Precipitating factors

An episode of PCC is thought to relate to a sudden increase in catecholamine release causing widespread systemic effects and organ damage. The mechanisms that lead to a surge in catecholamine release are varied and not fully understood, but some widely accepted precipitants have been identified, examples of which are detailed in Table 3. For a more detailed review, see Eisenhoffer et al. 2007.[31]

Table 3. Precipitants of PCC
PrecipitantExamples/details
Well Established
Insufficient/compromised tumour blood supplyTumour haemorrhage or infarction[24]
Direct physical stimulus to tumourSurgical manipulation or biopsy[32]
Indirect physical stimulus to tumourTrauma[33]
General anaesthesia/Nonadrenal surgeryGeneral anaesthesia, endotracheal intubation[31]and muscle relaxants[34]
Drugs

Metoclopramide and other dopamine antagonists[26]

Beta-blockers, including labetalol, without prior alpha-blockade[35]

PregnancyEspecially third trimester and peripartum[36]
Occasional case reports
Drugs

Glucagon[37]

Sympathomimetics[38]

Steroids[39] and synthetic ACTH[40]

Tricyclic antidepressants[41]

Isolated case reports
 

Radiofrequency ablation[42]

High-osmolality ionic radiological contrast agents (seldom used in modern practice)[43, 44]

Dobutamine stress echo[45]

Mountaineering (presumed due to hypoxia)[46]

There are case reports describing the use of intravenous contrast as a precipitant for phaeochromocytoma crisis.[47] The majority of these reports relate to the use of high-osmolality ionic contrast agents, which are now seldom used. A prospective study of 22 patients with phaeochromocytoma demonstrated that low-osmolar radiological contrast had no appreciable effect on catecholamine release,[48] and a single-centre retrospective review of 25 patients with phaeochromocytoma who received contrast also showed no adverse events.[49]

Pathophysiology of PCC

Catecholamines, acting primarily on α-adrenergic receptors, cause profound arterial vasoconstriction leading to hypertension and relatively reduced intravascular volume. This leads to reduced end-organ perfusion and tissue ischaemia and is the primary mechanism for organ failure in PCC.

Cardiac crisis occurs because of coronary artery vasoconstriction and vasospasm, which causes myocardial ischaemia and potentially infarction, but in addition, catecholamines have a direct toxic effect on myocytes causing catecholamine cardiomyopathy.[50, 51] The classic presentation is takotsubo (apical ballooning) cardiomyopathy so called because the apex resembles the shape of a ‘takotsubo’, the conical Japanese pot used for catching octopus. Inverted takotsubo cardiomyopathy (apical sparing) has also been described.[52] Myocardial dysfunction secondary to ischaemia would be expected to resolve more quickly than myocardial dysfunction due to catecholamine cardiomyopathy, but both are potentially reversible.[53]

Shock and sustained hypotension are the defining features of a type B crisis, but the pathological processes that give rise to them are not well understood. Previously, it was thought that hypotension only occurred with tumours that predominantly or exclusively secreted adrenaline, and the mechanism was presumed to be the stimulation of β2 receptors causing vasodilation.[54] However, it is recognized that hypotension can also occur with exclusively noradrenaline-secreting tumours, and this is thought to relate to myocardial dysfunction, hypovolaemia and desensitization of baroreflexes.[55, 56]

In patients who present with crisis, the type of catecholamine secreted by the tumour does not appear to predict the nature of the crisis. Reviewing the literature from the last 5 years, the catecholamine profile is described in only 51 of the 106 cases and so is unknown in 55 of the cases (see supplementary Table S4 for details). Of those described, 78% (40 of 51) have a mixed profile secreting adrenaline and noradrenaline, and the remainder secrete either adrenaline (2 of 51) or noradrenaline (9 of 51) alone. Furthermore, a noradrenaline-induced crisis, for example, does not appear to be clinically distinct from a mixed catecholamine crisis. This observation is consistent with the intensive care literature that shows no significant difference in physiological response or outcome to different catecholamine support strategies.[57]

Fever occurs in a minority of cases of PCC, despite the absence of a focus of sepsis.[5, 28] This is thought to relate to interleukin-6 secretion by the tumour and therefore resolves following surgical resection.[58, 59]

Diagnosis

Phaeochromocytoma crisis should be considered in any patient with unexplained shock or left ventricular failure, multi-organ failure, hypertensive crisis or unexplained lactic acidosis especially if also febrile. Prompt confirmation of the diagnosis is likely to improve survival, although we did not identify any studies demonstrating this. Initial investigations should include urine and plasma catecholamines and metanephrines, with samples obtained according to local protocols. The normal range for these tests relates to a resting subject, and there is no defined normal range in acute illness. In clinical practice, this does not normally present a diagnostic challenge since levels are almost always extremely high. In one surgical series, the mean concentration of catecholamines was 23 times the upper limit of normal.[6] There have been some reports where catecholamines were found to be close to, or within, the normal range in PCC,[6] but we presume that this relates to the timing of the collection after the onset of the crisis once catecholamine levels may have fallen. Furthermore, falsely positive (increased) catecholamines can occur with severe cardiac failure, in relation to certain medications, or be a result of appropriate excess catecholamine secretion in an unstable patient in critical care, and this can potentially cause diagnostic confusion.

Catecholamine and metanephrine results should be expedited if possible, but inevitably, in some centres, there will be a delay as not all laboratories can perform such tests.[8] Collaboration with a specialist laboratory may enable a rapid analysis of a random urine sample with a result made available in a few hours. If there is significant clinical suspicion, computed tomography (CT) imaging of the adrenal glands should be performed. Ultrasound is not the preferred method for imaging the adrenals, but in unstable patients too unwell to transfer, it may help at the bedside to identify an adrenal tumour.[26] More extensive imaging may be required if a paraganglioma crisis is suspected as these lesions are sometimes in unusual locations of sympathetic/parasympathetic tissue.

Mortality

Phaeochromocytoma crisis is historically regarded as a condition with a high mortality rate. A paper from 1979 that reviewed previous publications quoted a mortality rate of 85%.[60] The mortality from phaeochromocytoma multisystem crisis was reported as 45% after the review of 11 published cases from 1988–2009.[61] Scholten et al. (2013)[6] reported a 0% mortality in their series of 25 cases of PCC, and a 2% (1 of 58) mortality from a literature review they conducted (1990–2013). However, in both instances, patients were only selected if they had proceeded to surgery, and so their cohorts would not have included any patient who died prior to surgery. Excluding deaths that occur either during attempted medical stabilization or without the diagnosis of PCC being made greatly underestimates the mortality rate.

Our review of 106 cases published during the last 5 years demonstrates an overall mortality of 15% (15 of 106) with a higher rate of 28% in type B crises (11 of 40) compared with 6% (4 of 66) in type A (supplementary Table S2). There is no published prospective case series in PCC.

The significantly reduced mortality rate in more recent times likely reflects earlier diagnosis and better supportive care available in intensive care units.

Early recognition and prompt diagnosis of PCC with subsequent optimal management in an expert centre would be expected to result in a lower mortality, but as yet, there is no data to demonstrate this.

Management

The evidence for interventions is based on expert opinion, case reports and retrospective series. Some common approaches to management are necessary, but specific treatment decisions need to be tailored in each case to reflect which organ systems are involved and whether it is a type A or type B crisis.

Clinical environment and monitoring

By definition, patients with PCC will have haemodynamic instability and organ dysfunction. They should be managed in an intensive care environment to enable appropriate monitoring and circulatory support and general supportive care.

In type A crisis, non- or minimally invasive monitoring may be appropriate to note trend changes in cardiac index and oxygen delivery. However, in a more severe crisis, particularly where multiple organ failure has occurred, a pulmonary artery catheter in combination with frequent or even continuous transoesophageal echo would be appropriate. This is to permit real-time assessment of left ventricular function, including filling status, left ventricular outflow tract dimensions and regional wall abnormalities. Care should be co-ordinated by an experienced intensivist.

Fluid resuscitation

Profound sympathetic vasoconstriction is a universal feature of PCC, and this causes relative intravascular hypovolaemia. The hypovolaemia may not be clinically apparent initially, but rapidly becomes so when any vasodilating treatment is given including alpha-blockade. Intensive intravenous fluid resuscitation is very likely to be needed concurrent with, or prior to, the commencement of alpha-blockade to prevent severe hypotension. The use of crystalloid intravenous fluids is recommended on the basis of safety and cost.[62] The speed and adequacy of fluid resuscitation should be guided by circulatory monitoring and the measurement of mixed or central venous saturation.

Patients who have cardiac involvement (cardiomyopathy and/or severe left ventricular failure) similarly have relative intravascular hypovolaemia, but require a more cautious approach to resuscitation. If pulmonary oedema develops in this context, positive pressure ventilation and/or intubation may be required.

Alpha-blockade

Initiating alpha-blockade in a cautious but sustained manner is the most widely accepted specific intervention for the management of phaeochromocytoma crisis.[4] The role of alpha-blockade is to reverse vasoconstriction and hypertension and to suppress arrhythmias.[63] Initiating alpha-blockade in the context of a type A crisis should be uncomplicated. There are a number of different agents and routes of administration available, and experience of the supervising clinician is important in choosing which agent to use. In an unstable patient, intravenous blockade would normally be used initially. Maintenance treatment with oral blockade may subsequently be used. Phenoxybenzamine is the most commonly used alpha-blocker (see Table 4). It is noncompetitive, nonselective and relatively long-acting.[4] Phenoxybenzamine can be given intravenously, orally or via nasogastric tube, in divided doses (typically two-three times per day). The initial intravenous dose is 0·5 mg/kg IV over 5 h. Elective protocols advise a dose of 60–100 mg or 1 mg/kg/day to achieve a mean arterial BP <100.[64-67] In the UK, there have been occasions where supply of phenoxybenzamine has been restricted/problematic.

Table 4. Medical therapy used to achieve adrenergic blockade in the recent published literature (2008–2013) (see supplementary Table S4 for details)
Medical blockadeNumber of cases
Alpha-blockade69
Phenoxybenzamine41
Phentolamine8
Doxazosin6
Prazosin1
Terazosin1
Phentolamine and phenoxybenzamine3
Alpha-blocker used not specified9
Calcium channel blockade3
Nicardipine2
Calcium channel blocker used not specified1
Alpha- and calcium channel blockade1
Magnesium and alpha-blockade1
No medical blockade25
Unknown7
 106

Phentolamine is an alternative alpha-blocker. It is competitive and short-acting and therefore less useful to establish stable blockade. It is administered intravenously at a dose of 1 mg/min to correct severe hypertensive crisis due to phaeochromocytoma. An infusion of 20–100 mg/h can be used for maintenance, but obtaining sufficient supply of the medication can be problematic.

Doxazosin is a competitive alpha-1-selective blocker and is therefore theoretically less appropriate than phenoxybenzamine; it is also only available orally. However, there are case reports of its successful use at moderate doses (8 mg/day) to manage PCC.[29]

Our review of the 106 cases published in the past 5 years showed that alpha-blockade was used in 69 cases (65%) and phenoxybenzamine was the most commonly used alpha-blocker (see Table 4.)

In patients with a type B crisis, the initiation of alpha-blockade is more problematic. Whilst alpha-blockade would theoretically reverse the underlying pathological process, the presence of hypotension limits its use. Fluid resuscitation and mechanical circulatory support are likely to be required initially to improve hypotension, prior to introduction of alpha-blockade to reduce vasoconstriction.

Table S3 (supplementary data) collates the mortality of patients depending on alpha-blockade administration published in the literature (2008–2013). The mortality of those not commenced on alpha-blockade was 40% (14 of 35), whereas 99% (70 of 71) of patients who received alpha-blockade survived. It is possible that alpha-blockade was contraindicated, due to profound hypotension, in some patients who died; nevertheless, a strong association between the use of alpha-blockade and survival remains (P = 0·00000026).

Calcium channel blockers

There are a small number of case reports describing the use of calcium channel blockers as a single agent to provide medical control in severe phaeochromocytoma crisis.[12, 68] The specific medication that has been used is nicardipine[12, 68, 69] or clevidipine, which is an ultra-short-acting calcium blocker.[70]

Magnesium sulphate

Magnesium sulphate is recognized as a useful therapeutic agent in phaeochromocytoma crisis.[71] It acts as a functional calcium antagonist causing arteriolar vasodilation and correcting hypertension,[70] has an alpha-blocking effect inhibiting catecholamine secretion and is effective at preventing or terminating arrhythmias.[72] There are numerous cases that report the successful use of magnesium in stabilizing different forms of PCC including hypertensive encephalopathy and catecholamine cardiomyopathy; however, all but one were published prior to 2005.[36, 71] One particular advantage of magnesium is its routine availability and familiarity of use in critical care settings compared with other suitable agents. The dose used is 4 g as an intravenous bolus over 5 min followed by an infusion, initially of 1 g/h, which is the same dose as prescribed in the hypertensive crisis of pre-eclampsia.[73]

Specific treatments for hypertension

Hypertension in PCC can be severe, but can also rapidly alternate with hypotension. The most effective treatments for hypertension are likely to be those proposed above: intravenous fluid resuscitation, alpha-blockade, calcium channel blockers and magnesium. In some cases, specific additional treatment for hypertension will be needed.

Agents that have been used include sodium nitroprusside, hydralazine and glyceryl trinitrate (GTN). Sodium nitroprusside can be given intravenously and lowers blood pressure by vasodilatation. It has a half-life of 2 min. Hydralazine is similarly given intravenously and treats hypertension by vasodilatation.[74]

Beta-blockers should not be used prior to alpha-blockade. The rationale for this is that in the presence of catecholamine excess, the stimulation of β2 receptors promotes vasodilation, which attenuates the hypertensive and vasoconstrictive elements of a crisis. The use of a beta-blocker will remove this moderating effect and allow unopposed alpha-adrenergic activity to exacerbate a hypertensive crisis. Furthermore, giving beta-blockade early after initiation of some alpha-blockade can cause hypotension, because it will prevent protective tachycardia induced by relative intravascular depletion. After adequate alpha-blockade and fluid resuscitation, beta-blockers can sub-sequently be used to control reflex tachycardia or tachyarrhythmia. If beta-blockade use is contemplated without prior alpha-blockade, extreme caution should be exercised, as this can worsen haemodynamic status. A low-dose, short-acting beta-blocker such as esmolol with careful monitoring is preferable if felt required. Labetalol should be avoided because, even though it has some alpha-blocking properties, these are insufficiently disproportionate to its beta-blocking effects and so can exacerbate a crisis.

Combining blockade

Severe type A crisis can be difficult to treat and may require multiple agents, in combination, at high doses to achieve medical stabilization. Using a combined approach is well described, for example, James et al. reported a case of a 27-year-old female who required the co-administration of increasing doses of sodium nitroprusside, alpha-blockade and magnesium to achieve medical control.[71]

Appendix 1 summarizes the practical detail of how to prepare and safely administer all the medications available for treatment of PCC.

Hypotension/mechanical circulatory supportive treatment

Transient hypotension may occur in type A crises as a consequence of labile blood pressure with alternating hypertension, whereas type B crises by definition demonstrate sustained hypotension and shock. Therefore, conventional supportive treatment for type B crises is volume resuscitation. Case reports describe the use of various inotropes and vasopressors (including adrenaline, noradrenaline, dopamine, dobutamine, vasopressin and levosimendan) in an attempt to manage sustained hypotension and circulatory compromise.[75-77] It is unclear which if any of these provide significant benefit in the circumstances of catecholamine excess, but desensitization to noradrenaline/adrenaline may be noted. Theoretically, it would be preferable to use agents that do not act directly via adrenergic receptors. There are no trials to provide direct guidance, but the literature more generally would support the use of vasopressin.[78]

Patients unresponsive to these interventions were previously treated as moribund and were considered for emergency adrenalectomy to remove the source of excess catecholamine production as their mortality was regarded as highly probable without surgical intervention.[79]

Prior to 2008, there were isolated reports of mechanical circulatory support in type B crisis using intra-aortic balloon pump (IABP) and cardiopulmonary bypass (CPB).[80, 81] However, since 2008, there have been frequent reports of such circulatory support being successfully used.

In a number of cases, IABP has been used to excellent effect.[75, 82] If IABP provides insufficient mechanical circulatory support, then extra-corporeal life support (VA-ECMO), through either femoral or central access, or cardiopulmonary bypass has been used successfully.[12, 27, 68, 75] Once established on mechanical circulatory support, patients will often improve either as a direct effect of treatment or as their crisis recedes. Such circulatory support also enables the co-administration of alpha- or calcium channel blockade, which would have otherwise been contraindicated because of the sustained hypotension. Such combined approach to treat the hypotension and the pathological insult should therefore achieve sustainable medical control in most of these cases and allow surgery to be delayed. However, if emergency surgery is deemed to be required, then VA-ECMO or CPB will enable perioperative circulatory control.[27, 83]

Review of the literature from the last 5 years confirms that mechanical circulatory support is strongly associated with survival of type B crisis: 22 of the 24 patients (92%) with type B crisis treated with mechanical support survived, whereas, of the 16 patients not treated with mechanical support, only 7 (44%) survived (see Table 5).

Table 5. Use of mechanical circulatory support for type B crisis in the literature (2008–2013) (see supplementary Table S4 for details)
 SurvivalaDeath
  1. a

    P = 0·0025 (Fisher's exact test).

Use of mechanical support (IABP VA-ECMO CPB)22 2
No mechanical support 7 9
Total2911

Timing of surgery

Surgical resection is the definitive management, but there is controversy about the optimal timing of surgery. In patients who are not in crisis, it is widely agreed that alpha-blockade should be achieved prior to surgery.[65, 84, 85] Similarly, if possible, surgery is deferred in patients who present with PCC until medical stabilization and titration of alpha-blockade have been achieved.

If a patient is very unstable and/or medical stabilization has failed, some argue that emergency adrenalectomy, with or without partial alpha-blockade, is appropriate as this will rapidly remove the source of excess catecholamines and therefore enable rapid stabilization. The availability of laparoscopic surgery has reduced the risk of surgical intervention.

In 1988, Newell reported three cases of severe PCC, two of which received emergency operation and survived and a third whose emergency surgery was deferred due to suspected sepsis and subsequently died. There are other case reports that appear to also show emergency surgery as an effective treatment in desperate circumstances[61, 82, 86] as well as others that report a fatal outcome in patients who were managed medically.[79] Uchida et al. came to a similar conclusion after reviewing a series of 11 patients: 6 of the 11 patients (55%) who had surgery survived albeit some with significant morbidity, whereas the other five patients (45%) who did not have surgery died.[61] Their rationale for emergency surgery was that it ‘was the only means of halting progression of the disease’.[61]

Scholten et al. recently published a large single-centre retrospective cohort study of patients who underwent surgery for phaeochromocytoma/paranganglioma.[6] Twenty-five cases of PCC were identified from their operative/histopathological database. All of the patients were treated with at least 10 days of alpha-blockade prior to surgery, the scheduled timing of which was determined by a subjective assessment of clinical severity, social factors and patient/clinician preference. The 15 patients who were discharged and readmitted for elective adrenalectomy had a reduced length of stay with significantly less postoperative complications and fewer admissions to intensive care, compared with the 10 patients who remained as inpatients prior to surgery. However, the group who remained as inpatients may have been more unwell or less physiologically stable, accounting for, at least in part, the decision not to discharge them. As the study was not prospective or randomized, it should not be used to guide management decisions in future cases. The study asserts that no patients died whilst awaiting surgery, but their methodology was problematic as any patient who died prior to surgical intervention would not have been included in their study as they would not have appeared in their operative database. As none of their cohort received emergency surgery, or surgery without appropriate preoperative alpha-blockade, they are unable to provide additional evidence to address the role of the surgery in either the emergency setting or in those without adequate alpha-blockade.

As a second arm of their study, Scholten et al. reviewed the literature from 1944 to 2011 to identify cases who presented with PCC and had adrenalectomies. They found 97 cases, 33 of which had been operated on as emergency. Analysis of the reported cases after 1990 showed that 18 were treated with emergency surgery, and the mortality was 6% (1/18), which was not statistically different from the nonemergency cases, and may compare favourably with the expected mortality from such a severe crisis. Scholten et al.[6] concluded that emergency surgery should be avoided because of its high mortality and morbidity, but it is doubtful whether they had sufficient evidence to make this assertion.

Deferred surgery also exposes the patient to the risk of recurrent crisis with further organ dysfunction, which may be irreversible, and there is no reliable method of predicting when this might occur and how severe the episode would be. Scholten et al.[6] reported that 25% (5 of 25) of their cohort with PCC had experienced a previous episode of crisis. These observations support the assertion that, once stable, elective surgery should be performed without delay.

In almost all cases, it is appropriate to attempt medical stabilization prior to attempting surgery unless factors such as tumour rupture and haemorrhage occur. The safety of deferred surgery in a deteriorating patient with PCC remains uncertain.

Conclusion

Phaeochromocytoma crisis is a condition with significant mortality. Maintaining a high degree of clinical suspicion will facilitate prompt diagnosis of PCC, and utilizing the best available supportive treatments in an expert centre will give the patient the best chance of survival. Intravascular resuscitation and alpha-blockade are the specific treatments with the best evidence base. However, calcium channel blockers and magnesium sulphate are also effective particularly when combination therapy is required to achieve medical stabilization. Mechanical circulatory supportive therapy, including IABP, ECMO and cardiopulmonary bypass, is the treatment of choice in patients with type B crisis. There may be a role for emergency surgery in patients persistently unresponsive to such treatments, but this is controversial.

There is a need for collaboration between an endocrinologist and intensivist together with an endocrine surgeon and experienced anaesthetist in almost all cases of PCC. A national audit of current practice and subsequent formal management guidelines should be considered.

Key points

  • Currently there are no clinical guidelines for phaeochromocytoma crisis, and the evidence base is weak.
  • Experience in managing the condition is vital, and therefore, patients are best managed in an expert centre.
  • Alpha-blockade is the most widely accepted method of medical control. In the published literature, there is a strong association between the use of alpha-blockade and survival (99% vs 60%). There is far less data for calcium channel blockers and/or magnesium, although these may also be effective.
  • Sustained hypotension and multi-organ failure (type B crisis) are associated with a fivefold increase in mortality compared with type A crisis (28% vs 6%). Mechanical circulatory supportive therapy, including IABP, VA-ECMO and cardiopulmonary bypass, with subsequent alpha-blockade, is the treatment of choice in these patients.
  • The role of emergency surgery without prior medical stabilization is controversial, but is widely accepted to carry significant risk. In almost all cases, it would only be appropriate to attempt surgery after medical stabilization has been achieved.

Appendix 1: Drugs available in the management of PCC

 Make-up infusion:DoseNotes
Phentolamine (IV) Slow IV bolus 2·5–5 mg at 1 mg/minRepeat up to every 5 min
Phentolamine (Infusion)500 mg in 500 ml of 5% dextroseInitially 1 mg/minMaintenance 20–100 mg/h
Phenoxybenzamine (Intravenous)0·5 mg/kg infused over 5 h Up to 1–2 mg/kg/day
Phenoxybenzamine (Oral) 

Start 10 mg BD

Increase to 60–80 mg/day in 2–3 divided doses

Up to 250 mg/day needed in some cases

Maximal effect after 4 h

Doxazosin (Oral) 4–12 mg/day POIncrease up to 24 mg/day
Magnesium (IV)Infusion of 1 g/h IV, can increase to 4 g/h4 g as IV bolus over 5 minSide effects: feel hot and flushed during IV bolus
Hydralazine (IV) 10–50 mg IV repeat every 4–6 h 
Sodium nitroprusside (IV)50–100 mg in 500 ml 5% dextrose0·25–10 mcg/kg/min IV

Immediate onset.

Half-life 2 min

Specialised light-protective intravenous giving set is needed

GTN (IV)50 mg in 50 ml5–100 mcg/min 
Esmolol (IV)Infusion 0·1–0·3 mg/kg/minBolus 0·5 mg/kg over 1 min2–9 min half-life
Nicardipine (IV)20 mg in 200 ml dextrose or saline5 mg/h IV initially 3 mg/h IV maintenanceMaximum 15 mg/h
Clevidipine (IV)Available as vials of 50 or 100 ml; concentration 0·5 mg/ml

1–2 mg/h

Double dose every 2 min as needed

Max infusion rate: 32 mg/h
Metyrosine (oral) 250 mg PO BD to QDS

Slow onset of action

Can cause drowsiness

Ancillary