Introduction

Pheochromocytoma (PHEO) is a rare tumor arising from neural crest tissue, most commonly at the site of the adrenal medulla. Its incidence is currently unknown, but is estimated to range between 1.5 and 2.1 per million inhabitants per year. Catecholamine crisis (CC) associated with undiagnosed pheochromocytoma (UD-PHEO) may cause life-threatening cardiovascular conditions with very high mortality. In presenting this case of a patient who developed hemodynamic instability (HI) during induction of general anesthesia, we want to highlight the fact that CC may be triggered by anesthetics routinely used in PHEO surgery.

Case report

We present the case of a 75-year-old male (body mass index [BMI] 24), electively scheduled for resection of a neuroma with cervical myelon constriction. Medical history comprised arterial hypertension under treatment and carotid sclerosis. Preoperative anesthesiological assessment revealed no restrictions of cardiopulmonary capacity. Arterial blood pressure (BP) and heart rate (HR) were 145/84 mm Hg and 58 bpm, respectively. A cholecystectomy and tonsillectomy had previously been performed without any complications.

General anesthesia was induced with 0.2 mg fentanyl, 200 mg 1% propofol and 50 mg rocuronium and maintained with propofol infusion at 4 mg/kg body weight/h. Twenty seconds after administration of rocuronium, tachycardia up to 140 bpm with broad QRS-complexes and ST-line depletion occurred. Carotid pulse palpation led to the suspicion of hypertensive crisis and 1 mg of nitroglycerin and 0.3 mg of fentanyl were administered. First available BP was 263/179 mm Hg. Radial artery cannulation was performed and the airway secured via tracheal intubation. No sweating or changes in skin color, or any irregularities in ventilation, such as obstructions were noted. With normalizing blood pressure, the ST line depletion and ventricular arrhythmia resolved. All infusions were discontinued or replaced and drug error was excluded by double checking all syringes and ampoules. No antibiotics had been administered prior to HI. A second peak of BP (up to 255/94 mm Hg) could be controlled by 0.5 mg of nitroglycerin (Fig. 1). Due to the unclear HI the operative procedure was waived.

Fig. 1
figure 1

Course of blood pressure and heart rate during induction of general anesthesia in a patient with undiagnosed pheochromocytoma

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A following computed tomography (CT) scan revealed a right-sided adrenal mass (Fig. 2). After the CT scan, the patient was transferred to the intensive care unit where he was extubated shortly after without further hypertensive episodes. The patient was awake and hemodynamically stable. Initial postoperative serum metanephrine was 436 pg/ml (reference range <90 pg/ml) and serum normetanephrine 231 pg/ml (reference range <180 pg/ml). A metaiodobenzylguanidine scintigraphy scan confirmed a right-sided PHEO without metastasis (Fig. 3). Further investigations excluded hyperthyroidism, thyroid carcinoma, multiple endocrine neoplasia and hypercortisolism.

Fig. 2
figure 2

Transverse view of a computed tomography (CT) scan, performed after initial stabilization, showing a mass close to the adrenal gland (circle) highly suspicious for pheochromocytoma in the clinical context

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Fig. 3
figure 3

Selected slices of a metaiodobenzylguanidine scintigraphy scan 24 hours after tracer injection in the coronary (upper two rows) and transverse view (lower two rows) showing tracer uptake by right-sided pheochromocytoma and no sign of metastases

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Laparoscopic adrenalectomy was performed following a 3-day course of alpha-blocker therapy. Induction of anesthesia with fentanyl, propofol and cisatracurium was uneventful. Histopathological findings confirmed PHEO with a pheochromocytoma of the adrenal gland scaled score (PASS) of 1, indicating a benign course of disease. The patient recovered well. Neuroma resection was performed shortly thereafter without complications.

Discussion

Historically, it has been postulated that symptoms of PHEO are merely the result of catecholamine liberation from the tumor causing the triad of diaphoresis, palpitations, and headache. This triad, however, may be absent in the majority of patients. In fact, circulating catecholamine levels correlate poorly with the patient’s symptoms, especially hypertension, which was found to be paroxysmal in almost half of the patients and absent in more than 10% [2]. Some patients do not experience any symptoms, despite increased catecholamine levels in the circulation or proven post-mortem diagnosis. This clinical variation is best explained by a great genetic and phenotypic versatility of PHEO causing immense variation concerning the type (norepinephrine, epinephrine) and extent of catecholamine release [8, 10]. The effects of PHEO on the sympathetic nervous system (SNS) are complex and in part contradictory:

Grassi et al. reported a reduced central sympathetic outflow in PHEO patients which could not be solely attributed to a reflex inhibitory response to elevated BP [4]. Bravo and Tagle on the other hand, described the SNS as being well-preserved or even enhanced. They asserted that paradoxically increased activity of the SNS may be explained by an increased loading of sympathetic vesicles with catecholamines and a selective desensitization of presynaptic alpha2-adrenergic receptors; however, catecholamine desensitization of the cardiovascular system following long-term exposure to high circulating catecholamine levels may explain normal BP in some PHEO patients [2].

A PHEO-associated CC may occur in various clinical settings and even spontaneously. Trying to find out the true trigger in this case report, we were therefore faced with the following dilemma: there can be no certainty with respect to an actual causal relationship between a possible trigger and CC, since it is virtually impossible to exclude a spontaneous event. Hence, our strategy was to first review the literature for possible trigger mechanisms and then second, to analyze the likelihood of each trigger in our specific case.

After the literature review we divided possible trigger mechanisms into four groups, namely:

  1. 1.

    mechanical stress, e. g., palpation of the tumor, parturition, twisting and turning of the torso, coitus and defecation,

  2. 2.

    psychological stress, e. g., pain, anxiety, exertion, or

  3. 3.

    drug-related (Table 1),

  4. 4.

    without any observable exogenous event.

Table 1 Selected therapeutics that may induce hemodynamic instability and cardiovascular events in patients with pheochromocytoma
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Regarding the presented case, stimulation of the SNS due to psychological stress cannot be excluded with certainty; however, the patient seemed calm and showed no sign of anxiety. There were no abnormalities, especially tachycardia or hypertension, during a 30-min observational period in the induction room. Insufficient depth of anesthesia may be a possible explanation for CC, though mask ventilation was started after cessation of eyelash reflexes and performed with ease, indicating lack of oropharyngeal muscle tone and therefore deep sedation. There was no use of additional oropharyngeal airway devices (e. g., Guedel tube) and there was no attempt to perform laryngoscopy prior to HI. During the induction procedure, the patient’s position was not changed, nor was there any contact with the patient’s abdomen by the staff. Mechanical stress, therefore, seems unlikely. As previously mentioned, spontaneous CC developing simultaneously with induction of anesthesia cannot be excluded, although it seems unlikely.

Given the uncertainties discussed earlier, the close temporal relation, HI occurred within seconds after administration, makes anesthetic-related CC possible (Fig. 1). We therefore conducted another literature review regarding similar events and potential mechanisms relating to the substances used:

Propofol

Propofol’s hypnotic effects are accompanied by sympatholysis, reduced systemic vascular resistance, reduced cardiac contractility and decreased baroreceptor reflex. It attenuates hypertension during hypertensive crises [3]. A possible activation of the SNS with CC may be due to injection pain; however, to our knowledge there are no reports of such incidents in the literature.

Fentanyl

Fentanyl is a μ-receptor agonist and is the most often used opioid for intraoperative analgesia. In contrast to morphine, no histamine release and sympathoadrenal activation has been shown for fentanyl. Barancik described a case of HI after administration of 0.1 mg fentanyl and 4 mg diazepam in a patient with UD-PHEO during an endoscopy in 1989. Other possible factors (e. g., mechanical stimulation, psychological stress) were not discussed [1]. The literature search could not reveal any other fentanyl-related case of CC; however, dose-dependent positive inotropic effects that are thought to be explained by increased catecholamine release or adrenergic activation exist [5, 14]. Whether these mechanisms have a clinical impact remains unknown.

Rocuronium

Rocuronium is an aminosteroid non-depolarizing muscle relaxant (NDMR). Histamine release due to benzylisoquinoline muscle relaxants is a well-known mechanism for triggering CC in PHEO. No such effect is known for steroidal compounds, such as rocuronium; however, Sato et al. have shown that rocuronium may increase norepinephrine release from human atrial tissue [12]. It has been postulated that aminosteroid NDMR may have an atropine-like effect that inhibits acetylcholine-induced sympatholisis [13] and acetylcholine-mediated increase in neuronal norepinephrine reuptake [11]. In an in vitro study Gursoy et al. asserted positive inotropic effects of rocuronium due to direct stimulation of beta1 receptors [6]. Holldack reported HI in a patient with UD-PHEO. Invasive BP measurement detected decreases in HR and BP after induction with fentanyl and propofol and excessive hypertension shortly after administration of rocuronium and prior to laryngoscopy. The author considered rocuronium to be the most likely trigger for this crisis [7]. Myklejord reported a hypertensive crisis in an UD-PHEO patient during easy mask ventilation and before intubation. No assumptions were made with respect to what the trigger may have been, but the same combination of induction drugs (fentanyl, propofol, rocuronium) was used [9].

We present the following circumstantial evidence to assume that HI in our case occurred due to administration of anesthetic agents:

  1. 1.

    temporal relation,

  2. 2.

    pharmacodynamic mechanisms for activation of SNS exist,

  3. 3.

    similar events previously described in other case reports,

  4. 4.

    other possible triggers less likely.

All the substances used in this case have been used safely in patients with PHEO. The exact mechanism of CC remains unclear. The reason why certain substances cause HI in some but not in all patients is probably best explained by the genetic and phenotypic heterogeneity of PHEO and its complex effects on the SNS [2, 8, 10]. Also, elective PHEO resection is usually performed under alpha-blockade which may prevent drug-related CC.

In cases of suspected UD-PHEO as the cause of HI, stabilization of hemodynamics is essential. Hereto, fast-acting direct vasodilators, such as nitroprusside or nitroglycerin have shown to be advantageous. Further stimulation of the SNS needs to be avoided, therefore cancelation of the operative procedure needs to be discussed. Care has to be taken in order to prevent mechanical stimulation of PHEO.

In summary, sudden HI due to UD-PHEO is a rare but potentially life-threatening event. There is circumstantial evidence that even anesthetic agents that are routinely and safely used in planned PHEO surgery may be possible triggers for CC. In the presented case, fentanyl, rocuronium and propofol were administered during induction. Retrospectively, it was not possible to identify the substance responsible for HI. Fentanyl and rocuronium have been previously mentioned in association with CC in UD-PHEO. For both substances, possible mechanisms for activation of the SNS exist. A rationale why these drugs may initiate CC in some but not all PHEO patients remains unclear but may be explained by genetic and phenotypic heterogeneity of PHEO.

Practical conclusion

  • Pheochromocytomas show great clinical heterogeneity and can lead to profound changes in the sympathetic nervous system.

  • Undiagnosed pheochromocytomas are rare, but show high perioperative mortality.

  • Regularly used anesthetic agents can trigger a catecholamine crisis.