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Hemodynamic Changes and Catecholamine Release During Laparoscopic Adrenalectomy for Pheochromocytoma

Joris, Jean L. MD; Hamoir, Etienne E. MD; Hartstein, Gary M. MD; Meurisse, Michel R. MD; Hubert, Bernard M. MD; Charlier, Corinne J. PhD; Lamy, Maurice L. MD

doi: 10.1213/00000539-199901000-00004
Cardiovascular Anesthesia: Society of Cardiovascular Anesthesiologists

We investigated hemodynamics and plasma catecholamine concentrations in eight consecutive patients undergoing laparoscopic adrenalectomy for suspected pheochromocytoma.The same anesthesia protocol was used in all patients: a continuous infusion of sufentanil 0.5 [micro sign]g [center dot] kg-1 [center dot] h-1 and isoflurane 0.4% (end-tidal) in 50% N2 O/O2. Systolic arterial pressure was maintained between 120 and 160 mm Hg by adjusting an infusion of nicardipine, a calcium-channel blocker, while tachycardia (>100 bpm) was treated by 1-mg boluses of atenolol. Hemodynamics (thermodilution technique) and plasma catecholamine concentrations were measured before surgery, after the induction of anesthesia, after turning the patient to the lateral position, during pneumoperitoneum, during tumor manipulation, after adrenalectomy, and at the end of surgery. Two events resulted in significant catecholamine release: creation of the pneumoperitoneum and adrenal gland manipulation. As a consequence, a twofold increase in cardiac output was recorded. Adjustments of nicardipine infusion (2-6 [micro sign]g [center dot] kg-1 [center dot] min-1) minimized changes in mean arterial pressure. Beta-adrenergic blockade was necessary in six patients. In conclusion, laparoscopic adrenalectomy for pheochromocytoma results in marked catecholamine release during pneumoperitoneum and tumor manipulation. Titration of a nicardipine infusion allowed easy and quick control of the hemodynamic aberrancies related to these processes. Implications: Pneumoperitoneum during laparoscopy, now used for adrenalectomy, may complicate anesthetic management of patients with pheochromocytoma. In this study, laparoscopic adrenalectomy was associated with catecholamine release during the creation of pneumoperitoneum and tumor manipulation. Adjustments of a nicardipine infusion readily attenuated the subsequent hemodynamic aberrancies.

(Anesth Analg 1999;88:16-21)

Departments of (Joris, Hartstein, Hubert, Lamy) Anesthesiology and Intensive Care Medicine, (Hamoir, Meurisse) Endocrine Surgery, and (Charlier) Clinical Toxicology, University Hospital of Liege, Liege, Belgium.

Presented in part at the 1996 annual meeting of the American Society of Anesthesiologists, New Orleans, LA.

Accepted for publication October 8, 1998.

Address correspondence and reprint requests to: Dr. Jean Joris, Department of Anesthesiology and Intensive Care Medicine, CHU of Liege, Domaine du Sart Tilman, B-4000 Liege, Belgium. Address e-mail to

Until recently, open laparotomy had been used for resection of pheochromocytoma because manual exploration of the abdomen was necessary to exclude accessory tumor deposits. Currently available imaging techniques, such as computed tomography, metaiodo-benzylguanidine (MIBG) scintigraphy, magnetic resonance imaging, and positron emission tomography (PET scan) using C-11 hydroxyephedrine, provide accurate localization of the tumor in patients with pheochromocytoma. The precision of this information allows the use of a more selective surgical approach to the tumor, such as by laparoscopy [1,2]. Indeed, the use of the laparoscopic approach for adrenalectomy provides several advantages compared with conventional open surgery: less pain, reduced hospital stay, and more rapid return to normal activity [3,4].

Anesthesia for the patient with pheochromocytoma remains a clinical challenge [5]. As stated by Engelman [6], "Successful surgery for pheochromocytoma depends more on the activities cephalad to the anesthetist's drapes than to those in the immediate operative field." Laparoscopy further complicates the management of anesthesia. Resections of pheochromocytomas, which are generally larger than other secreting adrenal tumors, require more operating time [7]. Moreover, and more particularly, pneumoperitoneum induces hemodynamic changes and catecholamine release [8-10], both of which could conceivably be aggravated in the case of pheochromocytoma [5]. Palpation of the abdomen can cause catecholamine release from a pheochromocytoma. Whether the increase in intraabdominal pressure during conventional pneumoperitoneum is sufficient to trigger catecholamine release is, however, unknown. However, handling and dissection of intraabdominal viscera during laparoscopy, considered to be more gentle than during open surgery, may lead to less catecholamine release. We therefore investigated hemodynamics and plasma catecholamine concentrations in eight consecutive patients undergoing laparoscopic adrenalectomy for pheochromocytoma.

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After approval of our Institutional Ethics Committee and consent of the involved patients, eight consecutive patients scheduled for laparoscopic adrenalectomy for suspected pheochromocytoma were studied. Diagnosis of pheochromocytoma relied on clinical signs of pheochromocytoma associated with one or more of the following criteria: increased plasma and/or urine concentrations of catecholamines and/or their metabolites, and positive MIBG scintigraphy or PET scan using C-11 hydroxyephedrine.

The same protocol was used for all patients. Individual antihypertensive treatments were maintained until the morning of surgery, with the exception of the angiotensin-converting enzyme inhibitors, which were stopped the day before surgery [11]. Preoperative preparation with alpha1-adrenergic blocking agents was not uniformly applied. Intraoperative infusion of nicardipine, a calcium-channel blocker, was used to treat and prevent increases in arterial blood pressure as proposed for removal of pheochromocytoma via laparotomy [12]. Patients were given 75 mg of hydroxyzine and 1 mg of alprazolam orally for premedication. A nicardipine infusion (1 [micro sign]g [center dot] kg-1 [center dot] min-1) was started 15 min before anesthesia. After arterial cannulation, anesthesia was induced with sufentanil 0.5 [micro sign]g/kg and etomidate 0.2 mg/kg. Orotracheal intubation was facilitated with 0.5 mg/kg atracurium. Anesthesia was maintained with 0.5 [micro sign]g [center dot] kg-1 [center dot] h-1 sufentanil and isoflurane 0.4% (end-tidal) in a mixture of N2 O/O2 (1:1). Muscle relaxation was achieved by a continuous infusion of 0.3 mg [center dot] kg-1 [center dot] h-1 atracurium.

After the induction of anesthesia, a flow-directed pulmonary artery catheter was inserted. Nicardipine infusion was adjusted to maintain systolic arterial pressure between 120 and 160 mm Hg. Tachycardia (>100 bpm) was treated by 1-mg bolus doses of atenolol IV. Lactated Ringer's solution and colloid solution (polygeline; Haemaccel, Behring, Germany) were infused to obtain a pulmonary artery occlusion pressure (PAOP) between 10 and 12 mm Hg before insufflation. During pneumoperitoneum, the fluid infusion rate was held at 4 mL [center dot] kg-1 [center dot] h-1. Intraabdominal pressure was maintained at 14 mm Hg. Ventilation was adjusted to keep PETCO2 between 32 and 38 mm Hg. The laparoscopic procedure (transabdominal approach in lateral position) was the same for all patients [1].

Arterial blood samples were collected for determination of plasma concentrations of epinephrine and norepinephrine just before the induction of anesthesia; 20 min after the induction of anesthesia; 5 min after tilting the patient to the lateral position and before peritoneal insufflation; 5, 15, and 30 min after peritoneal insufflation; during adrenal gland manipulation; 5 min after clamping of the adrenal vein; 5 min after gland resection; and at the end of surgery. Normal values of epinephrine and norepinephrine plasma concentrations are 0-100 ng/L and 0-500 ng/L, respectively. Hemodynamics were measured simultaneously with blood samples at the end of expiration, except before anesthesia. The pressure transducers were located at the level of the right atrium and moved to the same level with changes in patient position. The time points of this study were similar to those of our study investigating hemodynamic and endocrine changes during laparoscopic cholecystectomy [10]. Comparison of these two studies should facilitate assessment of the specificity of the response of a pheochromocytoma to laparoscopy.

Data are presented as means +/- SD. Data were analyzed using one-way analysis of variance followed by Scheffe's test for multiple comparisons. For epinephrine and norepinephrine, analysis was applied after logarithmic transformation. A probability less than 0.05 was considered statistically significant.

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Patient characteristics are shown in Table 1. Two events were associated with catecholamine release (Figure 1): creation of pneumoperitoneum (median [range] increases in epinephrine were 92 ng/L [48-5,801] and 568 ng/L [88-3,688], and increases in norepinephrine were 821 ng/L [144-7,122] and 1848 ng/L [711-6,706] 5 min and 15 min, respectively, after peritoneal insufflation as compared with before pneumoperitoneum) and adrenal gland manipulation (increase in epinephrine was 5150 ng/L [93-11,440] and increase in norepinephrine was 8,774 ng/L [962-29,089] compared with before pneumoperitoneum). Consequently, cardiac output increased dramatically (Table 2). However, the hemodynamic repercussions were markedly attenuated by adjustments of the infusion rate of nicardipine (2-6 [micro sign]g [center dot] kg-1 [center dot] min-1), which significantly reduced systemic vascular resistance (Table 2). All increases in mean arterial pressure >25% above baseline values were corrected within 5 min by these adjustments. As a consequence, mean arterial pressure increased only mildly during pneumoperitoneum and did not change significantly during tumor manipulation. Intraoperatively, the use of beta-blockers was necessary in six of eight patients: 1-mg bolus doses of atenolol were administered once to Patients 1, 2, 3; twice to Patients 5 and 6; and three times to Patient 7. Although the two remaining patients (4 and 8) did not require intraoperative atenolol, beta-blockers had already been given with their premedication as part of the preoperative antihypertensive treatment. No cardiac arrhythmias developed. Neither vasoconstrictive drugs nor inotropic drugs were needed. Immediately after adrenalectomy, plasma catecholamine concentrations significantly decreased. Consequently, cardiac output and arterial pressure also decreased, and the nicardipine infusion was discontinued. Mean arterial pressure was, however, >65 mm Hg in all patients except Patient 6, in whom it was 62 mm Hg after adrenalectomy and 64 mm Hg at the end of surgery. The reduction in arterial pressure required neither pharmacologic nor fluid therapy.

Table 1

Table 1

Figure 1

Figure 1

Table 2

Table 2

The duration of laparoscopy was 84 +/- 32 min (73 [59-148] min). Patients awakened in the operating room. During the first 24 h postoperatively, an infusion of 2000-2500 mL of fluid (a mixture of crystalloid and colloid) afforded stable hemodynamics without the use of vasopressors. The day after surgery, ambulation and oral intake were resumed. Postoperatively, all patients except Patient 8 were normotensive with no treatment. The duration of postoperative stay was 4.5 +/- 3.1 days (4 [3-13] days).

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This study suggests that laparoscopic adrenalectomy for pheochromocytoma results in marked catecholamine release during pneumoperitoneum and tumor manipulation. The resulting hemodynamic changes were easily controlled using a continuous infusion of nicardipine combined with beta-blockade.

Laparoscopic adrenalectomy to treat pheochromocytoma provides several advantages compared with open surgery [1]. However, the use of laparoscopy raises some concerns. Pneumoperitoneum itself induces hemodynamic changes [8-10]. Vasoactive hormones such as catecholamines and vasopressin are released [8-10]. Peritoneal insufflation of CO2 results in increased CO2 absorption [13]. Consequently, hypercapnia and secondary increased sympathetic tone can develop. During pneumoperitoneum, intrapleural pressure also increases [14]. Consequently, the hydrostatic PAOP measured by the pulmonary artery catheter no longer accurately reflects cardiac filling pressures, which are important variables to assess in these potentially hypovolemic patients [5]. Finally, the mechanical effect of pneumoperitoneum on catecholamine release by the pheochromocytoma itself is unknown. All these pathophysiologic changes could increase the well documented risk of hemodynamic instability seen during open adrenalectomy.

This study reveals that the induction of CO2 pneumoperitoneum in the presence of pheochromocytoma results in a marked release of catecholamines, greater than that measured in our study during pneumoperitoneum for laparoscopic cholecystectomy (in that study, increases in epinephrine were 82 [0-643] and 107 [0-1,007] ng/L, and increases in norepinephrine were 82 [0-427] and 119 [0-790] ng/L 5 and 15 min, respectively, after peritoneal insufflation compared with before pneumoperitoneum) [10]. In the present study, we used larger doses of opioid than those shown to prevent adrenergic responses to incision [15], and we still observed catecholamine release early during pneumoperitoneum, when no major surgical stimulus or visceral dissection had yet been performed. The anesthetic technique therefore cannot be incriminated for the increased adrenergic activity associated with peritoneal insufflation. Nicardipine-induced vasodilation can result in reflex sympathetic stimulation and consequently may increase catecholamine release from pheochromocytoma. The catecholamine release secondary to sympathetic activity associated with doses of nicardipine similar to those administered at the beginning of pneumoperitoneum [16] is less than that observed in our study. However, catecholamine release from pheochromocytoma is usually autonomous and independent of neurogenic physiologic control [5]. Finally, nicardipine may partially reduce catecholamine release from pheochromocytoma [17,18]. Therefore, the measured increase in catecholamine plasma concentrations is probably not secondary to the use of nicardipine. Rather, catecholamine release at the beginning of pneumoperitoneum is likely to be related to a direct mechanical effect of pneumoperitoneum on the tumor. Adrenal manipulation and dissection during laparoscopy, although gentle, result in further hormone releases of a magnitude similar to those reported during nonlaparoscopic pheochromocytoma resection managed with nicardipine [12].1,2 These hormone releases produced significant hemodynamic consequences, however, they were easily and quickly controlled by titrating the infusion of nicardipine, combined with a beta-blocking agent in the case of tachycardia.

(1) Joris J, Rebeix JP, Meurisse M, et al. Management of pheochromocytoma with nicardipine (abstract). Anesthesiology 1992;77:A74.

(2) Elman A, Maillard C, Gaudin C, et al. Hemodynamic and plasma catecholamine changes during anesthesia for pheochromocytoma resection: effect of nicardipine [abstract] Anesthesiology 1993;79:A149.

Preoperative preparation with alpha1-adrenergic blocking agents is the most widely used regimen, and it is recommended to attenuate intraoperative hypertension during open adrenalectomy for pheochromocytoma [5]. A continuous intraoperative infusion of nicardipine is also proposed to treat hemodynamic changes secondary to catecholamine release [12].1,2 Several factors motivated our choice of nicardipine to manage our patients. Nicardipine is a potent peripheral and coronary vasodilator. Its rapid onset, short duration of action, and low incidence of side effects are valuable properties for a drug used to treat acute cardiovascular disorders [19,20]. Because of its pharmacokinetic and safety profile, it compares favorably to nitroprusside. Both drugs allow rapid titration to desired effect. Nicardipine, however, has advantages compared with nitroprusside: no reduction of preload, less heart rate increase, less potential for hypotension, no cyanide toxicity, and photoresistance [19,20]. In cases of hypertension, including perioperative hypertension, nicardipine allows for more rapid control of blood pressure and requires fewer dose adjustments than nitroprusside [21,22]. Finally, all these properties make nicardipine particularly suitable to correct hemodynamic changes induced by pneumoperitoneum. Provided that latent hypovolemia is corrected before inducing pneumoperitoneum, nicardipine infusion should beneficially reduce the pathophysiologic hemodynamic repercussions of both pheochromocytoma and pneumoperitoneum. We therefore chose to use this drug for laparoscopic adrenalectomy.

Because the induction of anesthesia and orotracheal intubation may also result in catecholamine release, we started the infusion of nicardipine before arterial cannulation and induction of anesthesia [5]. Vasodilators can unmask latent hypovolemia and should be introduced carefully. No acute hypotensive episodes (mean arterial pressure <60 mm Hg) were noted in our patients, probably because they had already received vasodilators and/or were normotensive before surgery.

The hemodynamic management of our patients combined nicardipine and beta-blockade. Small doses of beta-blocking agents can be given safely to treat tachycardia, provided that the plane of anesthesia is adequate and that the patient is sufficiently loaded with vasodilator. Indeed, if beta-adrenergic receptors are blocked without concomitant use of vasodilators, alpha-adrenergic receptor agonism may be intensified, with aggravation of hypertension [5]. In this study, we used atenolol. Esmolol, because of its short action, may be a more easily titratable beta-blocking drug. Unfortunately, this drug was not available in Belgium when we started laparoscopic adrenalectomy for pheochromocytoma. Because we were satisfied with atenolol, we decided to continue to use it for our series of eight laparoscopic adrenalectomies for pheochromocytoma.

Although several anesthetic techniques have been used successfully for resection of pheochromocytoma [5], only anesthetics known for their hemodynamic stability were selected in this protocol. Adequate fluid loading, guided by the pulmonary artery catheter, should be achieved before insufflation to reduce hemodynamic changes induced by pneumoperitoneum [23] and to avoid severe hypotension after adrenalectomy, when catecholamine release markedly decreases [5]. During pneumoperitoneum, PAOP increased despite large doses of nicardipine. This paradoxical increase, secondary to an increase in intrapleural pressure, highlights the limitations of the pulmonary artery catheter in this situation, because it does not provide accurate information on cardiac preload during pneumoperitoneum. During laparoscopy, a continuous infusion of muscle relaxant was used to avoid sudden changes in the level of muscle relaxation, with consequent increases in intraabdominal pressure, which could lead to acute ventilatory and hemodynamic changes and exacerbate catecholamine release.

Because of the hemodynamic and endocrine changes resulting from laparoscopic adrenalectomy for pheochromocytoma, this procedure must be performed by an endocrine surgeon well versed in laparoscopic technique, as well as an anesthesiologist aware of the pathophysiologic repercussions of both pheochromocytoma and pneumoperitoneum.

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