Neuroendocrine tumors (NETs) have rarely been reported after organ transplantation, in particular, cardiac, kidney, and liver transplants.1–3 An association has been made between cyanotic congenital heart disease and NETs, potentially due to hypoxic stress or common genetic and developmental factors.4 Historically, these tumors have a high surgical mortality that has fallen due to improved surgical and anesthetic techniques,5,6 although the risk of complications remains high given the potential for severe hemodynamic perturbations.
We present the perioperative management of a patient diagnosed with bilateral NETs soon after heart-lung transplantation, who underwent staged surgeries, of a left laparoscopic adrenalectomy followed by a right laparoscopic-assisted open adrenalectomy. Consideration is given to the implications and unique physiology of a transplanted heart in this unusual context. The patient has kindly provided written consent for publication of this case.
Our patient is a 47-year-old woman, weight 41 kg, height 152 cm, who underwent an en bloc heart-lung transplant for Eisenmenger syndrome with situs inversus caused by a large uncorrected congenital ventricular septal defect. At the time of transplant, her baseline pulmonary artery systolic pressure was 75 mm Hg with a room air oxygen saturation of 83% from right to left shunt that limited her exercise capacity to 600 m over 15 minutes. The patient demonstrated no additional hemodynamic issues during her workup for transplant suitability.
The immediate postoperative period after heart-lung transplantation was complicated by graft failure requiring veno-arterial extracorporeal membrane oxygenation from days 0 to 4, ischemic hepatitis, and acute renal failure requiring temporary dialysis. Of note, she had labile blood pressures (BP) from postoperative day 1 with systolic BPs (SBP) of up to 220 mm Hg that continued over the next few weeks, prompting consideration of a pheochromocytoma. Plasma metanephrines were elevated and an abdominal computerized tomography scan on postoperative day 22 demonstrated bilateral adrenal masses, the right measuring 18 × 22 × 21 mm and left measuring 39 × 38 × 42 mm. Dotatate positron emission tomography and computerized tomography scan on postoperative day 31 showed moderate to marked dotatate activity in the adrenal masses compatible with bilateral NETs.
After multidisciplinary consultation, 2-staged adrenalectomies were planned, the first of which was scheduled for 6 months after transplantation. This staggered approach was chosen to avoid the increased surgical and pulmonary morbidity associated with the large transverse abdominal incision and extended surgical time required for bilateral adrenalectomy surgery. The main disadvantage of a staged approach was an increased risk of catecholamine crisis due to the remaining in situ NET after the first stage. The patient was admitted for optimization 3 days before each surgery and managed by a multidisciplinary team including anesthesia, endocrine, renal, urology, cardiology, and heart and lung transplant physicians.
STAGE 1: LEFT LAPAROSCOPIC ADRENALECTOMY
Preoperative management goals were set to achieve a BP of 120/80 mm Hg without significant orthostatic hypotension7 and a heart rate (HR) of 60–90 bpm. In addition to her admission, medications of phenoxybenzamine and propranolol, amlodipine 2.5 mg was commenced on the day of admission and increased to 5 mg twice daily to achieve the hemodynamic targets.
The patient’s baseline cardiac, respiratory, and renal functions were all appropriately optimized before the first stage procedure. She had normal pulmonary function tests (forced vital capacity 1.9 L, forced expiratory volume in 1 second 1.4 L, and forced expiratory volume in 1 second/forced vital capacity ratio 73%) and renal tests (urea 7.7 mmol/L, creatinine 84 μmol/L, estimated glomerular filtration rate 77 mL/min/1.73 m2). A preoperative transthoracic echocardiogram showed normal left and right ventricular size and function, left ventricular ejection fraction of 60%, no valvular abnormalities, and mild tricuspid regurgitation, with a pulmonary artery systolic pressure of 20 mm Hg plus right atrial pressure.
Preoperative preparation, induction, and maintenance of anesthesia are described in Table 1. Before right lateral positioning, a transesophageal probe was placed and an echocardiogram was performed that confirmed the preoperative cardiac findings. A BP rise to 120/60 mm Hg was observed with pneumoperitoneum and remifentanil target-controlled infusion8 was increased to 4.5 ng/mL, and labetalol infusion was discontinued. The BP declined to 90 mm Hg and a metaraminol infusion was commenced up to a maximum of 5 mg/h, to maintain a stable SBP ranging from 90 to 110 mm Hg. Hartmann solution intravenous (IV) was infused at 10 mL/kg/h with additional two 200 mL boluses titrated to left ventricular end-diastolic area observed in the transgastric short-axis view by echocardiography. Transient hypotension (SBP, 85 mm Hg) after removal of the left adrenal gland was treated with norepinephrine 10 μg/kg/min. Total operative time was 170 minutes.
Before intensive care unit (ICU) transfer, fentanyl 50 μg, ondansetron 4 mg, paracetamol 1 g, and neostigmine/glycopyrrolate 2.5/0.4 mg were administered IV, and norepinephrine was discontinued. Postoperatively the patient remained intubated. Hemodynamic goals were set at a SBP 110–120 mm Hg, in the context of a residual right-sided NET. She required labetalol and sodium nitroprusside infusions, in addition to oral amlodipine, phenoxybenzamine, and propranolol once extubated the following day, to achieve the BP targets. She was transferred to the surgical ward where she continued on amlodipine, propranolol, and phenoxybenzamine maintaining SBPs of between 110 and 120 mm Hg without major fluctuations. She was discharged home 5 days after her operation.
The surgical pathology report of the resected adrenal mass demonstrated a pheochromocytoma with a pheochromocytoma of the adrenal gland scaled (PASS) score of 8, as well as background adrenal medullary hyperplasia.
STAGE 2: RIGHT LAPAROSCOPIC CONVERTED TO OPEN ADRENALECTOMY
Eight weeks later, the patient returned for a planned admission 3 days before her right adrenalectomy. Admission antihypertensive medications of phenoxybenzamine and propranolol were supplemented by oral amlodipine in 5-mg aliquots to treat asymptomatic hypertension with SBPs up to 158 mm Hg.
On the day of surgery, she received 1 L of IV 0.9% normal saline from midnight and her usual morning doses of phenoxybenzamine and propranolol. On this occasion, she was persistently hypertensive in the anesthetic bay with a noninvasive BP of 170/100 mm Hg. A total of 4 mg of IV midazolam premedication was given and a left arm 18 g peripheral venous cannula and 20 g left radial arterial line was placed. After this, her invasive BP measured at 195/95 mm Hg and a labetalol infusion was commenced at 20 mg/h. Despite this, her BP increased to 210/100 mm Hg requiring uptitration of the labetalol infusion to 30 mg/h, which continued throughout the case. The induction and maintenance of anesthesia are described in Table 1.
After 315 minutes of operative time, the procedure was converted from a laparoscopic to open adrenalectomy, because significant adhesions impeded surgical access to the adrenal gland. Despite her initial hypertension, her BP remained stable after induction with a SBP of between 95 and 130 mm Hg and a diastolic pressure of between 50 and 65 mm Hg with intermittent use of a labetalol infusion (10–30 mg/h). Three liters of Hartmann solution and 1 unit of packed red blood cells were transfused during the total operative time of 510 minutes.
Postoperatively, she remained intubated and was transferred to the ICU. She became oliguric with an acute kidney injury indicated by creatinine rise from 100 to 130 μmol/L. She was extubated successfully the following day and restarted on her regular oral antihypertensives. However, she remained hypertensive up to 170/70 mm Hg despite ongoing sodium nitroprusside infusion, which was gradually weaned off 48 hours after her procedure, titrating to a mean arterial pressure <90 mm Hg. She required an increase in her regular amlodipine to 10 mg at night and additional aliquots of IV hydralazine.
On postoperative day 3, she was discharged from the ICU with a SBP between 120 and 160 mm Hg and diastolic pressure between 40 and 80 mm Hg on oral antihypertensives only. Over the next 3 days, her BP gradually normalized, requiring reducing doses of phenoxybenzamine, propranolol, and amlodipine. She was discharged home 8 days after surgery with a SBP of 120–145 mm Hg on no antihypertensive agents.
Surgical pathology reported a right paracaval mass consistent with a paraganglioma, although metastatic pheochromocytoma could not be excluded. The adrenal gland itself was unremarkable.
This case is the first to describe staged bilateral adrenalectomy surgeries in a post–heart-lung transplant patient and highlights the importance of careful multidisciplinary input, patient optimization, intraoperative management, and individualized therapy. Clinicians caring for heart transplant patients must have a thorough understanding of their unique hemodynamic physiology. The key factors to be considered are the change in cardiovascular responses and the pharmacological management of the denervated heart,9 and the key anesthetic considerations are presented in Table 2.
The transplanted heart has a resting HR of 90–110 bpm as there is neither sensory, sympathetic, nor parasympathetic innervation.9,10 Stimulatory neurohormonal pathways that govern compensatory increases in HR and contractility in the normal heart are absent, thus the cardiac output depends on venous return and is often referred to as “preload dependent.”10 In hypovolemia, systemic catecholamine release increases cardiac output but with some delay. Over time, the transplanted heart may demonstrate some reinnervation but this is unpredictable.10 Preoperatively, the patient’s fluid status was optimized with the administration of intravenous fluids to ensure an adequate preload to maintain cardiac output.
There are specific pharmacological considerations in the transplanted heart. The HR is unaltered by agents that depend on autonomic reflexes (atropine and digoxin) or alter afterload (nitroprusside, nitroglycerin, and phenylephrine). Bradycardia is absent with the administration opioids or anticholinesterase inhibitors. In an emergency situation, direct agonists such as epinephrine, isoprenaline, and dobutamine are required to increase HR.9
The choice of agents, in this case, reflected consideration of these issues, with preference for short-acting, titratable intravenous drugs. At induction, invasive monitoring and a metaraminol infusion were utilized to avoid any transient vasodilatation, hypotension, and an acute decrease in preload. The transplanted heart would be unable to mount a reflex tachycardia in response to these altered hemodynamics. A combination of intravenous labetalol administered preinduction and remifentanil coinduction was used to prevent a potential acute increase in afterload. During surgery, an adequate preload and a norepinephrine infusion helped maintain a predetermined SBP 110–120 and allowed ongoing titration in ICU if required. Additionally, while we ensured phentolamine was available in the operating suite, it was not required.
The anesthetic considerations of NET resection begin in the preoperative period. Preoperative optimization focuses on arterial pressure control, reversal of chronic circulating volume depletion, HR and arrhythmia control, assessment and optimization of myocardial function, and the reversal of glucose and electrolyte disturbances. Intraoperatively, real-time assessment of fluid status and targeted fluid administration can be achieved by the use of intraoperative transesophageal echocardiography (TEE); this has the added benefit of earlier detection of myocardial wall motion abnormalities aiding the diagnosis of intraoperative myocardial ischemia.6
The anesthetic goals for NET surgery are to maintain stable hemodynamics in the face of catecholamine surges associated with laryngoscopy, pneumoperitoneum, surgical incision, tumor handling, and hypotension associated with tumor removal. While hypotension is a recognized postoperative complication, there is evidence that many patients, such as ours, have ongoing postoperative hypertension that may persist for up to a week.6 There is little evidence on which to base drug selection to achieve these goals; however, the drugs must be direct-acting titratable intravenous agents. The mainstay includes α- and β-blockade, and labetalol; however, alternative agents that have been used effectively include phentolamine, sodium nitroprusside, glyceryl trinitrate, and esmolol.6
Pre- and intraoperative hemodynamic targets had to be understood in the context of the posttransplant denervated heart, with a resting tachycardia potentially confounding assessment of α- and β-blockade and cardiac output being preload dependent.9 While controversy exists regarding the need and regimen for preoperative α- and β-blockade,5 we felt the patient’s underlying cardiorespiratory status warranted carefully titrated preoperative hemodynamic control, early admission to hospital, and judicious preoperative fluid loading. Additionally, α- and β-blockade should have continued on the day of surgery of the first adrenalectomy, but was erroneously omitted due to fasting state, highlighting the need for clear communication with ward medical and nursing staff.
Despite similar preoperative management, the patient’s hemodynamics was markedly different preinduction between the first and second adrenalectomy. This could be due to differing levels of anxiety with sympathetic activation, and reinforces the variability in preoperative status between patients, and even in the same patient, and need for experience with potent, titratable vasoactive drugs during NET surgery. Further consideration was also given to steroid supplementation due to the risk of steroid-induced neuroendocrine crisis,11 and a reduced dose of hydrocortisone 25 mg IV was administered during the first adrenalectomy. The patient demonstrated no hypertensive episodes until after the transplant; this may have occurred in the context of posttransplant high-dose steroid administration.
The role of intraoperative TEE in noncardiac surgery remains unclear and is predominantly used for assessment of unexplained cardiovascular instability. In this case, TEE provided valuable real-time assessment of cardiac function and filling in the context of rapid hemodynamic change and preload dependence.12 Fluid administration and responsiveness was titrated to a qualitative assessment of left ventricular end-diastolic area. In addition, myocardial contractility and cardiac output may be adversely affected acutely by catecholamine surges causing a Takotsubo cardiomyopathy or the negative inotropy of β-blockers and anesthetic agents.13 For these reasons, we would strongly recommend the use of intraoperative TEE monitoring.
Unplanned staged adrenalectomy has been reported previously in patients who have deteriorated during the first stage of bilateral adrenalectomy. In a series of 26 patients, undergoing single-stage laparoscopic bilateral adrenalectomy, 3 required a staged procedure. In 2 patients, respiratory depression necessitated a staged procedure, and in another patient, body habitus made operative dissection difficult and led to an operative time of 570 minutes.14 In our patient, concern over the difficulty of surgical dissection, the risk of postoperative respiratory compromise, and that a single-stage bilateral adrenalectomy would most likely result in a large transverse upper abdominal incision further increasing respiratory compromise resulted in a multidisciplinary consensus to electively conduct a staged adrenalectomy.
Perioperative management of NET resection remains challenging and requires individualized planning. Improvements in anesthetic and surgical techniques have seen mortality rates fall dramatically and further advances continue to be made in both intraoperative monitoring and pharmacologic agents, with magnesium, clevidipine, and vasopressin showing promise.15 While adrenalectomy for NETs in a post–heart-lung transplant patient is a rare occurrence, attention to the unique physiology, careful multidisciplinary input, and use of titratable vasoactive agents can enable safe anesthetic care in such challenging patients.
Name: Amy C. Liu, MD.
Contribution: This author helped search the literature and compose the manuscript.
Name: Gareth Andrews, MD.
Contribution: This author helped compose the manuscript.
Name: Erez Ben-Menachem, MD, FANZCA, FCICM.
Contribution: This author helped search the literature and compose the manuscript.
This manuscript was handled by: Mark C. Phillips, MD.
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