Perioperative Management and Outcome of Bilateral Adrenalectomy in 9 Dogs
Michelle L. Oblak1, Nicholas J. Bacon2, and Jennifer L. Covey3
1Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, Canada, 2Fitzpatrick Referrals, Guildford, United Kingdom and 3Oakland Veterinary Referral Services, Bloomfield Hills, Michigan
| Corresponding Author | Objective: To report perioperative care, postoperative management, and long-term outcomes in dogs undergoing bilateral adrenalectomy. |
| Michelle L. Oblak | |
| Department of Clinical Studies | Study Design: Retrospective case series. |
| Ontario Veterinary College | Animals: Dogs undergoing bilateral adrenalectomy from 2008 to 2013 (n=9). |
| University of Guelph | Methods: Data retrieved from the record, when available, included signalment, |
| Guelph, Ontario N1G2W1, Canada moblak@uoguelph.ca | preoperative clinical signs, laboratory data, diagnostic imaging, blood pressure measurement, preoperative treatment for adrenal gland disease, intraoperative |
| Submitted July 2015 | procedures, treatments and complications, postoperative treatment and diagnostics |
| Accepted April 2016 DOI:10.1111/vsu.12514 | during hospitalization, diagnostics and management following discharge, histopathologic diagnosis, and survival. Results: Seven dogs underwent concurrent bilateral adrenalectomy and 2 dogs had staged adrenalectomy. Surgery was uncomplicated in most cases. All dogs received IV dexamethasone SP intraoperatively. Eight dogs received intramuscular desoxycorticosterone pivalate intraoperatively. Histopathology revealed adrenocortical adenoma (7 dogs), adrenocortical carcinoma (4), pheochromocytoma (6), and adrenocortical atrophy (1). One dog died perioperatively and the remainder died due to unrelated causes. Postoperative management of hypoadrenocorticism included oral prednisone and intramuscular desoxycorticosterone pivalate (6 dogs), oral prednisone and fludrocortisone (1), and oral fludrocortisone alone (1). The median survival time in dogs surviving to hospital discharge was 525 days (range 67-966 days). No dogs developed metastatic disease or died due to signs of hypoadrenocorticism. Conclusion: Based on the cases reported here, the perioperative mortality in dogs undergoing bilateral adrenalectomy may be lower than previously reported. Management of postoperative hypoadrenocorticism is both achievable and straightforward. |
Primary adrenal tumors are an uncommon cause of neoplasia in dogs and account for 1-2% of all canine neoplasms.1 Adrenal tumors are divided into functional and nonfunctional tumors that originate from the adrenal cortex, medulla, or as metastatic secondary lesions.2-1º Functional tumors most commonly diagnosed include adrenocortical adenomas, carci- nomas, and pheochromocytomas.2-10 Nonfunctional tumors often fall into the category of adrenal incidentalomas, defined in humans as adrenal nodules >1 cm identified with advanced imaging in a patient without another primary malignancy or clinical evidence of adrenal disease.11,12
Preoperative diagnosis of adrenal tumors is based on biochemical endocrine testing, blood pressure measurement and diagnostic imaging. Confirmation of a cortisol-secreting tumor and suspected hyperadrenocorticism (HAC) is rela- tively straightforward and well described. However, diagno- sis of a pheochromocytoma can be challenging due to limited access to assays, the potential cyclic nature of hyper- tension, and the fact that hypertension is frequently present in dogs with HAC.13-18 Hypertension is experienced by up
to 80% of people with HAC.19 In addition, some dogs have been reported to have both an adrenal pheochromocytoma and pituitary-dependent HAC concurrently or may have mixed or multiple tumors involving both the adrenal cortex and medulla.20,21 The physiologic effects of functional adre- nal tumors may contribute to an increased perioperative complication rate as these dogs can experience thromboem- bolic events, pancreatitis, cortisol deficiency, acute renal failure, and cardiovascular arrest.3-10,22 As a result of this increased perioperative mortality, preoperative targeted treatment in the form of phenoxybenzamine, trilostane, or mitotane may be employed to attempt to decrease tumor- associated risks. 10,23,24
Surgery is the treatment of choice for adrenal tumors with good long-term outcomes in cases surviving the periop- erative period.3-10 In recent studies, elective surgical man- agement of unilateral adrenal tumors has been described with improving success rates.3-1º Bilateral adrenal tumors are less commonly reported in the literature and surgery may not be performed due to concerns of high morbidity rates
and challenges associated with peri- and postoperative management. 4-7,10,25
There is a lack of comprehensive data in the veterinary literature for indications, outcomes, and long-term manage- ment of dogs undergoing bilateral adrenalectomies for natu- rally occurring adrenal pathology. The purpose of this study was to describe peri- and postoperative management and out- come in 9 dogs undergoing bilateral adrenalectomy (7 con- current and 2 staged) at a single institution and resulting in iatrogenic hypoadrenocorticism.
MATERIALS AND METHODS
All dogs that underwent concurrent or staged bilateral adre- nalectomy at the University of Florida College of Veterinary Medicine (UFCVM) from September 2008 to February 2013 were identified and medical records were reviewed. Dogs were included if they were undergoing concurrent bilateral adrenalectomy or had previously undergone unilateral adre- nalectomy and were having a contralateral adrenalectomy. If undergoing 2 separate adrenalectomies, management and postoperative data were reported at the time of the second surgery. Median survival time and range were reported for all dogs that died, were euthanatized, or were still alive >180 days postoperatively.
Data retrieved from the record, when available, included signalment, preoperative clinical signs, laboratory data, blood pressure measurement, diagnostic imaging, preoperative treat- ment for adrenal gland disease, intraoperative procedures, treatments and complications, postoperative treatment and diagnostics during hospitalization, diagnostics and manage- ment after discharge, histopathologic diagnosis, and survival.
Dogs were preoperatively treated for their adrenal dis- ease with phenoxybenzamine or mitotane. Phenoxybenz- amine was prescribed at the clinician’s discretion. Mitotane was prescribed when a low dose dexamethasone suppression test confirmed HAC, if medical management was elected.
Three-view thoracic radiographs (right and left lateral, ventrodorsal), abdominal ultrasound, and a combination of thoracic, abdominal, and pelvic computed tomography (CT) were used for staging and surgical planning.
The perioperative period was defined as the time from induction of anesthesia until discharge from the hospital. Gen- eral anesthesia was induced with a standard intravenous proto- col and maintained with inhalation anesthesia. Cefazolin (22 mg/kg IV) was administered within 30 minutes of the pro- cedure start time and every 90 minutes thereafter. Dogs received opioid analgesia as an IV continuous rate infusion. The standard protocol for treating planned iatrogenic hypo- adrenocorticism included IV dexamethasone SP and intramus- cular desoxycortisterone pivalate (DOCP) either immediately before surgery or during the surgical procedure.
Adrenalectomy was performed as has been previously described.26 Briefly, a ventral midline celiotomy was per- formed for all dogs. Blunt and sharp dissection with Metzen- baum scissors, unipolar electrocoagulation, and a bipolar
vessel-sealing device (Ligasure, Covidien, Mansfield, MA) were used to free the adrenal gland from the surrounding tis- sues and coagulate small vessels. Hemostasis was achieved with direct pressure and electrocoagulation. Ligation of the phrenicoabdominal vein with 3-0 polydioxanone was per- formed last using a circumferential or transfixing suture on the vessel if no thrombus was present. If a thrombus was pres- ent, temporary occlusion of the caudal vena cava was accom- plished with Rummel tourniquets, created from 9 Fr red rubber feeding tubes and 2-0 polypropylene, placed cranial and caudal to the visible thrombus. The Rummel tourniquets were temporarily tightened to occlude blood flow to the vena cava and an incision was made in the ventral surface of the phrenicoabdominal vein at the junction of the vena cava and extending into the vena cava as necessary. After removal of the thrombus, a Satinsky clamp was placed parallel to the vena cava incision and Rummel tourniquets released to allow restoration of blood flow to the vena cava. The cavotomy inci- sion was then repaired primarily with a simple interrupted or continuous suture pattern with 4-0 or 5-0 polypropylene.
Intraoperative complications included any unplanned surgical procedures, bradycardia (<50 bpm) refractory to anticholinergic treatment, hypotension (systolic blood pres- sure <60 mmHg) refractory to dopamine (5-10 [µg/(kg min IV)]), or blood transfusion. Postoperative complications included the need for intervention, including oxygen therapy, blood pressure support, or blood transfusion. Intraopera- tively, hypertension (systolic blood pressure >180 mmHg) was not treated. All tissue samples were submitted to the UFCVM Diagnostic Laboratory for standard histopathologic evaluation with hematoxylin and eosin stain.
All dogs were maintained in the small animal intensive care unit postoperatively on an intravenous balanced electrolyte solu- tion and opioid analgesia. Electrolytes were monitored every 12 hours. Dexamethasone SP was administered every 24 hours (0.25 mg/kg IV). Prednisone (0.25 mg/kg orally every 12 hours) was administered when dogs were eating and continued at dis- charge. If dogs were doing well, the dose was decreased to 0.25mg/kg/day orally at 14 days. After discharge, electrolytes were monitored every 7 days and at days 21, 23, and 25 after the first dose of DOCP with a recommendation to recheck electro- lytes in all dogs at 21, 23, and 25 days after administration of subsequent DOCP doses until a stable routine was established. Medical records and phone calls to owners and referring veteri- narians were used to report management after discharge and long-term outcome. Follow-up conversations in all cases occurred >2 months after surgery. Survival time was defined as the time in days between surgery and death or euthanasia. Cause of death was indicated as tumor-related or nontumor-related based on data available from history before euthanasia or death, restaging performed, or postmortem evaluation.
RESULTS
Nine dogs were included in the study. Seven dogs had bilat- eral adrenalectomies in a single procedure. Two dogs (dogs
2 and 9) had staged bilateral adrenalectomies performed as 2 separate procedures; 17 of 18 adrenalectomies were per- formed at UFCVM with one of the staged adrenalectomies (dog 2) having had the first adrenalectomy elsewhere before presentation. All surgeries performed at UFCVM involved a single surgeon (NB), a Diplomate of the American College of Veterinary Surgeons with fellowship training in surgical oncology, and varied involvement of a surgical oncology fellow.
Historical and Laboratory Data
Six dogs were castrated males and 3 were spayed females. Breeds represented included Dachshund (3 dogs), Shih Tzu, Maltese, Chow Chow, and Miniature Schnauzer (1 each), and mixed breed (2). The median age was 11.5 years (range 10.5-14.5 years). The median body weight was 7.6 kg (range 4.3-35.5 kg). Clinical signs included contin- uous polyuria and polydipsia in 5 dogs, weakness, most prominent in the pelvic limbs, in 2 dogs, episodic weakness and collapse in 1 dog, and obesity and ringworm in 1 dog (suspected to be due to immunosuppression; Table 1). Two dogs presented without clinical signs. Dog 7 was consid- ered to be without clinical signs attributed to the adrenal tumor but had occasional polyuria and polydipsia that the owner attributed to stress. No dog had a preoperative hemoabdomen and all procedures were considered elec- tive. A complete blood count, biochemistry profile, and urinalysis were performed in all dogs and no abnormalities were noted to be consistent between dogs. Endocrine tests performed included a combination of the following: urine cortisol to creatinine ratio (3 dogs), adrenocorticotropic hormone stimulation test (5 dogs), and low dose dexameth- asone suppression test (6 dogs). Two dogs did not have endocrine testing performed. Endocrine testing indicated a diagnosis of HAC in 6 dogs. In 4 of 6 dogs with HAC, test- ing was consistent with pituitary-dependent HAC at the time of presentation for bilateral concurrent or the second side of staged bilateral adrenalectomy (Table 1). All 9 dogs had normal coagulation testing with prothrombin and partial thromboplastin time performed before surgery. Four of the 5 dogs undergoing blood pressure measurement pre- operatively had at least 1 measurement consistent with hypertension (Table 1).
Diagnostic Imaging
Four dogs had 3-view thoracic radiographs and 5 dogs had CT evaluation of the thorax with no evidence of pulmonary metastasis. All dogs had an abdominal ultrasound performed before presentation and bilateral adrenal masses were identi- fied in 7 of 9 dogs. In dog 2, bilateral adrenal masses were present on the initial ultrasound but surgery was only elected for the right adrenal gland, which was performed before pre- sentation to UFCVM. In dog 6, a mass was present on the right adrenal gland with severe atrophy of the left. In dog 9, the second mass was not present at the time of the original imaging or surgery. It was identified on follow-up CT stag-
ing that was being performed every 6 months due to diag- nosed multiple endocrine neoplasias, including previously irradiated pituitary macroadenoma and nasal adenocarcinoma.
Abdominal CT was performed in all dogs for staging as well as to determine tumor displacement of, and invasion into, surrounding structures. The maximal length of the adre- nal masses ranged from 8.3 to 48 mm (median 23 mm). Met- astatic disease was not identified in any dog on initial staging. Local recurrence in the region of the left adrenal gland was suspected in dog 9 based on the presence of a small nodule in the region of the previous adrenal gland. Vascular invasion was present in 2 dogs on CT. In dog 8, there was left vascular invasion into the phrenicoabdominal vein, right vascular invasion into the phrenicoabdominal vein and a 3 mm thrombus in the caudal vena cava. In dog 9, a thrombus, extending from the phrenicoabdominal vein, 5 mm into the vena cava, was present at the time of the first adrenal surgery. No thrombus was present on CT before the second surgery.
Brain imaging was performed in 2 dogs. Imaging in dog 8 was performed due to neurologic signs consistent with a brainstem lesion suspected to be contributing to the present- ing complaint of weakness and depression. Imaging was per- formed in dog 9 due to the previous history of irradiation for a pituitary macroadenoma. A pituitary macroadenoma was diagnosed on brain MRI and radiation planning CT in dog 8. Brain CT was normal in dog 9. The remaining dogs did not have brain imaging. No dogs had evidence of metastatic dis- ease at the time of surgery based on CT imaging.
Preoperative Medical Therapy
Five dogs were prescribed phenoxybenzamine preopera- tively; 3 of these dogs were hypertensive. Phenoxybenz- amine was used at a median dose of 0.6 mg/kg orally every 12 hours (0.6-2.5 mg/kg) for a median of 10 days (range 10- 14 days) preoperatively. Mitotane was used in 2 dogs (dogs 6 and 7) at unknown doses to treat suspected pituitary HAC. In dog 6, mitotane was used for 2 years before surgery and the dog was receiving this medication at the time of presen- tation but was considered resistant. In dog 7, mitotane was used for an unknown period of time, 2 years before surgery. The clinical signs resolved and the medication was discon- tinued when the dog was considered in remission.
Perioperative Management
In 16 of 17 adrenal glands, a mass was noted at the time of surgery. In dog 2, the right adrenal gland was previously removed and a mass was present in the left. In dog 6, a right adrenal mass was present and a concurrent left adrenalec- tomy was elected for the management of suspected pituitary- dependent HAC. In dog 9, the left adrenal gland was previously removed but a small (5 mm) mass was present in the region of the previous surgical site and a mass was pres- ent on the right and removed. Surgery was performed as described above. Vena cava invasion necessitating a
| Dog # | Left | Right | Clinical signs | Preop endocrine testing; Max BP | Preop therapy | Surgery | Complications | Other |
|---|---|---|---|---|---|---|---|---|
| 1 | Adenoma | Adenoma | PUPD | AD HAC; 210 mmHg | None | Concurrent | None | |
| bilateral | ||||||||
| 2 | Adenoma (Sx 2) | ACA (Sx 1, elsewhere) | PUPD, diarrhea | Not performed | None | Staged | Hypoxia, flow by O2 | |
| bilateral, | required for 24 | |||||||
| 1 year apart | hours | |||||||
| 3 | ACA | ACA | PUPD, obesity, dermatitis | AD HAC | None | Concurrent bilateral | None | |
| 4 | Adenoma | Adenoma | Pelvic limb weakness | PD HAC | Phenoxybenzamine 2.5 mg/kg PO Q12h x 14d | Concurrent bilateral | None | |
| 5 | Pheo | Adenoma | None, incidental finding | Not performed; 140 mmHg | Phenoxybenzamine 1 mg/kg PO Q12h x10d | Concurrent bilateral | Iatrogenic VC tear, blood transfusion | Adrenal masses noted incidentally during ultrasound staging for a hepatic mass |
| 6 | Severe atrophy | ACA | PUPD | PD HAC | Mitotane for 2 years | Concurrent bilateral | None | Considered resistant to high dose mitotane |
| 7 | Pheo | Adenoma | Incidental, occasional PUPD | PD HAC; 180 mmHg | Mitotane previously - in remission; phenoxybenzamine 0.6 mg/kg PO Q12h x 10d | Concurrent | Postop hemoabdomen | Previous history of suspected PD HAC, in remission |
| bilateral | ||||||||
| 8 | Pheo | Pheo | PUPD, episodic weakness and collapse, depression | PD HAC; 235 mmHg | Started phenoxybenz- amine but did not tolerate | Concurrent bilateral | Refractory postop hypotension, cardiac arrest, Possible DIC | Pituitary tumor |
| 9 | Pheo (Sx 1) | Pheo (Sx 2) | Weakness | Normal; 205 mmHg | Phenoxybenzamine 0.6 mg/kg PO Q12h, | Staged bilateral, | None | History of pituitary tumor treated with SRS |
| duration unknown | cavotomy | |||||||
| (Sx 1), | ||||||||
| 4 years | ||||||||
| apart |
PUPD, polyuria and polydipsia; BP, blood pressure; Sx, surgery; ACA, adrenocortical carcinoma; Pheo, pheochromocytoma; adenoma, adrenocortical adenoma; AD HAC, adrenal-dependent hyperadrenocorticism; PD HAC, pituitary-dependent hyperadrenocorticism; VC, vena cava; SRS, stereotactic radiosurgery.
cavotomy was present unilaterally associated with the right adrenal gland in dog 8. Cavotomy was performed at the time of the first surgery in dog 9 and was not necessary during removal of the second adrenal gland. None of the other dogs required a cavotomy. No dogs required a nephrectomy. No dogs had evidence of metastatic disease at the time of sur- gery based on abdominal exploration.
Intraoperative treatment of planned iatrogenic hypoa- drenocorticism was performed as described above in 8 dogs with dexamethasone SP (median 0.25 mg/kg IV; range 0.02- 0.4 mg/kg) and DOCP (median 2.2 mg/kg IM; range 1.9- 2.5 mg/kg). In dog 9 the owner requested oral fludrocorti- sone therapy postoperatively so DOCP was withheld and flu- drocortisone was initiated at 0.02 mg/kg orally every 24 hours starting 24 hours postoperatively.
No dogs died intraoperatively. Intraoperative complica- tions occurred in 1 dog. In dog 5, a tear in the vena cava was inadvertently made during dissection of a large (4 cm) left- sided pheochromocytoma. The tear was repaired using a sim- ple interrupted pattern of 5-0 polypropylene after isolating the disrupted vena cava with Rummel tourniquets. This dog received 1 unit of packed red blood cells during surgery and recovered uneventfully. No dogs experienced sustained tach- ycardia, refractory bradycardia, or hypotension.
Postoperative complications occurred in 3 dogs. Dog 2 became hypoxic and hypercapneic on extubation and required 24 hours of flow-by nasal oxygen therapy. This dog recovered uneventfully and no additional complications were noted, nor was a cause of the hypoxia found. Dog 7 had a drop in the packed cell volume (PCV) to 24% and an abdom- inal ultrasound revealed a moderate amount effusion with a PCV of 14% on abdominocentesis. This dog received 150 mL of packed red blood cells and the peripheral PCV increased to 35% with no further decrease at re-evaluation 24 hours later. Dog 8 had postoperative hypotension with sustained periods of systolic blood pressures <60 mmHg that was refractory to dopamine (2-10 µg/kg/min IV) and norepinephrine (0.05-0.4 µg/kg/min IV) therapy. Initially, the hypotension would improve to 60-80 mmHg systolic pressure with crystalloid fluid boluses but the response was not sustained. A packed red blood cell and plasma transfu- sion was given with no significant improvement in clinical signs. Profuse hematochezia and hemorrhagic diarrhea developed in addition to the development of a distended abdomen with hemorrhagic fluid. The dog experienced car- diovascular arrest 8 hours postoperatively and closed chest cardiac compressions were attempted but unsuccessful in resuscitation. On postmortem examination the cavotomy site was intact and there was evidence of hemorrhage within the thoracic and abdominal cavities. A definitive cause of death could not be identified based on the postmortem examination but based on the amount of hemorrhage in the gastrointestinal tract, thorax, and abdomen it was suspected that the dog had developed disseminated intravascular coag- ulation (DIC) either intra- or postoperatively. In addition this dog had evidence of a heart-base chemodectoma and a pituitary macroadenoma that were previously suspected on the MRI and CT scans.
After surgery, all dogs received dexamethasone SP at a median dose of 0.2 mg/kg IV every 24 hours until eating. Oral prednisone was administered when dogs were eating at a median dose of 0.25 mg/kg orally every 12 hours (range 0.1-1 mg/kg/day) until discharge, with the discharge dose continued for a median of 14 days after discharge (range 10- 30 days). Dog 7 was given an additional dose of DOCP (0.5 mg/kg IM) due to progressively decreasing sodium and increasing potassium 18 hours postoperatively. This dog ini- tially received a 2 mg/kg IM dose of DOCP intraoperatively and was otherwise doing well. The sodium and potassium levels returned to normal after 2 days. All dogs had normal electrolytes at discharge. The median duration of hospitaliza- tion for all dogs was 4 days (range 3-6 days). Types of lesions identified based on histopathology performed at UFCVM included adrenocortical adenoma (7 dogs), adreno- cortical carcinoma (3), pheochromocytoma (6), and adreno- cortical atrophy (1).
Follow-Up
Six dogs were maintained on a combination of oral predni- sone (median 0.25 mg/kg/day) and IM DOCP (median 2.2 mg/kg every 21-30 days). Dog 3 was maintained solely on long-term fludrocortisone (0.7 mg/day orally). Dog 9 was maintained on prednisone (0.25 mg/kg orally every 24 hours) and fludrocortisone (0.02 mg/kg orally every 24 hours). After some reported episodes of nonspecific signs of weak- ness in early cases after stressful events, it was recommended in all cases to double the prednisone dose when dogs were placed in stressful situations, such as vet visits, boarding, or travelling. Follow-up with owners and veterinarians at least 60 days after discharge indicated that all dogs were stable and management of hypoadrenocorticism was straightfor- ward with minimal modifications to the discharge protocol required.
All dogs were followed until they died. The median sur- vival time of all dogs surviving to discharge was 525 days (range 83-966 days). Cause of death was tumor-related in one dog that died 8 hours postoperatively. In the remaining 8 dogs the cause of death was suspected to be unrelated to the primary tumor, although cause of death was not confirmed by postmortem evaluation. Local recurrence occurred in one dog. In this case, a small, 5 mm nodule was present at the site of the original adrenalectomy that was removed at the time of the staged second adrenalectomy and was diagnosed as a pheochromocytoma recurrence based on histologic com- parison with the original tumor. No other dogs developed local recurrence. No dogs were diagnosed with identifiable metastatic disease.
DISCUSSION
Our report describes the perioperative management of dogs undergoing concurrent and staged bilateral adrenalectomy and iatrogenic hypoadrenocorticism. In this subset of dogs, we report that bilateral adrenalectomy is technically feasible
with similar complication rates to unilateral adrenalectomy and a decreased mortality rate to what has been previously reported.3-1º In addition, treatment of postoperative iatro- genic hypoadrenocorticism was simple to initiate, titrate, and manage long-term.
At our institution, bilateral adrenalectomy is performed in dogs in the following circumstances: 1) dogs with suspi- cion of a functional adrenal disease and bilateral asymmetri- cal adrenomegaly; 2) dogs with poorly controlled, medically managed hyperadrenocorticism plus bilateral asymmetrical adrenomegaly; 3) evidence of bilateral asymmetrical adreno- megaly with macrovascular invasion; or 4) bilateral adrenal masses that continue to increase in size with serial monitor- ing over at least 3 months despite the absence of associated clinical signs.
The majority of dogs in our study had clinical signs con- sistent with some form of adrenal disease. Testing for hyper- adrenocorticism was performed in 7 dogs at the discretion of the surgeon. Five dogs had a low dose dexamethasone sup- pression test result consistent with pituitary-dependent HAC, despite the presence of an adrenal tumor. In 3 of these dogs, adrenocortical adenomas were present on histopathology. No brain imaging was performed in these dogs. In the remaining 2 dogs, bilateral pheochromocytomas were present in addi- tion to a documented pituitary tumor. Multiple endocrine neoplasia syndrome is a well-described condition in people, often with a hereditary component. This syndrome has been reported in various case reports in the dog.20,21,27 The pres- ence of concurrent pituitary tumors and pheochromocytomas has been infrequently reported in people and are suspected to be a variant of multiple endocrine neoplasia syndrome.2 Concurrent pituitary macroadenomas and pheochromocyto- mas have been previously reported in 6 dogs and such a pos- sibility should be considered in dogs that present with bilateral asymmetrical adrenomegaly and signs of HAC.21
Because HAC signs alone do not rule out the presence of a pheochromocytoma, adjunctive diagnostic tests should be considered to assist in preoperative evaluation. Meta- nephrines, normetanephrines, or inhibin were not evaluated in our dogs due to a lack of availability at the time these dogs were being treated. However, based on recent reports in the veterinary literature describing the use of these preopera- tive assays, they may be helpful to identify dogs with pheo- chromocytomas and should be considered.15-18 These preoperative assays may aid in the identification of which dogs should receive phenoxybenzamine preoperatively, but have not been validated in dogs with both pituitary- dependent HAC and a pheochromocytoma, so careful inter- pretation is recommended.1
The goal of obtaining a preoperative diagnosis in dogs with adrenal tumors is to provide preoperative therapy that decreases the physiologic effects of adrenaline and corti- sol.4-7,10 Despite these efforts, not all complications can be prevented and adrenal surgery is associated with a higher complication rate than many other elective procedures.3-10 While minor in the majority of cases, complications occurred in 44% of dogs in our study, with one complication occurring intraoperatively and the remainder occurring postopera-
tively. Among the postoperative complications, 2 of 3 were self-limiting and resolved with supportive care; however, one dog died in the postoperative period. Previous reports of bilateral adrenalectomy for adrenal tumors have reported a perioperative mortality rate of 29%, based on 10 dogs reported over 4 studies.4-7 In these reports, all dogs had adre- nocortical tumors and in 3 dogs there is no information regarding perioperative morbidity or outcome. Perioperative mortality in our study was 11%. Unfortunately due to the paucity of information available in the literature it is difficult to compare our findings to those in the literature for bilateral adrenalectomy. Our mortality rate was similar to what has been previously reported in veterinary medicine for elective unilateral adrenalectomy.3-10
In our study, the dog that died (dog 8) had bilateral pheochromocytomas, with right-sided vena cava invasion, in addition to a large pituitary macroadenoma and heart-based mass. This dog initially presented with neurological signs (presumed due to the previously diagnosed pituitary macro- adenoma) and large bilateral adrenal tumors were identified on staging tests before stereotactic radiosurgery of the intra- cranial mass. This dog had severe hypertension with a sys- tolic blood pressure >200 mmHg despite previous treatment with a calcium channel blocker and angiotensin-converting enzyme inhibitor, and became weak and nauseous with the administration of phenoxybenzamine (0.6 mg/kg orally every 12 hours). After further discussions with the owners it became evident that the clinical signs were more related to episodic weakness and collapse and suspected to be related to cyclic hypertension associated with the adrenal tumors. Based on this information, surgery was elected despite a high known risk of mortality. The dog survived the surgery without complication but developed refractory hypotension postopera- tively, and ultimately cardiac arrest. This refractory hypoten- sion was suspected to be due to the loss of chronic catecholamine exposure from bilateral pheochromocytomas and resultant changes in vascular compliance, or may also be attributed to the development of systemic inflammatory response syndrome and DIC.29 During the progression of recovery, the dog developed hemorrhagic effusion within the gastrointestinal tract in addition to the abdomen and thorax and it was suspected that the dog had developed DIC as a result of surgical trauma, although due to the comorbidities in this dog, an alternative cause of DIC could not be ruled out. This dog ultimately suffered cardiac arrest 8 hours postopera- tively. Post-mortem examination confirmed the previously identified heart-based mass and pituitary macroadenoma in addition to diffuse blood in the gastrointestinal tract, abdo- men, and thorax, which was not attributed to surgical dehis- cence of the cavotomy incision or adrenalectomy sites.
While morbidity and mortality can be high with adrenal- ectomy, outcomes in these dogs is often very good if they survive the perioperative period, as was seen in our popula- tion. Metastasis after adrenalectomy for adrenal neoplasia has been reported to occur in <25% of cases, although follow-up is variable and often not based on postmortem examination.3,4,6-9 In our study, late metastasis in the contra- lateral adrenal gland occurred in dog 9, 4 years after the first
surgery for a pheochromocytoma. In this dog, no further metastatic disease was evident on staging or at the time of surgery and the dog died due to sick sinus syndrome approxi- mately 3 months later. One hypothesis for the lack of meta- static disease in the remainder of dogs in our population is that surgical intervention occurred early in the course of dis- ease when tumors were relatively small, with the tumors removed being a median maximal length of 23 mm. In the veterinary literature, size has been evaluated as an inconsis- tent predictive measure of outcome, but has not been consid- ered with respect to metastatic potential.3,4,6,8,10 In addition, inherent in retrospective studies is a lack of objective follow- up and postmortem confirmation of findings. In our study, many dogs were older and had concurrent co morbidities that were suspected to have been their cause of death. Despite this suspicion, we cannot be absolutely certain that metasta- sis or their adrenal insufficiency did not contribute to their clinical signs or ultimate death or euthanasia.
Long-term management of adrenalectomized dogs was straightforward in most cases. Previously, in a study of dogs treated with bilateral adrenalectomy for pituitary-dependent HAC, mortality due to Addisonian crises was reported in 2 dogs within the first 30 days of surgery.3º In our population, no dogs had Addisonian crises or died within the 30 days after discharge. Early in the study period, dogs were noted to have nonspecific weakness or lethargy after periods of high stress, suspected to be due to adrenal fatigue. As a result, it was recommended that an additional dose of corticosteroids be administered in dogs before and during stressful events.30 This change in the protocol resolved any previous concerns and based on follow-up conversations with owners and refer- ring veterinarians, at least 2 months after discharge, satisfac- tion with the management of Addison’s disease was perceived as high with most dogs remaining on the same pro- tocol long-term as recommended at discharge.
Based on our experience, the following guidelines may be helpful for preoperative, intraoperative, and postoperative treatment of dogs undergoing bilateral adrenalectomy. It is important to consider individual animal factors whenever pursuing any of these treatments. These protocols were developed over the progression of the cases reported and represent the authors’ current approach to cases requiring bilateral adrenalectomy. The coexistence of pheochromocytoma and pituitary HAC was identified in a surprisingly high number of dogs in our population and a pheochromocytoma should be considered possible in all cases, even with a lack of clinical signs. Therefore, preoperatively the authors use phenoxybenzamine in all cases of bilateral adrenalectomy at a median dose of 0.6 mg/kg orally every 12 hours without dose escalation, even in the face of endocrine testing consistent with HAC. This protocol is further supported if inhibin levels are low or plasma metanephrines are elevated.15-18 Intraoperatively dogs are administered DOCP (2.2 mg/kg IM) in addition to dexamethasone SP (0.25 mg/kg IV) and dexamethasone SP is continued every 24 hours until voluntary eating resumes. When the dog is eating, prednisone (0.25 mg/kg orally every 12 hours) is initiated for 7-14 days postoperatively and then tapered to a dose of 0.1-0.25 mg/kg
orally once daily long-term based on clinical signs.31 Clients are instructed to double the maintenance prednisone dose for the duration of any stressful situations. Electrolytes are moni- tored every 6-12 hours while in hospital and then at 7, 14, 21, 23, and 25 days postoperatively and the frequency of DOCP dose adjusted and re-administered when the potassium is >6.0 mEq/L. For the first 2-3 months, electrolytes are moni- tored at 21, 23, and 25 days after administration of DOCP until a constant pattern is identified. In our experience, one of the major benefits of managing adrenalectomized dogs is that once a protocol is developed, it can be easily followed long- term and does not require significant adjustment.
Based on our findings, bilateral adrenalectomy should be considered in dogs with documented bilateral adrenal abnormalities. Despite a moderate morbidity rate, the periop- erative complications were minor and self-limiting in most cases and did not extend hospitalization in these dogs. No dogs died due to Addisonian crises postoperatively. Manage- ment of postoperative hypoadrenocorticism was easily achieved and managed by the owner.
DISCLOSURE
The authors declare no conflicts of interest related to this report.
REFERENCES
1. Lunn KF, Page RL: Tumors of the endocrine system, in Withrow SJ, Vail DM, Page RL (eds): Withrow and MacEwen’s small animal clinical oncology (ed 5). St. Louis, MO, Saunders Elsevier, 2014, pp 504-526
2. Labelle P, De Cock H: Metastatic tumors to the adrenal glands in domestic animals. Vet Pathol 2005;42:52-58
3. Massari F, Nicoli S, Romanelli G, et al: Adrenalectomy in dogs with adrenal gland tumors: 52 cases (2002-2008). J Am Vet Med Assoc 2011;239:216-221
4. Anderson CR, Birchard SJ, Powers BE, et al: Surgical treatment of adrenocortical tumors: 21 cases (1990-1996). J Am Anim Hosp Assoc 2001;37:93-97
5. Kyles AE, Feldman EC, De Cock HE, et al: Surgical management of adrenal gland tumors with and without associated tumor thrombi in dogs: 40 cases (1994-2001). J Am Vet Med Assoc 2003;223:654-662
6. Lang JM, Schertel E, Kennedy S, et al: Elective and emergency surgical management of adrenal gland tumors: 60 cases (1999- 2006). J Am Anim Hosp Assoc 2011;47:428-435
7. Van Sluijs FJ, Sjollema BE, Voorhout G, et al: Results of adrenalectomy in 36 dogs with hyperadrenocorticism caused by adreno-cortical tumour. Vet Q 1995;17:113-116
8. Schwartz P, Kovak JR, Koprowski A, et al: Evaluation of prognostic factors in the surgical treatment of adrenal gland tumors in dogs: 41 cases (1999-2005). J Am Vet Med Assoc 2008;232:77-84
9. Barrera J, Bernard F, Ehrhart E, et al: Evaluation of risk factors for outcome associated with adrenal gland tumors with or
without invasion of the caudal vena cava and treated via adrenalectomy in dogs: 86 cases (1993-2009). J Am Vet Med Assoc 2013;242:1715-1721
10. Herrera MA, Mehl ML, Kass PH, et al: Predictive factors and the effect of phenoxybenzamine on outcome in dogs undergoing adrenalectomy for pheochromocytoma. J Vet Intern Med 2008;22:1333-1339
11. NIH state-of-the-science statement on management of the clinically inapparent adrenal mass (“incident- aloma”). NIH Consens State Sci Statements 2002;19:1-25
12. Kapoor A, Morris T, Rebello R: Guidelines for the management of the incidentally discovered adrenal mass. Can Urol Assoc J 2011;5:241-247
13. Peterson ME: Diagnosis of hyperadrenocorticism in dogs. Clin Tech Small Anim Pract 2007;22:2-11
14. Wilson SD, Withrow SJ, Wheeler SL, et al: Pheochromocytoma in 50 dogs. J Vet Intern Med 1994;8:228-232
15. Brömel C, Nelson RW, Feldman EC, et al: Serum inhibin concentration in dogs with adrenal gland disease and in healthy dogs. J Vet Intern Med 2013;27:76-82
16. Gostelow R, Bridger N, Syme HM: Plasma-free metanephrine and free normetanephrine measurement for the diagnosis of pheochromocytoma in dogs. J Vet Intern Med 2013;27:83-90
17. Green BA, Frank EL: Comparison of plasma free metanephrines between healthy dogs and 3 dogs with pheochromocytoma. Vet Clin Pathol 2013;42:499-503
18. Salesov E, Boretti FS, Sieber-Ruckstuhl NS, et al: Urinary and plasma catecholamines and metanephrines in dogs with pheochromocytoma, hypercortisolism, nonadrenal disease and in healthy dogs. J Vet Intern Med 2015;29:597-602
19. Singh Y, Kotwal N, Menon AS: Endocrine hypertension- Cushing’s syndrome. Indian J Endocrinol Metab 2011;15 (Suppl 4):S313-S316
20. Thuróczy J, van Sluijs FJ, Kooistra HS, et al: Multiple endocrine neoplasias in a dog: corticotrophic tumour, bilateral
adrenocortical tumours, and pheochromocytoma. Vet Q 1998; 20:56-61
21. von Dehn BJ, Nelson RW, Feldman EC, et al: Pheochromocytoma and hyperadrenocorticism in dogs: six cases (1982-1992). J Am Vet Med Assoc 1995;207:322-324
22. Rose L, Dunn M, Bedard C: Effect of canine hyperadrenocorticism on coagulation parameters. J Vet Intern Med 2013;27:207-211
23. Helm JR, Mclauchlan G, Boden LA, et al: A comparison of factors that influence survival in dogs with adrenal-dependent hyperadrenocorticism treated with mitotane or trilostane. J Vet Intern Med 2011;25:251-260
24. Feldman EC: Evaluation of twice-daily lower-dose trilostane treatment administered orally in dogs with naturally occurring hyperadrenocorticism. J Am Vet Med Assoc 2011;238:1441-1451
25. Emms SG, Johnston DE, Eigenmann JE, et al: Adrenalectomy in the management of canine hyperadrenocorticism. J Am Anim Hosp Assoc 1987;23:557-564
26. Fossum TW: Surgery of the endocrine system, in: Fossum TW (ed): Small animal surgery textbook (ed 4). St. Louis, MO, Mosby, 2013, pp 633-684
27. Proverbio D, Spada E, Perego R, et al: Potential variant of multiple endocrine neoplasia in a dog. J Am Anim Hosp Assoc 2012;48:132-138
28. Breckenridge SM, Hamrahian AH, Faiman C, et al: Coexistence of a pituitary macroadenoma and pheochromocytoma-a case report and review of the literature. Pituitary 2003;6:221-225
29. Hanna NN, Kenady DE: Pheochromocytoma, in: Holheimer R, Mannick J (eds): Surgical treatment: evidence-based and problem oriented. Munich, Germany, Zuckschwerdt, 2001, pp 1-22
30. Emms SG, Johnston DE, Eigenmann JE, et al: Adrenalectomy in the management of canine hyperadrenocorticism. J Am Anim Hosp Assoc 1987;23:557-564
31. Klein SC, Peterson ME: Canine hypoadrenocorticism: part II. Can Vet J 2010;51:179-184