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Dogs
Management of life-threatening hypertension in a 12-year-old bichon frise undergoing an adrenalectomy for phaeochromocytoma excision
  1. Jacques Paul Ferreira and
  2. Joanna Raszplewicz
  1. University of Liverpool School of Veterinary Science, Small Animal Teaching Hospital, Liverpool, UK
  1. Correspondence to Jacques Paul Ferreira, jpf{at}liv.ac.uk

Abstract

A bichon frise, previously diagnosed with a phaeochromocytoma, underwent phenoxybenzamine treatment 17 days before adrenalectomy. Preoperative haematology, biochemistry and oscillometric blood pressure readings for the 12 year old were typical. Before anaesthesia, methadone and medetomidine were administered intramuscularly. Anaesthesia was induced using propofol titrated to permit endotracheal intubation and maintenance of anaesthesia using an isoflurane in oxygen mixture. Invasive blood pressure monitoring by a cannula in a dorsal pedal artery promptly revealed life-threatening hypertension. Rapid increase in isoflurane concentration, multiple intravenous fentanyl boluses administration and commencement of an esmolol citrate infusion were unsuccessful in attenuating the hypertension observed. Rapid rises in end-tidal carbon dioxide and resultant tachypnoea necessitated atracurium intravenously and positive pressure ventilation. Hypertension was eventually abolished using intravenous acepromazine, which ultimately caused a hypotensive nadir. Reduction in anaesthetic depth and aggressive fluid therapy resolved hypotension before termination of anaesthesia. Management of hypertension in dogs with phaeochromocytoma remains challenging.

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Background

Dogs diagnosed with a phaeochromocytoma are at risk of suffering a number of complications, most notably life-threatening hypertension. Phenoxybenzamine (PBZ) administration before anaesthesia has been reported to reduce the risk of mortality in both human beings and dogs (Herrera and others 2008); however, there is little veterinary evidence reporting guidelines to administer the drug for optimal effect. This case report describes severe life-threatening hypertension refractory to various previously reported interventions in a 12-year-old, male-neutered bichon frise undergoing adrenalectomy. The dog had been prophylactically placed on PBZ treatment from time of diagnosis 17 days before adrenalectomy.

Case presentation

A 12-year-old bichon frise, with a three-month-old history of polydipsia, polyuria, weight loss and chronic kidney disease (International Renal Interest Society (IRIS) stage II), was referred for further investigation of suspected hyperadrenocorticism. Abdominal ultrasound examination, CT and clinical pathology revealed an enlarged left adrenal gland invading the lateral wall of the caudal vena cava, as well as elevated catecholamine circulation and excretion (urine normetadrenaline:creatine ratio (3.59 µmol/l, RI<0.14) and methoxytyramine:creatinine ratio (0.27 µmol/l RI<0.19)). The findings were highly suggestive of an actively secreting phaeochromocytoma.

Investigations

Shortly after diagnosis of a phaeochromocytoma, an oral antihypertensive medication, PBZ (Dibenzyline; Wellspring), was commenced at 2.5 mg/kg twice a day for two weeks. Sixteen days later, the dog was readmitted to the hospital for preanaesthetic assessment, fasting and surgical excision of the adrenal tumour.

Preanaesthetic assessment including non-invasive oscillometric blood pressure measurements, haematology and serum biochemistry revealed normotension (121/84 mmHg; Table 1), hypercholesterolaemia (6.84 nmol/l, reference intervals (RI) 3.2–6.5 nmol/l), elevated urine protein to creatinine ratio (1.24, RI 0.5–1.0), mild azotaemia (urea: 9.2 mmol/l, RI 3.5–6.0 mmol/l; creatinine: 152 µmol/l, RI: 20–110 μmol/l) and mild hypercalcaemia (total calcium: 3.07 mol/l, RI 2.20–2.70 mol/l). The following day, the 12-year-old male-neutered dog presented to the anaesthesia service bright and alert, but anxious. Physical examination revealed mild tachycardia (168 bpm) and a grade II/VI left-sided mid-systolic murmur. In lieu of the impending surgery, the resident board-certified cardiologist examined the dog. The cardiologist's echocardiography study and clinical examination reported no significant structural or functional abnormalities precluding general anaesthesia.

TABLE 1:

Perianaesthetic blood pressure and pulse rate readings in a bichon frise undergoing adrenalectomy (phaeochromocytoma)

Treatment

The preanaesthetic findings prompted administration of a premedication protocol consisting of methadone (0.3 mg/kg Comfortan; Eurovet) and medetomidine hydrochloride (0.003 mg/kg Dormilan; Lintbells) injected into the gluteal muscles. Twenty minutes after premedication administration, the dog displayed mild sedation sufficient to facilitate percutaneous cannulation of the right cephalic vein, using a 20-G over-the-needle cannula (intravenous catheter; Abbott), followed directly by five minutes of oxygen administration via an appropriately sized, clear facemask. Induction of anaesthesia was performed using intravenous titration of propofol (2 mg/kg/minute Propoflo; Abbott) in order to achieve an adequate anaesthetic depth to permit endotracheal intubation. Immediately after intubation of an appropriately sized endotracheal tube and adequate inflation of the cuff, the dog was connected to a circle breathing system and allowed to spontaneously ventilate an isoflurane in oxygen gas mixture; initially set to deliver a fresh gas flow (FGF) rate of 2 l/minute (FGF decreased to 0.5 l/minute after five minutes of administration) and targeting an end-tidal isoflurane concentration of 1–1.3 per cent. Perianaesthetic monitoring consisting of three-lead electrocardiogram, transmittance pulse oximetry, side-stream capnography with agent analyser and oesophageal temperature displayed on a multiparameter monitor (Datex AS/3 Compact multiparameter monitor; GE Healthcare) commenced directly afterwards. Active warming was provided using an electronic heating pad initially set to 40°C, targeting an oesophageal temperature range of 37.5–38.5°C. Non-invasive oscillometric blood pressure monitoring using a dedicated device (Cardell 9401; Midmark) was performed during the surgical preparation period using a correctly sized (cuff width equivalent to a third of the forearm circumference) cuff placed on the right forelimb, distal to the elbow. Blood pressure measurements taken during the surgical preparation period were not dissimilar to those observed the day before (128/77 mmHg; Table 1). Before routine aseptic preparation of the surgical site, the dog was manipulated into lateral recumbency in order to facilitate placement of a central venous catheter (Milacath; MILA) via the right jugular vein using the Seldinger technique, as well as epidural administration of preservative-free morphine (0.1 mg/kg morphine sulphate BP; Martindale Pharmaceuticals) using a 22-G spinal needle introduced at the lumbosacral intervertebral space. Intravenous fluid therapy (Hartmanns Lactated Ringers’; B. Braun) was initiated at 5 ml/kg/hour using a peristaltic infusion pump (Infusomat; B. Braun).

Once surgical preparation was complete, the dog was moved to theatre where anaesthetic maintenance and monitoring continued unchanged with the exception of blood pressure, which was monitored invasively using a 22-G over-the-needle cannula (intravenous catheter; Abbott), preplaced in the dorsal pedal artery of the right hindlimb. The catheter was coupled using non-compliant tubing to a calibrated (zeroed at the level of the shoulder) electronic strain-gauge transducer and multiparameter monitor. Immediately after commencement of invasive monitoring and completion of a ‘fast flush test’, life-threatening systolic hypertension (220/78 mmHg: Table 1) was observed. Two minutes later, a rapid rise in end-tidal carbon dioxide (66/mmHg/8.28 kPa) and tachypnoea (35 breaths/minute) was recorded. The hypertension was refractory to a rapid increase in volatile anaesthetic administration (Vaporizer set to 4 per cent) and multiple fentanyl citrate (Fentadon; Dechra) boluses totalling 20 μg/kg in addition to a constant rate infusion of 5–10 μg/kg/hour. Hypercapnia was initially treated with commencement of an intermittent positive pressure ventilation (IPPV) using a pressure-controlled ventilation mode. Peak inspiratory pressure, positive end-expiratory pressure and frequency initially set to 12 cmH2O, 4 cmH2O and 12 breaths/minute, respectively, were commenced in order to maintain end-tidal carbon dioxide between 35 and 50 mmHg/4.5–6.5 kPa. Continual bucking of the ventilator and excessive movement necessitated intravenous atracurium (0.2 mg/kg Tracurium; GlaxoSmithKline) administration, which resulted in adequate muscle relaxation to permit both IPPV and adrenalectomy. Hypertension remained unchanged for a further 10 minutes, and shortly after first incision, a further rise in blood pressure exceeding the range of the multiparameter monitor (maximum systolic arterial pressure recorded was 304 mmHg; however, a truncated arterial waveform indicative of obtunded readings was observed) and increased pulse rate (110 bpm; Table 1) necessitated esmolol hydrochloride (Orpha-devel handels und Vetrgriebs) administration at an initial dose rate of 0.1 mg/kg/minute titrated to effect. At this point, the surgeon remarked on greater-than-expected haemorrhage being observed at the incision site. Within minutes of esmolol citrate administration, pulse rate decreased from 110 to 78 bpm; however, the hypertension persisted. Ten minutes after initiation of esmolol constant rate infusion, acepromazine (0.01 mg/kg ACP; Novartis) was administered intravenously, which effected a marked reduction in blood pressure (158/62 mmHg; Table 1) 20 minutes later, reaching a hypotensive (93/43 mmHg; Table 1) nadir 30 minutes after administration. Hypotension persisted for a further 20 minutes, responding to decreased isoflurane (end-tidal isoflurane % <1.0 per cent) and fentanyl (constant rate infusion: 3 μg/kg/hour) administration in combination with aggressive fluid therapy (40 ml/kg/hour of crystalloid and 10 ml/kg of gelatin-based colloid (Gelofusine; B.Braun)). Blood pressure continued to improve for the remaining 30 minutes of surgery, resulting in mild hypotension (MAP>60 mmHg) shortly before recovery from anaesthesia. Before return of spontaneous ventilation and termination of anaesthesia, acceleromyographic monitoring with a neuromuscular transmission monitor (TOF watch; Warday Premise) placed adjacent to the peroneal nerve of the right hindlimb failed to reach a train-of-four ratio of 0.9, necessitating a 0.01 mg/kg neostigmine methysulphate (West-Ward pharmaceuticals) administration. Ten minutes after neostigmine administration, the train-of-four ratio of greater than 0.9 was observed, permitting weaning from the ventilator and return to spontaneous ventilation. No significant bradycardia warranting anticholinergic administration was observed with reversal of the neuromuscular blockade. No further blood pressure derangements were noted during invasive monitoring postoperatively, and the dog remained normotensive for the remainder of its 96-hour stay in the intensive care unit. Self-limiting diarrhoea lasting approximately 24 hours was noted a few hours after recovery from anaesthesia, but the dog remained otherwise bright and alert, continuing to display a moderate appetite.

Outcome and follow-up

Following resolution of the diarrhoea, satisfactory haematology and serum biochemistry results, the dog was released into the owner's care and has subsequently returned for two follow-up examinations 10 and 21 days post surgery, which were satisfactory. Histopathological examination of the excised tumour confirmed it to be an actively secreting phaeochromocytoma.

Discussion

This case report highlights a number of challenges associated with blood pressure management in a dog requiring adrenalectomy for a phaeochromocytoma. Difficulty in attaining effective PBZ treatment, premedication selection, accurate blood pressure measurement and intraoperative management of life-threatening hypertension were particular noteworthy difficulties.

The decision to commence PBZ in the present case was based upon previous literature reporting a decrease mortality in dogs administered PBZ before adrenalectomy compared with untreated dogs (Herrera and others 2008). PBZ non-competitively binds to α-adrenergic receptors, which undergo irreversible alkylation and inhibition. In doing so, PBZ non-competitively inhibits adrenaline and noradrenaline from effecting life-threatening vasoconstriction and hypertension (Maher and McNiel 1997). The exact duration of action in dogs has yet to be elucidated. However, in human beings, a 72-hour half-life has been reported (Murrell 2015). Veterinary literature reports a wide variation in antihypertensive PBZ dose and length of administration in dogs, ranging from 0.2 to 1.5 mg/kg twice a day and 7–120 days, respectively (Herrera and others 2008, Wise and Boveri 2016). At time of initial diagnosis, the present case had no history or clinical manifestations of hypertension. It was decided therefore to administer a relatively conservative dose of PBZ (2.5 mg/kg twice a day) in accordance with those reported by Maher and others (1997), while following the human guidelines, which required a minimum of 14 days of administration before attempting anaesthesia (Pace and Buttigieg 2003). Administration of ACP in the present case competitively antagonises α-adrenergic receptor-mediated vasoconstriction in a similar, but not identical, manner to PBZ. The success of ACP in ameliorating the hypertension observed intraoperatively in this case questions the efficacy of the PBZ dose administered for two weeks before surgery (Rankin 2015). Failure to achieve efficacy of PBZ in the present case highlights the need for further investigation and, if possible, establishment of treatment guidelines in dogs with phaeochromocytoma. To ensure hypertension was relatively controlled and to safeguard against hypotension as a result of PBZ treatment, it was decided to perform blood pressure measurements on readmission, 24 hours before adrenalectomy. Considering the long half-life of PBZ in human beings, terminating treatment at this point would have done little to amend any hypotension. In future, earlier (e.g. three days before adrenalectomy) blood pressure measurement may provide sufficient time to correct any blood pressure abnormalities before surgery.

Non-invasive oscillometric blood pressure readings performed on the dog at admission indicated adequate stabilisation (124/81 mmHg: Table 1) and in accordance with preanaesthetic blood pressure guidelines (<160/90 mmHg) in human patients with phaeochromocytomas (Pace and Buttigieg 2003). Similar readings were observed (128/78 mmHg: Table 1) directly after anaesthetic induction in the present case; however, directly after commencement of invasive monitoring, severe systolic hypertension (220/78 mmHg: Table 1) was observed. In addition to mild chronic renal failure and hypercalcaemia present in the dog, a number of factors may have contributed to the hypertension observed, namely invasive and non-invasive blood pressure measurement errors, as well as a sudden hypertensive crisis caused by the actively secreting phaeochromocytoma (McCubbin and others 1956, Eiam-Ong and others 2004, Wise and Boveri 2016). Comorbidities, namely chronic renal failure (Mc Cubbin and others 1956) and hypercalcaemia (Eiam-Ong and others 2004) as observed in the present case, have been reported to induce hypertension in dogs; however, the magnitude of hypertension observed was unlikely to have resulted from these abnormalities alone. Invasive blood pressure monitoring may also have contributed to the discrepancy. Underdamping (e.g. arterial catheter artefact) and cannulation of peripheral arteries compared with central arteries may contribute to false systolic blood pressures being measured (Rothe and Kim 1980, McMurphy and others 2006). In the present case, the invasive blood pressure apparatus was thoroughly checked for underdamping before coupling and a fast flush test was performed once coupled in order to reduce the magnitude and incidence of measurement error. However, cannulation of the dorsal pedal artery was performed, which may have contributed to increasing the magnitude of difference between the diastolic and systolic blood pressure readings obtained (Rothe and Kim 1980). In addition to invasive reading errors, oscillometric blood pressure monitoring may have failed to identify existing hypertension both before and during anaesthesia (McMurphy and others 2006). In a publication by McMurphy and others (2006), they reported reduced accuracy in diagnosing artificially induced hypertension in dogs using oscillometric blood pressure devices compared with invasive monitoring (McMurphy and others 2006). The magnitude of the discrepancy between invasive and oscillometric blood pressure measurements observed in the present case is substantial. A sudden hypertensive crisis occurring just before or during initiation of invasive blood pressure monitoring is a plausible explanation that cannot be ruled out. In dogs with phaeochromocytomas, the reported incidence of hypertensive crises is variable, ranging from 21 to 85 per cent and may have occurred spontaneously in the present case (Wise and Boveri 2016). Lastly, the α2-adrenergic agonists medetomidine hydrochloride may have contributed to the hypertension observed in the present case. Medetomidine has been widely reported to induce systemic vasoconstriction and increased blood pressure in dogs (Pypendorp and Verstegen 1998, Ueyema and others 2008). Intramuscular administration of medetomidine has been reported to increase blood pressure 10–20 minutes after administration, returning to preadministrative values after 45 minutes (Ueyema and others 2008). In the present case, the low dose of medetomidine was administered intramuscularly, approximately 60 minutes earlier, and was unlikely to have contributed significantly to the hypertension observed (Ueyema and others 2008).

ACP was not chosen as part of the premedication due to stabile preoperative blood pressures as well as concern with inducing prolonged hypotension (three to four hours duration) postoperatively (Wise and Boveri 2016). Instead, medetomidine was chosen in place of ACP to provide sedation in the fractious dog. Medetomidine has the benefit of providing sedation and sympatholysis, which the authors anticipated would provide some degree of inhibition of catecholamine-induced hypertension (Murrell 2015). Medetomidine is not ordinarily the sedation of choice in geriatric dogs due to the potent reduction in cardiac output associated (Pypendorp and Verstegen 1998). In the present case, however, based on the recommendations of the cardiologist and the degree of anxiousness displayed by the dog on presentation, the potential of a stress-induced hypertensive crisis was deemed to be of greater risk than cardiac decompensation, warranting the intramuscular administration of a low dose of medetomidine (Pypendorp and Verstegen 1998).

Persistent and severe hypertension as observed in the present case can be life-threatening and should be addressed as soon as reasonably possible. In the present case, ACP was administered intraoperatively, which successfully resolved the life-threatening hypertension before producing hypotension shortly afterwards (93/43 mmHg; Table 1). The hypotension was responsive to a combination of aggressive fluid therapy and rapid reduction in anaesthetic depth with no complications encountered postoperatively. Ideally, a short-acting hypotensive drug such as sodium nitroprusside (SNP), phentolamine or labetalol would have been preferred to ACP; however, none of these agents was available at the time of the surgery (Kyles and others 2003, Murrell 2015). SNP is a short-acting agent, which when administered intravenously causes nitric oxide-mediated vasodilation of arteries and veins lasting approximately 10 minutes (Peck 2008). The rapid metabolism of SNP in plasma reduces the risk of prolonged hypotension as observed in the present case. Similarly, phentolamine, a competitive α1-adrenergic agonist, facilitates approximately 20 minutes of vasodilation (Peck 2008). Lastly, labetalol, an α1 and β-adrenergic receptor antagonist, may have been a superior choice to ACP, reducing α-adrenoceptor-mediated vasoconstriction and limiting β-adrenoceptor-mediated tachyarrhythmia (Saito and others 1986).

Isoflurane and fentanyl have been reported to reduce arterial blood pressure by attenuating noradrenaline's vasopressor effects and central inhibition of vasomotor centre, respectively (Wise and Boveri 2016). A recent case report (Wise and Boveri 2016) describes the successful treatment of a hypertensive crisis with incremental increases in isoflurane and fentanyl administration. The present case failed to respond in a similar manner, however, which compelled the anaesthetist to commence esmolol administration. Esmolol hydrochloride is an ultra-short-acting β-blocker indicated to decrease heart rate and β1-receptor-mediated inotropy (Myburgh and others 2003, Stewart and others 2015). The administration of esmolol in the present case resulted in mild reduction in heart rate and negligible reduction in blood pressure. The administration of esmolol to inadequately PBZ-treated patients is controversial and may worsen SAP due to loss of β2-receptor-mediated vasodilation (Pace and Buttigieg 2003). Fortunately, this complication was not observed in the present case; however, failure to resolve the hypertension further supports the restricted use of esmolol to cases demonstrating severe tachyarrhythmia-induced hypertension only.

  • Received August 9, 2016.
  • Revision received October 3, 2016.
  • Accepted October 14, 2016.

References

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Footnotes

  • Contributors Both authors contributed comprehensively to the case report. JPF primarily managed the case under direct guidance of JR. Both authors were involved in the composition, critiquing and final approval of the draft attached.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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