Management of hyperparathyroid‐induced hypercalcaemic crisis with intracardiac thrombi

Summary

A 29‐year‐old previously healthy patient presented with a hyperparathyroid‐induced hypercalcaemic crisis refractory to conventional therapy. The patient developed ventricular fibrillation and subsequently required emergency parathyroidectomy and extracorporeal membrane oxygenation support. Extensive intracardiac and pulmonary trunk thrombi were identified soon after the commencement of extracorporeal membrane oxygenation, despite full anticoagulation. In this report we highlight the non‐specific presentations of hypercalcaemia which may lead to delayed diagnosis, and discuss the incidence, risk factors and treatment of a hyperparathyroid‐induced hypercalcaemic crisis. We emphasise the role of emergency parathyroidectomy as a salvage therapy in medically refractory We consider the likely factors leading to intracardiac thrombi formation in this case, including how hypercalcaemia may have been a contributing factor.

Introduction

Hyperparathyroid‐induced hypercalcaemic crisis is a rare but potentially fatal complication of primary hyperparathyroidism. Prompt diagnosis and aggressive treatment are required in order to avoid devastating complications such as arrhythmia or cardiac arrest. For hypercalcaemia refractory to first‐line medical therapy, haemodialysis and emergency parathyroidectomy should be considered. There is no consensus about optimal timing of parathyroidectomy; however, response to medical treatment is usually effective after 48 h of treatment. Therefore, it is reasonable to consider definitive surgery if there is no response after this time. Emergency parathyroidectomy has a comparable success rate to the elective operation, but has a higher risk of peri‐operative mortality 1.

Primary hyperparathyroidism is associated with thrombotic events. These include arterial and venous thromboses, potentially resulting in ischaemic stroke, deep vein thrombosis and pulmonary embolism. This is the first reported case of hyperparathyroid‐induced hypercalcaemic crisis associated with the need of extracorporeal membrane oxygenation (ECMO) support and subsequent development of intracardiac thrombi. Multiple factors contribute to intracardiac thrombus formation associated with ECMO, including intracardiac stasis and exposure to the extracorporeal circuit. The mean time taken for diagnosis of intracardiac thrombi is 3 days and mainly occurs in the left‐sided circulation 2. In our patient, intracardiac thrombi was detected within hours of ECMO initiation despite full anti‐coagulation and occurred extensively in all four cardiac chambers and the pulmonary trunk. We propose that the hypercalcaemia may have been one of the contributing factors for the development of intracardiac thrombi in this case.

Report

A 29‐year‐old man with no past medical history presented to the emergency department with repeated vomiting and constipation of 3 days duration. He had no family history of parathyroid tumours or multiple endocrine syndromes. He was severely dehydrated on presentation. Blood biochemistry revealed hypercalcaemia with a total calcium of 5.35 mmol.l⁻¹, ionised calcium of 2.73 mmol.l⁻¹ and normal plasma phosphate concentrations. He had impaired renal function with creatinine of 240 μmol.l⁻¹ and parathyroid hormone was > 1500 pg.ml⁻¹. Bed‐side ultrasound scanning demonstrated a 2 cm solitary right inferior parathyroid nodule. Primary hyperparathyroidism with a hypercalcaemic crisis was diagnosed.

The patient was admitted to the intensive care unit for aggressive fluid resuscitation and diuresis with furosemide. Intravenous calcitonin, pamidronate and cinacalcet were administered. Urine output was maintained at 400 ml.h⁻¹. Plasma calcium concentrations decreased only minimally, so low‐calcium haemodialysis was commenced. Renal ultrasound revealed multiple renal stones without obstructive features. Tumour localisation with Technetium‐99m sestamibi scan and early operation were planned to be done after stabilising the hypercalcaemic episode.

The hypercalcaemia, however, persisted and the patient developed a witnessed ventricular fibrillation cardiac arrest 6 days following admission. Return of spontaneous circulation was achieved after 6 min advanced life support. The surgeons decided to proceed to emergency parathyroidectomy due to the refractory hypercalcaemia. Fluid resuscitation and diuretic therapy were continued peri‐operatively. The patient remained haemodynamically stable with no recurrence of arrhythmia during surgery. The intra‐operative findings showed a 3.5 cm, soft, well‐encapsulated right inferior parathyroid gland. Parathyroid pathology subsequently confirmed a benign adenoma.

Despite a relatively unremarkable intra‐operative course, the patient had increasing ventilatory and oxygen requirements postoperatively. The Murray lung injury score was 3.5 with chest X‐ray showing infiltrates in three lung quadrants, a PaO₂/F_IO₂ ratio of 73, a positive end‐expiratory pressure (PEEP) of 14 cmH₂O and lung compliance of < 19 ml.cmH₂O⁻¹. An echocardiogram showed a small rim of pericardial effusion without tamponade and normal left ventricular size and function. Optimising measures such as PEEP, sedation, neuromuscular blockade and diuresis resulted in no ventilatory improvement. In view of deteriorating respiratory function, the patient was started on veno‐venous ECMO (VV‐ECMO).

The patient developed shock with escalating inotropic support on day 1 postoperatively and was changed to veno‐arterial ECMO (VA‐ECMO). An echocardiogram several hours later revealed a poor biventricular systolic function with large thrombi at both ventricular apices (Fig. 1). Activated partial thromboplastin time (APTT) was increased from 62.4 s to > 120 s by heparin infusion. Plasma calcium concentrations on day 1 postoperatively were decreasing but still elevated (Table 1). He was transferred to a tertiary centre for cardiothoracic surgery support and open cardiac surgery. There were fresh thrombi in all four cardiac chambers and the entire pulmonary artery from the main trunk to distal arteries. All clots were successfully retrieved and the patient was changed from peripheral to central ECMO support.

Figure 1.

Transthoracic echocardiogram showing apical long axis two‐chamber view of the left ventricular intracardiac thrombus taken at the initial diagnosis of intracardiac thrombi. The box arrows point to the left ventricular intracardiac thrombus. LA, left atrium; LV, left ventricle.

Table 1.

Total and ionised calcium concentrations trend in the peri‐operative period. The reference range for total calcium is 2.29–2.63  mmol.l⁻¹ and for ionised calcium is 1.12–1.3  mmol.l⁻¹

	Total calcium (mmol.l−1)	Ionised calcium (mmol.l−1)
Admission	5.35	2.73
Immediately before cardiac arrest	4.01	2.42
Immediately postoperatively	4.62	2.31
Day 1 postoperatively	3.79	2.02
Day 2 postoperatively	1.93	—
Day 3 postoperatively	2.01	—

Unfortunately, the patient developed right acute lower limb ischaemia, compartment syndrome and rhabdomyolysis as a result of the prior peripheral ECMO, necessitating a right above‐knee amputation. A further echocardiogram showed no residual intracardiac thrombi and ventricular function was normalised. The patient was discharged and commenced on warfarin for 1 year with a plan for aspirin thereafter. There has been no recurrence of hypercalcaemia since the parathyroidectomy.

Discussion

The incidence of hyperparathyroidism is 1:500 in women and 1:2000 in men over 40 years old 3. Patients with hyperparathyroidism are often asymptomatic (22–80%) but may also present with nephrolithiasis (17–37%), hypercalciuria (40%) or skeletal changes (1–14%) 4. The incidence of asymptomatic patients has increased significantly in recent years with wider availability of investigations and earlier detection. Other symptoms can be represented by the mnemonic of ‘painful bones, renal stones, abdominal moans and psychiatric groans’. These are often non‐specific and can lead to misdiagnosis or treatment delay. Common causes of primary hyperparathyroidism include single gland adenoma (57–85% of cases) and multiple gland adenomas (two glands in 2–12%, three glands in < 1–2%, and four or more in < 1–15%) 4. It is rarely associated with parathyroid carcinoma and multiple endocrine neoplasm type one.

Hyperparathyroid‐induced hypercalcaemic crisis is a rare but potentially fatal complication of hyperparathyroidism with severe hypercalcaemia (> 3.5 mmol.l⁻¹) and is associated multiple organ dysfunction. The incidence ranges from 2% to 21% 5. Risk factors for hyperparathyroid‐induced hypercalcaemic crisis include double adenoma, carcinoma (seen in 5–10% of patients), a heavier mass of adenoma and higher concentrations of parathyroid hormone on assay 1. Hyperparathyroid‐induced hypercalcaemic crisis is a medical emergency and should be aggressively treated regardless of symptoms. Common treatments include saline rehydration, forced diuresis after adequate fluid replacement, calcitonin and bisphosphonates. Low‐calcium or calcium‐free haemodialysis should be considered, particularly in medically refractory hypercalcaemia and those with renal failure.

The optimal timing for parathyroidectomy is unknown. In general, it is suggested that plasma calcium concentrations should be controlled before surgery as untreated severe hypercalcaemia is associated with increased life‐threatening cardiac arrhythmias peri‐operatively. There is no consensus on target calcium concentrations, however, Singh et al. suggest a target level < 3 mmol.l⁻¹ 5. Fluid resuscitation and diuresis are the mainstays of therapy for hyperparathyroid‐induced hypercalcaemic crisis, however, bisphosphonates appear to have a role in accelerating the reduction in serum calcium. In a case series by Singh et al., the average time taken to lower calcium to the desired range of 2.6 mmol.l⁻¹ was 4.5 days with the use of bisphosphonates compared with 14.6 days without 5. However, in refractory hypercalcaemia, urgent parathyroidectomy may be the only salvage treatment. Hsin et al. suggested that medical response is usually evident after 48 h of treatment. Therefore, if there is no response by 48 h, surgical intervention should be considered and could be lifesaving 6.

With the advancement in pre‐operative imaging modalities (e.g. ultrasound, sestamibi scan) and intra‐operative parathyroid hormone monitoring, the success of emergency parathyroidectomy in hyperparathyroid‐induced hypercalcaemic crisis is 95%, comparable to that of elective patients of 97% 7. Among patients undergoing emergency parathyroidectomy, 98% remained eucalcaemic after initial operation and 96% after 6 months 8. The overall postoperative mortality rate was higher in those with hyperparathyroid‐induced hypercalcaemic crisis of 2.8% compared to 0.1% in those without 1.

In our patient with hyperparathyroid‐induced hypercalcaemic crisis complicated by ventricular fibrillation, the key intra‐operative strategy included: continuation of treatment for hypercalcaemia by fluid rehydration and diuretic therapy; judicious drug and anaesthetic doses; and a high vigilance for recurrence of arrhythmia. Extra care should also be taken during laryngoscopy and positioning for surgery as pathological fractures may occur in prolonged hypercalcaemia resulting in cervical spine injury.

Ventricular arrhythmia is a rare cardiac manifestation of hypercalcaemia. More common cardiac manifestations include ECG changes (e.g. prolonged PR and QRS intervals, short QT intervals), left ventricular hypertrophy and vascular calcification. Other manifestations include atrial fibrillation, sinus tachycardia, heart failure, cardiomyopathy or atrioventricular block.

The postoperative respiratory failure in our case was likely a result of acute respiratory distress syndrome (ARDS) or cardiogenic pulmonary oedema. Possible risk factors for ARDS included pulmonary contusion from chest compressions, ischaemia‐reperfusion injury, ventilator‐induced lung injury and a systemic inflammatory response associated with post‐cardiac arrest syndrome. Congestive heart failure related to postparathyroidectomy hypocalcaemia has been infrequently reported 9. We postulate that the decrease in calcium, a positive inotrope, relative to the patient's long‐standing elevated baseline may have resulted in cardiac decompensation, leading to pulmonary oedema.

The exact pathophysiology relating primary hyperparathyroidism and thrombotic events is not fully understood. Proposed mechanisms include direct activation of prothrombotic factors (e.g. calcium‐triggered vasoconstriction, calcium activation of clotting system and platelet aggregation and relative dehydration), increased baseline cardiovascular risk factors due to long‐standing hypercalcaemia or a combination of both. Nonetheless, both arterial and venous thromboses have been reported, resulting in major ischaemic stroke, pulmonary embolism and deep vein thrombosis 10.

To the best of our knowledge, this is the first report of hyperparathyroid‐induced hypercalcaemic crisis associated with the need for ECMO support and subsequent development of intracardiac thrombi. VA‐ECMO is an increasingly popular intervention for critically ill patients with cardiogenic shock. Intracardiac thrombus formation is a rare but well‐recognised complication of VA‐ECMO with a high mortality rate. The true incidence of intracardiac thrombi during VA‐ECMO is not well‐documented but there is an increasing trend given the more prevalent application of ECMO. Various factors contribute to intracardiac thrombi formation, which follow the Virchow's triad of altered circulatory flow (cardiogenic shock, low‐flow state, blood stasis), vascular injury (exposure to foreign surface, ischaemic or pro‐inflammatory states) and altered coagulability (balance between anticoagulation and procoagulant factors).

In a review by Williams et al., the mean time to diagnosis of intracardiac thrombi associated with VV‐ECMO was 3 days (range 1–7 days) and diagnosis by echocardiogram was usually prompted by haemodynamic instability or failure to wean from extracorporeal support 2. The majority of cases occurred in the left‐sided circulation. One out of 12 patients was found to have intracardiac thrombus formation in both ventricles and the pulmonary artery on day 3 of ECMO. Our patient developed diffuse thrombi in all four cardiac chambers within hours after initiation of ECMO, while on full anticoagulation therapy. Multiple factors may contribute to the clot formation including a deterioration in ejection fraction, intracardiac haemostasis and procoagulant stimuli through exposure to ECMO circuit. The calcium concentrations at the time of cardiac thrombi formation were still elevated, albeit decreasing. We postulate that hypercalcaemia was a significant contributing factor in the formation of intracardiac thrombi in our patient. Further studies would be required to elucidate the interplay of hypercalcaemia and intracardiac thrombus formation while on ECMO in vivo.

In conclusion, hyperparathyroid‐induced hypercalcaemic crisis requires immediate medical treatment. Emergency parathyroidectomy has high success rate and should be considered earlier, for example, 48 h after treatment if there is refractory hypercalcaemia. Hypercalcaemia is associated with thrombotic complications and high vigilance should be maintained for such patients, even in the early postoperative period.