Synchronous Diaphragmatic Flutter Secondary to Primary Hypoparathyroidism in a Dog

Introduction

Synchronous diaphragmatic flutter (SDF), also known as “thumps,” is a rare condition characterized by hiccup-like contractions of the diaphragm leading to repetitive, involuntary abdominal wall contractions synchronous with the heartbeat.¹ It is most likely caused by normal electrical depolarization activity in the heart with aberrant depolarization in the phrenic nerve that passes by the heart on its way to the diaphragm. The aberrant depolarization is enabled by increased phrenic nerve irritability that can be a result of hypocalcemia.² Primary hypoparathyroidism is not a rare cause of hypocalcemia in dogs, but it usually presents with other clinical signs. In the case reported here, SDF was the only clinical sign of the hypocalcemia and resolved when the hypocalcemia was corrected.

Case Report

A 3 yr old, spayed, female miniature schnauzer was presented to The Ohio State University Veterinary Medical Center for persistent, involuntary contractions across the costal arches and abdomen. The clinical signs started 4 days prior to the presentation and were first observed after a walk. The intensity of contractions increased during exercise and decreased with rest. The dog was lethargic with no other neurologic signs or abnormal behavior observed. The day before the development of the contractions, the dog had one episode of vomiting and diarrhea.

On physical examination, the dog was bright and alert with normal vital signs (heart rate 90/min, respiratory rate 20/min, and temperature of 38.1°C) and a regular heart rhythm. Spontaneous contractions of the abdominal wall and across the costal arches were observed, most pronounced on the left side (Supplementary Video I). The rate of the contractions coincided with the heart rate. Venous blood gas analysis and electrolytes on admission revealed hypocalcemia and hypomagnesemia (iCa⁺² 3.9 mg/dL, reference interval [RI] 4.9–5.8 mg/dL; iMg⁺² 0.98 mg/dL, RI 1.11–1.53 mg/dL) with normal acid-base parameters (pH 7.42, RI 7.38–7.48; base excess −5.1 mmol/L, RI −5.6–0.8, HCO₃ 19.6 mmol/L, RI 16.9–24.2). Thoracic radiographs showed a slight increase in cardiac silhouette size consistent with mild cardiomegaly or an individual variant. A single-lead surface electrocardiogram identified a normal heart rate (98/min); regular sinus rhythm; and normal PR (100ms), QRS (40ms), and QT (200ms) intervals. The ST segment was isoelectric. Continuous telemetric electrocardiogram monitoring over 18 hr confirmed normal sinus rhythm with no ectopy noted. A serum biochemistry panel revealed a total calcium concentration of 6.5 mg/dL (RI 9.3–11.6 mg/dL), phosphorus concentration of 6.1 mg/dL (RI 3.2–8.1 mg/dL), and an albumin concentration of 4.0 g/dL (RI 2.9–4.2 g/dL). Repeated venous blood gas analysis confirmed the presence of persistent hypocalcemia (iCa²⁺ 3.66 mg/dL). Echocardiographic examination revealed a structurally normal heart with mild tricuspid regurgitation. Serum cardiac troponin I concentration was normal (0.08 ng/mL, RI <0.11 ng/mL). Abdominal ultrasound revealed no significant abnormalities and SPEC cPL was within the reference range (171 ug/L, RI <200 ug/L). Fluoroscopic examination performed with the patient in sternal and left lateral recumbency showed intermittent, sudden contractions of the left diaphragmatic crus. These contractions were asynchronous with the respiratory pattern but synchronous with cardiac contractions (Supplementary Video II). The movement of the right diaphragmatic crus was normal.

The dog was treated with intravenous lactated Ringer's solution at the rate of 7 mL/kg/hr. Ten hr later the blood pH decreased slightly (7.39), ionized calcium concentration increased to 3.95 mg/dL, and clinical signs resolved. The dog was discharged with oral calcium supplementation (calcium carbonate 55 mg/kg q 12 hr per os [PO]) while results of the parathyroid hormone (PTH) concentration were pending.

Four days after discharge, the dog presented for reevaluation. The owners reported the return of the spontaneous, persistent abdominal contractions with periodic increase and decrease of the intensity. No episodes of vomiting or diarrhea were noticed and the dog's appetite was slightly decreased. Physical examination showed pronounced abdominal contractions. Ionized calcium remained persistently below the normal range (4.05 mg/dL). The dog was administered an intravenous bolus of 10% Calcium Gluconate (0.5 mL/kg over 5 min) leading to normalization of ionized serum calcium concentration (5.02 mg/dL) and termination of abdominal contractions. Fluoroscopic exam was repeated and compared to the previous study. The asynchronous contractions of the left diaphragmatic crus were less pronounced and less frequent. Mild asynchronous contractions of the right crus were also seen. A serum parathyroid panel (drawn at the first visit, 4 days earlier) showed low ionized calcium concentration (0.74 mmol/L, RI 1.25–1.45 mmol/L), PTH concentration (0.4 pmol/L, RI 0.5–5.8 pmol/L), and a normal 25-hydroxyvitamin D concentration (91 nmol/L, RI 60–215 nmol/L) consistent with the diagnosis of primary hypoparathyroidism. To further support this diagnosis, an ultrasound examination of the neck using a high frequency (18 megahertz) linear transducer was performed. No parathyroid glands were seen. Calcitriol treatment was initiated (0.02 mcg/kg q 12 hr PO) in addition to oral calcium carbonate.

On a recheck evaluation one wk later, the owners reported complete resolution of clinical signs. Ionized calcium was within the normal range (5.09 mg/dL) and fluoroscopy confirmed absence of the previously documented diaphragmatic flutter.

The dog represented 10 days later for polyuria and polydipsia due to ionized hypercalcemia (6.37 mg/dL, RI 4.9–5.8 mg/dL) despite previous discontinuation of calcium carbonate supplementation. The calcitriol dose was decreased to 0.016 mcg/kg q 12 hr PO and further rechecks showed normalization of ionized calcium and magnesium with no recurrence of clinical signs.

Discussion

To the authors' knowledge, this is the first report of diaphragmatic flutter secondary to hypocalcemia due to primary hypoparathyroidism in a dog. Six dogs were described in the English literature with spontaneous synchronous diaphragmatic contractions between 1955 and 1969, but calcium was not measured in these cases.^1,3,4 This condition seems to be extremely rare with reported occurrence of 4 out of 33,092 dogs leading to limited awareness among veterinarians and potential for misdiagnosis.¹ Clinical signs can be dramatic and easily misinterpreted as heart disease because the rhythmic contractions may look like forceful heartbeats. Moreover, the flutter-like phenomenon may easily be confused with a heart murmur on cardiac auscultation. Arrhythmias (secondary to hypocalcemia) can further increase the suspicion a primary heart disease, but they were not observed in our case. An arterio-venous fistula or a dissecting distal aortic aneurysm may appear similar due to its synchronicity with the beating heart.⁵

The etiology and pathophysiology of this rare condition is not fully elucidated. The diaphragmatic contractions are most likely related to electrical or mechanical stimulation of phrenic nerves.¹ Mechanical stimulation by the movement of the heart seems unlikely since this condition is usually transient and responsive to medical management. The most likely explanation is increased phrenic nerve irritability due to hypocalcemia and its stimulation by the cardiac action potentials.² An early report from 1911 described development of SDF for the first time in one dog after parathyroidectomy with a positive response to IV calcium administration.⁶ The more common clinical signs of hypocalcemia result from the increased excitability of the peripheral and central nervous system.⁷ Normal electrical depolarization activity in the heart causes aberrant depolarization in the phrenic nerve and results in stimulation of the diaphragm. Five out of the six dogs reported having SDF in the literature had a history of persistent vomiting. The authors hypothesized that subsequent alkalosis and hypocalcemia could have led to phrenic nerve irritability; however, no blood gas analyses were performed. Exploratory laparotomy was unremarkable in one dog. In the sixth dog, clinical signs developed after whole body trauma (hit by car) and ceased spontaneously after a few hours.

The diagnosis of this condition depends on documentation of the diaphragmatic contractions by fluoroscopic examination. The contractions can be bilateral, but, in the majority of dogs, they were lateralized to the left side, similar to our case. This is likely due to the anatomic variability of the right and left phrenic nerve course. The phrenic nerve arises from the fifth, sixth, and seventh cervical nerves.⁸ The right phrenic nerve crosses the body of the right auricle while the left phrenic nerve passes close to the right ventricle and over the base of the left ventricle. The proximity to both ventricles makes the left phrenic nerve more susceptible to the cardiac electric current stimulation (Figures 1, 2).

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Synchronous diaphragmatic flutter has been a well-recognized condition in horses for at least the past 180 years⁹. Hypocalcemia, hypokalemia, and metabolic alkalosis have been incriminated as likely contributors due to their effects on nerve irritability. The triggering condition causes loss of these electrolytes through lactation, stress, or sweat-provoking work.^10,11 Only one case of SDF due to primary hypoparathyroidism in a horse has been published.¹² The SDF in the horse occurs consistently at the time of atrial depolarization, while in dogs, SDF is synchronous with ventricular depolarization. The difference can be explained by a slightly different anatomic location of the phrenic nerves, which in horses are in contact exclusively with the atria rather than the ventricles.⁹ The condition commonly resolves with resting or after administration of calcium containing fluids.

Diaphragmatic flutter in people, also called Leeuwenhoek's disease, is a rare disorder first described in 1723 by Antony Van Leeuwenhoek when he was afflicted with this condition.¹³ Most of the cases in human literature describe diaphragmatic contractions unrelated to the heart beat.¹⁴ The causative pathophysiological mechanism in people is thought to be related to abnormal excitation of the phrenic nerve from a location distinct from that in animals. In people, the primary lesion can be localized in the central nervous system or caused by a direct irritation of the phrenic nerve along its path or irritation of the diaphragm. Direct irritation of the phrenic nerve or diaphragm can be caused by lung disease, pleurisy, peritonitis, fractured xiphoid process, cervical disc herniation, lymphoma, or lymphadenitis.^14,15 To the authors' knowledge, only one case report describes SDF occurring in hypoparathyroidism in a 7 yr old child with hypocalcemia.¹⁶ Causative disorders of the central nervous system include encephalitis, neoplasia, or non-organic conditions, such as psychogenic disturbances and anxiety.^14,15 Medical management of SDF in humans depends on the underlying condition, but may include anticonvulsant, antipsychotic, anxiolytic, and hypnotic medications.^17,18 Cases resistant to pharmacological therapy can be treated with phrenic nerve crush surgery.¹⁴

In previous reports of this syndrome, some dogs recovered spontaneously after fluid therapy with Lactated Ringer's solution and one dog was cured after a single dose of phenobarbital.³ It is difficult to prove the cause and effect relationship in the latter case. In the dog reported here, initial treatment with IV fluids resolved the clinical signs. Fluoroscopy was not performed at this time and it is therefore possible that subclinical contractions persisted and became more pronounced after discharge from the hospital. To prove the relationship between hypocalcemia and SDF, intravenous calcium was administered. Serum ionized calcium normalized promptly, and the clinical signs disappeared immediately after the administration. A fluoroscopic exam confirmed a marked decrease in the intensity of the contractions, but complete resolution was only observed one wk later after starting calcitriol in addition to the oral calcium supplement.

Conclusion

The diagnosis of primary hypoparathyroidism was confirmed based on measurement of PTH concentration and exclusion of other causes. Clinical signs of primary hypoparathyroidism in people typically include neuromuscular abnormalities similar to the clinical signs seen in dogs; however, other unusual signs are reported, such as bronchospasm, laryngospasm, and congestive heart failure.¹⁹ If the disturbance is chronic, even patients with remarkably low levels of ionized calcium may be asymptomatic due to their ability to adapt to low calcium levels. On the other hand, even a mild reduction in serum calcium concentration can lead to severe symptoms requiring intravenous calcium therapy. It is unknown why the dog described in this case report did not show other typical signs of hypocalcemia, but it may be speculated that chronicity of the condition or the only mild decrease in the calcium concentration observed may be contributing factors.²⁰