Neonatal Calcinosis Cutis After Treatment of Hypocalcemia with Calcium Gluconate: A Report of 2 Cases

Introduction

Calcinosis cutis was first identified by Rudolf Virchow in 1855 [1]. It is a rare disease involving skin and subcutaneous tissue deposition of calcium and phosphate hydroxyapatite crystals [1]. Incidence and frequency data are unavailable in the United States [2,3]. Dystrophic calcinosis cutis is the most common type [2,3]. No sex predilection has been documented [2,3]. The pathogenesis includes multiple failed trials of venous or arterial access insertion, leakage of blood trans-fusion or fluid replacement into the adjacent skin or subcutaneous tissues, and transient increase of calcium level in blood or adjacent tissue, or it can be idiopathic [4]. Calcium gluco-nate is used to treat neonatal hypocalcemia, severe hyperkalemia, and neonatal convulsions [5]. Neonatal iatrogenic calcinosis cutis is mostly seen in the neonatal intensive care unit (NICU) after leakage of calcium gluconate infusion in subcutaneous tissues [1]. There are a few reports in the literature of neonatal calcinosis cutis secondary to calcium gluconate infusion [6–8]. Cherian et al reported a case of iatrogenic calcinosis cutis in a 3-week-old neonate who was diagnosed with hypocalcemia in the NICU, and the hypocalcemia was treated with peripheral calcium gluconate infusion. After 2 weeks, he developed calcinosis cutis in his leg, which was treated conservatively [6]. Chen et al presented a case of a neonate who was diagnosed with calcinosis cutis secondary to leakage of an intravenous calcium gluconate infusion. The case was complicated with a devastated compartment syndrome that required urgent surgical fasciotomy [7]. Pu et al retrospectively analyzed 16 neonates with calcinosis cutis caused by calcium gluconate extravasation during management of hypocalcemia and hyperkalemia. They reported successful results with symptomatic supportive management without negatively affecting the extremity’s function [8]. Furthermore, generalized and localized forms of calcification have been reported in the literature secondary to calcium gluconate infusion to manage hypocalcemia. The clinical and radiological resolution of calcinosis cutis in both cases were achieved without any surgical intervention [9,10]. This report presents 2 cases of neonatal calcinosis cutis following treatment of hypocalcemia with calcium gluconate.

Case Reports

CASE 1:

A 12-day-old male neonate presented to the emergency room (ER) with right foot mass and redness for 3 days. The patient was 39 weeks’ gestation of a healthy gravida 3, para 2 mother post-cesarean-section delivery because of cephalopelvic disproportion. His birth weight was 3.6 kg, and his Apgar score was 7, with good perfusion and tone. Then, he was admitted for 5 days into the NICU to manage newly-developed seizures with anticonvulsant medication. Afterward, the seizures were discovered to be secondary to a subdural hematoma, for which the neurosurgery team did surgical evacuation. He was discharged in good condition from the hospital at age 8 days. Later, he was brought to the ER after the family noticed a mass in the right foot for the last 3 days. There was no history of fever or trauma at home. During physical examination, the patient had swelling in the right foot just anterosuperior to the medial malleolus. It was hard, round, and measured 1×1 cm. The overlying skin was erythematous but there was no open wound or skin discharge (Figure 1A). The mass was not mobile with a full range of motion at the right ankle, but there was no tenderness. His radiographs showed medial foot and ankle soft tissue calcification (Figure 1B, 1C).

Laboratory test results were within normal ranges; thus, the cause of the foot mass was unclear. A few hours later, after reviewing the patient’s clinical data from the NICU records, it was found that the patient had received 2 peripheral IV infusions of 10% calcium gluconate at a dose of (400 mg/kg), each infusion administered over a 10-min period, in his right saphenous vein to manage hypocalcemia during his previous NICU admission. There was mild skin erythematous reaction around the injection site noticed immediately after the injection. The diagnosis of iatrogenic calcinosis cutis was confirmed based on these clinical data and radiological findings.

The management plan was primarily conservative treatment with topical 2% corticosteroid cream and home observation for any change in mass size, color, or overlying skin breakdown. The patient’s family was informed about the risk of ulcers or infection over the mass, and a 1-week follow-up appointment was scheduled. At the second visit, there were no clinical signs of skin necrosis or infection, and a new radiograph was performed, which showed increased soft tissue radiological calcification (Figure 2). The family was informed about the result and agreed to symptomatic treatments. A 1-month appointment was schedule, but the family did not show up because they lived far away. A telemedicine appointment was arranged at that time, and the mother reported full resolution of the swelling 3 weeks later.

CASE 2:

A 1-month-old female infant was admitted under Pediatric Pulmonology, then was referred to Orthopedics because of swelling in her left leg. She was born at 36 weeks of gestation to a healthy, gravida 2, para 1 mother. She was delivered by cesarean section because of abruptio placenta. Her birth weight was 3 kg, and her Apgar score was 8, with good perfusion and tone. The patient was originally diagnosed with cystic fibrosis and was admitted to the NICU at another hospital for 5 days because of meconium ileus and electrolyte imbalance. Then, she was transferred to the Orthopedic Surgery Department, College of Medicine, University of Jeddah to manage meconium ileus through an exploratory laparotomy followed by NICU admission.

Clinical assessment of the patient revealed no recent history of fever or trauma to the left leg. Physical examination showed a swelling of the left foot and lower leg antero-medially. It measured 5×2 cm, was hard in consistency, and the overlying skin was free (Figure 3A). The mass was not mobile. She had full range of motion of the left ankle. A radiograph was performed, and results revealed calcification in the left leg and ankle (Figure 3B, 3C).

The laboratory test results were within normal ranges; therefore, the cause for the foot and leg swelling was ambiguous. We requested the patient’s parents provide a medical report from the medical facility where the patient had recently been hospitalized. Two days later, the parents brought in the medical report, which showed that their neonate had received 3 doses of 10% calcium gluconate at a dose of 600 mg/kg each infusion administered over a 15-min period in the left saphenous vein to manage hypocalcemia during her last hospitalization. There was a small area of skin erythema and mild swelling around the injection site noticed immediately after the injection, which was managed with local corticosteroid cream. The diagnosis of iatrogenic calcinosis cutis was confirmed based on the medical history, clinical assessment, and radiological results.

The patient was managed with symptomatic treatments and observation. The patient’s parents were informed about the nature of the disease and the management plan. The patient was followed daily while she was hospitalized to look for any complications such as skin ulceration or infection. She continued to have local corticosteroid cream applied on the area of swelling for 10 days. Before discharge from the hospital, a 1-month follow-up appointment was scheduled to check on her lower-extremity swelling. At the 1-month follow-up, the left ankle and foot examination showed almost complete disappearance of the swelling without any skin ulceration or necrosis. A radiograph showed that the calcification was almost completely resorbed (Figure 4).

Discussion

We report 2 rare cases of neonatal calcinosis cutis following treatment of hypocalcemia with calcium gluconate. In the present report, extravasation of the calcium gluconate into the skin’s soft tissue resulted in peripheral localized masses and erythema that mimic several differential diagnoses. Meticulous review of the patient’s medical history, clinical examination, and radiographic investigations helped to achieve accurate early diagnosis and management. This report emphasizes the need for careful observation of neonates managed with IV calcium gluconate infusion, who may develop skin erythema or swelling secondary to calcinosis cutis.

Calcinosis cutis can be 1 of 5 types [6]:Dystrophic calcinosis cutis is the commonest type. It appears at injured skin or subcutaneous tissues, with ordinary ratio of blood calcium and phosphorus [6].Metastatic calcinosis cutis arises at healthy skin or subcutaneous tissues, with an abnormal ratio of blood calcium and phosphorus [6].Iatrogenic calcinosis cutis is a rare disorder that is most common in neonates and children exposed to recurrent failed trials of venous or arterial access insertion in their peripheral limbs at critical care units. The pathogenesis involves injection and leakage of calcium or phosphate comprising medicines or solutions into the skin or adjacent subcutaneous tissues [6].Calciphylaxis develops secondary to hypersensitivity of the skin or surrounding subcutaneous layer, causing calcium deposition in the minute blood vessels following exposure to specific chelating materials [6].Idiopathic calcinosis cutis is diagnosed only when none of the above causes is identified [6].

The clinical presentation of both cases in our report was almost identical. They presented with a solitary localized foot and ankle mass identified a few days after the infusion of IV calcium gluconate. This clinical presentation was similar to that reported by Alghaith et al, but the mass in their report was in the upper limb [10]. Pu et al found that among 16 neonates with calcinosis cutis, the foot and ankle was the most common site for development of a nodule or swelling following IV infusion of calcium gluconate [8]. Puvabanditsin et al reported an unusual clinical presentation of an infant diagnosed with iatrogenic calcinosis cutis after receiving prolonged IV calcium gluconate therapy to manage hypocalcemia. Their patient had a generalized form of calcinosis cutis that presented as multiple nodules and erythema over the trunk, arms, legs, and face [9].

The 2 cases in the present report had similar clinical courses, and both had been admitted to an NICU. This agrees with a case series of 5 cases of neonatal iatrogenic calcinosis cutis reported by Pacheco et al [11], showing that 55% of the cases were patients admitted to the NICU. However, they found that the most common sites for this lesion are on the wrist and hand [11]. Hypocalcemia is a disorder usually treated with IV calcium in the NICU using a saphenous vein route, which can lead to extravasation of calcium to surrounding tissue and can cause iatrogenic calcinosis cutis [7]. In addition, the neonates had multiple needle pricks, which possibly contributed to development of the disease [8].

The challenge in our 2 cases was accurate diagnosis, since both patients presented with local inflammatory signs that can easily be mistaken for abscess, cellulitis, septic arthritis, myositis ossificans, osteomyelitis, periostitis, or thrombophlebitis [8]. This was the situation in many case reports and series in the literature, leading to unnecessary administration of antibiotics or exposing the patient to avoidable surgical interventions [6–11]. When obtaining the medical history of these 2 cases, it was important to rule out any history of fever or trauma to narrow down the differential diagnosis, since fever can be associated with infection. Moreover, the development of a mass or swelling in a neonate following any trauma suggests the possibility of musculoskeletal injury as a definitive diagnosis. Therefore, it is imperative to correctly diagnose this condition to avoid ordering unnecessary laboratory or radiological investigations and maladministration of antibiotic therapy. The diagnosis mainly depends on detailed history (eg, previous NICU admission), clinical examination (eg, a hard mass), and calcification seen on radiographs [10]. The pathological effect of the iatrogenic extravasation of calcium gluconate in our 2 cases were in the mild stage. Early diagnosis of this disease would have saved the patients and medical facilities the cost of unnecessary interventions.

The clinical course in the cases reported by Arora et al revealed that the mean time between fluid administration and manifestation of the mass was 13 days, with a range of 2 h to 24 days [12]. The administered calcium-containing fluids are radiolucent; therefore, radiographs performed 1–3 weeks after injection of the fluid could reveal calcification in the skin or surrounding tissue layers [12]. This matches both cases in the present report regarding the clinical course and the time frame of discovering the swelling and visualizing the calcification by radiography. However, this disease can lead to serious complications, such as pain and desquamation of the dermis with superimposed infection [8]. Therefore, such patients are often exposed to multiple investigations and advanced interventions to identify the cause of any vascular occlusion [8]. Chen et a. reported a case of a neonate diagnosed with calcinosis cutis, who developed compartment syndrome after leakage of IV calcium gluconate infusion [6]. In most reported cases, gradual disappearance of tissue calcification happens without any specific intervention at 8 weeks from the commencement of the disease to 6 months, when the calcification entirely dissolves [7–12].

There are currently no standardized protocols or guidelines to manage iatrogenic calcinosis cutis [8]. In the present cases, observational and symptomatic management with local corticosteroids cream was sufficient, which is similar to the management plans in other case reports in the literature [9,10]. However, there are few reports or case series in the literature that divide the management into different stages according to the severity of the disease [8]. Pu et al proposed to manage simple stages of iatrogenic calcinosis cutis secondary calcium gluconate extravasation with conservative treatment that includes removal of the IV cannula and elevation of the affected limb, local cold or hot compression, local or systemic antibiotics, and local or systemic use of corticosteroids [8]. They also recommended using these measures for patients at advanced stages, with addition of local hyaluronidase or sodium thiosulfate IV injections [8]. Needle aspiration of the calcified mass was also suggested for advanced-stage patients to reduce the pressure effect and minimize skin necrosis [8].

Medical treatments for this condition tend to have inconsistent effects, but intralesional corticosteroids could be advantageous due to their anti-inflammatory action and suppression of fibroblast function [3]. Diltiazem, a calcium channel blocker, has also shown a variable effect in the management of calcinosis cutis [14]. Myo-inositol hexaphosphonate is a dietary substance that plays a role in inhibition of calcium crystallization, as demonstrated in animal studies, making it possibly beneficial to humans [15]. Intravenous sodium thiosulfate is used in the management of calciphylaxis [16]. Furthermore, electric shock wave lithotripsy was shown to be a successful treatment for calcinosis cutis associated with dermatomyositis and scleroderma [17]. Surgical interventions can be an option in case of persistent pain, ulcer or abscess formation, recurring infection, and functional disability [7,8]. However, the soft tissue damage from the surgical treatment itself could enhance the calcification process [7,8].

Preventive measures to avoid iatrogenic calcinosis cutis in clinical practice should be applied at neonatal medical facilities, especially in NICUs. This should include education and awareness of the medical teams regarding complications and early reporting of any sign of extravasation of calcium solution [7]. Moreover, oral calcium supplement could be utilized, when possible, instead of IV calcium gluconate in case of hypocalcemia to reduce the risk of iatrogenic calcinosis cuties [9]. If IV calcium gluconate is used, then the rate of administration should be less than 2 mL/min without adding any anions such as sulfate, bicarbonate, or phosphate, which increase calcium precipitation [9]. The IV canula sites should be consistently alternated and checked frequently for any canula malposition or blockage before starting IV calcium administration [9]. Finally, starting acute simple interventions such as removal of the IV canula, extremity elevation, cryotherapy followed by heat treatment, and compressive dressing could reduce the possibility of large mass formation [7].

Conclusions

This report has highlighted the importance of monitoring neonates treated with calcium gluconate, who may develop skin rashes or nodules due to calcinosis cutis.