Iatrogenic neonatal hyperphosphatemia due to phosphate-containing enema

Background: Denosumab is a RANK-l inhibitor that, in addition to the treatment of osteoporosis, is used in patients with advanced cancer and metastatic bone disease to prevent skeletal-related events. Although denosumab is generally safe and effective, it can cause hypocalcemia which in some patients can be severe and life threatening. We present a case of severe prolonged hypocalcemia after a single dose of denosumab in a patient with metastatic prostate cancer. Case: A 78-year-old male with a past medical history of stage 4 prostate cancer on antiandrogen treatment with GnRH antagonist presented with severe hypocalcemia. Physical exam revealed a blood pressure 125/80 mm Hg, pulse 115 per min and weight 135 lb with negative Chvostek’s and Trousseau’s signs. The electrocardiogram showed supraventricular tachycardia with prolonged QTc interval of 503 ms (<430 ms). Labs showed serum calcium 4.9mg/dL (8.5–10.5), albumin 2.5g/dL (3.6–5.1), corrected calcium 5.7 mg/dL, ionized serum calcium 0.64mmol/L (1.05–1.3), creatinine 1.10mg/dL (0.7–1.2), eGFR >60, phosphorus 2.0mg/dL (2.5–4.5), magnesium 1.9 mg/dL (1.6–2.6), 25-OH vitamin D 29.7 ng/mL (30–100), 1,25 dihydroxy vitamin D 174 pg/mL (18–64), iPTH 244.0 pg/mL (11–68) and PSA 1860 ng/mL. Three weeks prior to presentation, the patient received 120 mg of subcutaneous denosumab. Pre-treatment serum calcium was 9.2 mg/dL (8.5–10.5), and Tc-99m bone scan showed multiple osteoblastic osseous metastatic lesions involving both axial and appendicular skeleton. The patient was diagnosed with denosumab-induced severe hypocalcemia and started on intravenous (IV) calcium gluconate infusion, oral phosphate 250 mg twice daily, and ergocalciferol 50,000 IU twice weekly. He required IV calcium gluconate up to 10 g per day in addition to oral calcium carbonate 2 g t.i.d. for 2 weeks to resolve hypocalcemia and normalize QTc interval. Patient was discharged to nursing home on calcium carbonate 2 g q.i.d. with IV calcium gluconate as needed to keep corrected calcium >8.0 mg/dL. After discharge he required up to 4 g of IV calcium and 8 g of oral calcium per day. Unfortunately, he presented again with severe hypocalcemia 5 weeks after discharge. In addition to current regimen of oral and IV calcium boluses, low dose calcitriol was started. We were only able to maintain his serum calcium>8.0 mg/dL by administering high daily dose of oral calcium carbonate 8 g /day and calcitriol 2 mcg daily. Due to poor prognosis, he was transitioned to hospice care and died 2 weeks later. Discussion: There are not many case reports on severe prolonged hypocalcemia secondary to denosumab in cancer patients but normal kidney function. Our patient remained on high dose of calcium even 101 days after denosumab administration. Reference: 1. Milat F et al. Prolonged hypocalcemia following denosumab therapy in metastatic hormone refractory prostate cancer. Bone. 2013 Aug 1;55(2):305–8.

Objectives Hypocalcemia following total thyroidectomy (TT) is relatively common. It may result in significant morbidity, prolonged hospital stay, and increased costs. Treatment with intravenous (IV) calcium gluconate may also carry significant risks. In pediatrics, management consensus guidelines are lacking. Methods At Phoenix Children's Hospital, a team of pediatric endocrinologists, surgeons and otolaryngologists developed a clinical pathway for patients undergoing TT. It was a Quality Improvement (QI) project with the primary aim of decreasing IV calcium gluconate use from a baseline of 68% to less than 40% over 15months. Secondary aims included reducing hypocalcemia and length of hospitalization. Interventions included sending weekly pathway reminder emails, starting pre-operative calcium, and pathway implementation into the electronic health record. Results Twenty-seven patients underwent TT over 15months. IV calcium gluconate use dropped to 48%. Hypocalcemia and length of hospitalization were 96% and 52.7h (range 21.1-115.7) respectively. Pathway adherence improved after targeted interventions. Eleven (73%) of the 15 patients whose post-operative parathyroid hormone (PTH) nadir was below 15pg/mL required IV calcium gluconate vs. two (17%) out of 12 with levels above this threshold. Conclusions Standardizing care allowed for objective outcome analysis. We learned that post-operative serum PTH level was the main risk factor for requiring IV calcium gluconate. Implementing the pathway as a QI project allows for revisions based on outcomes, ultimately resulting in a pathway that best utilizes our infrastructure to optimize care. Other pediatric institutions may face similar challenges and can potentially learn from our experience.

A 3-month-old infant presented to the pediatric emergency department with respiratory distress and tetany after ingestion of a phosphate-containing oral laxative. The initial phosphorus level was 38.3 mg/dL. With aggressive fluid resuscitation and intravenous calcium administration, the infant completely recovered. Although the risks of phosphate-containing enemas are well described, life-threatening hyperphosphatemia can also result from administration of phosphate-containing oral laxatives. Aggressive fluid hydration is the mainstay of treatment. Intravenous calcium administration may be necessary to avoid hemodynamic collapse despite the theoretical possibility of metastatic calcifications. Physicians should be alerted to the possibility of phosphate toxicity and hypocalcemic tetany in young children when treated with over-the-counter laxatives. Caregivers should be advised not to administer over-the-counter laxatives to infants without physician supervision.

Patients often present with advanced chronic kidney disease (CKD) complicated with severe hypocalcemia that may be accompanied by electrocardiographic changes. The management of this kind of patients may require hemodialysis (HD). However, initiation of renal replacement therapy in this scenario needs special attention to avoid complications such as cardiac arrhythmias. A 22-year-old male presented to our emergency department with severe renal failure, hypocalcemia, hyperphosphatemia, severe acidosis, and QT prolongation on electrocardiography. The patient was kept in the emergency department under cardiac monitoring. He was started on IV calcium gluconate 1 g every 6 h aiming to increase his adjusted calcium level to 1.8 mmol/L. He subsequently received the first HD session with low blood flow, increased calcium, and decreased bicarbonate dialysate bath. There were no arrhythmias or hemodynamic instability. Intravenous calcium was discontinued; adjusted calcium improved progressively after dialysis and reached 1.9 mmol/L by the time of discharge and after receiving three sessions of HD. This case describes a not so infrequent presentation of advanced renal impairment with profound hypocalcemia, hyperphosphatemia in the setting of CKD-associated mineral bone disorder. Intravenous calcium administration may promote vascular and metastatic calcification, particularly with the coexistence of hyperphosphatemia, and hence, it is best avoided. There are no guidelines to direct initiating HD in this context. However, it appears that using a high calcium bath is prudent to minimize cardiovascular complications, particularly if there is the prolongation of the corrected QT interval on electrocardiography.

Clinical and hemodynamic effect of intravenous calcium administration in cardiac surgery: A systematic review.

A patient with prolonged QTc interval, paroxysmal ventricular tachycardia, and syncope was studied. Her syncopal episodes were often precipitated by stress or unexpected stimuli. Neurological evaluation showed no abnormalities. Right and left stellate ganglion blockade and intravenous atropine, calcium gluconate, and digoxin did not shorten QTc-interval duration. Ventricular pacing and intravenous phenobarbital suppressed ventricular tachyarrhythmias. Sodium diphenylhydantoin (Dilantin Sodium®) produced QTc shortening and controlled ectopic rhythms. Neural influence on synchrony of ventricular repolarization may predispose to the paroxysmal arrhythmias associated with this syndrome. Central nervous and asymmetrical cardiac sympathetic nervous stimulation may produce an increase in temporal dispersion of repolarization and a prolonged refractory period, thus facilitating reentrant rhythms and tachyarrhythmias. Sodium diphenylhydantoin shortens repolarization and effective refractory period and increases the conduction velocity of ectopic ventricular impulses, reducing temporal dispersion and suppressing reentrant rhythms. QT-prolongation syndromes are potentially lethal and may account for a number of cases of "atypical epilepsy."

The standard treatment of hypoparathyroidism is to control hypocalcemia using calcitriol and calcium supplementation. However, in severe cases this approach is insufficient, and the risks of intravenous (i.v.) calcium administration and prolonged hospitalization must be considered. While the use of recombinant human parathyroid hormone 1-34 [rhPTH(1-34)] for long-term control of hypocalcemia has been established, the benefits of short-term rhPTH(1-34) treatment in children have not been explored. We report two patients with hypoparathyroidism treated with rhPTH(1-34). Patient 1 is a 10-year-old female with polyglandular autoimmune syndrome type 1. Patient 2 is a 12-year-old female with hypoparathyroidism after total thyroidectomy. Both patients showed poor response to i.v. and oral calcium and calcitriol, and patient 1 did not respond to phosphate binders. Patient 1 had rapid increase in serum calcium with a decrease in serum phosphate after a 3-day course of subcutaneous rhPTH(1-34). Patient 2 had normalization of calcium and phosphate levels after a 7-day course of rhPTH(1-34). These cases support a role for rhPTH(1-34) in the acute management of hypoparathyroidism in hospitalized patients to more rapidly correct hypocalcemia and hyperphosphatemia, shorten hospitalization, and reduce the need for frequent i.v. calcium boluses.

Background: Resuscitation from hypoxic cardiac arrest presenting with pseudo-electromechanical dissociation (P-EMD) may be associated with hypotension after ROSC. This hypotension may be refractory to catecholamine pressors. Reversing hypotension is critical for stabilizing patients successfully resuscitated from P-EMD, so other therapeutic avenues should be explored. Hypothesis: The post-resuscitation phase after hypoxic pseudo-EMD cardiac arrest may be associated with hypocalcemia. The refractory hypotension may be responsive to intravenous calcium. Methods: Using our hypoxic pseudo-EMD swine model, we measured blood pressure, hemodynamics, and electrolytes after ROSC. In 12 animals with refractory hypotension we administered 37 boluses of intravenous calcium in the dosage range of 5 -20 mg. Physiological data were analyzed on a heartbeat by heartbeat basis. The midpoint of the calcium response was defined using change of curvature feature detection. Hemodynamic parameters were shifted such that the value at the midpoint was equal to zero. Comparisons were made between the average values in the time period 40-35 seconds before the bolus and 35-40 seconds after the bolus. Results: Of the 37 administered boluses, 34 manifested a reaction in the aortic blood pressure. Mean aortic pressure, systolic and diastolic pressures all increased due to the calcium bolus. Aggregating the timepoints in the range -40 s to -36 s and comparing with the timepoints in the range 36 s to 40 s shows that the mean aortic pressure increased 11.2 ± 0.6 mmHg, the systolic pressure increased 16.2 ± 0.8 mmHg, and the diastolic pressure increased 8.0 ± 0.5 mmHg. Conclusions: Resuscitation from hypoxic pseudo-EMD is often associated with hypotension and hypocalcemia. Administration of intravenous calcium is associated with an abrupt pressor-like response. Calcium as a therapeutic in this setting should be further studied.

BackgroundCalcinosis cutis is a rare condition, characterized by an accumulation of calcium salts in the skin and subcutaneous tissue. There are several types of this condition, including dystrophic, metastatic, idiopathic, calciphylaxis, and iatrogenic calcinosis cutis. The type related to our case is iatrogenic calcinosis cutis, and one its possible causes is calcium intravenous infusion. Physicians should be aware of this condition when giving calcium infusion.Case presentationHere we report the case of a 9-month-old Arabic - Saudi baby boy, who presented with abnormal movement for 1 day. Upon further investigation, his abnormal movement was found to be a manifestation of hypocalcemia and vitamin D deficiency. He was treated with intravenous calcium gluconate. Later, he had a treatment-related complication of intravenous calcium at the site of venipuncture causing swelling, which was initially soft but progressed to hard, over the left hand. Eventually, he was diagnosed with a case of iatrogenic calcinosis cutis due to intravenous calcium treatment.ConclusionThere are multiple differential diagnoses of calcinosis cutis, as it resembles many other conditions. Careful history-taking, physical examination, and other investigations, such as radiological investigations, will aid in reaching a more accurate diagnosis and, thus, early treatment and intervention. Frequently checking the intravenous line and diluting the intravenous calcium may help reduce the occurrence of iatrogenic calcinosis cutis.

Effect of prophylactic intravenous calcium gluconate on uterine atony during intrapartum cesarean delivery with spinal anesthesia: a placebo controlled, randomized clinical trial.

Verapamil is a useful drug in supraventricular tachycardias, atrial flutters, and fibrillations. However, its usage is accompanied by an undesirable side effect of hypotension. This limits its usage in patients where even the slightest reduction of blood pressure for a brief period may prove detrimental, e.g., in patients with critical coronary artery disease. Intravenous calcium given as pretreatment to verapamil prevented verapamil-induced hypotension. Its usage after hypotension restored the blood pressure to its baseline level. All these occur without the loss of the antiarrhythmic effect of verapamil. Furthermore, the pharmacokinetics of verapamil is unaltered in patients with chronic kidney disease. Thus, no dosage adjustment is required in this population. Here we describe a case of verapamil-induced hypotension in a patient with end-stage renal failure, which was reverted with intravenous calcium administration without altering the atrioventricular blockade effect of verapamil.

Chapter 52 - Treatment of Hypoparathyroidism

Background Calcinosis cutis involves the deposition of calcium salt in the subcutaneous tissues and skin. This is commonly linked to connective tissue disorders or damaged tissues with normal or abnormal calcium/phosphorus metabolism. Iatrogenic cases are also there though rare. Case Descriptions Two male neonates born late preterm presented at 20 days (Case 1) and four weeks (Case 2), with firm linear erythematous swellings over extremities. Both neonates had a neonatal intensive care unit (NICU) stay after the birth for prematurity-related issues. Both were administered intravenous calcium during their NICU stay. There were no swellings at the time of discharge in both neonates. Radiologically, both cases had calcification around the tibia and fibula (Case 1) and deposits in the right upper limb (Case 2). Both cases had normal calcium profiles and a negative sepsis workup. Both neonates improved clinically and radiologically on conservative management. Management and Follow-up Both cases were managed conservatively. Follow-up after three months showed complete resolution in Case 1 and partial resolution in Case 2. Regular monitoring is crucial for assessing progress. Conclusion Iatrogenic calcinosis cutis can arise from intravenous calcium administration and is generally self-limiting. Healthcare providers must be aware and careful in following up to manage and monitor this condition effectively.

Exchange blood transfusion (EBT) is a form of whole blood transfusion in which the total blood volume is replaced within a few hours. In perinatal and neonatal medicine, EBT is most often used in the management of severe anaemia or severe hyperbilirubinaemia in the first week of life. Hypocalcaemia, one of the common morbidities associated with EBT, is thought to arise from the chelating effects of the citrate commonly used as an anticoagulant in the donor's blood. This disorder manifests with muscular and nervous irritability and cardiac arrhythmias. To determine whether the use of prophylactic calcium reduces the risk of hypocalcaemia-related morbidities and death among newborn infants receiving EBT. We used the standard search strategy of the Cochrane Neonatal Review group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 5), MEDLINE via PubMed (1966 to 29 June 2016), Embase (1980 to 29 June 2016), and CINAHL (1982 to 29 June 2016). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. All randomised and quasi-randomised trials of prophylactic intravenous calcium in EBT for newborns. Two review authors independently assessed and extracted data on methods, participants, interventions, and outcomes (mean total and ionised serum calcium before and after EBT and the presence of adverse events such as hypoglycaemia, apnoea, cardiac arrest, and death immediately after EBT). We reported results as means difference (MD) with 95% confidence intervals (CI) for continuous outcomes and risk ratio (RR) and risk differences (RD) and 95% CIs for dichotomous outcomes. We assessed quality using the Cochrane 'Risk of bias' assessment tool and the GRADE system. We found only one quasi-randomised trial with 30 participants that met our inclusion criteria. In the small trial, total and ionised serum calcium levels were measured immediately before and immediately after EBT. All the participants were included in the final analysis and all the important outcomes were reported. Primary outcomesThere was one death in each group (RR 1.00, 95% CI 0.07 to 14.55; RD 0.00, 95% CI -0.18 to 0.18; participants = 30; studies = 1). The study did not report the presence of cardiac arrhythmias within one week of EBT and the number of infants with serum calcium levels (total less than 8 mg/dL (2 mmol/L) or ionised less than 4.4 mg/dL (1.1 mmol/L)).Pair-wise comparison of EBT with intravenous 10% calcium gluconate versus EBT without intravenous calcium (change from baseline) showed mean total serum calcium was raised in the intervention group compared to the control group (MD -0.46, 95% CI -0.81 to -0.11; participants = 30; studies = 1). Very low-quality evidence also indicated an increase in the levels of mean ionised serum calcium in the intervention group compared to the control group (MD -0.22, 95% CI -0.33 to -0.11; participants = 30; studies = 1). Secondary outcomesAdverse reactions to intravenous calcium therapy included cardiac arrest in one neonate in the intervention arm (RR 3.00, 95% CI 0.13 to 68.26; RD 0.07, 95% CI -0.10 to 0.23; participants = 30; studies = 1). There was apnoea and hypoglycaemia (RR 1.00, 95% CI 0.07 to 14.55; RD 0.00, 95% CI -0.18 to 0.18; participants = 30; studies = 1) in the two neonates who died. Data were not available for other major secondary outcomes such as the number of infants with reduced serum magnesium, reduced parathormone, increased calcitonin, presence of seizures, carpopedal spasm, jitteriness and prolonged QTc interval on electrocardiography within one week of EBT. Very low-quality data from one quasi-randomised controlled trial suggested that the mean serum total and ionised calcium increased in the study group but decreased in the control group immediately after EBT. However, the mean values of total and ionised calcium in both arms of studies remained within international reference ranges. Unfortunately, data were not available to assess the trend of total and ionised serum calcium to the end of the first week after EBT. Therefore, due to the very low quality of evidence available, it is difficult to support or reject the continual use of prophylactic intravenous calcium in newborn infants receiving EBT. Researchers are encouraged to conduct more robustly designed trials with larger numbers of participants, and particularly, addressing the pattern of differences based on gestational age of participants, type of anticoagulant used, and the volume of blood used.

An Infant with Recurrent Hypocalcemic Seizures.