Mir Mohammad Yusuf*
Assistant Professor, Critical Care Pediatric, Bangladesh Institute of Child Health (BICH), Dhaka Shishu (Children) Hospital, Bangladesh
*Corresponding Author: Mir Mohammad Yusuf, Assistant Professor, Critical Care Pediatric, Bangladesh Institute of Child Health (BICH), Dhaka Shishu (Children) Hospital, Bangladesh.
Received: December 17, 2019; Published: December 26, 2019
Citation: Mir Mohammad Yusuf. “Hypocalcemia in Neonates: A Significant Concern ”. Acta Scientific Paediatrics 3.1 (2020):39-44.
Hypocalcemia is frequently observed clinical and biochemical abnormality in neonates. In this population, however, the diagnosis of hypocalcemia is complicated by limitations in the interpretation of the total plasma calcium concentration. These limitations are principally the result of the effects of hypoalbuminemia and disorders of acid-base balance on the total calcium concentration. Thus, measurement of ionized calcium must be essential in determining an individual’s true serum calcium status. Small changes in ionized serum calcium levels are poorly tolerated. It is responsible for initiating neuromascular action potentials and is involved in many of the cellular enzymatic reactions as cofactor. Ionic calcium is also crucial for other biochemical process including blood coagulation and cell membrane integrity. Healthy term neonates undergo a physiological nadir in serum calcium levels by 24-48 hours of age. This nadir may drop to hypocalcemia levels in high risk neonates including prematures, infants of diabetic mothers and infants of perinatal asphyxia. This early onset hypocalemia which presents within 72 hours.
Hypocalcemia in this period generally asymptomatic; screening for hypocalcemia at the 24th and 48th hour after birth is warranted for neonates with high risk of developing hypocalcemia and requires treatment with calcium supplementation for at least 72 hours. In contrast, late onset hypocalcemia- which is generally symptomatic, develops after the first 72 hour and toward the end of the first week of life. Babies with this disorder occurs not in preterm. Term babies having excess phosphate intake, hypomagnesemia, hypoparathyroidism, vitamin D deficiency are commonest causes of late onset hypocalcemia and requires longer term therapy. Hypocalcemia in neonates may have apnea, hypotonia, tachycardia, tachypnea, poor feeding, jitteriness, tetany and/or seizures. In this review, we first describe the regulation of normal calcium metabolism and then focus on the various etiologies of hypocalcemia, which are encountered in the neonatal care settings. The approach to the treatment of hypocalcemia and the current consensus on treatment of hypocalcemia in neonates is also presented.
Keywords: Hypocalcemia; Neonates; Calcium Therapy
Calcium has widespread extra and intracellular actions, including effects that influence hormone secretion and responsiveness, enzyme activity, nerve conduction, muscle contraction, membrane potential. In addition, calcium plays a structural role as a component of the mineralized matrix of bone. Although a highly regulated system exists to maintain to extracellular concentrations of ionized calcium within narrow physiological range, hypocalcemia is common in pediatric critically ill patients [1-3]. However, obvious metabolic defects in the hormonal control of calcium homeostasis (such as hypoparathyroidism or vitamin D deficiency) or physicochemical disturbances such as massive transfusions precipitating atric patients. More frequently, the precise basis for hypocalcemia is unknown. For instance, hypocalcemia is common in sepsis [4-6], and when circulating cytokines that accumulate during sepsis can impair parathyroid hormone secretion [7,8]. In this article, we provide the guiding principles of calcium hemostasis and describe our current understanding of the pathophysiology of hypocalcemia in the critically ill paediatric patient.
The majority (99%) of total body calcium is stored in bone as (1) hydrtoxyapatite crystals and (2) to a lesser extent, as noncrystaline, readily mobilizeable calcium salts. The remainder resides within extracellular fluids and soft tissues. At normal serum protein concentrations, approximately 50% of total serum calcium is in ionized form, biologically active (Ca2+). An additional 8% to 10% is complexed to organic and inorganic acids (eg, citrate, sulphate, and phosphate).
The remaining 40% of serum calcium is protein-bound, primarily to albumin (80%) and also to globulins (20%) and is not biologically active [9]. Changes in the ionized component of serum calcium are responsible for symptoms related to hypocalcemia. Increases in extracellular fluid concentrations of anions such as phosphate, citrate, bicarbonate, or edetic acid, will chlelate calcium and decreases the concentrations of ionic calcium but will not affect the total calcium concentration. Similarly, an alkaline pH will reduce the Ca2+ via an increase in the affinity of albumin for calcium, without altering the total serum calcium. Acidosis has the opposite effect.
Free fatty acids also enhance the binding of calcium to albumin [10]. Overall calcium homeostasis is controlled by a complex feedback system. Parathyroid hormone directly targets the bone resorption and renal calcium reabsorption and indirectly by stimulating renal 1-ᾳ hydroxylase, the rate-limiting enzyme in vitamin D activation, to convert 25-hydroxyvitamin D into calcitrol. Renal tubules typically resorb about 99% of filtered calcium in the cortical portion of the thick ascending limb. parathyroid hormone and calcitrol regulate active transport by increasing activity and/ or expression of multiple calcium transport proteins in the distal nephron [11].
During intrauterine life, the fetus acquires calcium via placental transfer that involves both active and passive diffusion. As a result cord blood calcium level is 1 meq/litre higher than maternal concentration. The fetus acquires 80% of its calcium in the last trimester of pregnancy and the accretion rate averages 100-150 mg/kg/ day.
The normal serum calcium concentration in children lies between 9.9 to 10.1 mg/dl, the corresponding levels for iomnized calcium being 4.4 to 5.1 mg/dl. Lower values are seen in normal neonates. Healthy term neonates undergo a physiological nadir in serum calcium levels by 24-48 hours of age. This nadir may drop to hypocalcemia levels in high risk neonates including prematures [12], low birth weight [13], infants of diabetic mothers and perinatal asphyxia [14]. This early onset hypocalemia which presents within 72 hours. Hypocalcemia in this period generally asymptomatic; screening for hypocalcemia at the 24th and 48th hour after birth is warranted for neonates with high risk of developing hypocalcemia and requires treatment with calcium supplementation.
Early neonatal hypocalcemia, which occurs within first 3 days of birth, arises from inadequate secretion of PTH by immature parathyroid glands [15] and/or inadequate responsiveness of the renal tubule cells to PTH. Risk factors include prematurity [12], diabetes mellitus mother [13] and asphyxiated neonates [14]. A more severe form of transient neonatal hypoparathyroidism occurs born to mothers with hypercalcemia [16]. Neonatal hypocalcemia that occurs after the first 3 to 5 days of life classically arises from an excessive phosphate intake in infants who are fed cow’s milk or cow’s milk-based infant formulas [17]. The ensuing hyperphosphatemia leads to hypocalcemia. Transient hypoparathyroidism may also manifest during this time. Less commonly maternal.
Hypercalcemia [16], congenital defects in PTH production, secretion, or action, and specific magnesium deficiency disorders can cause neonatal hypocalcemia. When hypocalcemia is severe, neonates may having laryngospasm. Localized or generalized seizures as well as more vague symptoms as hyperirritability may also occur. Hypocalcemia delays ventricular depolarization and prolongs the Q-T and ST intervals on the ECG and rarely, a reversible form of congestive cardiac failure may develop. Neuromuscular irritability is the hallmark of hypocalcemia and manifests as neonatal tetany.
Congenital defects in parathyroid gland development may be isolated or, more commonly, occur in association with other developmental defects. In particular, syndromic hypoparathyroidism must be considered if with congenital heart defects and immune defects or during intercurrent illness. The most common cause of congenital hypothyroidism is the DiGeorge sequence, also known as velocardiofacial syndrome. The complete DiGeorge sequence refers to the triad of congenital absence of the thymus, congenital hypoparathyroidism, and cardiac anomalies, commonly of the outflow tract or aortic arch [18] heterozygous deletion of 22q11.2 is the most common cause with an incidence of 1 in 2000 to 4000 births. Familial occurrence of DiGeorge sequence has been describe. Other chromosomal abnormalities and teratogens have also been implicated in the DiGeorge sequence [19].
Hypocalcemia is common in critically ill neonates. Prematurity is an important example of hypocalcemia. This can also follow intrapartum hypoxia, possible due to defective renal hydroxylation of 25-hydroxicholecalciferol. Jitteriness as a good guide to this condition. In some cases, the basis will be clear: acute renal insufficiency, fluid overload after dialysis, transfusion with citrated blood or alkalosis. During alkalosis decreases and acidosis increases the proportion of ionized calcium, symptomatic hypocalcemia may occur during the rapid correction or overcorrection of acidosis or with alkalosis. There are many drugs associated with hypocalcemia [20].
Chemotherapeutic agents such as the use of Cisplatinum as well as many diuretics, can induce hypomagnesemia and thereby cause hypocalcemia.
For the majority of patients, hypocalcemia reflects a hypoalbuminemic state [21]. The cause or pathophysiology of hypocalcemia will not be readily apparent; in a study, ˃50% of patients had no identifiable etiology for the hypocalcemia. Sepsis is a well-recognized risk factor for hypocalcemia. In nonseptic, critically ill neonates with hypocalcemia (defined as ionized calcium ˂1.16mmol/L) has also been recognized [4]. Vitamin D deficiency [7,22] as well as acquired, “relative” hypoparathyroidism, vitamin D resistance, and 1ᾳ hydroxylase deficiency are proposed mechanisms for hypocalcemia in critically ill pediatric patients [7]. Patients with toxic shock syndrome or gram-negative bacteria sepsis may have elevated levels of tumor necrosis factor ᾳ (TNF-ᾳ) that have also been associated with hypocalcemia. These observations suggest that increased sensitivity of parathyroid cells to the extracellular Ca2+ concentration can provide a mechanism for hypocalcemia in the setting of an inflammatory process such as sepsis. The direct contribution, if any, of hypocalcaemia to decreased survival is still being explored. In the neonates,1 ionized hypocalcemia has been associated with more severe illness. Thus, hypocalcemia may be a marker of greater disease severity rather than a cause of increased mortality. Although neuronal irritability, a classic sign of hypocalcaemia- is absent in critically ill neonates with hypocalcaemia [7], the relevance of this finding to other pathological effects of hypocalcaemia is not known. Perhaps most relevant to critically illness, hypocalcaemia has been shown to contribute to cardiac dysfunction and hypotension [7,23], and case reports of cardiomyopathy and heart failure reversible with chronic hypocalcemia due to hypoparathyroid states [23,24]. Additionally, calcium administration improved ventricular function during critically illness with ionized calcium˂1.05mm0l/L [25]. Heart failure has also been associated with hypocalcemia in the setting of vitamin D-deficient rickets [26]. However, the specific contributions to cardiac function of hypophosphatemia and vitamin D, both of which are important in muscle function [27] have not been elucidated. Because of the association of hypocalcaemia with worse clinical outcomes, and the effects of hypocalcemia on cardiovascular status, a logical question is “does treatment of hypocalcemia in critically ill patients improve outcome?
In 1995, Jankowski and Vincent reviewed the available evidence for the use of calcium in providing cardiovascular support in critically ill patients and concluded “calcium may improve cardiovascular status in critically ill patients, but at the cellular level its administration may be deleterious” and called for additional studies [25]. Nearly 15 years later, we still lack evidence-based guidance as no randomized-controlled trial has been published that examined the effect of parenteral calcium administration on mortality other markers of poor prognosis, or complications of calcium therapy [28]. By contrast in 2000, the American Heart Association updated practice guidelines in children that restricted the administration of parenteral calcium during cardiopulmonary resuscitation to pediatric patients with hypocalcemia, hypermagnesemia, hyperkalemia, and calcium channel blocker overdose [29]. Despite these guidelines, a recent multicenter study found that nearly 5 years after publication of the revised American Heart Association (AHA) guidelines, calcium continued to be administered to nearly half of the children during cardiopulmonary resuscitation and was associated with increased mortality and worse neurologic outcomes except in patients with metabolic abnormalities [30]. Subsequent pediatric advanced life-support guidelines published by the AHA in continue to restrict the use of calcium to specific circumstances, including hyperkalemia, documented hypocalcemia, hypermagnesemia and calcium channel blocker overdose [31]. Finally, the guidelines developed by the Surviving Sepsis Campaign do not recommend calcium administration as a therapeutic measure [32]. The common practice of administering calcium during cardiopulmonary resuscitation to individuals who do not have specific metabolic abnormalities derive from a lack of evidence of benefit plus concerns that calcium administration may lead to worse clinical outcomes. One possible explanation may be that the administration of calcium may potentiate the accumulation of cytosolic calcium, which several studies have implicated as the final common pathway of cell death [33]. For instance, brain ischemia is associated with an increase in intracellular calcium. Accumulation of intracellular calcium through specific routes can then over activate pathways for which calcium is a second messenger, generating reactive oxygen species and trigger cell death mechanisms, reviewed by Szydlowska and Tymianski [34]. Similarly, the cardiomyocyte, reviewed by Murgia et al, and other cell types are subjected to this same unrestrained activation of programmed cell death and necrosis [35].
In classic endocrine disorders, the approach to management of severe, symptomatic hypocalcemia is fairly straightforward. The two most commonly used calcium solutions for intravenous use are 10% calcium chloride and 10% calcium gluconate. A 10-mL ampule of 10% calcium Chloride contains three times more elemental calcium (272 mg) than a 10-mL ampule of 10% calcium gluconate (90 mg). Intravenous calcium solutions are hyperosmolar and should be administered through a large central vein if possible. Calcium gluconate has a lower osmolalitly and is the preferred calcium salt to administer if a peripheral vein is used. A bolus dose of intravenous calcium gluconate (1-2 mg of elemental calcium per kg) that is administered over 5 to 10 minutes can raise the serum calcium by 0.5 to 1mg/ml. A bolus dose of calcium will raise the serum level transiently and levels will begin to fall again after 30 minutes. Therefore, a bolus dose of calcium (1-3 mg elemental calcium/ kg per h in children) then 0.5 to 1.5 mg of elemental calcium/kg per h is administered as a continuous infusion.
Individual responses to intravenous calcium will vary, so calcium dosing must be guided by periodic monitoring of the level of ionized calcium in blood. Intravenous calcium is continued until a stable oral regimen is achieved.
Magnesium depletion is common in patients in intensive care units and is a frequent cause of hypocalcemia. Thus, hypomagnesemia should also be treated. The concordant administration should also be treated as activated forms of vitamin D such as calcitriol (15-50 ng/kg per day in 2-3 divided doses), can provide more stable control of the serum calcium concentration and may allow early discontinuation of intravenous calcium.
Administration of intravenous calcium should be reserved for specific situations as this treatment can have significant risks. Patients taking digitalis may have increased sensitivity to intravenous calcium. Rapid administration of calcium can result in cardiac arrhythmias so that intravenous calcium administration should be carefully monitored. Local vein irritation can occur with solutions ˃200 mg/dl of elemental calcium. Extravasation into soft tissues can lead to inflammation and local calcification. Calcium phosphate deposition can occur in any organ and is more likely to occur if the calcium-phosphate ratio exceeds solubility product. Calcium infusions can promote vasoconstriction and ischemia of vital organs, particularly in patients with low cardiac output and preexisting poor perfusion. Excessive cytosolic calcium can induce cell death. It seems most prudent to limit the use of intravenous calcium to patients who have signs or symptoms of hypocalcemia.
Chronic treatment depends on underlying etiology: calcitriol and calcium supplementation in hypoparathyroidism, and vitamin D-resistant rickets. Vitamin D deficiency is treated with ergocalciferol or cholecalciferol; dosing is based partly on underlying etiology with malabsorptive disorders requiring much larger doses long term. Over replacement of calcium and/or vitamin D can cause hypercalcemia or hypercalciuria, and nephrocalcinosis and nephrolithiasis are attendant risks. The management of hypocalcemia in the critically ill patient is more problematic: hypocalcemia may produce symptoms ranging from seizures, laryngospasm, prolonged QT, and cardiac dysfunction and intravenous calcium as described above is appropriate. Treatment of hypocalcemia in the setting of hypotension or circulatory collapse in the absence of specific hypocalcemia- attributable symptoms has been called into question, however, for concerns that such treatment may aggravate the disease process. A recent systematic review of the literature identified no studies that examined meaningful outcomes beyond increases in calcium levels following intravenous calcium administration. The concluded that “there is no clear evidence that parenteral calcium supplementation impacts the outcome of critically ill neonates” [28].
Hypocalcemia is frequently observed clinical and biochemical abnormality in neonates. Endocrine disorders and medication side effects are common culprits, and management is generally unambiguous in such cases. However, the etiology of hypocalcemia in the neonates is uncertain and potentially multifactorial. While mechanisms that disrupt normal calcium homeostasis are being uncovered, the precise treatment approach that ultimately benefits during critically illness with hypocalcemia has yet to be delineated. So, on the evidence of the role of calcium supplementation in neonates highlights the need for further investigation.
Copyright: © 2020 Mir Mohammad Yusuf. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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