Hypocalcemia

ABSTRACT. Background: Recent data indicate that critically ill, adult multiple trauma patients receiving specialized nutrition support commonly experience hypocalcemia (ionized serum calcium [iCa] ≤ 1.12 mmol/L). However, validated methods for the treatment of acute hypocalcemia are lacking. Methods: The efficacy of a single dose of calcium gluconate using an empiric IV calcium gluconate graduated dosing regimen was evaluated in 37 patients. Patients with an iCa of 1-1.12 mmol/L (mild hypocalcemia) were provided 1-2 g of IV calcium gluconate. Patients with an iCa of

Aberration in calcium metabolism is an important but often undetected metabolic problem in the critically Ul patient. Most laboratories report total calcium concentrations that are inaccurate in the critically ill patient, even when the serum albumin concentration is taken into consideration.1 Severe hypocalcemia, if untreated, can lead to serious neurologic and cardiovascular complications.2,3 We have previously shown that 21% of adult multiple trauma patients receiving specialized nutrition support (reflective of the population in this study) have acute hypocalcemia.1 Unfortunately, there is a lack of published, validated methods for the treatment of acute hypocalcemia in this population. The intent of this investigation was to evaluate the efficacy of a graduated intravenous (IV) calcium gluconate regimen for critically ill, multiple-trauma patients.

MATERIALS AND METHODS

Adult patients, at least 18 years of age, admitted to the Elvis Presley Memorial Trauma Center at the Regional Medical Center at Memphis who were referred to the Nutrition Support Service (about 60%-70% of total trauma intensive care unit admissions) were identified for potential inclusion into the study. Only trauma intensive care unit patients were potentially enrolled for study. Serum chemistries, arterial blood gas measurements, nutrition markers, and ionized calcium concentration were simultaneously obtained from each patient. The blood was obtained at approximately 3 AM via an indwelling arterial or venous catheter while the patient lay supine in bed. Nutrition assessment measurements were also conducted. Laboratory tests were ordered by the patient's primary service or the Nutrition Support Service and performed by the hospital laboratory as part of the patient's routine clinical care. Each patient contributed only once to the data pool. The total serum calcium was measured colorimetrically, whereas the serum ionized calcium concentration (iCa) was determined usiner an ion-selective electrode method.

Those who received blood products, calcium or vitamin D therapy, furosemide, or therapeutic doses of heparin within 24 hours before the laboratory measurements were excluded from the analysis. Additional exclusion criteria included patients with pancreatitis, hyperphosphatemia (>6 mg/dL), hyperbilirubinemia (>3.5 mg/dL), hypomagnesemia (≤1.5 mg/dL), or renal failure requiring dialysis. Patients with a history of cancer, bone disease, or parathyroid disease were also excluded.

Patients were given enterai nutrition by a small-bore, nasoenteric feeding tube or jejunostomy. Patients who could not receive enterai nutrition received parenteral nutrition. Parenteral nutrition was given via the subclavian or external jugular vein when enterai feeding was contraindicated. The enteral formulas contained 40 mEq of calcium per L and the parenteral nutrition solution contained 5 mEq of calcium gluconate per L. The parenteral nutrition's calcium gluconate content was increased to 10 mEq/L if the patient's iCa indicated hypocalcemia. Hypocalcemic patients receiving enterai nutrition received IV calcium gluconate supplementation without additional calcium added to their feeding. Patients who required phosphorus supplementation were given an IV dosage scheme that has been previously shown to not significantly influence serum ionized or total calcium concentrations.11,12 Additional phosphorus was often added to the enterai feeding or parenteral nutrition solution for hypophosphatemic patients. We attempted to give the IV calcium and phosphorus infusions sequentially. To ascertain whether any relationship existed between calcium intake upon serum phosphorus concentration changes, patients from each hypocalcemia severity group were further subdivided into those who received phosphorus therapy on the same day as calcium therapy and compared with those who were given calcium therapy without phosphorus supplementation.

Continuous data were expressed as means ± SD, All data analysis was conducted using SPSS for Windows, version 12 (SPSS, Inc, Chicago, IL). Comparisons of interval data between 2 independent groups were performed by the Student's t test for unpaired variables. Nominal data were evaluated by χ^sup 2^ analysis or the Fisher exact probability test. Goodness of fit of the linear model between 2 variables was assessed from the coefficient of determination (r^sup 2^), which was derived from linear correlation using the Pearson product moment correlation coefficient. A p value of ≤.05 was established as statistically significant. The study was approved and conducted in accordance with the guidelines established by the University of Tennessee Health Science Center institutional review board. Because all measurements were performed as part of the routine metabolic evaluation of the patient, confidentiality procedures for the patient were maintained, and the data were collected retrospectively, the requirement for informed consent was waived.

RESULTS

Thirty-seven patients with hypocalcemia admitted to the trauma intensive care unit (TICU) from June 2004 to December 2004 who were referred to the Nutrition Support Service were studied. Only patients treated for hypocalcemia with PV calcium gluconate according to our dosing guidelines cited in the methods were studied. Six patients not given calcium therapy according these guidelines were excluded from the analysis. The majority of the critically ill population was admitted due to a motor vehicle accident or gunshot wound and were ventilator dependent (Table I). Nearly half (43%) of the patients had received a blood transfusion within 48 hours of identification of hypocalcemia (Table I). The hypocalcemic patients were given IV calcium gluconate therapy 5 ± 4 days after admission to the TICU. The majority of the population (78%) experienced mild hypocalcemia, whereas the remaining patients had moderate to severe hypocalcemia. There was no significant difference between mild and moderate to severe hypocalcemia groups with respect to gender, admission diagnoses, body temperature, white blood cell count, trauma score, blood transfusion, or with presence of head injury, sepsis, vasopressor therapy, or ventilator dependency (Table I).

The majority of patients (76%) received specialized enterai nutrition support. One patient received both enteraL and parenteral nutrition transitional feeding during the study. The remaining patients were given parenteral nutrition. Patients were given a polymeric, fiber-containing, high-nitrogen enteraL formula (62 or 80 g of protein/L) or a high-amino-acid-containing parenteral nutrition solution (50-70 g of amino acids/L). Patients were generally assigned a caloric goal of 30-35 kcal/kg/d and protein goal of about 2 g/kg/d. Most patients were adequate in body weight for height but had marked serum protein depletion and negative nitrogen balance (Table II). A nitrogen balance determination was conducted 6 ± 4 days after admission, which revealed a mean balance of -8.7 ± 8.8 g/d while receiving 35% ± 24% of the goal nutrition intake. The percentage of goal nutrition intake was reflective of a nitrogen balance determination within 1-2 days of initiating specialized nutrition support and of the slow initiation characteristics of providing enteraL nutrition. Nitrogen balance also tended to be worse for the moderate to severe hypocalcemiC group, but this difference between groups did not achieve statistical significance (Table II) due to the variability of the nitrogen balance determinations.

Patients had a statistically significant rise in serum iCa and total calcium concentration after the calcium infusion (Table III). The postdose iCa determination was done 14 ± 6 hours after completion of the calcium gluconate infusion. One to 2 g of calcium gluconate, administered at 1 g/h, corrected 79% of the patients (23 out of 29) with mild hypocalcemiA (Table IV). A single dose of 2-4 g of calcium gluconate was effective for only 38% of the patients (3 of 8) with moderate to severe hypocalcemia (Table IV). There was wide variability in response, as evidenced by the pH-corrected change in serum iCa, at each dosage, respectively (Figure 1). Additionally, there was no significant correlative linear relationship for pH-corrected change in serum iCa by dose when adjusted for body weight (mg/kg; Figure 2).

One patient exhibited mild hypercalcemia, with an iCa of 1.34 mmol/L after a 4-g calcium gluconate dose for a pretreatment iCa of 0.71 mmol/L. The postdose iCa was done approximately 19 hours after completion of the infusion. In addition, the patient had worsening acidemia, with a pH of 7.23 on the postdose day at the same time the repeat iCa was determined. No adverse events were recorded in the patient's medical chart.

About two-thirds of the patients also required IV phosphorus supplementation (Table V). Twenty-one patients from the mild hypocalcemia group received a mean IV phosphorus dose of 44 ± 18 mmol on the same day as the calcium infusion. Three patients from the moderate to severe hypocalcemia group received a mean phosphorus dose of 25 ± 9 mmol on the same day as the calcium infusion. The calcium and phosphorus infusions were given separately to avoid calcium-phosphate precipitation. Patients who received combined calcium and phosphorus infusions had significant increases in serum calcium and iCa without a significant change in serum phosphorus concentration (Table V). However, patients who received IV calcium supplementation without phosphorus therapy demonstrated a decline in serum phosphorus from 4.0 to 3.1 mg/dL (p = NS) and from 4.1 to 2.5 mg/dL (p ≤ .05) for the mild and moderate-severe hypocalcemic groups, respectively (Table V). No clinically relevant adverse events were recorded in the patient's medical chart.

DISCUSSION

Information regarding alterations in calcium homeostasis during critical illness has markedly expanded over the past 2 decades.1,2,13-21 Despite this emergence of data, hypocalcemia is often unappreciated in the critically ill patient because serum proteins, particularly albumin, decreases in response to stress.22 It is often inappropriately assumed that the serum total calcium concentration is falsely low due to decreased serum albumin because calcium is highly protein bound. We have previously reported that hypocalcemia, defined as a serum iCa of ≤1.12 mmol/L, occurs in 21% of our population and cannot be accurately identified by using "corrective equations" that consider serum albumin, total protein, and serum calcium concentrations, or pH.1

Severe hypocalcemia may lead to serious alterations in cardiovascular and neurologic function, including hypotension, impaired cardiac contractility, arrhythmias, muscle weakness, seizures, paresthesias, and tetany. The presence of hypocalcemia also may be related to increased mortality and severity of disease.17'23'24 The exact mechanism for hypocalcemia in our critically ill multiple trauma population was likely multifactorial, including altered calcium affinity for binding to albumin, alkalemia, and blood transfusions.10,18,20,24 More recent data indicate that the hypocalcemia observed during critical illness is related to the cytokine-mediated inflammatory response and not due to attenuated bone resorption or increased urinary excretion of calcium.21 It has also been suggested that possibly an alteration in the calcium-sensing receptor by the parathyroid gland is involved in the pathogenesis of hypocalcemia during critical illness.21

Some investigators have questioned the validity of treating asymptomatic hypocalcemia during critical illness. Neuromuscular symptoms including tetany, spasms, seizures, and paresthesias are infrequent in critically ill patients at ionized serum calcium concentrations >0.8 mmol/L.25 However, electrocardiographic abnormalities characteristic of hypocalcemia can occur with low serum iCa >0.8 mmol/L.26 A prolonged QT^sub c^ interval with periodic premature ventricular contractions due to hypocalcemia without overt evidence of clinical symptomatology has been recently reported in a case series of 22 patients.27 The electrocardiographic manifestations corrected after oral calcium and vitamin D supplementation.27 Zivin and coworkers17 reported a surprisingly high incidence of asymptomatic hypocalcemia (88% as defined by a serum ionized calcium of

Part of the reluctance to treat asymptomatic hypocalcemia during critical illness stems from studies in animal models23,28,29 which have shown that aggressive IV calcium therapy worsens outcome when given as part of the resuscitation during septic shock. All of our patients were treated for hypocalcemia after resuscitation, and about a third (38%) of our population was considered to have sepsis according to the 2000 consensus definitions.5 Most patients who received inotropic therapy were receiving low-dose dopamine therapy. In addition, we used the calcium gluconate salt form for the treatment of hypocalcemia as opposed to calcium chloride (used in the animal studies), which contains one-third as much elemental calcium as the chloride salt form. IV calcium administration may also increase digoxin toxicity; however, none of the patients in our study received digoxin therapy.

Effective therapy for acute hypocalcemia during critical illness is an enigma due to the lack of any established and proven dosing regimens. For symptomatic patients or those with an ionized serum calcium concentration of

Despite conservative dosing, 1 patient experienced mild hypercalcemia at 1.34 mmol/L (with the high end of the normal range by our laboratory at 1.32 mmol/L). The patient was given 4 g of calcium gluconate for a serum iCa of 0.71 mmol/L. During alkalemia, hydrogen ion is released from the protein and the calcium ion will bind, reducing its free or ionized concentration.10 The converse is true during acidosis. This pH phenomenon may have partially explained this apparent hypercalcemia because the patient's acidemie worsened during the course of therapy. No clinically relevant adverse effects were noted in the medical chart.

We have previously shown that our IV phosphorus dosage scheme does not significantly alter serum total or iCa.11,12 However, the effect of our empiric IV calcium gluconate dosage regimen upon serum phosphorus concentrations was unknown until this study. Serum phosphorus declined in both the mild and moderate to severe hypocalcemia groups when patients were given calcium without phosphorus supplementation (Table V). However, only the moderate to severe group's decrease in serum phosphorus was statistically significant. When phosphorus therapy was given sequentially with calcium therapy, the decline in serum phosphorus was attenuated. It is unclear whether the calcium therapy itself caused a fall in serum phosphorus or whether the patients may have been having refeeding issues11,12 or a whether it was due to a combination of both physiologic effects. Further study is warranted to provide more meaningful interpretation of these data.

CONCLUSIONS

In the treatment of mild hypocalcemia, 1-2 g of IV calcium gluconate infused at 1 g/h was effective in normalizing serum iCa in 23 out of 29 patients (79%). In the treatment of moderate to severe hypocalcemia, 2-4 g of calcium gluconate infused at 1 g/h was effective in 3 out of 8 patients (38%). One patient experienced mild hypercalcemia (1.34 mmol/L) at the highest dosage (4 g). The individual response to calcium therapy (g/d) or when normalized to body weight (mg/kg/d) was highly variable. A decline in serum phosphorus concentration was noted for those who received calcium without phosphorus therapy. It is unclear whether the observed fall in serum phosphorus concentration was more reflective of refeeding issues, a causative effect from the calcium infusion, or both. Further study with frequent serial ionized serum calcium and phosphorus determinations and electrocardiographic monitoring appears indicated for patients with moderate to severe hypocalcemia.

REFERENCES

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Roland N. Dickerson, PharmD*; Laurie G. Morgan, RN[double dagger]; April D. Cauthen, PharmD*; Kathryn H. Alexander, MS, RD§; Martin A. Croce, MD[dagger]; Gayle Minard, MD[dagger]; and Rex O. Brown, PharmD*

From the * Departments of Pharmacy and [dagger] Surgery, University of Tennessee Health Science Center, Memphis, Tennessee; and the [double dagger] Departments of Pharmacy and § Food and Nutrition, Regional Medical Center at Memphis, Memphis, Tennessee

Received for publication March 4, 2005.

Accepted for publication June 30, 2005.

Correspondence: Roland N. Dickerson, PharmD, Professor of Pharmacy, University of Tennessee Health Science Center, 26 South Dunlap St., Room 210, Memphis, TN 38163. Electronic mail may be sent to rdickerson@utmem.edu.

Presented, in part, at the Fourth Annual Nutrition Week, January 31, 2005, Orlando, Florida.

Copyright American Society for Parenteral and Enteral Nutrition Nov/Dec 2005
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