Hypercalcitoninemia and inappropriate calciuria in the acute trauma patient

Hypercalcitoninemia Stephen

Matthew

and Inappropriate Trauma Patient

Koch, Uwe Mehlhorn,

Eric Baggstrom,

Diedra

Calciuria Donovan,

in the Acute

and Steven Jeffrey

Allen

Purpose: This study was undertaken to determine the role of calcium-regulatory hormones (calcitonin [CT], parathyroid hormone [PTH], and vitamin D analogs) during the first 48 hours after acute trauma. Met/rods: Eleven acutely traumatized patients admitted to the shock-trauma intensive care unit (STICU) in a tertiary care teaching hospital were enrolled. Eleven same-day elective surgery patients served as the control group. Levels of ionized calcium (Ca2+), total calcium, magnesium, phosphate, CT, PTH, vitamin D analogs, electrolyte supplementation, and renal electrolyte loss were recorded during the first 48 hours after admission to the STICU. Control-group measurements consisted of Ca2+ and CT. Results: At admission, 91% of the patients had ionized hypocalcemia (1.04 f 0.10 mmol/L). Ca2+ levels increased significantly over time (1.13 + 0.08 at 24 hours; 1.18 f 0.07 at 48 hours) but remained below the control-group value (1.28 f 0.05; P < .05) despite supplementation. Ninety-one percent of the patients

had increased CT values at admission, 91% at 24 hours, and 78% at 48 hours. Median CT values in the trauma patients were higher throughout the study than in the control group (P < .05). Urinary calcium loss in the trauma patients was within the normal range. PTH and vitamin D analog values were within the normal range throughout the study. Multiple regression analysis did not show any significant correlation between electrolytes and hormone or protein concentrations. Conclusions: Acute trauma patients have ionized hypocalcemia associated with inappropriate urinary calcium loss, increased CT levels, and normal PTH and vitamin D analog values. We believe the degree of calciuria we observed was inappropriate in the context of ionized hypocalcemia. The cause of these increased CT levels is unclear. Our results suggest that Ca2+regulatory mechanisms may be disrupted in the acute trauma patient. Copyright o 1996 by WA Saunders Company

ALCIUM is essential for a wide variety of C bodily functions, including muscle contraction, intracellular metabolism, bone structure,

cipitation or chelation of Ca*+, halothane administration, acute changes in acid-base status, blood product preservatives, infusions of fresh frozen plasma, albumin, lipids, or propofo1.5,6,22,24 The role of calcitonin (CT) in acute Ca*+ metabolism in the critically ill is not well defined. This study was undertaken to evaluate whether CT and PTH play a role in Ca*+ metabolism in the acute trauma patient in the first 48 hours in the shock-trauma intensive care unit (STICU).

membrane stability, coagulation, and cellular secretion and as a cofactor in enzymatic reactions.** The physiologically active and regulated blood calcium fraction is ionized calcium (Ca*+).** Ca*+ must be measured directly because it cannot be reliably estimated from total plasma calcium levels. 11,24Derangements in calcium-regulatory mechanisms are therefore represented by alterations in plasma Ca*+ rather than total plasma calcium concentrations. Ionized hypocalcemia occurs frequently in a wide variety of critically ill patients.5s6*22*24Ionized hypocalcemia has been shown to occur in meningococcemia,” sepsis,1,23 toxic shock syndrome,19 and fat embolism syndrome.7 However. studies in acute trauma patients have yielded inconsistent results. Skeletal injury has been associated with normal total calcium concentration,3,‘2 total hypocalcemia,7 and ionized hypocalcemia.18 Ca*+ concentration is regulated primarily by parathyroid hormone (PTH) and vitamin D.** Ionized hypocalcemia in critically ill patients may result from dilution, alteration in protein binding, changes in protein values, decreases in PTH levels, impaired vitamin D synthesis, preJournalofCriticalCare,

Vol 11, No 3 (September),

1996: pp 117-121

MATERIALS

AND METHODS

After approval by the Committee for the Protection of Human Subjects of the University of Texas Health Sciences Center, we obtained informed consent from 11 acutely traumatized patients. Subjects were enrolled from consecutive patients who met admission criteria to the STICU. Forty patients were evaluated for inclusion. Subjects were excluded from the study if they were pregnant, had a history of smoking, had a known disorder of calcium metabolism, had an endocrine-related diagnosis that may influence

From the Department of Anesthesiology The University of Texas Medical School, Houston, Texas. Address reprint requests to Stephen M. Koch, MD, Depatiment of Anesthesiology, 6431 Fannin, MSB 1020, Houston, TX 77030-l 501. Copyright 0 1996 by W B. Saunders Company 0883-944119611103-0002$05.00l0 117

118

KOCH

CaZ+, or had taken medications before admission known to affect calcium metabolism; if more than 4 hours had elapsed since the injury, or if they were not enrolled within 1 hour of STICU admission by one of the investigators. Patients were also excluded if they had a neck injury or shock requiring vasopressors or if they developed hepatic (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] level greater than two times normal) or renal (creatinine level of > 1.5 mg/dL) dysfunction during the study. Acute Physiology Score and Chronic Health Evaluation (APACHE) II and Therapentic Intervention Scoring System (TISS) scores were determined on admission and for each 24-hour period of the study. Ca2+, magnesium, sodium, potassium, phosphorus, total protein, and albumin were measured upon admission to the STICU and at 24 and 48 hours thereafter. Electrolyte intakes were recorded for each 24-hour period. Electrolytes were supplemented as part of the routine treatment of these patients. Urine was collected in two consecutive 24-hour samples for creatinine clearance determination as well as electrolyte output. m, 1,25dihydroxycholecalciferol (1,25[OH]zD3); 25-hydroxycholecalciferol(25[OH]D3); and PTH levels were obtained at the time of the electrolyte measurements. Gastrin and thyroid function studies (thyroxine [T4] and thyroid-stimulating hormone [TSH]) were performed at admission. All samples were collected from arterial lines and immediately placed on ice. We obtained blood anaerobically in 3-mL tubes (VACUTAINER; Becton-Dickinson, Rutherford, NJ) for Ca2+ and in lo-mL tubes (VACUTAINER) for CT. Ca*+ was assayed within 5 minutes of collection using a BGA 1400 Blood Gas Analyzer (Instrumentation Laboratory Inc, Lexington, MA). CT, 1,25(OH)zD3, 25[OH]D3, and PTH samples were placed on ice and centrifuged within 10 minutes at 5,000 ‘pm for 5 minutes. Supernatant was aliquoted into two fractions, frozen, and stored in metal-free plastic vials at -5°C. One aliquot of supernatant was sent to Mayo Medical Laboratories (Rochester, MN) and assayed for CT (radioimmunoassay after cartridge extraction), 1,25(OH)zD3, and 25[OH]D3 (highpressure liquid chromatography and radioreceptor assay). The second aliquot of supernatant was assayed for PTH, gastrin, and thyroid function. Mg, Na, K, P, total protein, and albumin were measured in our hospital laboratory. Table

1. Patient

To determine the impact of hospital admission on Ca*+ and CT, 11 patients presenting for outpatient surgery (arthroscopy, hernia repair, etc) were recruited and matched for age and gender with the study patients. Inclusion and exclusion criteria were identical to those for STICU patients. Blood samples were collected from the unoccluded antecubital vein and processed as in the STICU patients.

Statistical Analysis To test for changes over time we performed an analysis of variance (ANOVA) for repeated measures with Tukey honestly significant difference (HSD) test for posthoc comparison. To compare Ca2+ in control and study patients, we used an unpaired Student’s t test. CTvalues were compared using a Mann-Whitney U test. P < .05 was considered significant. RESULTS

Patient demographics are shown in Table 1. None of the patients died during the study. At admission, 10 of the 11 STICU patients had Ca2+ concentrations below the normal range of our hospital laboratory (Fig 1). Despite significant increase over time, mean Ca2+ levels remained below those of the control group. Ten of 11 patients had admission CT values above normal, and CT values remained significantly elevated throughout the study (Fig 2). CT results in Fig 2 are presented logarithmically because of the wide range of our results (7 to 85,000 rig/L). For all the other hormones measured we did not find significant differences from normal values. Neither Ca2+ nor CT levels were affected by hospital admission in the same-day surgery patients (Figs 1 and 2). Multiple regression analysis did not show any significant correlation between electrolyte and hormone or protein concentrations. Demographics

APACHE II Score(h) 24

48

72

Fractures

Head Injury

Pulmonary Injury’

2

9

8

8

Yes

No

IO 3 8 14

9

9

15 7 6

IO 6 15 16

10 24

12 18

Yes Yes Yes Yes

No Yes Yes No

M M M

10 8 5

7 9 13

2 12 13

5 17 11

8 IO

Yes No No

F M F

7 3 3

24 17 21

15 21 20

13 22 16

13 12

Yes Yes No

Admission GCS

Age w

SW

44

M

15

24 39 25 57

M

a

F M

36 25 24 56 19 52

M

Abbreviations: *Contusion,

0

GCS, Glasgow Coma Score; APACHE, aspiration, ARDS, edema, pneumothorax.

Acute

ET AL

Physiology

Score

Mechanical Ventilation Initial

End

Yes No

Yes Yes

Yes Yes

No Yes Yes

No Yes Yes

No Yes Yes

No Yes Yes

No No No

Yes Yes Yes

No Yes Yes

Yes Yes Yes

No Yes No

Yes Yes Yes

Yes Yes Yes

and Chronic

Health

Evaluation.

HYPERCALCITONINEMIA

AND

IONIZED

119

HYPOCALCEMIA

...-.. #0.*..

fresh-frozen plasma, albumin, lipids, or propofol during the study course. Intravenous input and urinary output for Ca2+, Mg, and P levels are shown in Table 2. We did not find a significant correlation between Ca*+ level and urinary calcium loss. DISCUSSION

0 0

I.1

I

Admission (0) Fig 1. individual sion, after 24 hours, and deviation measured in Dotierf lines represent hospital laboratory.r4 #P sion.

26h

dh

and mean (0) Caz+ levels at admisafter 48 hours. n , Mean + standard the 11 same-day surgery patients. the normal reference range of our < .OOl v control; *P c .OLi Y admis-

All study patients had normal renal function as measured by serum creatinine, blood urea nitrogen, and creatinine clearance values. None of the study patients had elevation of transaminase (AST, ALT) levels more than two times our normal laboratory values. None of the patients received enteral feeding, parenteral nutrition, halothane anesthesia, or infusions of (85000)

0

(2800)

0

d

0

0

0

8

0

Q#

8

l

#

0 0 cl -’ -- 4 .-.-.__.-__.-____-____ 10

:’

0

0

1 Admission

Our data show that acute trauma patients have ionized hypocalcemia throughout the first 48 hours after their injuries. At admission, mean Ca*+ concentration was 1.04 Jt 0.10 mmol/L, which is significantly lower than the same-day surgery group value of 1.28 + 0.05 mmol/L. According to our hospital laboratory normal range, this represents ionized hypocalcemia in 10 of 11 study patients. We observed ionized hypocalcemia, inappropriate calciuria, increased CT levels, and normal parathyroid hormone and vitamin D analog values, which have not been reported previously in the acute trauma patient. Normally, hypocalcemia is associated with low CT level and decreased urinary Ca2+ Ioss.~,~~However, our study patients had significantly increased CT levels associated with ionized hypocalcemia. Furthermore, our patients showed urinary Ca*+ loss that we believe was inappropriate in the presence of ionized hypocalcemia. Mean daily calcium loss was 106 mg, which is excessive in the presence of ionized hypocalcemia. This suggests that the observed ionized hypocalcemia could be caused by inappropriately high urinary calcium loss induced by increased CT levels. Thus, it appears that the feedback mechanisms for calcium regulation may be deranged in the acute trauma patient. Dysfunction of Ca2+ feedback mechanisms is

24 h

Fig 2. Individual (0) and median (0) calcitonin sion, after 24 hours, and after 48 hours. l , Control levels (n = 11). The dottedline represents the upper range limit (Mayo Medical Laboratories, Rochester, ,001 v control. Note logarithmic presentation of values.

Table

2. Electrolyte

8#

and Output

Oto24h

9. - -

Calcium Intake

8 I

output Magnesium Intake

48 h at admiscalcitonin reference MN). #P < calcitonin

Intake

output Phosphorus Intake

180 + 153 93 k 108

NOTE.

176 k 99 120 + 126

(mg) 1,057 + 1,039

1,364 + 2,370

1,250 + 1,430

2,660 + 3,530

129 + 124

165 + 163 450 t 320

(mg)

output

tion.

24to48h

(mg)

All results

480 2 370 are expressed

as mean

? standard

devia-

120

also supported by our finding of normal PTH and vitamin D analogs. Increased PTH has been shown to be associated with ionized hypocalcemia in cardiopulmonary bypass (CPB) patients.” Robertie et all7 showed decreases in Ca2+ concentrations from 1.14 +- 0.02 mmol/L to 0.91 f 0.03 mmol/L during CPB. In their patients, PTH levels initially decreased because of hemodilution but gradually increased in response to persistent ionized hypocalcemia, with maximal PTH levels at the end of CPB. In our patients, persistent ionized hypocalcemia did not appear to be a stimulus for PTH secretion. Possible reasons for inappropriately normal PTH levels in our patients include decreased responsiveness of the parathyroid gland to ionized hypocalcemia, increased PTH breakdown, hypomagnesemia, or circulating inflammatory mediators that could interfere with the PTH assay, resulting in spuriously low values. Mild hypomagnesemia was present on admission in our patients, but the degree of hypomagnesemia we observed is not generally believed to affect PTH levels. Normal values for vitamin D analogs also support the possibility that calcium hemeostatic mechanisms may be disrupted in the acute trauma patient. Normal vitamin D values could be caused by decreased renal responsiveness to PTH or insufficient time for vitamin D metabolism to respond to acute changes in Ca2+ levels. Alternatively, normal vitamin D values associated with normal PTH levels could be appropriate, implying that feedback is disrupted before vitamin D-PTH interaction. Ionized hypocalcemia in critically ill patients has been associated with halothane anesthesia. Halothane was not used in any of these patients. In addition, infusions of fresh-frozen plasma, albumin, lipids, and propofol could affect ionized calcium values; however none of these products were used in the study patients. Alteration in protein concentration could produce changes in Ca2+ levels. We observed albumin and total protein levels below the normal range throughout the study. Decreased protein and albumin levels would provide fewer sites for calcium binding. A decrease in available calciumbinding sites would allow more calcium to circulate in the extracellular fluid as Ca2+, thus

KOCH

ET AL

resulting in increased and not decreased Ca2+ levels. Our study patients did not receive enteral or parenteral nutrition, and therefore no exogenous lipid or albumin was infused. Propofol was not used in the STICU during the study period. Packed red blood cells (PRBC) contain citrate as a preservative. Citrate can chelate Ca2+ and produce ionized hypocalcemia. However, on average, our patients received less than one unit of PRBC during the course of the study, and we believe the amount of citrate contained in this quantity of blood was insufficient to produce the results we observed. Another possible explanation for the observed ionized hypocalcemia at admission could be dilution attributable to resuscitation fluids. The concentration of Ca2+ in the extracellular fluid (ECF) is normally 1.24 mmol/L.20 Thus, ECF would have to increase by 3.2 L or 23% (ECF in a 70-kg individual is 14 L [20% of body weight]) to account for the observed initial ionized hypocalcemia, which we believe unlikely. We found increased CT in 91% of the patients at admission and at 24 hours and in 78% at 48 hours (Fig 2). What could have been the stimulus for the this increased CT level? Several factors, such as hyperoxia, hypoxia, hypercapnia, positive-pressure ventilation, inhalation injury, and B-adrenergic hyperactivity, have been shown to be associated with increased CT leve1s.10J5J6,21 Increased CT is thought to be caused by pulmonary neuroendocrine cells, which produce peptides, including CT, and release them into the systemic circulation.2,g All of our patients were exposed to either hyperoxia or positive-pressure ventilation, although no patients had inhalation injury at presentation or developed clinically significant pulmonary contusion during the course of the study. Thus, pulmonary neuroendocrine cell stimulation might have caused the observed increases in CT levels. All of our patients were also under stressful conditions that have been shown to be associated with increased CT levels; however, levels of stress hormones such as epinephrine were not measured.15*21 Another mechanism for increased CT levels could involve bony fractures. Previous studies of acute skeletal injuries have shown elevated CT

121

HYPERCALCITONINEMIAAND IONIZED HYPOCALCEMIA

levels associated with either normaL increased,* or decreased total calcium concentrations14; however, Ca2+ values were not presented. We found low total calcium and low Ca2+ levels associated with increased CT. However, we did not find differences in CT values between patients with and without fractures. The range of CT levels in the eight patients with fractures was 7 to 2,800 rig/L, and CT levels ranged from 49 to 85,000 rig/L in the three patients without fractures. Our results do not support the concept that skeletal injury alone produced the observed increases in CT levels. Thus, it appears that another mechanism is responsible for

increased CT levels in acutely traumatized patients. Our data suggest that Ca*+-regulatory mechanisms may be disrupted in the acute trauma patient, resulting in ionized hypocalcemia. We believe that routine calcium supplementation in these patients is not sufficient to prevent ionized hypocalcemia. ACKNOWLEDGMENT The authors thank the Hermann Hospital Shock-Trauma nurses for their technical assistance and Anne Starr for assistance in preparation of the manuscript.

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13. Mallet E, Lanse X, Devaux AM, et al: Hypercalcitoninemia in fulminant meningococcaemia in children. Lancet 1:294, 1983 14. Meller Y, Shainkin-Kestenbaum R, Shany S, et al: Parathyroid hormone, calcitonin, and vitamin D metabolites during normal fracture healing in humans: A preliminary report. CIin Orthop 183:238-245, 1984 15. Metz SA, Deftos LJ, Baylink DJ, et al: Neuroendocrine modulation of calcitonin and parathyroid hormone in man. J Clin Endocrinol Metab 47:151-159, 1978 16. O’Neill WJ, Jordan MH, Lewis MS, et al: Serum calcitonin may be a marker for inhalation injury in burns. J Burn Care Rehabil13:605-616,1992 17. Robertie PG, Butterworth JF, Royster RL, et al: Normal parathyroid hormone responses to hypocalcemia during cardiopulmonary bypass. Anesthesiology 75:43-48. 1991 18. Sibbald WJ, Sardesai V, Wilson RF: Hypocalcemia and nephrogenous cyclic AMP production in critically ill or injured patients. J Trauma 17:677-683,1977 19. Sperber SJ, Blevins DD, Francis JB: Hypercalcitoninemia, hypocalcemia, and toxic shock syndrome. Rev Infect Dis 12:736-739, 1990 20. Toffaletti JG, Jones PJ: Electrolytes, in Bishop ML, Duben-Engelkirk JL, Fody EP (eds): Clinical Chemistry. Philadelphia, PA, Lippincott, 1992, pp 269-298 21. Vora NM, Williams GA, Hargis GK, et al: Comparative effect of calcium and of the adrenergic system on calcitonin secretion in man. J Clin Endocrinol Metab 461567-571, 1978 22. Zaloga GP: Hypocalcemia in critically ill patients. Crit Care Med 20:251-262,1992 23. Zaloga GP, Chernow B: The multifactorial basis for hypocalcemia during sepsis. Ann Intern Med 107:36-41, 1987 24. Zaloga GP, Chernow B, Cook D, et al: Assessment of calcium homeostasis in the critically ill patient. Ann Surg 202587-594, 1985