0021-972X/99/$03.00/0
The Journal of Clinical Endocrinology & Metabolism
Copyright © 1999 by The Endocrine Society
Vol. 84, No. 8
Printed in U.S.A.
Hypocalcemia Induced during Major and Minor
Abdominal Surgery in Humans
R. LEPAGE, G. LÉGARÉ, C. RACICOT, J.-H. BROSSARD, R. LAPOINTE,
M. DAGENAIS, AND P. D’AMOUR
Research Center, Campus Saint-Luc, and the Departments of Biochemistry (R.L.), Medicine, and
Surgery (G.L., C.R., R.L., M.D.), Centre Hospitalier de l’Université de Montréal, Montreal, Canada
ABSTRACT
Hypocalcemia has only been rarely reported during surgical procedures not involving massive blood transfusions. The frequent observation in our hospital of a low serum ionized calcium level during
surgery in nonacutely ill patients prompted us to investigate the
calcium-PTH axis in three groups of subjects undergoing major (hepatectomy; n 5 10), moderately severe, or minor surgery under general
anesthesia (colectomy; n 5 7, herniorrhaphy; n 5 9) compared to that
in one group of minor surgery cases under epidural anesthesia (herniorrhaphy; n 5 15). Serum samples were obtained before anesthesia,
after anesthesia but before surgery, and 40 and 120 min after the
beginning of surgery in all groups of patients and for up to 3 days in
major and moderately severe cases. Significant falls (P , 0.01), always proportional to the severity of the surgical/anesthesia procedure, were observed for ionized calcium (6 –20%), total calcium
H
YPOCALCEMIA is not an unusual finding in patients
hospitalized for critical illnesses and has also been
described during postsurgical procedures (1– 8). Numerous
factors have been suggested as causing the hypocalcemia in
these situations, such as changes in albumin affinity for calcium (9 –11), chelation by citrate from blood transfusions (12,
13), or resistance to PTH or vitamin D action (14). In the
absence of massive blood transfusion, only slight decreases
in calcium levels within the normal range have been reported
during surgical procedures, mostly attributed to pH variations (11, 15, 16).
Ionized calcium measurements are not routinely performed in our hospital during surgery, except during liver
transplantation. Since the installation of a new blood gas
analyzer giving simultaneous measurements of blood gas
parameters and ionized calcium, we have, however, observed that low ionized calcium levels were frequent during
surgery in anesthetized patients even in the absence of frank
alkalosis or other obvious cause of hypocalcemia. We therefore decided to investigate possible changes in the calciumPTH axis during major and minor abdominal surgery under
general anesthesia in noncritically ill human subjects, comparing results to those obtained in subjects undergoing minor surgery under local anesthesia.
Received January 12, 1999. Revision received April 28, 1999. Accepted
May 4, 1999.
Address all correspondence and requests for reprint to: Pierre
D’Amour, M.D., Centre de Recherche du Centre Hospitalier de
l’Université de Montréal, Campus Saint-Luc, 264 René Lévesque boulevard East, Montreal, Quebec, Canada H2X 1P1
(8 –19%), and albumin (8 –23%) accompanied by increases in intact
PTH (105– 635%). The decrease in ionized and total calcium correlated with a decrease in albumin (P , 0.001). Phosphorus, pH,
and magnesium levels remained within the normal range. Adjustment of ionized calcium for variation in albumin revealed that
50 –100% of the variation in ionized calcium could be attributed to
a fall in albumin resulting from fluid administration to patients
before admission to the surgery ward and between the onset of
anesthesia and the end of surgery (1.2–5.6 L). Albumin- and pHindependent residual ionized calcium decreases of 12.2% in the
hepatectomy group, 4.6% in the group of moderately severe and
minor cases under general anesthesia, and 3.7% in the control
group reflected the severity of the surgical/anesthesia procedure.
(J Clin Endocrinol Metab 84: 2654 –2658, 1999)
Subjects and Methods
A total of 41 subjects scheduled for elective surgery participated in
this study. They were assigned to 1 of 3 study groups: group I comprised
10 subjects undergoing major surgery under general anesthesia (partial
hepatectomy) for hepatic metastasis secondary to colon cancer (n 5 5),
hepatic focal necrosis (n 5 3), giant hemangioma (n 5 1), or hydatic cyst
(n 5 1); group II included 16 subjects scheduled for either moderately
severe or light surgery under general anesthesia: colectomy for colon
neoplasia (n 5 4), polyposis (n 5 3), or herniorrhaphy (inguinal: n 5 5;
other: n 5 4); and group III comprised 15 subjects submitted to inguinal
herniorrhaphy under epidural anesthesia. Nineteen of the 24 herniorrhaphy cases were admitted through the 1-day care unit. Exclusion
criteria were: age less than 18 yr or more than 80 yr; emergency surgery,
diabetes, alcoholism (.60 g/day), cirrhosis, malnutrition (albumin ,30
g/L or recent loss of .10% of body weight), chronic renal disease
(creatinine .150 mmol/L), septicemia, steroids in the last 3 months, or
antacids or diuretics in the week preceding surgery or during the study
phase. Patients with significant respiratory (pCO2, ,30 mm Hg) or
metabolic (HCO32, .35 mmol/L) alkalosis (pH . 7.45) during the study
phase were also excluded.
Experimental protocol
The study protocol was approved by a local ethics committee, and
informed consent was obtained from all participants. Anesthesia protocols were standardized. For general anesthesia, only the following
agents could be used: midazolam, propofol, fentanyl, sulfentanyl, enflurane, isoflurane, doxacurium, mivacurium, and succinylcholine. The
regional anesthesia protocol consisted of intraspinal administration of
xylocaine and fentanyl. If necessary, narcotics or anxiolytics could be
used parenterally. Total fluid administration before and during surgery
amounted to 5.6 6 0.5 L (mean 6 se) in group I, 2.3 6 0.4 L in group
II; and 1.2 6 0.08 L in group III. For subjects undergoing moderate and
major surgery, blood samples were obtained on the day before surgery,
after induction of anesthesia but before surgery (time zero), then every
20 min until the end of surgery and on days 1 and 3 postsurgery. For
herniorrhaphy subjects (part of group II and group III), sampling was
2654
HYPOCALCEMIA DURING SURGERY
2655
performed on the morning of the surgery, after anesthesia but before
surgery, then at 20 and 40 min during surgery and before the subjects
left the 1-day care unit.
Laboratory methods
Sodium, potassium, and ionized calcium (reported at pH 7.40) were
measured within 30 min after sampling by direct ISE on a Corning 288
Blood Gas System (Ciba Corning Diagnostics, Medfield, MA). Serum
creatinine, total calcium, phosphorus, albumin, and magnesium were
measured on the day of sampling by automated colorimetry (Baxter
Paramax, Irvine, CA). Serum was also aliquoted, kept at 220 to 270 C
and thawed only once before batch measurement of intact PTH (Allegro,
Nichols Institute Diagnostics, San Juan Capistrano, CA).
Mathematical and statistical analysis
Results are the mean 6 sem. Comparisons against time within each
group of patients were made by ANOVA for repeated measurements
followed by Dunnett’s test for multiple comparisons. Results in the three
subject groups at various time points were compared by ANOVA followed by Bonferroni adjustment for multiple comparisons using Instat
2.03 software (GraphPad Software, Inc., San Diego, CA).
Results
Except for age and male/female ratio, the baseline characteristics of the three groups of subjects, including weight
and creatinine level, were similar. Patients in group II were
older (53.4 6 3.7 vs. 43.5 6 3.1 and 40.8 6 3.3 yr, respectively,
for groups I and III). The proportion of male subjects was
higher in group III (100% vs. 69% and 25% in groups I and
II, respectively). As shown in Fig. 1, significant differences
were also noted before surgery for phosphorus (group I) and
total calcium and albumin levels (groups I and II).
Figure 1 shows that ionized and total calcium, albumin,
and intact PTH levels varied during surgery. Compared to
presurgical levels, the changes were statistically significant
(not shown) for all parameters at all sampling times from
time zero (immediately at the onset of anesthesia but before
surgery) up to 12 h postsurgery in the three groups of subjects with the exception of intact PTH in group III, which did
not differ significantly from presurgical levels. Levels of ionized calcium dropped from normal in each group to minimal
values of 0.99, 1.11, and 1.16 mmol/L at 2 h in groups I–III,
respectively. Total calcium showed similar changes with nadirs at 2 h of 1.84, 2.05, and 2.22 mmol/L. Changes in albumin
levels paralleled those affecting either total or ionized calcium with minimum levels varying from 29 (group I at 0 h),
28 (group 2 at 60 h) to 38 g/L (group III at 40 min). The
relative change in each of these three parameters during
surgery was systematically greater in group I (major surgery), with intermediate results in group II. Finally, intact
PTH levels, although increasing in each of the three groups,
reached abnormal levels only in groups I and II (23.5 and 7.3
pmol/L). Again, the order of change was the same: major
surgery . minor to moderately severe surgery under general
anesthesia . minor surgery under epidural anesthesia.
Phosphorus levels fell significantly in all groups of subjects, but remained within the normal range except for group
I at 60 h, when the fall was significantly greater in group I
(248.6%) than in group II (227.8%). The mean pH remained
within the normal range in each subject (7.36 –7.45), and no
patient had to be excluded from this study because of alkalosis. There was, however, a small, but expected, rise in pH
FIG. 1. Variation (mean 6 SE) in ionized calcium, total calcium, albumin, phosphorus, pH, and intact PTH during major surgery (f;
group I; n 5 10), moderately severe and minor surgery under general
anesthesia (Œ; group II; n 5 16), and minor surgery under epidural
anesthesia (F; group III, n 5 15). Anova followed by Bonferroni adjustment. *, **, and***, P , 0.05, P , 0.01, and P , 0.001 vs. group
III. 1, 11, and 111, P , 0.05, P , 0.01, and P , 0.001 vs. group II.
in the two groups of subjects under general anesthesia; this
was significant only in group I. As also expected, pH showed
no tendency to increase in subjects that were not mechanically ventilated (group III). Magnesium, sodium, and potassium levels were stable during the different surgical procedures (results not shown).
As the changes in ionized and total calcium were very
similar to the fall in albumin, a regression analysis was conducted to evaluate the influence of albumin on both parameters, analyzing separately all pairs of results obtained within
each group during the complete surgical procedure and,
when available, postsurgery samples. The regression parameters are shown in Table 1. All correlations were statistically
significant, with r2 . 0.33 for ionized calcium in groups I and
II. The lower correlation coefficient observed in group III for
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Vol 84 • No 8
LEPAGE ET AL.
TABLE 1. Regression analysis of ionized and total calcium vs. albumin during surgical procedures/anesthesia of different severity
in humans
Calcium
Slope
Intercept
r2
Syzx
P
Major surgery/general anesthesia
Ionized
Total
0.0105
0.0249
0.775
1.204
0.395
0.591
0.778
0.132
,0.0001
,0.0001
Moderate-light surgery/general anesthesia
Ionized
Total
0.0080
0.0236
0.890
1.360
0.328
0.664
0.619
0.895
,0.0001
,0.0001
Light surgery/epidural anesthesia
Ionized
Total
0.0513
0.0174
0.976
1.580
0.106
0.314
0.498
0.826
0.0028
,0.0001
Group
TABLE 2. Variation in albumin-independent ionized and total calcium during surgical/anesthesia procedures of varying severity
in humans
Group
Calcium
Calcium (mmol/L)
Pre
0h
0.7 h
2h
a,b
a,c
12 h
60 h
I
Ionized
Total
1.23 (0.01)
2.27 (0.03)a
1.18 (0.02)
2.14 (0.03)a,b
1.14 (0.02)
2.13 (0.04)a,c
1.08 (0.03)
2.05 (0.05)a,d
1.14 (0.03)
2.05 (0.06)
1.21 (0.03)
2.17 (0.04)b
II
Ionized
Total
1.25 (0.01)
2.32 (0.02)f
1.20 (0.01)
2.27 (0.03)
1.20 (0.01)e
2.27 (0.03)f
1.18 (0.02)
2.22 (0.03)f
1.23 (0.03)
2.20 (0.05)
1.30 (0.03)
2.35 (0.04)
III
Ionized
Total
1.23 (0.01)
2.42 (0.02)
1.21 (0.01)
2.36 (0.02)
1.25 (0.01)
2.39 (0.02)
1.21 (0.01)
2.34 (0.02)
ND
ND
ND
ND
Results are means 6 SE. Group I, Major surgery/general anesthesia (n 5 10); group II, moderate-light surgery/general anesthesia; group III,
light surgery/epidural anesthesia. Significance was determined by ANOVA followed by Bonferroni adjustment.
a
P , 0.001 vs. group III.
b
P , 0.05 vs. group II.
c
P , 0.01 vs. group II.
d
P , 0.001 vs. group II.
e
P , 0.05 vs. group III.
f
P , 0.01 vs. group III.
ionized calcium reflected the modest span of values in this
group of subjects.
Ionized and total calcium levels were adjusted for albumin
variation according to the respective regression parameters.
Albumin- and pH-independent residual variations in ionized and total calcium are shown in Table 2. A residual
variation in ionized calcium that was significantly greater in
groups I and II than in group III can still be noted. In the first
2 h, this difference averaged, respectively, 28.0%, 24.6%,
and 20.5%. The greatest change was observed at 2 h in group
I (212.2%), compared to 24.6% and 23.7% in groups II and
III, respectively.
Discussion
In the absence of massive blood transfusions (12, 13), only
minor falls in ionized calcium have been reported during
standard surgical procedures and have been mostly attributed to changes in pH due to mechanical respiration (15, 16,
18). We are not aware of studies indicating falls in ionized
calcium as important as those reported in this study. The
observed fall in ionized calcium was systematic in all groups
of patients, very rapid (already apparent before surgery),
major (fell below the lower limit of the normal range), and
varied according to the severity of the surgical intervention
(20% to 6%). This decrease in ionized calcium was confirmed
by similar changes in total calcium levels, before and after
correction for the accompanying hypoalbuminemia.
Even though the increase in circulating intact PTH levels
indicated true acute in vivo lowering of ionized calcium levels, sampling of some patients through a heparin lock (group
I and colectomy patients from group II) could have resulted
in underestimation of measured ionized calcium levels (19).
Heparin interferes, however, only with ionized and not with
total calcium measurements (20). A significant heparin interference would have manifested itself as a disproportionate
decrease in the ionized calcium fraction, a situation that we
did not observe. Similar falls of both total and ionized calcium also eliminated any potential interference from an unmeasured in vitro or in vivo chelator (such as globulins or
citrate).
Hypoalbuminemia has been reported as causing a negative interference in the measurement of ionized calcium (21–
29). This interference is approximately 0.0027 mmol/L ionized calcium per g/L albumin when saturated KCl is used in
the reference electrode as was the case in this study (24).
Partial correction of ionized calcium for this interference
represented maximally 0.02 mmol/L in our subjects, still
leaving a significant fall of ionized calcium in each group of
patients that appeared related to the diminished albumin
concentration. This residual fall could not be further modified by adjusting for the small variations of pH observed in
mechanically ventilated subjects. The average rise of 0.024 –
0.038 units of pH corresponded to an insignificant decrease
in ionized calcium of 0.001– 0.002 mmol/L according to the
equation used by the Corning ionized calcium analyzer: Ca21
at pH 7.40 5 Ca21 actual 3 [1 2 0.41 3 (7.4 2 pH)].
The in vivo fall in ionized calcium triggered an immediate
increase in circulating intact PTH proportional to the severity
of the surgical/anesthesia procedure (105– 635%). The increase in intact PTH remained within the physiological range
observed during acutely induced hypocalcemia (30, 31) except for a few points in group I that were well over this range.
HYPOCALCEMIA DURING SURGERY
These points were observed at 120 min in three subjects
subjected to 25–30 min of hylar clamping of the liver. Clamping of both the portal vein and hepatic artery during bouts
of 15 min separated by 10 min of unclamping possibly reduced the major catabolic pathway for intact PTH (32), resulting in excessively high intact PTH levels for the prevailing hypocalcemia.
The fall in albumin already apparent at time zero was
probably the result of the impressive amount of physiological saline administered to patients during surgery, particularly in group I (5.6 6 0.5 L) and group II (2.3 6 0.4 L)
compared to that in group III (1.2 6 0.08 L). An important
fraction of this fluid proportional to the expected length of
the surgery had already been administered upon arrival in
the surgical ward and between the onset of anesthesia and
the beginning of surgery (time zero). This could also explain
why most of the changes in albumin level (and calcium
fractions) were already apparent at time zero, then tended to
stabilize.
At least half of the fall in ionized calcium during the first
40 min of surgery could be attributed to a combined dilutional/measurement effect of albumin. We are not aware of
reported cases of hemodilutional ionized calcemia during
surgery, except through the absorption of hypotonic irrigating fluids (33, 34). This was not the case here, as normal saline
was used in all cases, with only minimal amounts of albumin
or starch in two patients only. Furthermore, with hypotonic
fluid absorption, hyponatremia accompanied ionized hypocalcemia (33, 34). This is not the case here, with completely
stable sodium levels during surgery. It has already been
proposed that dilutional ionized hypocalcemia could result
from acute changes in extracellular water volume considering that the half-time for calcium equilibration from loosely
bound bone salts is around 70 min (35). The exact cause of
the nonalbumin-associated residual decrease in ionized calcium remains to be established, as all of the other major
causes of hypocalcemia (1–16, 36 –38) were not present in our
subjects.
Part of the hypophosphatemia reported in this study may
also have resulted from renal losses of phosphorus due to
extracellular volume expansion (39). The decrease in phosphorus at 60 h after surgery in group I has been observed in
patients undergoing major liver surgery. In addition to all
other known causes of hypophosphatemia in major surgery
patients, posthepatectomy hypophosphatemia has been attributed to a massive intracellular shift of phosphorous in the
already regenerating liver (40, 41).
In conclusion, ionized hypocalcemia accompanied by significant elevation of intact PTH was present during surgical
procedures of varying severity. An important part of this fall
in ionized calcium was apparently associated with falls in
albumin resulting from acute hemodilution by physiological
saline. If one considers that the symptomatic level of hypocalcemia is quite variable and depends largely on its speed
of onset (42), the relatively modest, but very rapid, fall in
ionized calcium observed at the beginning of surgery may
have clinical consequences; however, these remain to be
established.
2657
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