Acta Med. Okayama, 2015
Vol. 69, No. 4, pp. 197ﾝ204
CopyrightⒸ 2015 by Okayama University Medical School.

http://escholarship.lib.okayama-u.ac.jp/amo/

Hemodynamic Effects of Intravenous Calcium Administration
on Septic Shock Patients: A Retrospective Study
Naoki Ishibashia, Koji Miyashoa, Tetsuhisa Kitamurab, Takaaki Ookumaa,
Nobuhiro Kashitania, Nobuhiko Beikaa, Takahiro Yamashitaa, and Yoshihito Ujikec＊
a

‑

b
c

‑
‑

We evaluated the hemodynamics and outcomes of septic shock (SS) patients who did not respond to
ﬂuid resuscitation, after treatment with or without intravenous calcium. We retrospectively collected
information on 154 eligible SS patients who were admitted to Fukuyama City Hospital Emergency
Medical Center and did not respond to ﬂuid resuscitation. To compare their degree of hemodynamic
impairment, we compared the changes in the vasoactive-inotropic score (VIS) in the calcium-treatedgroup (n ＝ 112) and the noncalcium-treated group (n ＝ 42). We compared the length of stay in the intensive care unit (ICU) and hospital, in-hospital deaths, 28-day deaths, and changes in the Sequential
Organ Failure Assessment score within 72h of ICU admission between the 2 groups. Changes in the
VIS at 1h after the baseline time were signiﬁcantly greater in the calcium-treated group than in the
noncalcium-treated group (1.41 vs. −1.25, respectively; ＜ 0.001). However, the changes in the VIS at
3, 6, 24, 48, and 72h did not diﬀer between the 2 groups. The secondary outcomes also did not diﬀer
between the groups. Our ﬁndings indicate that calcium administered to SS patients might reduce their
hemodynamic stabilization, but only for a short time after its administration.
Key words: hemodynamics, calcium, shock, sepsis

Severe sepsis and septic shock cause high mortality in intensive care units (ICUs) [1, 2].
Although potent antibiotics and procedures have beendeveloped for these diseases, the mortality rate iscurrently 30‑50ｵ in patients with severe sepsis andcan exceed 50ｵ in septic shock (SS) patients [3].
The incidence of patients with severe sepsis is also
increasing [4, 5]. Guidelines for the management ofsevere sepsis and septic shock have not been well
Received September 25, 2014 ; accepted January 30, 2015.
Corresponding author. Phone :＋81ﾝ86ﾝ235ﾝ7426; Fax :＋81ﾝ86ﾝ235ﾝ6601
E-mail : ujike@cc.okayama-u.ac.jp (Y. Ujike)＊established, and the development of eﬀective strategies for the treatment of SS patients is an important
issue worldwide [6].
It has been reported that the concentration of ionized calcium is reduced in septic patients and that thisreduction is associated with the severity of sepsis andpatient mortality [7, 8]. A paper has also suggested
that the administration of calcium reduces the doses ofinotropic and vasopressor agents required by criticallyill patients with ionized hypocalcemia, by increasing
Conﬂict of Interest Disclosures: No potential conﬂict of interest relevantto this article was reported.

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Ishibashi et al.

the myocardial contractility and vascular tonus [9]. In
animal model studies, the administration of calcium
increased the mortality of septic rats [10], whereas
it improved sepsis-related myocardial suppression withno deleterious events [11]. Human studies have shown
no beneﬁts of calcium administration to septic patients[12, 13]. The eﬀectiveness of calcium administration
to septic patients thus remains unclear.
In the Emergency Medical Center of Fukuyama
City Hospital, intravenous calcium is sometimes
administered to SS patients with ionized hypocalcemia
who are receiving inotropic and/or vasopressor agents.
This retrospective study assessed the hemodynamics
and outcomes of SS patients treated with or without
intravenous calcium.

Subjects and Methods
This was a retrospective,
single-center study. We enrolled SS patients who had
been admitted to the Emergency Medical Center of
Fukuyama City Hospital and were administered intravenous catecholamine. The catecholamine, predominantly dopamine or noradrenaline, was administered
to those SS patients who did not respond to ﬂuid
resuscitation. The observational period was from
April 1, 2005 to March 31, 2013. The study protocol was approved by the Institutional Review Board of
Fukuyama City Hospital.
Fukuyama City
Hospital, located in the eastern area of Hiroshima
Prefecture, Japan, has 506 beds and 7 regular intensivists in its Emergency Medical Center (24 beds in
the ICU). In the ICU, the attending doctors from eachdepartment are responsible for the treatment of theirpatients in collaboration with the intensivists.
Approximately 1,400 patients are admitted to thiscenter every year, and 60 of them had sepsis during
the study period. Intravenous calcium was administered to the SS patients receiving a catecholamine
based on the judgment of the attending physicians
and/or intensivists.
In accordance with the deﬁnition of the American
College of Chest Physicians/Society of Critical Care
Medicine Consensus Conference Committee [14, 15],
we deﬁned sepsis as a systemic inﬂammatory response
to infection; we deﬁned severe sepsis as sepsis associated with organ dysfunction, hypoperfusion, orActa Med. Okayama Vol. 69, No. 4

hypotension, and we deﬁned septic shock as severe
sepsis with persistent hypotension (systolic bloodpressure ＜ 90mmHg or a reduction of ｧ 40mmHg
from baseline), associated with organ perfusion abnormalities that were not improved by ﬂuid resuscitation,or with normotension sustained by inotropic or vasopressor agents. The SS patients were treated according to the guidelines for the management of severe
sepsis and septic shock [6, 16, 17].
The exclusion criteria for this study were:children aged ＜ 18 years, pregnant women, patientswith burns, terminally ill patients (do-not-attemptresuscitation), and patients with postcardiac arrest,
neutropenia caused by chemotherapy, a history oforgan transplantation, or nonseptic shock ( , anaphylactic shock) within 72h of admission. Patients
without data on the dose of catecholamine within 72h
after admission were also excluded.
Information on the characteristics and outcomes of
the SS patients was extracted retrospectively fromtheir medical records, including age, sex, the Acute
Physiology and Chronic Health Evaluation (APACHE)
II score [18], the Sequential Organ Failure Assessment(SOFA) score [19], the type and dose of inotropic
and vasopressor agents given, mean arterial pressure,
intravenous calcium administered, laboratory data at
ICU admission (white blood cell count, concentrationsof ionized calcium, sodium, potassium, and creatinine), 24-h urine volume, renal replacement therapy,transfusion of red cell concentrate, fresh frozen
plasma, or platelet concentrate, corticosteroid therapy, treatment for disseminated intravascular coagulation, the time interval from admission to calcium
administration, the lengths of ICU and hospital stays,
in-hospital death, and 28-day death.
Among the SS patients who received a catecholamine, we deﬁned those who were administeredintravenous calcium within 24h of admission as the“calcium-treated group,” and those who were notadministered intravenous calcium within 24h of admission as the “noncalcium-treated group.”
The primary endpoint was
the change in the vasoactive-inotropic score (VIS)[20], an index of the required amount of hemodynamic support, which can be used as a surrogate forthe degree of hemodynamic impairment. A higher VIS
indicates a greater vasopressor requirement. We were
therefore able to assess the hemodynamic diﬀerences

August 2015

Calcium for Septic Shock Patientsamong the SS patients treated with or without intravenous calcium by comparing the changes in their
VISs. The formulae for the VIS and inotropic score
are:
VIS ＝ inotropic score ＋ 10 × milrinone dose ( g/kg/min) ＋ 10,000 × vasopressin dose (U/kg/min) ＋
100 × noradrenaline dose ( g/kg/min) [20]Inotropic score ＝ dopamine dose ＋ dobutamine dose
＋ 100 × adrenaline dose (all doses in g/kg/min) [21]The secondary endpoints were the lengths of ICU andhospital stays, in-hospital deaths, 28-day deaths, andthe change in the SOFA score 72h after ICU admission.
The patient characteristics and outcomes of the 2 groups ( , the groups withand without intravenous calcium) were compared.
Continuous variables are presented as means and 95ｵ
conﬁdence intervals (CIs), and diﬀerences were analyzed with the Mann-Whitney U-test; categoricalvariables are expressed in percentages (n/N), anddiﬀerences were analyzed with the χ2 test or Fischerʼsexact test. We compared changes in the VIS values ofthe 2 groups at 1, 3, 6, 24, 48, and 72h from base-

Septic patients admitted to
Fukuyama City Hospital Emergency
Medical Center from April 1, 2005
to March 31, 2013
n = 452

Septic shock patients who received
catecholamine n = 164line. We deﬁned the baseline as the time at which
intravenous calcium was administered for the ﬁrst
time (the calcium-treated group) or when the patient
was admitted to the ICU (the noncalcium-treatedgroup), because the patientʼs hemodynamic condition
would be most unstable at the baseline. All data wereanalyzed with SPSS Statistics software, version
21.0J (IBM Corp. Armonk, NY, USA). Two-sided-values ＜ 0.05 were considered signiﬁcant, and we
also used the Bonferroni correction method to correct
the problem of multiple comparisons for changes in the
VIS values of the 2 groups.

Results
Between April 2005 and March 2013, 452 septic
patients were admitted to the Emergency Medical
Center of Fukuyama City Hospital (Fig. 1). We
excluded 181 patients who were not in shock, 65 who
did not receive a catecholamine within 72h of ICU
admission, 42 who did not meet our inclusion criteria,
and 10 who had no available data on the dose of catecholamine. Therefore, 154 SS patients who wereNo shock patients n = 181
Septic patients not administered catecholamine within
72 h of ICU admission n = 65
Did not meet our criteria n = 42
Burn n = 16
DNAR n = 9
CPA n = 8
Other shock n = 5Child n = 1
Other n = 3
No available data on the dose of catecholamine n = 10

Eligible patientsn = 154

Calcium-treated groupn = 112Fig. 1

199

Noncalcium-treated groupn = 42

Patient ﬂow. ICU, intensive care unit; DNAR, do-not-attempt-resuscitation; CPA, cardiopulmonary arrest.

200

Ishibashi et al.

administered a catecholamine (112 in the calciumtreated group and 42 in the noncalcium-treated group)
were eligible for our analysis.
Table 1 shows the characteristics of the SS
patients who received a catecholamine, with or without intravenous calcium, at ICU admission. There
were no signiﬁcant diﬀerences in the age or sex of the
2 groups. The dose of vasopressin (0.008 vs. 0.003
units/min, respectively; ＝ 0.032), the requirement
for fresh frozen plasma (11.0 vs. 7.3 units,
respectively; ＝ 0.013), and platelet concentrate (8.8
vs. 3.4 units, respectively; ＝ 0.032) were signiﬁcantly higher in the calcium-treated group than in the
noncalcium-treated group, and the number of whiteblood cells was signiﬁcantly lower in the calcium-

Acta Med. Okayama Vol. 69, No. 4

treated group (11,900 vs. 15,400/ L, respectively;＝ 0.012). However, all other factors were almost
identical between the 2 groups. In the calcium-treatedgroup, the mean time interval from ICU admission to
calcium administration was 3.3h.
To compare the degree of hemodynamic impairment
in the 2 groups, we compared the changes in VIS at
1, 3, 6, 24, 48, and 72h from baseline (Table 2).
The VIS values at baseline were similar in the calcium- and noncalcium-treated groups (7.10 vs. 7.08,
respectively; ＝ 0.872). The change in the VIS at 1hfrom baseline was signiﬁcantly greater in the calciumtreated group than in the noncalcium group (1.41 vs.
−1.25, respectively; ＜ 0.001). This -value wasstill signiﬁcant when the Bonferroni correction tested

Table 1
Characteristics of septic shock patients treated with a catecholamine with or without intravenous calcium administration at ICU
admission
Calcium‑treated group(n ＝ 112)
Age, yMen, no. (%)
APACHE II score
SOFA score＊
Mean arterial pressure, mmHg†
Noradrenaline, µg/kg/min†
Dopamin, µg/kg/min†
Vasopressin, units/min†
Inotropic score†
Laboratory data
White blood cell count, 1,000/µL
Ionized calcium, mmol/L
Sodium, mmol/L
Potassium, mmol/L
Creatinine, mg/dL
Diuresis, mL/24 hRenal replacement therapy, no. (%)
Transfusion‡
RCC, units
FFP, units
PC, units
Corticosteroids, no. (%)
DIC therapy, no. (%)
Time interval from ICU admission to calcium administration, hours

Noncalcium‑treated group(n ＝ 42)P value

72
73
33.5
11.5
68.1
0.017
3.7
0.008
3.91

(70‑74)65.2(32.1‑34.9)(10.8‑12.1)(64.9‑71.3)(0.007‑0.027)(3.0‑4.5)(0.005‑0.010)(3.16‑4.66)

74
24
30.5
10.4
74.3
0.014
4.7
0.003
5.12

(71‑78)57.1(28.0‑32.9)(9.3‑11.4)(67.8‑80.9)(0.001‑0.027)(3.0‑6.4)(0.000‑0.006)(3.36‑6.88)

0.320
0.358
0.068
0.094
0.234
0.792
0.433
0.032
0.326

11.9
1.12
133
3.8
2.2
3,473
36

(10.0‑13.9)(1.11‑1.14)(132‑134)(3.7‑4.0)(1.9‑2.5)(2,845‑4,101)
32.1

15.0
1.15
133
3.9
2.1
3,878
10

(12.1‑17.8)(1.12‑1.17)(131‑135)(3.7‑4.0)(1.1‑3.2)(2,927‑4,829)
23.8

0.024
0.181
0.889
0.748
0.083
0.238
0.314

2.7
11.0
8.8
43
81
3.3

(2.0‑3.4)(8.9‑13.1)(6.1‑11.4)
38.4
72.3
(2.5‑4.1)

1.7
5.3
3.4
14
25
‑

(0.8‑2.5)(2.8‑7.8)(1.0‑5.8)
33.3
59.5
‑

0.103
0.002
0.032
0.562
0.127

ICU denotes Intensive Care Unit; APACHE II, acute physiology and chronic health evaluation II; SOFA, sequential organ failure
assessment; RCC, red cell concentrate; FFP, fresh frozen plasma; PC, platelet concentrate; DIC, disseminated intravascular coagulation. Data are means (95% conﬁdence interval).
＊
The SOFA score was missing for 28 patients in the calcium-treated group and 14 in the noncalcium-treated group.
†
These values in the calcium-treated group were obtained when intravenous calcium was administered initially after ICU admission.
‡
Total transfusion units within 72 h after ICU admission.

7.10(5.55‑8.65)

1.62

3.05

7.45

8.32

8.23

8.51

(0.80‑2.45)

After 72 h

(2.09‑4.02)

After 48 h

(5.07‑9.83)

After 24 h

(6.45‑10.20)

After 6 h

(6.57‑9.90)

After 3 h

(6.88‑10.2)

After 1 h
(0.53‑2.30)(−0.20‑2.47)(−0.48‑2.92)(−2.16‑2.86)(−5.67 to −2.42)−5.47(−6.99 to −3.96)

Δ72 h (72 h‑baseline)−4.05

Δ48 h (48 h‑baseline)

0.35

Δ24 h (24 h‑baseline)

1.22

Δ6 h (6 h‑baseline)

1.13

Δ3 h (3 h‑baseline)

1.41

Δ1 h (1 h‑baseline)
7.08(4.35‑9.82)

Baseline†

1.06

1.93

3.97

6.18

6.60

5.84

(0.47‑1.66)

After 72 h

(0.99‑2.87)

After 48 h

(2.72‑5.21)

After 24 h

(3.99‑8.36)

After 6 h

(4.03‑9.17)

After 3 h

(3.03‑8.64)

After 1 h

Noncalcium-treatedgroup (n ＝ 42)(−2.06 to −0.44)(−1.47‑0.49)(−2.28‑0.46)(−5.88‑0.35)(−8.13 to −2.18)−6.02(−8.86 to −3.18)

Δ72 h (72 h‑baseline)−5.15

Δ48 h (48 h‑baseline)−3.12

Δ24 h (24 h‑baseline)−0.91

Δ6 h (6 h‑baseline)−0.49

Δ3 h (3 h‑baseline)−1.25

Δ1 h (1 h‑baseline)

0.871

0.638

0.178

0.313

0.087

−2.4

(−3.2 to −1.7)(7‑11)(29‑41)
27.7
21.6

ICU denotes Intensive Care Unit; SOFA, sequential organ failure assessment.
＊
The SOFA score was missing for 49 patients in the calcium-treated group and 24 in the noncalcium-treated group.

Change in SOFA score 72 h after ICU admission, mean (95% conﬁdence interval)＊

9
35
31
24

Calcium-treated group(n ＝ 112)

−2.3

9
45
7
5

(−3.2 to −1.4)(6‑11)(30‑61)
16.7
11.9

Noncalcium-treated group(n ＝ 42)

Secondary endpoints of septic shock patients treated with a catecholamine with or without intravenous calcium administration

ICU stay, day, mean (95% conﬁdence interval)
Hospital stay, day, mean (95% conﬁdence interval)
In-hospital death, no. (%)
28-day death, no. (%)

Table 3

＊

0.932

0.495
0.290
0.158
0.178

P value‡＜0.001

P value＊

P values assess the diﬀerences between the changes in the physiological endpoints at 1, 3, 6, 24, 48, and 72 h from baseline in the calcium-treated and noncalcium-treated groups.
†
Baseline time in the calcium-treated group means the time of ﬁrst calcium administration, and in the noncalcium-treated group means the time of ICU admission.
‡
This P value was statistically signiﬁcant when the Bonferroni correction tested each individual hypothesis at α＝ 0.05/6 ＝ 0.00833.
All data are means (95% conﬁdence intervals).

Vasoacitve-inotropic
score (VIS)

Baseline†

Calcium-treatedgroup (n ＝ 112)

Table 2
Changes in vasoactive-inotropic score (VIS) at 1, 3, 6, 24, 48, and 72 h from baseline among septic shock patients treated with a catecholamine with or without
intravenous calcium administration
August 2015
Calcium for Septic Shock Patients
201

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Ishibashi et al.

Acta Med. Okayama Vol. 69, No. 4each individual hypothesis at α＝ 0.05/6 ＝ 0.00833.
The changes in the VIS at 3, 6, 24, 48, and 72h did
not diﬀer between the 2 groups.
The secondary outcomes,, the lengths of the
ICU and hospital stays, in-hospital deaths, 28-day
deaths, and changes in the SOFA score 72h after
ICU admission, did not diﬀer between the 2 groups(Table 3).

Discussion
The results of this retrospective single-center
study demonstrated that the changes in VIS among SS
patients at 1h from baseline were signiﬁcantly greaterin the patients treated with calcium compared to theno-calcium group, whereas the changes in the VIS at
3, 6, 24, 48, and 72h were similar between the 2groups. These results suggest that the administrationof calcium temporarily increases the requirement for
inotropic and vasopressor agents in SS patients andhas a deleterious eﬀect on their hemodynamic stabilization.
The guidelines for the management of severe sepsis
and septic shock do not recommend the routine use of
pulmonary artery catheters for SS patients [6], andinformation on these patientsʼ hemodynamics, including
the cardiac index and the systemic vascular resistanceindex (which are measured directly from the pulmonary catheter) is not available for most SS patients.
Therefore, unlike previous studies, we assessed thehemodynamics of SS patients who were treated withor without intravenous calcium by using the VIS,
calculated from the patientsʼ requirement for inotropic
and vasopressor agents. The VIS was originallydeveloped as an index of cardiovascular support during
the perioperative period among infants who underwent
congenital heart surgery [20] and was also used toassess the hemodynamics of adult patients receiving
cardiac surgery [22].
Vasoactive agents such as vasopressin and milrinone are now available for the management of patientswith severe sepsis or septic shock [6, 16, 17, 23],
and we therefore assessed the hemodynamics in SS
patients by using the VIS, which can reﬂect the inﬂuence of these drugs. We thus believe that the present
studyʼs ﬁndings provide valuable information for thetreatment of SS patients.
Here we evaluated whether the intravenous admin-

istration of calcium aﬀects the hemodynamics andoutcomes of SS patients. Why is the ionized calcium
concentration reduced among septic patients, and is
this reduction associated with the severity of theirdisease and their mortality? Although the deﬁnitive
mechanism underlying hypocalcemia in septic patientsis unclear, their hypocalcemia might be partly explainedby hypoparathyroidism, vitamin D deﬁciency, resistance to parathyroid hormone or activated vitamin D,
or calcium inﬂux into the cells and tissues [12].
Cardiovascular dysfunction, caused by the depressionof myocardial contractility and the loss of vascular
tonus, occasionally occurs in septic patients [24,25]. The relationship between ionized hypocalcemia
and cardiovascular dysfunction is still contentious, but
it is speculated that cardiovascular dysfunction inseptic patients is caused not by ionized hypocalcemia
alone, but by complex processes mediated by manyfactors ( , tumor necrosis factor, interleukin 1,
platelet-activating factor, oxygen free radicals, andnitric oxide) [26, 27].
In this study, we found that the changes in the VIS
at 1h from baseline were signiﬁcantly greater in the
calcium-treated group than in the noncalcium-treatedgroup. The results of previous studies that assessed
the hemodynamics of septic patients treated with orwithout calcium are controversial. The continuous
administration of intravenous calcium increased themean arterial pressure in septic rats for only 15min[10]. Although the mechanism that causes intravenous calcium to aﬀect the cardiovascular systems of
septic patients only temporarily remains unclear, theresults of that animal study [10] are consistent withours in terms of the temporal eﬀects of calcium.
However, in contrast to our results, the eﬀect on the
cardiovascular system was positive.
A human study demonstrated that the administration of calcium was not associated with signiﬁcantchanges in the ﬂow, ﬁlling pressures, or systemic or
pulmonary vascular resistance in septic patients [28].
In other studies, calcium inﬂux into cells resulted inelevated intracellular calcium concentrations in septic
patients, and this elevation was associated with cell
dysfunction and death [29‑31].
In the present study, the secondary outcomes,
including the lengths of ICU and hospital stays, inhospital deaths, 28-day deaths, and changes in the
SOFA score at 72h from ICU admission did not diﬀer

August 2015

signiﬁcantly between the 2 groups. Importantly, theguidelines for the management of severe sepsis andseptic shock do not refer to the administration of calcium to SS patients [6, 23]. A recent systematic
review concluded that there was no evidence to support the treatment of critically ill patients for
hypocalcemia [13]. The results of our study support
this conclusion.
Moreover, an observational study of 870 septic
patients revealed that calcium administration was
associated with an increased risk of death, a signiﬁcantly increased risk of renal dysfunction, and a signiﬁcant reduction in ventilator-free days [32].
However, there are still few data on the eﬀects ofcalcium administration to septic patients, and large
observational studies or randomized controlled trials
that investigate the eﬀects of calcium administration
on SS patients are required to conﬁrm our results.
This study had some inherent limitations. First, it
was conducted retrospectively, and there was potential selection bias. For example, intravenous calcium
was administered to SS patients based on the judgement of the attending physicians and/or intensivists.
In addition, we did not investigate the method ofadministration or the target concentration of calcium.
Second, although the SS patients in this study weretreated according to the guidelines for the management of severe sepsis and septic shock [6, 16, 17],
there was no standard protocol for administering thecatecholamine ( , type, timing, and dose). Third,
we did not assess the inﬂuence of factors associatedwith calcium homeostasis, such as magnesium depletion, hypoparathyroidism, and vitamin D deﬁciency[12]. Finally, unmeasured confounding factors might
have inﬂuenced the association between the administration of calcium and the outcomes measured here.
In this retrospective single-center observational
study, we demonstrated that the change in the VIS of
SS patients at 1h from baseline was signiﬁcantly
greater in the calcium-treated patients than in the
noncalcium-treated patients, which suggests that theadministration of calcium to SS patients has a deleterious eﬀect on their hemodynamic stabilization for ashort time after its administration. Large observational studies or randomized controlled trials are
essential to verify the eﬀects of calcium administration on SS patients and to test our results.

Calcium for Septic Shock Patients203

Acknowledgments. We are deeply indebted to all the staﬀ and physicians at Fukuyama City Hospital.

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