5/5/2015
Calcium’s role
Impact of a national calcium gluconate
shortage in ICU patients receiving
parenteral nutrition
Jasmine U. Patel, PharmD
PGY1 Pharmacy Resident
Detroit Medical Center
Harper University Hospital
• Calcium is essential to many physiologic
functions:
– Cardiac contractility
– Blood coagulation
– Nerve conduction
– Muscle contraction
– Enzyme activity
The speaker has no actual or potential conflicts of interest in relation to this presentation.
Cochrane Database of Systematic Reviews 2008; 4:1-24.
Hypocalcemia: definition,
symptoms, and consequences
Parenteral calcium for ICU patients is
controversial
• Ionized calcium (iCa) < 1.13 mmol/L
• High prevalence in ICU patients; ~ 88%
• Severe hypocalcemia symptoms:
hypotension, decreased cardiac output,
seizures, and tetany
• Linked to increased ICU mortality
• Intracellular calcium dysregulation occurs
– Unknown if this association is causal
Cochrane Database of Systematic Reviews 2008; 4:1-24.
Parenteral nutrition (PN)
– Increased even when serum calcium is low
– Exogenous calcium may further increase
intracellular calcium leading to inflammation, cell
injury, and cell death
• Animal and observational studies report
calcium supplementation increases organ
dysfunction and mortality
• There are no randomized controlled trials
Cochrane Database of Systematic Reviews 2008; 4:1-24.
Crit Care Med 2013; 41:e352-e360.
Drug shortages have increased
• Direct intravenous (IV) feeding
• Enteral nutrition is preferred over PN because of
fewer complications and lower cost
• Guidelines recommend PN in ICU patients with a
non-functional GI tract after 7 days of starvation
– Sooner if patients are malnourished
• Components include macronutrients, electrolytes,
and micronutrients
• Although calcium gluconate is often added to PN
in the ICU, its effects have not been evaluated
Journal of Parenteral and Enteral Nutrition. 2009; 33(3): 277-316.
Mayo Clin Proc. 2014 Mar;89(3):361-73.
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Reasons for drug shortages
Our aim
• In ICU patients receiving PN, we
measured the impact of the calcium
gluconate shortage on:
– Calcium administration
– Serum iCa levels
– Clinical outcomes
Recreated from Drug Shortages and Quality Care in the
ICU. www.sccm.org. Last assessed March 23, 2015.
Study design
Retrospective study conducted in adults who received PN in the
ICU for ≥ 48 hours
Jan. 1, 2012
Feb. 1, 2013
Mar. 25, 2014
Pre-shortage
During-shortage
135 patients
Calcium gluconate
1-2 grams/day in PN
133 patients
No calcium gluconate in PN
IV calcium supplementation if required
Study was approved by DMC Institutional Review Board (IRB) and Wayne State University IRB
Three large teaching hospitals
Patient enrollment
• Harper University Hospital
• Inclusion criteria:
– 470 beds
• Detroit Receiving Hospital
– 248 beds
• Sinai-Grace Hospital
– 383 beds
– ≥ 18 years old
– Received PN in the ICU for ≥ 48 hours
• Exclusion criteria:
– Received plasmapheresis with citrated products
– Recent neck surgery
• Thyroidectomy, parathyroidectomy
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Data collection
Data collection
Clinical characteristics
Outcome variables
• Demographic information
• Type of ICU patient
• Acute Physiology and Chronic Health Evaluation
(APACHE) II score
• iCa prior to starting PN
• Factors that could affect iCa
• Duration of PN
• Amount of calcium added to
PN
• IV calcium supplementation
administered outside of PN
• Cumulative calcium
administration
• Whether each patient
received enteral calcium
Statistical analysis
Patient demographics
• Outcomes were compared between the preshortage and during-shortage groups
• Data reported as median with interquartile
ranges or percentages with 95% confidence
intervals
• Mann-Whitney U test
• Chi-square test
• Logistic regression was used to determine
predictors of death
• P-value < 0.05 significant
Pre-shortage
(n = 135)
During-shortage
(n = 133)
p
62 (51, 71)
59 (51, 71)
0.75
Gender, male (%)
61 (53 to 70)
57 (49 to 66)
0.47
African Americans (%)
72 (64 to 80)
67 (59 to 75)
0.18
79 (66, 96)
73 (62, 87)
0.01
Body mass index, kg/m2
26.6 (23.0, 32.0)
25.0 (21.0, 29.9)
0.01
Obese: BMI ≥ 30 (%)
36 (28 to 44)
25 (18 to 32)
0.05
5 (1 to 9)
12 (7 to 18)
0.047
Surgical ICU (%)
86 (80 to 92)
90 (85 to 95)
0.28
Sepsis (%)
62 (54 to 70)
67 (59 to 75)
0.42
20 (14, 24)
21 (15, 27)
0.16
19 (12 to 25)
29 (22 to 37)
0.04
Parameter
Age, years
Weight, kg
Underweight: BMI < 18.5 (%)
APACHE II score
APACHE II score > 25 (%)
Patient demographics
Calcium administered while on PN
Pre-shortage
(n = 135)
During-shortage
(n = 133)
p
1.13 (1.09, 1.19)
1.12 (1.05, 1.18)
0.038
4.0 (1.4, 7.4)
3.4 (0.6, 6.9)
6 (4, 13)
6 (4, 11)
Cancer (%)
27 (19 to 34)
Renal disease (%)
Received loop diuretics (%)
Parameter
Serum iCa pre-PN (mmol/L)
PN start after ICU admission (days)
PN duration in ICU (days)
Received enteral calcium (%)
Received IV calcium supplementation
while not on PN (%)
Total calcium supplemented (g)
Total calcium supplemented in
patients who required
supplementation (g)
• Lowest, highest, and mean
iCa
• Whether any iCa was < 1.13,
< 1, < 0.9, and > 1.32 mmol/L
• Measures of organ
dysfunction
• ICU length of stay
• Hospital length of stay
• ICU mortality
• In-hospital mortality
Pre-shortage
(n = 135)
During-shortage
(n = 133)
p
Received any calcium (%)
99 (98 to 100)
32 (24 to 40)
0.000
0.31
Total calcium received (g)
9.1 (5.6, 17.8)
0.0 (0.0, 1.0)
0.0000
0.80
Total daily calcium (g/day)
1.5 (1.0, 2.2)
0.0 (0.0, 0.2)
0.0000
26 (18 to 33)
0.84
Received calcium in PN (%)
99 (98 to 100)
8 (3 to 12)
0.000
27 (20 to 35)
34 (26 to 42)
0.25
Total calcium added to PN (g)
8.9 (5.3, 17.6)
0.0 (0.0, 0.0)
0.0000
41 (32 to 49)
47 (38 to 55)
0.33
Calcium added to PN (g/day)
7 (3 to 12)
3 (0 to 6)
0.11
Received IV calcium
supplementation
outside of PN (%)
Cumulative calcium
supplementation (g)
Total calcium supplemented in
patients who required
supplementation (g)
Parameter
38 (30 to 46)
38 (30 to 46)
0.99
0 (0, 2)
0 (0, 2)
0.87
3 (1, 4)
2 (1, 6)
0.79
1.5 (1.0, 2.2)
0.0 (0.0, 0.0)
0.0000
20 (13 to 27)
26 (19 to 34)
0.22
0.0 (0.0, 0.0)
0.0 (0.0, 1.0)
0.16
2.0 (1.0, 4.0)
(n = 27)
3.0 (1.0, 6.0)
(n = 35)
0.22
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Serum ionized calcium outcomes
Prevalence of hypo- and hypercalcemia
P=0.001
P=0.000
P=0.000
Predictors of mortality
Organ dysfunction, LOS, and mortality
Parameter
Required mechanical
ventilation (%)
Pre-shortage
(n=135)
During-shortage
(n=133)
p
64 (56 to 73)
64 (56 to 72)
0.93
Length of ventilation, hours
48 (0, 221)
48 (0, 156)
0.30
Required vasoactive support (%)
31 (23 to 39)
32 (24 to 40)
0.83
0 (0, 2)
0 (0, 2)
0.95
Duration of vasoactive support,
days
Duration of vasoactive support
for treated patients, days
3 (2, 6)
0.50
3 (2, 4)
Multivariate Analysis
Variables
OR
95% CI
p-value
Age > 75 years
1.8
0.7 to 4.6
0.25
APACHE II score > 25
2.7
1.2 to 5.9
0.02
During-shortage
0.76
0.4 to 1.6
0.46
iCa < 1
1.9
0.8 to 4.5
0.13
1.0
0.4 to 2.7
0.96
Acute kidney injury (%)
26 (19 to 34)
19 (12 to 26)
0.18
Mechanical ventilation
Acute hepatic dysfunction (%)
22 (15 to 29)
26 (19 to 34)
0.43
Vasoactive support
5.1
2.4 to 10.5
0.000
13.7 (8.0, 24.5)
13.3 (8.8, 23.3)
0.90
AKI
0.9
0.6 to 1.3
0.52
18 (11 to 24)
14 (8 to 20)
0.44
1.2
0.5 to 2.6
0.7
26.2 (18.2, 40.0)
26.7 (19.0, 40.9)
0.74
2.7
1.3 to 6.0
0.01
23 (16 to 30)
21 (14 to 28)
0.71
Sepsis
Acute hepatic
dysfunction
ICU length of stay, days
Deaths in the ICU (%)
Hospital length of stay, days
Deaths in the hospital (%)
Predictors of mortality
Study limitations
Multivariate Analysis
Variables
OR
95% CI
p-value
Age > 75 years
1.8
0.7 to 4.6
0.25
APACHE II score > 25
2.7
1.2 to 5.9
0.02
During-shortage
0.76
0.4 to 1.6
0.46
iCa < 1
1.9
0.8 to 4.5
0.13
Mechanical ventilation
1.0
0.4 to 2.7
0.96
Vasoactive support
5.1
2.4 to 10.5
0.000
AKI
0.9
0.6 to 1.3
0.52
Sepsis
Acute hepatic
dysfunction
1.2
0.5 to 2.6
0.7
2.7
1.3 to 6.0
0.01
• Retrospective observational study
• Small sample size
• Not powered to detect differences in clinical
outcomes
• Could not easily determine whether patients
with hypocalcemia were symptomatic
• The threshold for calcium supplementation
and replacement strategies may have varied
among providers and patients
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Study strengths
Conclusion
• Use of multivariate analysis to control for
confounding factors
• Use of objective outcomes
• Assessment period of 1 year before and
after the shortage to avoid confounding
from seasonal variation
• No major practice changes in our ICUs
during the study period
• Natural experiment
• A national calcium gluconate shortage
resulted in:
Learning question #1
Learning question #1
Which one of the following is a common
cause of drug shortages?
Which one of the following is a common
cause of drug shortages?
a. Available supplies that exceed demands
b. Manufacturing problems
c. Excess of raw materials
d. Financial incentives to produce a product
a. Available supplies that exceed demands
b. Manufacturing problems
c. Excess of raw materials
d. Financial incentives to produce a product
Learning question #2
Learning question #2
When would a provider recommend
administering parenteral calcium in an ICU
patient?
When would a provider recommend
administering parenteral calcium in an ICU
patient?
a. Patient with an iCa of 0.85 mmol/L, who is in
shock
b. Patient experiencing shortness of breath
c. Patient experiencing hypercalcemia
d. Patient with acute kidney injury
a. Patient with an iCa of 0.85 mmol/L, who is in
shock
b. Patient experiencing shortness of breath
c. Patient experiencing hypercalcemia
d. Patient with acute kidney injury
- Substantial decrease in calcium administration
- Lower iCa levels
- Increased prevalence of hypocalcemia
• Clinical outcomes were unaffected
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Acknowledgements
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Bryan Dotson, PharmD, BCPS
Peter Whittaker, PhD
Steven Tennenberg, MD
Lina Y. Qasem
Patrick Larabell, BA, BS
William Arthur, RPh
Kristoffer Wong, DO
Chaim Leiberman, RN
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