Parenteral calcium administration and outcomes of critically ill patients with hypocalcemia: a retrospective cohort study

doi:10.21203/rs.3.rs-3246669/v1

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Parenteral calcium administration and outcomes of critically ill patients with hypocalcemia: a retrospective cohort study

https://doi.org/10.21203/rs.3.rs-3246669/v1

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Background

Administration of calcium in patients with hypocalcemia admitted to the intensive care unit (ICU) remains disputed, as previous data show conflicting effects on outcome, with a lack of subgroup analyses. This study aimed to investigate the associations between parenteral calcium administration and clinical outcomes in septic and non-septic critically ill patients with serum hypocalcemia.

Methods

This retrospective study included patients who were admitted to a mixed medical-surgical adult ICU in a University-affiliated teaching hospital between October 1, 2015, and September 1, 2020. The primary outcomes were all-cause 180-day mortality and time to shock resolution. Subgroup analyses in septic and non-septic patients with mild or moderate hypocalcemia based on median splits were conducted.

Results

Among the 1,100 patients with hypocalcemia who met the inclusion criteria, 576 (52%) received intravenous calcium. The study found no significant difference in 180-day mortality between patients who received parenteral calcium and those who did not (aHR 1.18, 95% CI 0.90–1.56). Time to shock resolution was more likely to be longer in patients treated with intravenous calcium (aOR 1.23, 95% CI 1.06–1.42). Subgroup analyses revealed that septic patients with mild hypocalcemia in whom pareneteral calcium was administered exhibited an elevated risk of 90- and 180-day mortality (aHR 1.88, 95% CI 1.02–3.47 and 1.79, 95% CI 1.07-3.00, respectively).

Conclusions

The study indicates that intravenous calcium does not confer survival or shock resolution benefits for ICU patients with hypocalcemia and might even pose risks. Further research in the form of randomized controlled trials is needed to confirm this.

Intensive Care

Sepsis

Septic Shock

Calcium

Hypocalcemia

Calcium is an essential ion that fulfills many vital roles in the human body, including influencing hormone secretion, glycogen metabolism, nerve conduction, muscle contraction, blood homeostasis and cell division [1]. Approximately half of the serum calcium is bound to serum proteins and anions, while the other half is available as ionized calcium (iCa) [1, 2]. Serum iCa measurements are commonly used to assess calcium levels in patients admitted to the intensive care unit (ICU) due to changes in albumin and acid-base status [1, 2].

Hypocalcemia, a condition characterized by low levels of calcium in the blood, is very prevalent among ICU patients [1, 2]. It has been suggested that it is facilitated by catecholamines and systemic inflammation in critical illness [1, 3–5], and is associated with poor outcomes, particularly in those who fail to normalize iCa levels during the early stages of critical illness [6–12]. However, several studies did not prove an independent association between low iCa levels and mortality [4, 5, 13, 14]. In addition, most ICU patients do not experience health problems that can directly be related to a hypocalcemic state (i.e., seizures, tetany, and cardiac arrhythmias) [1, 2]. Nevertheless, ICU physicians regularly attempt to correct hypocalcemia by administering calcium [2, 3, 15], driven by studies suggesting that correcting hypocalcemia may improve critically ill patients' hemodynamics by enhancing left ventricular function and vascular resistance [16, 17]. Alongside, critical care guidelines suggest administering intravenous calcium in case of significant hemorrhage accompanied by hypocalcemia or hyperkalemia-related changes on electrocardiogram (ECG) [18, 19]. However, its efficacy in trials has never been confirmed. There is also some evidence that calcium supplementation may be harmful. In murine septic models, calcium administration worsened organ dysfunction and survival rates, possibly by worsening the sepsis-induced calcium imbalance by causing a direct shift of additional calcium into the cells [20–22]. This over-activates calcium/calmodulin-dependent protein kinase pathways, adds to mitochondrial dysfunction, and generates reactive oxygen species resulting in cell injury and vascular leak [20–25]. This hypothesis is supported by increasing evidence that septic patients using calcium-channel antagonists before hospital admission may have better clinical outcomes by inhibiting extracellular calcium from shifting into the cells excessively [26–28].

Previous studies have focused on the association between calcium administration and short-term mortality [14, 23, 29, 30]. However, this may overlook harmful effects of calcium administration that manifest in the longer term (i.e., oxidative stress, mitochondrial dysfunction, and cell damage) [20, 24], as was observed in a recently published, early-terminated clinical trial with calcium administration in cardiac arrest [31]. Even though calcium supplementation is common during ICU admission, only one retrospective cohort study has shown benefit [29], while several others have demonstrated no effect or harm [14, 20, 23, 30]. Moreover, the pathophysiological mechanisms involved in calcium dysregulation may be more profound in sepsis patients, while in non-sepsis patients, calcium administration may improve hemodynamics. Therefore, we aimed to investigate the association between parenteral calcium administration (PCA) and clinical outcomes, including long-term mortality and time to shock resolution, in septic and non-septic critically ill hypocalcemic patients.

Study design and setting

This retrospective cohort study was conducted at a University-affiliated teaching hospital, Gelderse Vallei Hospital, Ede, The Netherlands, which has two adult ICU units with 12 and 5 beds. The study cohort included ICU patients admitted between October 1, 2015, and September 24, 2020. The study was approved by the institutional Review Board (approval nr.2101-012) in compliance with the Helsinki Declaration of 1975 and the Strengthening The Reporting of Observational studies in Epidemiology (STROBE) guideline [32].

Inclusion and Exclusion Criteria

For the study, we included all ICU patients who were at least 18 years old, stayed in the ICU for at least 48 hours, and had at least one iCa measurement available. Patients who received renal replacement therapy (RRT) were excluded to focus on endogenic hypocalcemia. Only the first ICU admission was evaluated, even if patients were readmitted during the same hospital stay.

Data collection

Data were collected from the local electronic patient data management systems; MetaVision® (iMDsoft, Tel Aviv, Israel) and NeoZIS® (MI Consultancy, Katwijk, The Netherlands), including the clinical parameters age, sex, body mass index (BMI), and pre-existing comorbidities. Acute Physiology and Chronic Health Evaluation IV (APACHE IV) score, admission diagnosis, and Barthel-index were extracted from ICU admission records. Daily laboratory results and Sequential Organ Failure Assessment (SOFA) scores were recorded for the first seven days of ICU admission. Data on the duration of vasopressor therapy and ventilator support throughout ICU admission were collected. Dates of death were obtained from the electronic patient record system Xcare® (Nexus, Vianen, the Netherlands) connected to the Dutch population register. All collected data were anonymized and stored on a secure computer system.

Subgroups

The study cohort was subdivided into sepsis and non-sepsis groups based on the assessment by the attending intensivist and recorded in the National Intensive Care Evaluation (NICE) system upon ICU admission. Furthermore, subgroups were formed with patients with hyperkalemia (potassium ≥ 5.5 mmol/L) or clinically significant hemorrhage (excluding cerebral hemorrhage).

Hypocalcemia

Hypocalcemia was defined as a serum iCa < 1.15 mmol/L, according to the local laboratory reference values (iCa 1.15–1.30 mmol/L). iCa measurements were obtained from arterial blood (ABL90 Flex Plus Analyser, Radiometer Medical ApS, Denmark) as part of routine daily measurements. The minimum value on the ICU admission day was used to diagnose hypocalcemia on that day. Patients with hypocalcemia during the first seven days of ICU admission were split into moderate hypocalcemia and mild hypocalcemia based on quartiles of the minimum iCa values of the whole cohort at baseline, as was conducted before [8]. Patients with mild and moderate hypocalcemia during ICU admission were assigned to the moderate hypocalcemia group.

Calcium administration

Calcium was not routinely administered in case of hypocalcemia but was given at the attending physician's discretion typically via intravenous 2000mg calcium gluconate bolus. If deemed safe, 500mg calcium carbonate once daily was continued in case the patient used it before hospital admission. For the study analyses, patients were assigned to the PCA group if they received intravenous calcium gluconate on the day hypocalcemia was observed. Otherwise, they were assigned to the control group. The total amount of intravenous calcium administered in grams during the first seven days of ICU admission was recorded.

Outcomes

The primary outcome was all-cause 180-day mortality. Secondary outcome parameters were duration of mechanical ventilation and vasopressor therapy, and ICU and hospital length of stay (ICULOS and HLOS, respectively). The time between start and 24 hours after cessation of vasopressor therapy was considered the time to shock resolution. Furthermore, ICU-, hospital-, 28-day, and 90-day all-cause mortality was recorded.

Statistical Analysis

Categorical variables are presented as counts and percentages, while continuous variables are presented as means and standard deviations or medians and interquartile ranges [IQR] depending on normality. Normality was tested using Kolmogorov-Smirnov tests and visual inspection of plots. Student’s T-tests were used for normally distributed data; otherwise, Mann-Whitney U tests were applied. Categorical variables were tested using Chi-square tests.

Cox regression analyses were performed to evaluate associations between PCA and outcome parameters, with possible confounders identified using a stepwise approach and the number of covariates matched to the one-to-ten rule. Covariates were excluded in case of multicollinearity (e.g., Spearman's correlation coefficient > 0.7) or when the proportional hazard assumption was violated. Whenever multivariable analyses provided significant associations PCA and 180-day mortality, additional multivariable models were generated for 28- and 90-day mortality. Survival function plots were generated, and a two-sided p-value < 0.05 was considered statistically significant. All statistical analyses were performed using IBM SPSS Statistics 29.0 (IBM Corporation, Armonk, NY, USA; 2022).

Study population

A total of 1,468 patients were newly admitted to the ICU from October 1, 2015, and September 24, 2020. After excluding patients who received RRT (n = 119) and did not have iCa measurements available (n = 29), 1,320 patients met the inclusion criteria (Fig. 1.). Of this group, 12,599 individual iCa measurements were available. Median iCa at baseline of the whole cohort was 1.10 mmol/L [IQR 1.06–1.15]. Based hereupon, iCa levels < 1.06 mmol/L were considered moderate hypocalcemia and 1.06–1.14 mmol/L was defined as mild hypocalcemia. In 1,100 (83%) patients, hypocalcemia was observed during the first seven days of ICU admission. These patients were included in the primary analyses. The median age of hypocalcemia patients was 70 [IQR 59–77] years; 59% were male, and 427 (39%) were admitted to the ICU due to sepsis.

[Insert Fig. 1 here]

Parenteral calcium administration

Of the 1100 patients with hypocalcemia, 576 (52%) received PCA. In most cases (62%), calcium was administrated within 24 hours of ICU admission. Fifty percent of the PCA group received calcium on day 2 of ICU admission and 30% on day 3. The median intravenous dosage of calcium that patients received throughout the first seven days of ICU admission was 2000mg [IQR 2000–6000]. A comparison between baseline and ICU admission characteristics of hypocalcemic patients who received PCA versus those who did not is shown in Table 1. Of the 73 patients with hyperkalemia (potassium ≥ 5.5 mmol/L), 40 (54%) received PCA.

Table 1

Baseline characteristics of study patients
Baseline variables	Total, n = 1100	No IV administration, n = 503	IV Administration, n = 576	p-value
Age, years	70 [59–77]	68 [56–76]	71 [61–78]	0.003
Sex, female	451 (41)	224 (43)	227 (39)	0.361
BMI on admission (kg/m²)	26.5 [23–30]	26.8 [23.5–30.5]	26.3 [23.0–30.1]	0.167
APACHE IV-score	69 [48–84]	67 [52–84]	74 [61–91]	< 0.001
SOFA-score	5 [3–7]	6 [3–8]	7 [5–9]	< 0.001
Barthel-index	20 [16–20]	20 [18–20]	20 [18–20]	0.596
Comorbidities
COPD	257 (23)	135 (26)	122 (21)	0.073
DM	275 (25)	123 (24)	152 (26)	0.265
Baseline blood tests
CRP (mg/L)	96 [18–214]	80 [15–211]	108 [24–216]	0.075
Albumin (g/L)	26 [21–32]	28 [23–34]	25 [20–29]	< 0.001
Creatinine (umol/L)	82 [61–123]	83 [64–123]	100 [71–151]	< 0.001
Arterial pH ^a	7.32 [7.24–7.40]	7.34 [7.25–7.41]	7.31 [7.23–7.39]	0.025
Arterial lactate ^b	2.2 [1.4–3.7]	1.8 [1.2]	2.6 [1.6–4.3]	< 0.001
Glucose (mmol/L) ^c	8.5 [7.3–10.3]	8.2 [7.2–10.0]	8.9 [7.36–10.5]	0.005
Baseline elektrolytes
Minimum iCa (mmol/L)	1.09 [1.05–1.13]	1.12 [1.09–1.14]	1.03 [1.07–1.10]	< 0.001
Maximum iCa (mmol/L)	1.16 [1.12–1.20]	1.17 [1.13–1.21]	1.15 [1.10–1.20]	< 0.001
Sodium (mmol/L) ^c	138 [135–141]	138 [135–141]	138 [135–141]	0.692
Magnesium (mmol/L) ^c	0.72 [0.61–0.83]	0.75 [0.64–0.85]	0.70 [0.59–0.81]	< 0.001
Potassium (mmol/L) ^c	3.9 [3.6–4.4]	3.9 [3.6–4.3]	4.0 [3.6–4.4]	0.123
Phosphate (mmol/L) ^c	1.05 [0.84–1.33]	1.05 [0.86–1.29]	1.05 [0.81–1.39]	0.528
ICU admission type
Elective surgical	99 (9)	43 (8)	56 (10)	0.290
Emergency surgical	213 (20)	72 (14)	142 (25)	< 0.001
Medical	782 (71)	407 (78)	375 (65)	< 0.001
ICU admission diagnosis
Sepsis	427 (39)	185 (35)	242 (42)	0.023
Hemorrhage ^d	48 (5)	11 (2)	37 (6)	< 0.001

Abbreviations: IV = intravenous; BMI = Body Mass Index; APACHE = Acute Physical and Chronic Health Evaluation; SOFA = Sequential Organ Failure Assessment score; COPD = Chronic Obstructive Pulmonary Disease; DM = Diabetes Mellitus; CRP = C-reactive Protein; iCa = ionized calcium; ICU = Intensive Care Unit; IQR = Interquartile Range
^aMinimum value on admission day; ^bMaximum value on admission day; ^cMean value on admission day; ^dExcluding cerebral hemorrhage
Categorical variables are presented as number (percentages) and continuous variables as median [IQR]
Missing data was observed in the following baseline characteristics (n): BMI (26), APACHE-IV (5), SOFA-score (4), Barthel-index (60), CRP (12), Albumin (28), Creatinine (12), Arterial pH (10), Arterial Lactate (12), Glucose (131), Sodium (12), Magnesium (51), Potassium (21) and Phosphate (49).

Outcome data

One-hundred-eighty-day survival was available for all patients included in the primary analysis. Two-hundred fifty-five patients (23%) in whom hypocalcemia was observed died within 180 days of ICU admission. A comparison of baseline characteristics between survivors and non-survivors is displayed in Table S1. Of the hypocalcemic patients in the PCA group, 153 patients (27%) died within 180 days after ICU admission, compared to 102 patients (19%) in the control group (Hazard Ratio [HR] 1.49, 95% confidence intervals [CI] 1.16 – 1.92). In multivariable analysis, PCA was not associated with 180-day mortality (adjusted HR [aHR] 1.19, 95% CI 0.90 – 1.56; Figure 2; Table S2).

[Insert Figure 2 here]

Sepsis and non-sepsis

Differences in baseline characteristics between patients that received PCA and those who did not, within the four subgroups, are depicted in Tables S3.1–S3.4. In both septic and non-septic patients, PCA was associated with increased 180-day mortality (HR 1.63, 95% CI 1.09 – 2.43, and HR 1.42, 95% CI 1.02 – 1.97, respectively; Figure 3.1 and 3.2; Table S4.1 and S4.2). In multivariable analysis,, the association between PCA and 180-day mortality reached near-significance (aHR 1.63, 95% CI 0.99 – 2.69) in septic patients, but in non-septic patients this was not significant (aHR 1.20, 95% CI 0.83 – 1.69).
Sepsis and non-sepsis patients were divided into patients with mild or moderate hypocalcemia. In sepsis patients with mild hypocalcemia, multivariable analyses revealed an association between PCA and increased 180- and 90-day mortality (aHR 1.79, 95% CI 1.07, 3.00 and 1.88, 95% CI 1.02 – 3.47, respectively; Table S4.1.1 and Table S4.1.2), but no difference in 28-day mortality (aHR 1.19, 95% CI 0.64, 2.23; Table S4.1.3). Multivariable analyses in the remaining subgroups provided no significant associations between PCA and 180-day mortality (Table S4.1.3–S4.2.2).

[Insert Figure 3A and Figure 3B here]

Time to shock resolution

Patients who received PCA had a longer duration of vasopressor therapy (3days [2 – 5] vs. 4days [3 – 7], p = 0.001). In multivariable regression analysis, a longer time to shock resolution was more likely to occur in the group that received PCA (adjusted Odds Ratio [aOR] 1.23, 95% CI 1.06 – 1.42; Table S5). Subgroup analyses revealed a longer time to shock resolution was more common in both septic and non-septic patients with mild hypocalcemia who received PCA (aOR 1.35, 95% CI 1.03 – 1.79 and aOR 1.41, 95% CI 1.09 – 1.84, respectively; Table S5.1.1 and Table S5.2.1).

Additional analyses
Univariable comparison between the PCA and control group of additional outcome parameters, including HLOS, mechanical ventilation duration, ICU, 28-day and 90-day mortality, within the subgroups are presented in Table S6.1, Table S6.2 and Table S6.1.1–Table S.2.2. The association between ICULOS and PCA was not significant in multivariable analysis (aOR 1.10, 95% CI 0.94, 1.29; Table S7). In patients with hemorrhage or hyperkalemia, PCA was not associated with 180-day mortality (HR 1.05, 95% CI 0.29 – 3.75 and HR 2.23, 95% CI 0.66, 7.52, respectively; Table S8) or shorter time to shock resolution (aOR 0.66, 95% CI 0.17 – 2.54 and aOR 1.34, 95% CI 0.61 – 2.95, respectively; Table S9.1 and Table S9.2)

In this retrospective cohort study among ICU patients with serum hypocalcemia, we found no evidence of benefit from intravenous calcium administration on long-term mortality and time to shock resolution. In fact, hypocalcemic patients who received intravenous calcium administration had longer durations of ICULOS, mechanical ventilation and vasopressor therapy, as well as lower survival rates in univariable comparison. After adjusting for covariates, intravenous calcium administration was independently associated with a longer time to shock resolution. Moreover, subgroup analyses revealed that PCA in sepsis patients with mild hypocalcemia was independently associated with increased all-cause 90- and 180-day mortality.

Serum hypocalcemia frequently occurs in critically ill patients, especially in those with excessive inflammation and catecholamine release [4, 12, 14, 20, 21]. The pathophysiological mechanisms are poorly understood. However, they may result from drug side effects and critical illness affecting calcium homeostasis, causing high intracellular calcium and low extracellular iCa [1, 3-5]. The reported prevalence rates of hypocalcemia among ICU patients vary, likely due to differences in studied populations and cutoff values used [2]. Our study found hypocalcemia, defined as iCa<1.15 mmol/L, in 83% of ICU patients during the first seven days of admission, consistent with previous studies [4, 5].

Retrospective studies report mixed results on the association between hypocalcemia and mortality in ICU patients [6-13, 30]. Severe and persistent hypocalcemia during critical illness show the strongest associations with mortality [4, 14, 28, 33]. Still, the causality between iCa levels and adverse outcomes remains unclear, and hypocalcemia could be an adaptive response to critical illness, reflecting severity of disease [2]. Furthermore, spontaneous normalization of iCa levels is often observed throughout critical illness [14, 15, 33]. Nevertheless, attempts to correct hypocalcemia by administering intravenous calcium are frequently undertaken in ICU patients [2, 15, 33], as was observed in more than half in our studycohort.

Currently, guidelines suggest supplementing calcium in patients with major bleeding and hypocalcemia since calcium plays a vital role in coagulation [18] and low iCa levels may be predictive of poor clinical outcomes in these patients [34]. However, no available data demonstrate benefits of pursuing normocalcemia in these patients [35]. Similarly, while it is common practice to administer calcium to stabilize the myocellular membrane in hyperkalemia-induced ECG abnormalities, no randomized controlled trial (RCT) has demonstrated its effectiveness [19]. In the current study, no association was observed between PCA and faster shock reversal or improved survival in the subsets of patients with hyperkalemia and hemorrhage.
Recently, an RCT showed no beneficial effects of calcium administration on the return of spontaneous circulation in patients with out-of-hospital cardiac arrest and was stopped prematurely because fewer patients in the treatment arm reported a favorable neurological outcome and quality of life at 90 days [31]. The authors hypothesized that administering calcium may result in cytosolic and mitochondrial calcium overload, which could stimulate oxidative stress and activate calcium-dependent proteolytic pathways. This hypothesis is similar to the mechanisms proposed for calcium-induced toxicity in critical illness, particularly sepsis. Several studies using septic animal models have demonstrated increased morbidity and mortality following PCA, possibly due to activation of destructive enzymes resulting in mitochondrial dysfunction and cell injury [20, 22, 24, 25, 36].

Older papers suggest calcium supplementation may improve hemodynamics by increasing vascular resistance, and left ventricular function by its positive inotrope effect [16, 17, 37]. However, a long-lasting clinically relevant benefit on hemodynamic parameters has never been described in the critically ill. Dotson et al. report that PCA is associated with in-hospital mortality, acute respiratory failure, and new-onset shock in ICU patients receiving parenteral nutrition [23]. In the current study, a longer time to shock resolution was observed in PCA patients, even after adjusting for confounders relevant to hemodynamic status, such as mechanical ventilation duration, albumin, and SOFA scores. Although causal inferences cannot be made from our data, it can be hypothesized that calcium administration may have increased vascular leak, causing more extended vasopressor dependency [20, 23].

Only one study has shown a potential benefit for calcium supplementation in ICU patients, indicating an independent association with lower mortality rates [29]. However, the proportion of patients admitted due to sepsis was not reported. A sub-analysis in sepsis patients derived from the same database demonstrated higher 28-day mortality after calcium supplementation when admission iCa was 1.01–1.20 mmol/L, while those with iCa<1.01 mmol/L could benefit from supplementation [30]. In the present cohort, PCA showed a trend toward significance in increasing 180-day mortality in sepsis patients with hypocalcemia. In those with mild hypocalcemia, PCA was associated with decreased 90- and 180-day survival, which is in line with the results of He et al. [30]. Nevertheless, the association between PCA and 28-day mortality was not significant. This observation is similar to the findings from the RCT by Vallentin et al. in cardiac arrest patients and may be explained by the long-term toxic effects of calcium overload, such as mitochondrial damage [21, 31]. Furthermore, duration of vasopressor therapy is known to contribute to ICULOS and ICU-acquired muscle weakness, which has been associated with morbidity and poor long-term outcomes [41-43]. Whether this has led to poor long-term outcomes in the present cohort remains unknown and requires investigation in a prospective trial with follow-up after ICU- and hospital discharge.

The results of this study should be interpreted considering some limitations. Firstly, this is a cohort study of retrospective nature, a design which has inherent limitations. Secondly, as in most ICUs, calcium was administered at the discretion of the attending ICU physician, potentially introducing selection bias as patients who received calcium administration may have been more seriously ill. Finally, the database was not sufficient to adjust for other potential covariates for vasopressor dependency, such as fluid balance and left ventricular function. Nevertheless, we were able to adjust for several strong predictors of mortality including age, APACHE IV, SOFA score, duration of vasopressor therapy, and Barthel index.

Hypocalcemia and calcium administration frequently occur in a large cohort of critically ill patients. However, we did not find that parenteral calcium administration was related to improved outcomes. Conversely, it may prolong the time to shock resolution and reduce long-term survival in septic patients. These findings should discourage routine calcium administration in critically ill patients with hypocalcemia. However, an RCT is warranted to confirm our findings, elucidate the underlying mechanisms, and establish evidence-based treatment guidelines.

iCa ionized calcium

ICU intensive care unit

ECG electrocardiogram

PCA parenteral calcium administration

STROBE Strengthening The Reporting of Observational studies in Epidemiology

RRT renal replacement therapy

BMI body mass index

APACHE IV Acute Physiology and Chronic Health Evaluation IV

SOFA Sequential Organ Failure Assessment

NICE National Intensive Care Evaluation

ICULOS ICU length of stay

HLOS hospital length of stay

IQR interquartile range

CI confidence intervals

HR hazard ratio

aHR adjusted hazard ratio

OR odd’s ratio

aOR adjusted odd’s ratio

RCT randomized controlled trial

Ethics approval and consent to participate
The study titled ‘Hypophosphatemia and hypocalcemia: course, supplementations and associations with outcome in the general intensive care population’ was approved by the institutional Review Board (approval nr. 2101-012) of Gelderse Vallei Hospital, Ede, on February 4^th, 2021.

Consent for publication
Not applicable

Availability of data and materials
The data supporting the conclusions of this article are not publicly available due to the requirements of the institutional review board committee, but can be considered by the institutional review board committee through reasonable request via the corresponding author.

Competing interest

The authors declare that they have no competing interests.

Funding
No funding was received to assist with the preparation of this manuscript.

Authors’ contributions
MM, HM and AvZ conceptualized and designed the study. TB and HM acquired the data. MM analyzed and interpreted the data. MM drafted the manuscript. MM, HM, TB, SvB and AvZ critically reviewed the manuscript for important intellectual content. AvZ supervised the project and guided the literature review. All authors read and approved the final version of the manuscript.

Acknowledgements

We would like to thank Dr. MJ Caldas Paulo (Wageningen University & Research, the Netherlands) for her guidance on the use of proportional hazard regression analyses.

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Parenteral calcium administration and outcomes of critically ill patients with hypocalcemia: a retrospective cohort study

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Abstract

Background

Methods

Results

Conclusions

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Background

Methods

Study design and setting

Inclusion and Exclusion Criteria

Data collection

Subgroups

Hypocalcemia

Calcium administration

Outcomes

Statistical Analysis

RESULTS

Study population

Parenteral calcium administration

Discussion

Conclusions

Abbreviations

Declarations

References

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