Uncontrolled exsanguinating hemorrhage after traumatic injury remains the most common cause of potentially preventable death,1 with 11% of all mortality and 13% of disability-adjusted life years globally attributed to injury.2 Death from hemorrhagic shock occurs rapidly within 2 to 6 hours postinjury,3–5 necessitating expeditious resuscitative strategies through a combination of hemostatic interventions and timely blood product administration.6
During hemorrhagic shock and subsequent resuscitation, pathways reliant upon calcium such as platelet function, intrinsic and extrinsic hemostasis, and cardiac contractility are disrupted.7,8 It has been suggested that, in hemorrhagic shock, hypocalcemia may result from intracellular flux secondary to ischemia and reperfusion.9,10 While blood components including ions such as calcium are lost in hemorrhagic shock,11 impaired calcium homeostasis and increased sympathetic activity also contribute to hypocalcemia in critically ill patients.12 Citrate containing products such as packed red blood cell and fresh frozen plasma are also known to perpetuate hypocalcemia during resuscitation,13 especially in shocked patients unable to metabolize citrate adequately because of reduced hepatic function secondary to hypoperfusion and hypothermia.14,15 Current literature has highlighted the pervasiveness of hypocalcemia as a metabolic derangement in critically ill patients, with incidence as high as 97.3%.16 It is therefore hypothesized that timely recognition and correction of hypocalcemia in the hemorrhaging major trauma patient may ameliorate such disruptions while also augmenting hemostatic, ionotropic, and chronotropic mechanisms.17
Current literature has focused on the effects of transfusion-induced hypocalcemia on hemorrhagic shock, while evidence on pretransfusion, hemorrhage-induced hypocalcemia, and impairments in calcium homeostasis are scant. The objective of this systematic review was to examine current literature for associations between pretransfusion, admission ionized hypocalcemia, and composite outcomes including mortality, blood transfusion requirements, and coagulopathy in adult trauma patients.
PATIENTS AND METHODS
This study was reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist (Fig. 1) (https://links.lww.com/TA/B849),18 which has been included in Appendix (PROSPERO Review Protocol and Registration, CRD42020105135).
This systematic review searched English and non-English literature. Subject headings (/) were used in the following way: (Calcium/bl, df [Blood, Deficiency] or Hypocalcemia/bl, co, mo [Blood, Complications, Mortality]) and (shock/or shock, hemorrhagic/or shock, traumatic/or Critical Illness/or “wounds and injuries”/or abdominal injuries/or amputation, traumatic/or back injuries/or contrecoup injury/or crush injuries/or foreign bodies/or fractures, bone/or multiple trauma/or neck injuries/or shock, traumatic/or spinal cord injuries/or thoracic injuries/or war-related injuries/or wounds, nonpenetrating/or wounds, penetrating/). Key words (“”) were used in conjunction with the “adjacent to one another within 5 words” function in the following way: ((hypocalc?emi* or ioni?ed calcium or ioni?edhypocalc?emia) adj5 (traum* or shock* or critical* ill*)).mp. Because of the paucity of current literature on the topic, we chose not to apply further limits to our studies, instead manually excluding studies as described hereinafter.
We included all trauma patients 18 years or older with an admission ionized calcium measurement before blood transfusion and all study types except case reports and series and studies on animals.
We excluded studies where patients had received blood products before the initial ionized calcium measurement, because of the well-known phenomenon of transfusion-induced hypocalcemia.19 Studies where ionized calcium concentrations were not obtained on arrival before blood transfusion were also excluded to maintain methodological consistency.
We searched for articles from Ovid MEDLINE extending from its commencement to May 3, 2020. We also screened reference lists of numerous studies for relevant articles that might not otherwise have been captured.
Following the search, duplicates were removed, and titles were subsequently appraised for eligibility independently by two authors (M.V. and J.K.M.). The abstracts of the selected titles were read, and full texts were sought for articles meeting the inclusion criteria. Reference lists of relevant articles were checked for additional studies.
We extracted data including hospital setting, study type, country of treatment, cohort size, incidence of admission ionized hypocalcemia, ionized hypocalcemia definitions, and the following outcomes: mortality, blood transfusion requirements, and coagulopathy.
Assessment of Quality
We used the Newcastle-Ottawa Scale20 to assess the quality of selected studies.
A total of 585 abstracts were screened through database searching and alternative sources. Six unique full-text studies were reviewed, of which three were excluded. Study characteristics are listed in Table 1, while a summary of the results has been tabulated in Table 2.
TABLE 1 -
Summary of Studies
|Cherry et al.21
||N = 396
*LoCa ≤1.0 mmol/L
|Magnotti et al.22
||N = 591
LoCa <1.0 mmol/L
|Vasudeva et al.23
||N = 226
LoCa <1.11 mmol/L
*LoCa — ionized hypocalcemia.
TABLE 2 -
Results of Studies
||Outcomes of Interest
|Cherry et al.21
||Mortality: 26.4%* vs. 16.7%**; p < 0.05; OR, 1.92
|Magnotti et al.22
||Mortality: 15.5%* vs. 8.7%**; p = 0.036
Transfusion (≥5 U): 17.1%* vs. 7.1%**; p = 0.005
Transfusion (≥10 U): 8.2%* vs. 2.2%**; p = 0.017
|Vasudeva et al.23
||Mortality: 25.6%* vs. 15.0%**; p = 0.047
Transfusion: 62.5%* vs. 37.5%**; p < 0.001
Coagulopathy*: aOR, 2.9; 95% CI, 1.01–8.3; p = 0.048
OR, odds ratio.
Admission ionized hypocalcemia (defined as ≤1.0 mmol/L) was associated with increased mortality and decreased time to death21 in 396 American trauma patients by Cherry et al.21 Twenty-three percent of the study population was hypocalcemic on admission. Mortality rates were 26.4% and 16.7% (p < 0.05; odds ratio, 1.92) in the hypocalcemic and normocalcemic groups, respectively.
Similarly, hypocalcemic trauma patients were found to experience a higher mortality rate (15.5% vs. 8.7%, p = 0.036) in a prospective study by Magnotti et al.22 Hypocalcemia was also associated with a need for both multiple (17.7% vs. 7.1%, p = 0.005) and massive transfusions (8.2% vs. 2.2%, p = 0.017). Hypocalcemia was defined as <1.0 mmol/L, with 56.2% of the study population displaying this aberrancy on admission. Multiple transfusions meant being administered ≥5 U of packed red cells in 24 hours, while massive transfusions meant being administered ≥10 U in 24 hours. Hypocalcemia was identified as an independent predictor of the need for multiple transfusions after accounting for age and injury severity (adjusted odds ratio [aOR], 2.294; 95% confidence interval [CI], 1.053–4.996).
A retrospective study of 226 level 1 trauma patients in Australia by Vasudeva et al.23 identified a higher mortality rate in the hypocalcemic cohort on hospital discharge (25.6% vs. 15.0%, p = 0.047). Requirement for blood transfusion was also associated with hypocalcemia (62.5% vs. 37.5%, p < 0.001). They also found hypocalcemia to be independently associated with coagulopathy (aOR, 2.9; 95% CI, 1.01–8.3; p = 0.048). In this study population, 50% of the study population was hypocalcemic, defined as <1.11 mmol/L.
Study selection, comparability of groups, and outcome ascertainment were assessed (S/C/O) with a total of eight items and a maximum score of 9 (S4/C2/O3).20 We also assessed quality based on study design, blinding, and number of reviewers. The overall quality of the studies was moderate. Magnotti et al.22 scored 7 over 9, Cherry et al.21 scored 6/9, and Vasudeva et al.23 scored 7/9. None of the studies were blinded nor explicitly stated the utilization of different reviewers for data collection and cross checking (Table 3).
||NOS Rating (S/C/O)
||Number of Reviewers
|Cherry et al.21
||Not explicitly stated
|Magnotti et al.22
||Not explicitly stated
|Vasudeva et al.23
||Not explicitly stated
NOS, Newcastle-Ottawa Scale.
This review identified three studies in Australia and United States with a total of 1,213 trauma patients. The studies identified an association between hypocalcemia and mortality, blood transfusion requirements, and coagulopathy. While Cherry et al.21 noted an incidence of 23.0% hypocalcemia on admission, Magnotti et al.22 and Vasudeva et al.’s23 studies saw higher incidences at 56.2% and 50%, respectively. This is in keeping with other studies that have reflected admission hypocalcemia in up to 74% of the study population.11
Higher mortality rates were observed in hypocalcemic patients in all three studies.21–23 Not surprisingly, numerous other studies have identified such an association in similar patient populations.24 For example, Ho and Leonard25 identified a correlation between hypocalcemia and mortality in trauma patients requiring blood transfusions, while Vinas-Rios et al.26 and Manuel et al.27 identified hypocalcemia as a prognostic factor for early mortality in traumatic brain injury. While Ho and Leonard’s25 study was confounded by the prior use of blood products in resuscitation, their analysis did attempt to adjust for the use of packed red cells. Similarly, Choi and Hwang16 identified hypocalcemia in adult trauma patients as a significant risk factor for mortality, albeit without excluding patients who had received blood products prior to ionized calcium measurement.
Vivien et al.,11 in a separate prospective study of 212 severe patients of whom 64% were hypocalcemic, identified hypocalcemia as a prognostic factor for mortality with an inversely proportionate relationship between mortality and ionized calcium levels. In hypocalcemic trauma intensive care unit (ICU) patients, hypocalcemia tends not to normalize,28 lending further credence to its prognostic value. A review of hemostasis in trauma by Lier et al.29 found that ionized hypocalcemia of <1.0 mmol/L significantly increases patient mortality regardless of injury severity, with a threefold increase in mortality noted when ionized calcium concentrations trend below 0.88 mmol/L.
While Magnotti et al.22 and Vasudeva et al.23 were able to identify an association between hypocalcemia and blood transfusion requirements, the severity of hypocalcemia in critically ill trauma patients has previously been shown to parallel transfusion requirements.24,30 Increased transfusion needs are also known to be an independent predictor of increased mortality31,32 in trauma patients. This makes ionized calcium a useful adjunct to other biochemical markers such as base excess and lactate in the early phase of resuscitation and prognostication of trauma patients.22
Hypocalcemia was significantly associated with coagulopathy on arrival to the emergency department (odds ratio, 5.5; 95% CI, 2.8–10.8; p < 0.001) in Vasudeva et al.’s23 study. A multivariate analysis including known associated clinical variables including Injury Severity Score, Glasgow Coma Scale, bicarbonate, and lactate identified an independent association between hypocalcemia and coagulopathy (aOR, 2.9; CI, 1.01–8.29). This is the only known study to have identified such an association in shocked trauma patients, lending credence to the previously proposed hypothesis associating hypocalcemia and poor clot strength25 in critically ill patients. This is especially so for ionized calcium concentration levels of <1.0 mmol/L, with one study suggesting a cutoff of 0.9 mmol/L for hypocalcemia to influence coagulopathy.33 The importance of this association is highlighted by studies that have identified coagulopathy in severely injured trauma patients before any blood product administration, which increases the risk of rapid exsanguination and death from hemorrhagic shock.34,35 Nonetheless, consensus data on what constitutes a clinically symptomatic cutoff for ionized hypocalcemia are scant, with the European guidelines suggesting replenishment of calcium when ionized calcium levels fall below 0.9 mmol/L, albeit in the context of transfusion.36 Furthermore, viscoelastic measurements may not directly highlight the negative impact of hypocalcemia on coagulation because of preanalysis blood sample recalcification, which makes ascertainment of a causative relationship challenging with standard viscoelastic testing.
No studies have examined the association between hypocalcemia and sudden cardiac arrest in critically ill trauma patients. However, ionized hypocalcemia on admission has been described in patients suffering from cardiac arrest by in a prospective series by Gando et al.37 Hypocalcemia has also precipitated cardiac arrhythmias and frank cardiac failure in massive transfusion patients.38,39 Vasopressor requirements can also be as high as 41% of hypocalcemic medical ICU patients as opposed to 14% in their normocalcemic counterparts.40 Cherry et al.21 were also able to appreciate the independent association between pre-hospital hypotension and hypocalcemia.
A 2020 review of two randomized controlled trials focusing on treatment of traumatic hemorrhagic shock with plasma identified a high risk of hypocalcemia in the plasma treatment arm, which was in turn associated with reduced survival and predictive of massive transfusion.41 These findings are particularly important in the context of the increasing ubiquity of plasma-based resuscitation in high-risk trauma patients, further highlighting the dangers of hypocalcemia in the periresuscitative period.
The cyclical and self-perpetuating relationship between blood loss, hypocalcemia, and abnormal coagulation unsurprisingly leads to significant mortality with a shorter median time to death in hypocalcemic patients.21 Because fluid resuscitation measures lead to hemodilution and exacerbate hypocalcemia, timely correction of hypocalcemia might arrest this vicious cycle and ameliorate mortality24,42 related to exsanguination and end-organ damage in the critically ill trauma patient population. Nonetheless, it remains to be seen if this will impact length of hospital stay, as Cherry et al.21 found no difference between hypocalcemic and normocalcemic bleeding trauma patients. However, in severe hypocalcemia, ICU length of stay is increased.43
Replacement of blood loss is a cornerstone of management in trauma patients.23 The European guideline on management of major bleeding and coagulopathy following trauma36 recommends ionized calcium levels be monitored and maintained within the normal range during massive transfusion with appropriate administration of calcium chloride to correct hypocalcemia. The prevalence of hypocalcemia in up to 97% of trauma patients within 24 hours of massive transfusions17 further highlights the importance of treating this aberrancy to ameliorate outcomes such as mortality, blood transfusion requirements, and coagulopathy.
While none of the studies included in this review studied the potential therapeutic benefit of timely correction of hypocalcemia in trauma patients, there is some evidence to suggest benefit in correction of hypocalcemia. In a retrospective review of 297 military combat trauma patients who received an average of 4 U of blood products before hospital admission, hypocalcemia was present in 28.3% of the cohort treated with 10 mL 10% intravenous calcium chloride, while hypocalcemia was evident in 70.0% of the nontreatment group.42 In shocked patients requiring colloids, calcium-containing haemaccel infusions have been reliably found to increase ionized calcium concentrations.44
Although in the context of transfusion, Giancarelli et al.17 identified a threshold of 0.9 mmol/L to commence calcium therapy in the form of 2 g of calcium chloride for every 2 to 4 U of blood products transfused given that even 1 U of blood can cause hypocalcemia in trauma patients.42 Dickerson et al.45 suggested a short-term infusion of 4 g of intravenous calcium gluconate for the treatment of moderate to severe hypocalcemia in critically ill, adult multiple injury patients. Correction of hypocalcemia in certain subsets of this patient population yields an improvement in left ventricular function and mean arterial pressure.46,47
Hypocalcemia has only been sparsely studied in the context of trauma patients and even less so in patients whose calcium levels have not been confounded by prior blood transfusions. We therefore had to exclude several studies,16,25 which examined the association between hypocalcemia and the composite outcomes discussed in this review. Our review is also subject to publication bias48 because studies that did not identify an association between hypocalcemia and any of the aforementioned outcomes in critically ill trauma patients might simply not have been published.
In considering Magnotti et al.’s22 results, only 10% of the study population required massive transfusions. This reduces the predictive power of hypocalcemia and the need for massive transfusions in the critically ill trauma patient. Vasudeva et al.’s23 study population was relatively small, with only 64 patients displaying coagulopathy. All three studies also failed to account for mechanistic variables such as coagulation factor levels and fibrinolysis, which could potentially confound the association between hypocalcemia and associated outcomes. These studies are observational and therefore only hypothesis generating, although providing ample clinical indication for protocolized calcium replacement in shocked patients through a randomized controlled trial.
It is also worth considering that a small subset of the critically ill trauma patient population might in fact suffer the often initially asymptomatic adverse effects of hypercalcemia including seizures and respiratory arrest,49,50 although this has only been noted in patients who have been immobilized for several weeks and not lost significant quantities of blood. In such a patient population, prehospital correction of presumed hypocalcemia may be superfluous or potentially even dangerous. In traumatic brain injury patient populations, ionized hypocalcemia has also displayed a protective function through mitigation of intracellular calcium-induced apoptosis through reduced lipase activation and reduced inhibition of mitochondrial enzymatic processes.26
In conclusion, hypocalcemia is a common finding in shocked trauma patients, in whom death can occur rapidly. Review of current published literature indicates a focus on transfusion related hypocalcemia or its association with mortality without accounting for prior blood product administration. This systematic review has identified moderate quality evidence on the association between transfusion-independent hypocalcemia and mortality, blood transfusion needs, and coagulopathy. However, further prospective trials are needed to corroborate this relationship and identify possible therapeutic measures that might mitigate the aforementioned outcomes.
M.V., J.K.M., and M.C.F. conceived the study methodology and design. M.V. conducted the literature search with study selection performed with J.K.M. M.V. and J.K.M. analyzed the data and drafted the article. All authors contributed substantially to revision of the article. M.V. takes responsibility for the article.
We thank Ms. Lorena Romero, Alfred Health Ian Potter Library, for her assistance in helping refine our database search strategy.
The authors declare no conflicts of interest.
1. Holcomb JB, McMullin NR, Pearse L, et al. Causes of death in U.S. Special Operations Forces in the global war on terrorism: 2001-2004. Ann Surg
2. Curtis K, Caldwell E, Delprado A, Munroe B. Traumatic injury in Australia and New Zealand. Australas Emerg Nurs J
3. Sauaia A, Moore FA, Moore EE, Moser KS, Brennan R, Read RA, Pons PT. Epidemiology of trauma deaths: a reassessment. J Trauma
4. Kauvar DS, Lefering R, Wade CE. Impact of hemorrhage on trauma outcome: an overview of epidemiology, clinical presentations, and therapeutic considerations. J Trauma
. 2006;60(Suppl 6):S3–S11.
5. Heckbert SR, Vedder NB, Hoffman W, Winn RK, Hudson LD, Jurkovich GJ, Copass MK, Harlan JM, Rice CL, Maier RV. Outcome after hemorrhagic shock
in trauma patients. J Trauma
6. Zink KA, Sambasivan CN, Holcomb JB, Chisholm G, Schreiber MA. A high ratio of plasma and platelets to packed red blood cells in the first 6 hours of massive transfusion
improves outcomes in a large multicenter study. Am J Surg
. 2009;197(5):565–570 discussion 70.
7. Kauvar DS, Holcomb JB, Norris GC, Hess JR. Fresh whole blood transfusion
: a controversial military practice. J Trauma
8. Palta S, Saroa R, Palta A. Overview of the coagulation system. Indian J Anaesth
9. Barry GD. Plasma calcium concentration changes in hemorrhagic shock
. Am J Physiol
10. Trunkey D, Holcroft J, Carpenter MA. Calcium flux during hemorrhagic shock
in baboons. J Trauma
11. Vivien B, Langeron O, Morell E, Devilliers C, Carli PA, Coriat P, Riou B. Early hypocalcemia
in severe trauma. Crit Care Med
12. Iqbal M, Rehmani R, Hijazi M, Abdulaziz A, Kashif S. Hypocalcemia
in a Saudi intensive care unit. Ann Thorac Med
13. Elmer J, Wilcox SR, Raja AS. Massive transfusion
in traumatic shock. J Emerg Med
14. Cote CJ, Drop LJ, Hoaglin DC, Daniels AL, Young ET. Ionized hypocalcemia
after fresh frozen plasma administration to thermally injured children: effects of infusion rate, duration, and treatment with calcium chloride. Anesth Analg
15. Sihler KC, Napolitano LM. Complications of massive transfusion
16. Choi YC, Hwang SY. The value of initial ionized calcium as a predictor of mortality
and triage tool in adult trauma patients. J Korean Med Sci
17. Giancarelli A, Birrer KL, Alban RF, Hobbs BP, Liu-DeRyke X. Hypocalcemia
in trauma patients receiving massive transfusion
. J Surg Res
18. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ
19. Dzik WH, Kirkley SA. Citrate toxicity during massive blood transfusion
. Transfus Med Rev
20. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol
21. Cherry RA, Bradburn E, Carney DE, Shaffer ML, Gabbay RA, Cooney RN. Do early ionized calcium levels really matter in trauma patients. J Trauma
22. Magnotti LJ, Bradburn EH, Webb DL, Berry SD, Fischer PE, Zarzaur BL, Schroeppel TJ, Fabian TC, Croce MA. Admission ionized calcium levels predict the need for multiple transfusions: a prospective study of 591 critically ill trauma patients. J Trauma
23. Vasudeva M, Mathew JK, Fitzgerald MC, Cheung Z, Mitra B. Hypocalcaemia and traumatic coagulopathy
: an observational analysis. Vox Sang
24. MacKay EJ, Stubna MD, Holena DN, Reilly PM, Seamon MJ, Smith BP, Kaplan LJ, Cannon JW. Abnormal calcium levels during trauma resuscitation are associated with increased mortality
, increased blood product use, and greater hospital resource consumption: a pilot investigation. Anesth Analg
25. Ho KM, Leonard AD. Concentration-dependent effect of hypocalcaemia on mortality
of patients with critical bleeding requiring massive transfusion
: a cohort study. Anaesth Intensive Care
26. Vinas-Rios JM, Sanchez-Aguilar M, Sanchez-Rodriguez JJ, Gonzalez-Aguirre D, Heinen C, Meyer F, Kretschmer T. Hypocalcaemia as a prognostic factor of early mortality
in moderate and severe traumatic brain injury. Neurol Res
27. Manuel VR, Martin SA, Juan SR, Fernando MA, Frerk M, Thomas K, Christian H. Hypocalcemia
as a prognostic factor in mortality
and morbidity in moderate and severe traumatic brain injury. Asian J Neurosurg
28. Ward RT, Colton DM, Meade PC, Henry JC, Contreras LM, Wilson OM, Fleming AW. Serum levels of calcium and albumin in survivors versus nonsurvivors after critical injury. J Crit Care
29. Lier H, Krep H, Schroeder S, Stuber F. Preconditions of hemostasis in trauma: a review. The influence of acidosis, hypocalcemia
, anemia, and hypothermia on functional hemostasis in trauma. J Trauma
30. Harrigan C, Lucas CE, Ledgerwood AM. Significance of hypocalcemia
following hypovolemic shock. J Trauma
31. Robinson WP 3rd, Ahn J, Stiffler A, Rutherford EJ, Hurd H, Zarzaur BL, Baker CC, Meyer AA, Rich PB. Blood transfusion
is an independent predictor of increased mortality
in nonoperatively managed blunt hepatic and splenic injuries. J Trauma
. 2005;58(3):437–444 discussion 44-5.
32. Malone DL, Dunne J, Tracy JK, Putnam AT, Scalea TM, Napolitano LM. Blood transfusion
, independent of shock severity, is associated with worse outcome in trauma. J Trauma
. 2003;54(5):898–905; discussion 905-7.
33. De Robertis E, Kozek-Langenecker SA, Tufano R, Romano GM, Piazza O, Zito Marinosci G. Coagulopathy
induced by acidosis, hypothermia and hypocalcaemia in severe bleeding. Minerva Anestesiol
34. Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy
. J Trauma
35. MacLeod JB, Lynn M, McKenney MG, Cohn SM, Murtha M. Early coagulopathy
in trauma. J Trauma
36. Spahn DR, Bouillon B, Cerny V, et al. The European guideline on management of major bleeding and coagulopathy
following trauma: fifth edition. Crit Care
37. Gando S, Igarashi M, Kameue T, Nanzaki S. Ionized hypocalcemia
during out-of-hospital cardiac arrest and cardiopulmonary resuscitation is not due to binding by lactate. Intensive Care Med
38. Howland WS, Schweizer O, Carlon GC, Goldiner PL. The cardiovascular effects of low levels of ionized calcium during massive transfusion
. Surg Gynecol Obstet
39. Hurley K, Baggs D. Hypocalcemic cardiac failure in the emergency department. J Emerg Med
40. Desai TK, Carlson RW, Thill-Baharozian M, Geheb MA. A direct relationship between ionized calcium and arterial pressure among patients in an intensive care unit. Crit Care Med
41. Moore HB, Tessmer MT, Moore EE, et al. Forgot calcium? Admission ionized-calcium in two civilian randomized controlled trials of pre-hospital plasma for traumatic hemorrhagic shock
. J Trauma Acute Care Surg
42. Kyle T, Greaves I, Beynon A, Whittaker V, Brewer M, Smith J. Ionised calcium levels in major trauma patients who received blood en route to a military medical treatment facility. Emerg Med J
43. Steele T, Kolamunnage-Dona R, Downey C, Toh CH, Welters I. Assessment and clinical course of hypocalcemia
in critical illness. Crit Care
44. Evans PA, Madira W, Riyatt MS, Errington M, Heptinstall S. Changes in plasma ionised calcium within 24 hours of trauma in patients infused with the calcium containing colloid Haemaccel during fluid resuscitation. J Accid Emerg Med
45. Dickerson RN, Morgan LM, Croce MA, Minard G, Brown RO. Treatment of moderate to severe acute hypocalcemia
in critically ill trauma patients. JPEN J Parenter Enteral Nutr
46. Vincent JL, Bredas P, Jankowski S, Kahn RJ. Correction of hypocalcaemia in the critically ill: what is the haemodynamic benefit? Intensive Care Med
47. Porter DL, Ledgerwood AM, Lucas CE, Harrigan CM. Effect of calcium infusion on heart function. Am Surg
48. Rosenthal R. The file drawer problem and tolerance for null results. Psychol Bull
49. Yusuf MB, Akinyoola AL, Orimolade AE, Idowu AA, Badmus TA, Adeyemi TO. Determinants of hypercalcemia and hypercalciuria in immobilized trauma patients. Bonekey Rep
50. Conley SB, Shackelford GD, Robson AM. Severe immobilization hypercalcemia, renal insufficiency, and calcification. Pediatrics