Restrictive calcium replacement in septic shock : a multicenter before-and-after intervention study = 패혈성 쇼크 환자의 임상적 예후에 칼슘 투여가 미치는 영향

다국어 초록 (Multilingual Abstract)

Purpose: Despite the high prevalence of hypocalcemia in critically ill patients, the potential clinical benefits of calcium administration in patients with septic shock are controversial. The purpose of this study was to investigate the association between hypocalcemia and clinical outcomes in septic shock patients and evaluate the impact of restrictive versus liberal calcium replacement.
Methods: This was a multicenter, before-and-after retrospective study. Patients who were admitted to intensive care units via emergency departments between May 2019 and April 2021 were allocated to the liberal group, while those who presented between May 2021 and April 2022 were assigned to the restrictive group (after implementation of the restrictive calcium replacement protocol). We used propensity score matching to compare the restrictive calcium replacement protocol intervention and clinical outcomes. The primary outcome measure was 28-day mortality, and secondary outcome measures were in-hospital mortality, shock reversal, and delta–Sequential Organ Failure Assessment (SOFA) score.
Results: Among 644 patients included in this study, 49% patients were hypocalcemic. Overall, the 28-day mortality was 33.7%, with no statistical difference between patients with and without hypocalcemia (P = 0.10). A total of 553 propensity score matched pairings were created (liberal group, n = 386 vs. restrictive group, n = 167). After propensity matching, there were no differences in 28-day mortality (35.3% vs. 32.3%, P = 0.56; hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.72–1.29; P = 0.81), shock reversal (81.5% vs. 83.8%, P = 0.54; HR 0.89, 95% CI 0.73–1.09, P = 0.27), or SOFA score reduction after 4 days (mean 2.1 points vs. 2.6 points, P = 0.20) between the liberal and restrictive groups. Moreover, neither the lowest ionized calcium level (adjusted odds ratio [aOR] 1.04, 95% CI 0.13–7.89, P = 0.97) nor restrictive calcium replacement (aOR 0.87, 95% CI 0.56–1.35, P = 0.54) showed an association with 28-day mortality.
Conclusions: In patients with septic shock, there was no difference in 28-day mortality between patients with and without hypocalcemia. Restrictive calcium replacement did not result in significantly lower (or higher) 28-day mortality compared to liberal calcium replacement. Our findings suggest that calcium replacement could be reduced without harmful effects in patients with septic shock.

목차 (Table of Contents)

• Chapter 1. Introduction 1
• Chapter 2. Methods 4
• Chapter 2. Methods 1. Study design 4
• Chapter 2. Methods 2. Restrictive calcium replacement protocol 5
• Chapter 2. Methods 3. Data extraction 6
• Chapter 2. Methods 4. Outcome measures 7
• Chapter 2. Methods 5. Subgroup analysis 7
• Chapter 2. Methods 6. Statistical analysis 8
• Chapter 3. Results 10
• Chapter 3. Results 1. Patient baseline characteristics 10
• Chapter 3. Results 2. Primary and secondary outcomes from hypocalcemia patients vs. non-hypocalcemia patients 13
• Chapter 3. Results 3. Calcium replacement in the liberal vs. restrictive groups 15
• Chapter 3. Results 4. Primary and secondary outcomes from liberal vs. restrictive groups 19
• Chapter 3. Results 5. Subgroup analysis 23
• Chapter 3. Results 6. Variables associated with 28-day mortality 24
• Chapter 4. Discussion 27
• Chapter 5. Conclusions 32
• References 33
• Appendix 40
• Abstract in Korean 43

참고문헌 (Reference)

1. No Title In, Hauser S, Longo D, Jameson JL, Loscalzo J, Fauci A, Kasper D, Harrison’s Principles of Internal 21e McGrawHill Education http://accesspharmacy. mhmedical. com/content. aspx?aid=1197729784, , 2022

2. Electrolyte quintet: Calcium, Monk RD, Bushinsky DA, Lancet (London, England)352(9124):306311. doi:10.1016/s01406736(97)123315, , 1998

3. Ionized hypocalcemia during sepsis, Zaloga GP, 28(1):266268. doi:10.1097/0000324620000100000054, , 2000

4. Calcium, ischemia and excitotoxicity, Szydlowska K, Tymianski M., 47(2):122 129. doi:10.1016/j. ceca.2010.01.003, , 2010

5. Hypocalcemia: Diagnosis and Treatment, Schafer AL, Shoback DM, In Feingold KR, Anawalt B, Blackman MR et al. eds, , 2000

6. Hypocalcemia in critically ill patients, Chernow B, McFadden E et al, Zaloga G, 10(12):848851. doi:10.1097/0000324619821200000008, , 1982

7. Diagnosis and management of hypocalcemia, Colangelo L, Pepe J, Biamonte F et al, Endocrine69(3):485495. doi:10.1007/s12020020023242, , 2020

8. Hypocalcemia in the critically ill patient, Kelly A, Levine MA, 28(3):166177. doi:10.1177/0885066611411543, , 2013

9. Human sepsis increases lymphocyte intracellular calcium, Black KW, Zaloga GP, Washburn D, Prielipp R., 21(2):196202. doi:10.1097/0000324619930200000009, , 1993

10. Ionized calcium: its significance and clinical usefulness, Forman DT, Lorenzo L., 21(5):297304, , 1991

11. KDIGO clinical practice guidelines for acute kidney injury, Khwaja, A, 120(4):c17984. doi:10.1159/000339789, , 2012

12. Less is more in critically ill patients: not too intensive, Kox M, Pickkers P., 173(14):13691372. doi:10.1001/jamainternmed.2013.6702, , 2013

13. Ionized hypocalcemia in critically ill patients with sepsis, Taylor B, Williams C., Holliday RL, Sibbald WJ, Edmonds MW, 21(5):429433, , 1978

14. Ionized calcium concentration and outcome in critical illness, Nichol A et al, Kim I, Egi M, 39(2):314321. doi:10.1097/CCM.0b013e3181ffe23e, , 2011

15. Ionized Calcium in the ICU: Should It Be Measured and Corrected?, Aberegg SK, Chest149(3):846855. doi:10.1016/j. chest.2015.12.001, , 2016

16. Assessment and clinical course of hypocalcemia in critical illness, KolamunnageDona R, Downey C, Welters I, Toh CH, Steele T, 17(3):R106. doi:10.1186/cc12756, , 2013

17. Ca(2+)related hepatocellular alterations during intraabdominal sepsis, Thompson KD, Sayeed MM, Rose S, 263(3 Pt 2):R5538. doi:10.1152/ajpregu.1992.263.3. R553, , 1992

18. Hypocalcemia: a pervasive metabolic abnormality in the critically ill., Zager RA, Gooley T, Ryan MJ, Zivin JR, 37(4):689698. doi:10.1016/s0272 6386(01)801165, , 2001

19. Major trauma enhances storeoperated calcium influx in human neutrophils, Garced M, Adams J, Hauser CJ, Fekete Z, Deitch EA, Livingston DH, 48(4):592598. doi:10.1097/0000537320000400000003, , 2000

20. Calcium administration increases the mortality of endotoxic shock in rats, Zaloga GP, Malcolm DS, Holaday JW, 17(9):900903. doi:10.1097/0000324619890900000012, , 1989

21. 34 Alterations in cellular Ca2+ regulation in the liver in endotoxic shock, Sayeed MM, 250(5 Pt 2):R88491. doi:10.1152/ajpregu.1986.250.5. R884, , 1986

22. NMDA receptordependent excitotoxicity: the role of intracellular Ca2+ release, MacDonald JF, Mody I, 16(10):356359. doi:10.1016/s01656147(00)890707, , 1995

23. Increased intracellular Ca2+: a critical link in the pathophysiology of sepsis?, Song SK, Hotchkiss RS, Ackerman JJ, Karl IE, 90(9):39333937. doi:10.1073/pnas.90.9.3933, , 1993

24. Disordered calcium homeostasis of sepsis: association with calcitonin precursors, Kränzlin M et al, Becker KL, Müller B, 30(9):823831. doi:10.1046/j.1365 2362.2000.00714. x, , 2000

25. Hypocalcemia during porcine endotoxemic shock: Effects of calcium administration, Lind L., Kiiski R, Larsson A, Eriksson M, Carlstedt F, 28(8):29092914. doi:10.1097/0000324620000800000037, , 2000

26. Ionized calcium, parathormone, and mortality in critically ill surgical patients, Gann DS, Forster J., Colliton J, Burchard KW, 212(4):543550. doi:10.1097/00000658199010000 00016, , 1990

27. Correction of hypocalcaemia in the critically ill: what is the haemodynamic benefit?, Jankowski S, Kahn RJ, Vincent JL, Bredas P,, 21(10):838841. doi:10.1007/BF01700968, , 1995

28. Controlling metabolism and cell death: at the heart of mitochondrial calcium signalling, Giorgi C, Rizzuto R., Murgia M, Pinton P, 46(6):781788. doi:10.1016/j. yjmcc.2009.03.003, , 2009

29. Hemodynamic management of septic shock: beyond the Surviving Sepsis Campaign guidelines, Kwon WY, et al, Shin TG, Suh GJ, 202310(3):255264. doi:10.15441/ceem.23.065, , 2023

30. Serum levels of calcium and albumin in survivors versus nonsurvivors after critical injury, Meade PC et al, Colton DM, Ward RT, 19(1):5464. doi:10.1016/j. jcrc.2004.02.011, , 2004

31. Association of Initial Serum Total Calcium Concentration with Mortality in Critical Illness, Wang B, Gong Y, Ying B, Cheng B, 2018:7648506. doi:10.1155/2018/7648506, , 2018

32. Calcium signaling in the ER: its role in neuronal plasticity and neurodegenerative disorders, Mattson MP, LaFerla FM, Geiger JD, Chan SL, Shepel PN, Leissring MA, Trends Neurosci23(5):222229. doi:10.1016/s01662236(00)015484, , 2000

33. Injuryenhanced calcium mobilization in circulating rat neutrophils models human PMN responses, Fekete Z, Adams JM et al, Hauser CJ, 16(1):1520. doi:10.1097/00024382 20011601000003, , 2001

34. Contractile dysfunction and abnormal Ca2+ modulation during postischemic reperfusion in rat heart, Morgan JP, Meissner A, 268(1 Pt 2):H10011. doi:10.1152/ajpheart.1995.268.1. H100, , 1995

35. Sepsis in Intensive Care Unit Patients: Worldwide Data From the Intensive Care over Nations Audit, Jaschinski U, Wittebole X, et al, Sakr Y, Open forum Infect Dis5(12):ofy313. doi:10.1093/ofid/ofy313, , 2018

36. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021, Rhodes A, Evans L, Alhazzani W, et al, 47(11):11811247. doi:10.1007/S0013402106506Y, , 2021

37. Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calciumdependent apoptosis, Kurosaki T, Glebova NO, Sedaghat L, Boehning D, Snyder SH, Patterson RL, 5(12):10511061. doi:10.1038/ncb1063, , 2003

38. Ionized calcium in normal serum, ultrafiltrates, and whole blood determined by ionexchange electrodes, Moore EW, 49(2):318334. doi:10.1172/JCI106241, , 1970

39. Low serum calcium is associated with poor renal outcomes in chronic kidney disease stages 34 patients, Kuo HT, Lim LM, Kuo MC et al, 15(1):19. doi:10.1186/14712369 15183, , 2014

40. Modification of calcium flux of twitch skeletal muscle in mice subjected to 20% body surface area burn, Tomera JF, Friend KD, Kukulka SP, Lilford K., 13(5):546 555. doi:10.1097/0000463019920900000007, , 1992

41. Increased cardiomyocyte intracellular calcium during endotoxininduced cardiac dysfunction in guinea pigs, Thompson M, Kliewer A, Maass D et al, 47(5):669676. doi:10.1203/0000645020000500000019, , 2000

42. Hemodynamic effects of intravenous calcium administration on septic shock patients: a retrospective study, Miyasho K, Kitamura T et al, Ishibashi N, Acta Med Okayama69(4):197 204. doi:10.18926/AMO/53555, , 2015

43. The multifactorial basis for hypocalcemia during sepsis. Studies of the parathyroid hormonevitamin D axis, Chernow B, Zaloga GP, 107(1):3641. doi:10.7326/00034819 107136, , 1987

44. A direct relationship between ionized calcium and arterial pressure among patients in an intensive care unit, Carlson RW, Geheb MA, Desai TK, ThillBaharozian M, 16(6):578582. doi:10.1097/0000324619880600000002, , 1988

45. Characteristics, management and clinical outcomes of patients with sepsis: A multicenter cohort study in Korea, Jeon K, Na SJ, Oh DK, et al, 34(3):179191. doi:10.4266/acc.2019.00514, , 2019

46. Dantrolene ameliorates the metabolic hallmarks of sepsis in rats and improves survival in a mouse model of endotoxemia, Karl IE, Hotchkiss RS, 91(8):3039 3043. doi:10.1073/pnas.91.8.3039, , 1994

47. Estimating TenYear Trends in Septic Shock Incidence and Mortality in United States Academic Medical Centers Using Clinical Data, Kadri SS, Strich JR, et al, Rhee C, Chest151(2):278285. doi:10.1016/j. chest.2016.07.010, , 2017

48. Effect of endotoxicosis and sepsis on intracellular calcium homeostasis in rat liver. Mitochondrial and microsomal calcium uptake, Spitzer JA, Deaciuc I V., Circ Shock18(2):8193, , 1986

49. The association of sepsis syndrome and organ dysfunction with mortality in emergency department patients with suspected infection, Angus DC, Howell MD, Bates DW, Ngo L, Talmor D., Shapiro N, 48(5):583590, 590. e1. doi:10.1016/j. annemergmed.2006.07.007, , 2006

50. Assessment of clinical criteria for sepsis for the third international consensus definitions for sepsis and septic shock (sepsis3), Iwashyna TJ, et al, Liu VX, Seymour CW, 315(8):762774. doi:10.1001/jama.2016.0288, , 2016

51. Necrotic cell death in C. elegans requires the function of calreticulin and regulators of Ca(2+) release from the endoplasmic reticulum, Tavernarakis N, Driscoll M., Xu K, 31(6):957971. doi:10.1016/s08966273(01)004329, , 2001

52. Shortterm hemodynamic response to calcium supplementation in patients with refractory septic shock: a retrospective observational study, Chang HS, Park JE, et al, Hwang SY, 30(6):529536. http://www. jksem. org/journal/view. php?number=2348, , 2019

53. Calcium supplementation improves clinical outcome in intensive care unit patients: a propensity score matched analysis of a large clinical database MIMICII, Zhang Z, Chen K, Ni H., Springerplus4(1). doi:10.1186/s4006401513877, , 2015

54. Effects of verapamil on calciuminduced rigidity and on filterability of red blood cells from healthy volunteers and patients with progressive systemic sclerosis, Kovacs IB, SowemimoCoker SO, Turner P., Kirby JD, 19(6):731737. doi:10.1111/j.1365 2125.1985. tb02707. x, , 1985

55. Epidemiologic trends of patients who visited nationwide emergency departments: a report from the National Emergency Department Information System (NEDIS) of Korea, Ro YS, Yoo HH, Ko E et al, 202310(S):S1S12. doi:10.15441/ceem.23.151, , 2018

56. The Positive and Negative Effects of Calcium Supplementation on Mortality in Septic ICU Patients Depend on Disease Severity: A Retrospective Study from the MIMICIII, He W, Luo H et al, Huang L, Crit Care Res Pract2022:112. doi:10.1155/2022/2520695, , 2022

57. A quick Sequential Organ Failure Assessment–negative result at triage is associated with low compliance with sepsis bundles: a retrospective analysis of a multicenter prospective registry, Shin TG, Park H, Kim WY, et al, 9(2):8492. doi:10.15441/ceem.22.230, , 2022