J Korean Med Sci.  2021 Aug;36(34):e221. 10.3346/jkms.2021.36.e221.

Effect of Sedatives on In-hospital and Long-term Mortality of Critically Ill Patients Requiring Extended Mechanical Ventilation for ≥ 48 Hours

• Lee H
• Choi S
• Jang EJ
• Lee J
• Kim D
• Yoo S
• Oh SY
• Ryu HG

• KMID: 2519597
• DOI: http://doi.org/10.3346/jkms.2021.36.e221

Abstract

Background
The purpose of this study was to assess the correlation between sedatives and mortality in critically ill patients who required mechanical ventilation (MV) for ≥ 48 hours from 2008 to 2016.
Methods
We conducted a nationwide retrospective cohort study using population-based healthcare reimbursement claims database. Data from adult patients (aged ≥ 18) who underwent MV for ≥ 48 hours between 2008 and 2016 were identified and extracted from the National Health Insurance Service database. The benzodiazepine group consisted of patients who were administered benzodiazepines for sedation during MV. All other patients were assigned to the non-benzodiazepine group.
Results
A total of 158,712 patients requiring MV for ≥ 48 hours were admitted in 55 centers in Korea from 2008 to 2016. The benzodiazepine group had significantly higher in-hospital and one-year mortality compared to the non-benzodiazepine group (37.0% vs. 34.3%, 55.0% vs. 54.4%, respectively). Benzodiazepine use decreased from 2008 to 2016, after adjusting for age, sex, and mean Elixhauser comorbidity index in the Poisson regression analysis (incidence rate ratio, 0.968; 95% confident interval, 0.954–0.983; P < 0.001). Benzodiazepine use, older age, lower case volume (≤ 500 cases/year), chronic kidney disease, and higher Elixhauser comorbidity index were common significant risk factors for in-hospital and oneyear mortality.
Conclusion
In critically ill patients undergoing MV for ≥ 48 hour, the use of benzodiazepines for sedation, older age, and chronic kidney disease were associated with higher in-hospital mortality and one-year mortality. Further studies are needed to evaluate the impact of benzodiazepines on the mortality in elderly patients with chronic kidney disease requiring MV for ≥ 48 hours.

Keyword

Sedative; Dexmedetomidine; Mortality; Benzodiazepine; Propofol

Figure

• 

  Fig. 1 The correlation of sales of sedative medications (Dexmedetomidine data from IQVIA Sales Audit from 2010 3Q to 2016 4Q).

Reference

1. Jacobi J, Fraser GL, Coursin DB, Riker RR, Fontaine D, Wittbrodt ET, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med. 2002; 30(1):119–141. PMID: 11902253.

2. Payen JF, Chanques G, Mantz J, Hercule C, Auriant I, Leguillou JL, et al. Current practices in sedation and analgesia for mechanically ventilated critically ill patients: a prospective multicenter patient-based study. Anesthesiology. 2007; 106(4):687–695. PMID: 17413906.

3. Mehlhorn J, Freytag A, Schmidt K, Brunkhorst FM, Graf J, Troitzsch U, et al. Rehabilitation interventions for postintensive care syndrome: a systematic review. Crit Care Med. 2014; 42(5):1263–1271. PMID: 24413580.

4. Devlin JW. The pharmacology of oversedation in mechanically ventilated adults. Curr Opin Crit Care. 2008; 14(4):403–407. PMID: 18614903.

5. Pandharipande PP, Pun BT, Herr DL, Maze M, Girard TD, Miller RR, et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA. 2007; 298(22):2644–2653. PMID: 18073360.

6. Kress JP, Pohlman AS, O'Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med. 2000; 342(20):1471–1477. PMID: 10816184.

7. Girard TD, Kress JP, Fuchs BD, Thomason JW, Schweickert WD, Pun BT, et al. Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial. Lancet. 2008; 371(9607):126–134. PMID: 18191684.

8. Morandi A, Brummel NE, Ely EW. Sedation, delirium and mechanical ventilation: the ‘ABCDE’ approach. Curr Opin Crit Care. 2011; 17(1):43–49. PMID: 21169829.

9. Fraser GL, Devlin JW, Worby CP, Alhazzani W, Barr J, Dasta JF, et al. Benzodiazepine versus nonbenzodiazepine-based sedation for mechanically ventilated, critically ill adults: a systematic review and meta-analysis of randomized trials. Crit Care Med. 2013; 41(9):Suppl 1. S30–S38. PMID: 23989093.

10. Barr J, Fraser GL, Puntillo K, Ely EW, Gélinas C, Dasta JF, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013; 41(1):263–306. PMID: 23269131.

11. Devlin JW, Skrobik Y, Gélinas C, Needham DM, Slooter AJC, Pandharipande PP, et al. Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018; 46(9):e825–e873. PMID: 30113379.

12. Park SY, Lee HB. Prevention and management of delirium in critically ill adult patients in the intensive care unit: a review based on the 2018 PADIS guidelines. Acute Crit Care. 2019; 34(2):117–125. PMID: 31723916.

13. Lee J, Lee JS, Park SH, Shin SA, Kim K. Cohort profile: the National Health Insurance Service-National Sample Cohort (NHIS-NSC), South Korea. Int J Epidemiol. 2017; 6(2):e15.

14. Quan H, Sundararajan V, Halfon P, Fong A, Burnand B, Luthi JC, et al. Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data. Med Care. 2005; 43(11):1130–1139. PMID: 16224307.

15. Elixhauser A, Steiner C, Harris DR, Coffey RM. Comorbidity measures for use with administrative data. Med Care. 1998; 36(1):8–27. PMID: 9431328.

16. van Walraven C, Austin PC, Jennings A, Quan H, Forster AJ. A modification of the Elixhauser comorbidity measures into a point system for hospital death using administrative data. Med Care. 2009; 47(6):626–633. PMID: 19433995.

17. Hughes CG, McGrane S, Pandharipande PP. Sedation in the intensive care setting. Clin Pharmacol. 2012; 4:53–63. PMID: 23204873.

18. Devlin JW, Roberts RJ. Pharmacology of commonly used analgesics and sedatives in the ICU: benzodiazepines, propofol, and opioids. Crit Care Clin. 2009; 25(3):431–449. PMID: 19576523.

19. McKenzie CA, McKinnon W, Naughton DP, Treacher D, Davies G, Phillips GJ, et al. Differentiating midazolam over-sedation from neurological damage in the intensive care unit. Crit Care. 2005; 9(1):R32–R36. PMID: 15693964.

20. Zhang Z, Chen K, Ni H, Zhang X, Fan H. Sedation of mechanically ventilated adults in intensive care unit: a network meta-analysis. Sci Rep. 2017; 7(1):44979. PMID: 28322337.

21. Ho KM, Ng JY. The use of propofol for medium and long-term sedation in critically ill adult patients: a meta-analysis. Intensive Care Med. 2008; 34(11):1969–1979. PMID: 18575838.

22. Kawazoe Y, Miyamoto K, Morimoto T, Yamamoto T, Fuke A, Hashimoto A, et al. Effect of dexmedetomidine on mortality and ventilator-free days in patients requiring mechanical ventilation with sepsis: a randomized clinical trial. JAMA. 2017; 317(13):1321–1328. PMID: 28322414.

23. Shehabi Y, Howe BD, Bellomo R, Arabi YM, Bailey M, Bass FE, et al. Early sedation with dexmedetomidine in critically ill patients. N Engl J Med. 2019; 380(26):2506–2517. PMID: 31112380.

24. Shehabi Y, Chan L, Kadiman S, Alias A, Ismail WN, Tan MA, et al. Sedation depth and long-term mortality in mechanically ventilated critically ill adults: a prospective longitudinal multicentre cohort study. Intensive Care Med. 2013; 39(5):910–918. PMID: 23344834.

25. Shehabi Y, Bellomo R, Reade MC, Bailey M, Bass F, Howe B, et al. Early intensive care sedation predicts long-term mortality in ventilated critically ill patients. Am J Respir Crit Care Med. 2012; 186(8):724–731. PMID: 22859526.

26. Shehabi Y, Bellomo R, Kadiman S, Ti LK, Howe B, Reade MC, et al. Sedation intensity in the first 48 hours of mechanical ventilation and 180-day mortality: a multinational prospective longitudinal cohort study. Crit Care Med. 2018; 46(6):850–859. PMID: 29498938.

27. Coursin DB, Skrobik Y. What is safe sedation in the ICU? N Engl J Med. 2019; 380(26):2577–2578. PMID: 31242368.

28. Lonardo NW, Mone MC, Nirula R, Kimball EJ, Ludwig K, Zhou X, et al. Propofol is associated with favorable outcomes compared with benzodiazepines in ventilated intensive care unit patients. Am J Respir Crit Care Med. 2014; 189(11):1383–1394. PMID: 24720509.

29. Kim HH, Choi SC, Ahn JH, Chae MK, Heo J, Min YG. Analysis of trends in usage of analgesics and sedatives in intensive care units of South Korea: a retrospective nationwide population-based study. Medicine (Baltimore). 2018; 97(35):e12126. PMID: 30170448.

30. Pandharipande P, Shintani A, Peterson J, Pun BT, Wilkinson GR, Dittus RS, et al. Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients. Anesthesiology. 2006; 104(1):21–26. PMID: 16394685.

31. Maldonado JR. Pathoetiological model of delirium: a comprehensive understanding of the neurobiology of delirium and an evidence-based approach to prevention and treatment. Crit Care Clin. 2008; 24(4):789–856. PMID: 18929943.

32. Salluh JI, Wang H, Schneider EB, Nagaraja N, Yenokyan G, Damluji A, et al. Outcome of delirium in critically ill patients: systematic review and meta-analysis. BMJ. 2015; 350:h2538. PMID: 26041151.

33. Gayat E, Cariou A, Deye N, Vieillard-Baron A, Jaber S, Damoisel C, et al. Determinants of long-term outcome in ICU survivors: results from the FROG-ICU study. Crit Care. 2018; 22(1):8. PMID: 29347987.

34. Hill AD, Fowler RA, Pinto R, Herridge MS, Cuthbertson BH, Scales DC. Long-term outcomes and healthcare utilization following critical illness--a population-based study. Crit Care. 2016; 20(1):76. PMID: 27037030.

35. Esteban A, Anzueto A, Frutos F, Alía I, Brochard L, Stewart TE, et al. Characteristics and outcomes in adult patients receiving mechanical ventilation: a 28-day international study. JAMA. 2002; 287(3):345–355. PMID: 11790214.

36. Lebiedz P, Knickel L, Engelbertz C, Lüders F, Gebauer K, Berdel WE, et al. Impact of preexisting chronic kidney disease on acute and long-term outcome of critically ill patients on a medical intensive care unit. J Nephrol. 2014; 27(1):73–80. PMID: 24519865.

37. Kahn JM, Goss CH, Heagerty PJ, Kramer AA, O'Brien CR, Rubenfeld GD. Hospital volume and the outcomes of mechanical ventilation. N Engl J Med. 2006; 355(1):41–50. PMID: 16822995.

38. Young MP, Gooder VJ, Oltermann MH, Bohman CB, French TK, James BC. The impact of a multidisciplinary approach on caring for ventilator-dependent patients. Int J Qual Health Care. 1998; 10(1):15–26. PMID: 10030783.

39. Brook AD, Ahrens TS, Schaiff R, Prentice D, Sherman G, Shannon W, et al. Effect of a nursing-implemented sedation protocol on the duration of mechanical ventilation. Crit Care Med. 1999; 27(12):2609–2615. PMID: 10628598.

40. Song SO, Jung CH, Song YD, Park CY, Kwon HS, Cha BS, et al. Background and data configuration process of a nationwide population-based study using the korean national health insurance system. Diabetes Metab J. 2014; 38(5):395–403. PMID: 25349827.

41. Hong SB, Oh BJ, Kim YS, Kang EH, Kim CH, Park YB, et al. Characteristics of mechanical ventilation employed in intensive care units: a multicenter survey of hospitals. J Korean Med Sci. 2008; 23(6):948–953. PMID: 19119434.

42. Devlin JW, Nasraway SA Jr. Reversing oversedation in the intensive care unit: the role of pharmacists in energizing guideline efforts and overcoming protocol fatigue. Crit Care Med. 2008; 36(2):626–628. PMID: 18216617.

43. Ouimet S, Kavanagh BP, Gottfried SB, Skrobik Y. Incidence, risk factors and consequences of ICU delirium. Intensive Care Med. 2007; 33(1):66–73. PMID: 17102966.