1. www.icnarc.org Critical care research in the UK and the recent trials Dr David Harrison Senior Statistician, ICNARC South East Coast CCN / SPACeR Conference 2 June 2015

2. www.icnarc.org Critical care research in the UK Recent UK critical care trials South East Coast CCN participation in ICNARC research studies Critical care research in the UK and the recent trials | David Harrison

3. www.icnarc.org Recent UK critical care trials Massive 12 months for UK trials in critical care and emergency medicine Seven multicentre RCTs with UK sites published in the Lancet, JAMA and New England Journal of Medicine Critical care research in the UK and the recent trials | David Harrison

4. www.icnarc.org P I C O Critical care research in the UK and the recent trials | David Harrison Summary of trials – PICO

5. www.icnarc.org P Participants I C O Critical care research in the UK and the recent trials | David Harrison Summary of trials – PICO

6. www.icnarc.org P Participants IIntervention C O Critical care research in the UK and the recent trials | David Harrison Summary of trials – PICO

7. www.icnarc.org P Participants IIntervention C Comparator O Critical care research in the UK and the recent trials | David Harrison Summary of trials – PICO

8. www.icnarc.org P Participants IIntervention C Comparator O Outcome(s) Critical care research in the UK and the recent trials | David Harrison Summary of trials – PICO

9. www.icnarc.org Critical care research in the UK and the recent trials | David Harrison Pearse et al. JAMA 2014; 311:2181-90

10. www.icnarc.org P 734 high-risk patients aged 50+ undergoing major gastrointestinal surgery at 17 UK hospitals I Cardiac output-guided haemodynamic therapy algorithm for IV fluid and dopexamine infusion during and for six hours after surgery C Usual care O 1°: mortality or major complications at 30 days 2°: POMS (day 7), infectious complications, critical care free days, mortality (30d/180d), hospital LOS Critical care research in the UK and the recent trials | David Harrison Pearse et al. JAMA 2014; 311:2181-90

11. www.icnarc.org Critical care research in the UK and the recent trials | David Harrison Pearse et al. JAMA 2014; 311:2181-90 No significant difference in composite primary outcome 134/366 (36.6%) vs 158/364 (43.4%) RR 0.84 (0.71-1.01) No significant differences in secondary outcomes

12. www.icnarc.org Critical care research in the UK and the recent trials | David Harrison Pearse et al. JAMA 2014; 311:2181-90

13. www.icnarc.org Critical care research in the UK and the recent trials | David Harrison Harvey et al. N Engl J Med 2014; 371:1673-84

14. www.icnarc.org P 2400 adult patients in 33 critical care units in England with unplanned admission, expected to receive nutritional support for ≥2 days and not planned for discharge within 3 days I Early nutritional support via the parenteral route (commenced within 36h, continued for 5 days) C Early nutritional support via the enteral route O 1°: 30-day mortality 2°: organ support, infectious/non-infectious complications, LOS (unit/hospital), mortality (unit/hospital/90d) Critical care research in the UK and the recent trials | David Harrison Harvey et al. N Engl J Med 2014; 371:1673-84

15. www.icnarc.org No difference in 30-day mortality 393/1188 (33.1%) vs 409/1195 (34.2%) RR 0.97 (0.86-1.08) No difference in secondary outcomes except reductions in – hypoglycaemia (ARR 2.5%; 0.8-4.2%) – vomiting (ARR 7.8%; 5.2-10.4%) Critical care research in the UK and the recent trials | David Harrison Harvey et al. N Engl J Med 2014; 371:1673-84

16. www.icnarc.org Critical care research in the UK and the recent trials | David Harrison McAuley et al. N Engl J Med 2014; 371:1695-703

17. www.icnarc.org Critical care research in the UK and the recent trials | David Harrison McAuley et al. N Engl J Med 2014; 371:1695-703 P 540 adult patients in 40 ICUs in the UK and Ireland that were intubated and ventilated and within 48h of the onset of ARDS (PaO 2 /FiO 2 < 300 mmHg) I Simvastatin (80 mg) once daily C Placebo O 1°: Ventilator-free days to day 28 (VFD28) 2°: Change in oxygenation index and SOFA (28d), days free of non-pulmonary organ failure to day 28, mortality (28d/ICU/hospital), LOS (ICU/hospital), days to breathing without assistance

18. www.icnarc.org No significant difference in VFD28 mean 12.6 vs 11.5 difference +1.1 (−0.6 to +2.8) No significant differences in secondary outcomes Increased adverse events – Mostly raised CK – Similar numbers of SAEs Critical care research in the UK and the recent trials | David Harrison McAuley et al. N Engl J Med 2014; 371:1695-703

19. www.icnarc.org Critical care research in the UK and the recent trials | David Harrison Perkins et al. Lancet 2015; 385:947-55

20. www.icnarc.org P 4471 adults with non-traumatic, out-of-hospital cardiac arrest attended by 418 emergency vehicles (cluster randomised) I Mechanical chest compressions (LUCAS-2 device) C Manual chest compressions O 1°: Survival to 30 days 2°: ROSC sustained to hospital transfer, survival to 3 and 12 months, CPC 1-2 at 3 months Critical care research in the UK and the recent trials | David Harrison Perkins et al. Lancet 2015; 385:947-55

21. www.icnarc.org No difference in survival to 30 days 104/1652 (6%) vs 193/2818 (7%) Adjusted OR 0.86 (0.64-1.15) No difference in secondary outcomes, except worse neurological outcome (CPC 1-2) 77/1649 (5%) vs 168/2815 (6%) Adjusted OR 0.72 (0.52-0.99) Critical care research in the UK and the recent trials | David Harrison Perkins et al. Lancet 2015; 385:947-55

22. www.icnarc.org Critical care research in the UK and the recent trials | David Harrison Murphy et al. N Engl J Med 2015; 372:997-1008

23. www.icnarc.org Critical care research in the UK and the recent trials | David Harrison P 2007 adult patients in 17 hospitals in the UK undergoing non-emergency cardiac surgery with a postoperative Hb < 9 g/dl I Restrictive transfusion threshold (Hb<7.5 g/dl) C Liberal transfusion threshold (Hb<9 g/dl) O 1°: Serious infection or ischaemic event (stroke, MI, gut infarction or AKI) within 3 months 2°: Units of RBC/other blood products transfused, LOS (ICU/HDU/hospital), survival to 3 months, costs at 3 months Murphy et al. N Engl J Med 2015; 372:997-1008

24. www.icnarc.org No significant difference in serious infection and ischaemic events at 3 months 333/944 (35.1%) vs 317/962 (33.0%) OR 1.11 (0.91-1.34) Reduced blood transfusions/associated costs Increased all-cause mortality at 90 days 42/1000 (4.2%) vs 26/1003 (2.6%) OR 1.64 (1.00-2.67) No difference in other secondary outcomes Critical care research in the UK and the recent trials | David Harrison Murphy et al. N Engl J Med 2015; 372:997-1008

25. www.icnarc.org Critical care research in the UK and the recent trials | David Harrison Lacroix et al. N Engl J Med 2015; 372:1410-8

26. www.icnarc.org Critical care research in the UK and the recent trials | David Harrison P 2510 adult patients in 64 ICUs in Canada and Europe (20 UK) requiring a first red cell transfusion within 7 days of admission and expected to require ventilation for at least 48h I Red cells stored for < 8 days (mean 6 days) C Standard issue red cells (mean 22 days) O 1°: 90-day mortality 2°: Mortality (28d/ICU/hospital), Major illnesses, MODS, duration of respiratory, haemodynamic and renal support, LOS (ICU/hospital) Lacroix et al. N Engl J Med 2015; 372:1410-8

27. www.icnarc.org No significant difference in 90-day mortality 448/1211 (37.0%) vs 430/1219 (35.3%) risk difference +1.7% (−2.1% to +5.5%) No difference in any secondary outcomes Critical care research in the UK and the recent trials | David Harrison Lacroix et al. N Engl J Med 2015; 372:1410-8

28. www.icnarc.org Critical care research in the UK and the recent trials | David Harrison Mouncey et al. N Engl J Med 2015; 372:1301-11

29. www.icnarc.org P 1260 patients presenting to 56 UK EDs with early signs of septic shock I Early goal-directed therapy (EGDT) – a six-hour resuscitation protocol with targets for CVP, blood pressure and ScvO 2 C Usual resuscitation O 1°: 90-day mortality, cost-effectiveness at 1 year 2°: SOFA score (6h/72h), organ support, LOS (ED/ICU/hospital), mortality (28d/hospital/1y), QOL (90d/1y), cost-effectiveness (90d/lifetime) Critical care research in the UK and the recent trials | David Harrison Mouncey et al. N Engl J Med 2015; 372:1301-11

30. www.icnarc.org No difference in 90-day mortality 184/623 (29.5%) vs 181/620 (29.2%) RR 1.01 (0.85-1.20) Increase in SOFA score (vasoactives), cardiovascular support and ICU LOS No difference in other secondary outcomes On average, higher costs mean £12,414 vs £11,424 Unlikely to be cost-effective Critical care research in the UK and the recent trials | David Harrison Mouncey et al. N Engl J Med 2015; 372:1301-11

31. www.icnarc.org Critical care research in the UK and the recent trials | David Harrison Mouncey et al. N Engl J Med 2015; 372:1301-11

32. www.icnarc.org Critical care research in the UK and the recent trials | David Harrison Angus et al. Intensive Care Med 2015

33. www.icnarc.org South East Coast CCN participation in ICNARC research studies South East Coast CCN has contributed to every prospective research study (in adults) co-ordinated by ICNARC… Critical care research in the UK and the recent trials | David Harrison

34. www.icnarc.org COPD & Asthma Outcome Study Admissions aged 45+ with COPD/asthma – 180-day survival March 2002 – September 2003 South East Coast CCN: – 3/95 sites – 20/832 participants Critical care research in the UK and the recent trials | David Harrison

35. www.icnarc.org Pulmonary Artery Catheters in patient Management ICNARC’s first RCT Patients that would have received a PAC – Randomised PAC vs no PAC October 2001 – March 2004 South East Coast CCN: – 5/65 sites – 127/1,041 participants Critical care research in the UK and the recent trials | David Harrison

36. www.icnarc.org Fungal Infection Risk Evaluation All admissions to critical care – risk factors and outcomes for invasive fungal disease July 2009 – March 2011 South East Coast CCN: – 5/96 sites – 2,862/60,778 participants Critical care research in the UK and the recent trials | David Harrison

37. www.icnarc.org Risk Adjustment In Neurocritical care Admissions with acute TBI – risk factors and six-month outcomes August 2009 – March 2011 South East Coast CCN: – 3/67 sites – 85/3,626 participants Critical care research in the UK and the recent trials | David Harrison

38. www.icnarc.org Sepsis Pathophysiological & Organisational Timing Deteriorating ward patients referred or admitted to critical care – Severity of illness at initial assessment and critical care unit admission November 2010 – December 2011 South East Coast CCN: – 7/96 sites – 5,132/35,169 participants Critical care research in the UK and the recent trials | David Harrison

39. www.icnarc.org Sepsis Pathophysiological & Organisational Timing – in detail Patients with a new diagnosis of pneumonia and SOFA ≥ 1 or CURB-65 ≥ 2 – Daily severity of illness and outcomes June 2012 – July 2013 South East Coast CCN: – 1/11 sites – 126/1,658 participants Critical care research in the UK and the recent trials | David Harrison

40. www.icnarc.org Optimisation of Cardiovascular Management to Improve Surgical Outcome June 2010 – November 2012 South East Coast CCN: – 2/17 sites – 26/734 participants Critical care research in the UK and the recent trials | David Harrison

41. www.icnarc.org Clinical and cost-effectiveness of early nutritional support via the parenteral versus the enteral route June 2011 – March 2014 South East Coast CCN: – 3/33 sites – 156/2,400 participants Critical care research in the UK and the recent trials | David Harrison

42. www.icnarc.org Protocolised Management In Sepsis February 2011 – July 2014 South East Coast CCN: – 4/56 sites – 88/1,260 participants Critical care research in the UK and the recent trials | David Harrison

43. www.icnarc.org Family Reported Experiences Evaluation Family members of patients staying at least 24h in the critical care unit – Family satisfaction (FS-ICU) May 2013 – June 2014 South East Coast CCN: – 2/20 sites – 1,376/12,346 participants Critical care research in the UK and the recent trials | David Harrison

44. www.icnarc.org Total participants recruited by South East Coast CCN sites… 9,998 Critical care research in the UK and the recent trials | David Harrison

45. www.icnarc.org Provision Of Psychological support to People in Intensive care – process and procedures pilot study Feasibility report to be submitted to funder (NIHR HS&DR programme) this week Selection of 24 sites for cluster RCT ongoing (subject to approval by funder) Critical care research in the UK and the recent trials | David Harrison

46. www.icnarc.org Provision Of Psychological support to People in Intensive care – process and procedures pilot study Medway Maritime Hospital (one of two sites) 47 patients recruited Critical care research in the UK and the recent trials | David Harrison

47. www.icnarc.org Total participants recruited by South East Coast CCN sites… 9,998 Critical care research in the UK and the recent trials | David Harrison

48. www.icnarc.org Total participants recruited by South East Coast CCN sites… 9,999 Critical care research in the UK and the recent trials | David Harrison

49. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,000 Critical care research in the UK and the recent trials | David Harrison

50. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,001 Critical care research in the UK and the recent trials | David Harrison

51. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,002 Critical care research in the UK and the recent trials | David Harrison

52. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,003 Critical care research in the UK and the recent trials | David Harrison

53. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,004 Critical care research in the UK and the recent trials | David Harrison

54. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,005 Critical care research in the UK and the recent trials | David Harrison

55. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,006 Critical care research in the UK and the recent trials | David Harrison

56. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,007 Critical care research in the UK and the recent trials | David Harrison

57. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,008 Critical care research in the UK and the recent trials | David Harrison

58. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,009 Critical care research in the UK and the recent trials | David Harrison

59. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,010 Critical care research in the UK and the recent trials | David Harrison

60. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,011 Critical care research in the UK and the recent trials | David Harrison

61. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,012 Critical care research in the UK and the recent trials | David Harrison

62. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,013 Critical care research in the UK and the recent trials | David Harrison

63. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,014 Critical care research in the UK and the recent trials | David Harrison

64. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,015 Critical care research in the UK and the recent trials | David Harrison

65. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,016 Critical care research in the UK and the recent trials | David Harrison

66. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,017 Critical care research in the UK and the recent trials | David Harrison

67. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,018 Critical care research in the UK and the recent trials | David Harrison

68. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,019 Critical care research in the UK and the recent trials | David Harrison

69. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,020 Critical care research in the UK and the recent trials | David Harrison

70. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,021 Critical care research in the UK and the recent trials | David Harrison

71. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,022 Critical care research in the UK and the recent trials | David Harrison

72. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,023 Critical care research in the UK and the recent trials | David Harrison

73. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,024 Critical care research in the UK and the recent trials | David Harrison

74. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,025 Critical care research in the UK and the recent trials | David Harrison

75. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,026 Critical care research in the UK and the recent trials | David Harrison

76. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,027 Critical care research in the UK and the recent trials | David Harrison

77. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,028 Critical care research in the UK and the recent trials | David Harrison

78. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,029 Critical care research in the UK and the recent trials | David Harrison

79. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,030 Critical care research in the UK and the recent trials | David Harrison

80. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,031 Critical care research in the UK and the recent trials | David Harrison

81. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,032 Critical care research in the UK and the recent trials | David Harrison

82. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,033 Critical care research in the UK and the recent trials | David Harrison

83. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,034 Critical care research in the UK and the recent trials | David Harrison

84. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,035 Critical care research in the UK and the recent trials | David Harrison

85. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,036 Critical care research in the UK and the recent trials | David Harrison

86. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,037 Critical care research in the UK and the recent trials | David Harrison

87. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,038 Critical care research in the UK and the recent trials | David Harrison

88. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,039 Critical care research in the UK and the recent trials | David Harrison

89. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,040 Critical care research in the UK and the recent trials | David Harrison

90. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,041 Critical care research in the UK and the recent trials | David Harrison

91. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,042 Critical care research in the UK and the recent trials | David Harrison

92. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,043 Critical care research in the UK and the recent trials | David Harrison

93. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,044 Critical care research in the UK and the recent trials | David Harrison

94. www.icnarc.org Total participants recruited by South East Coast CCN sites… 10,045 Critical care research in the UK and the recent trials | David Harrison

95. www.icnarc.org 10,045 Critical care research in the UK and the recent trials | David Harrison

96. www.icnarc.org Total participants recruited by South East Coast CCN sites… Thank you for all your hard work Please keep on participating! 10,045 Critical care research in the UK and the recent trials | David Harrison

97. www.icnarc.org CAOS was funded by the Medical Research Council (MRC) PAC-Man, FIRE, RAIN, CALORIES and ProMISe were funded by the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme (SPOT)light and (SPOT)id were funded by the Wellcome Trust Optimise was funded through an NIHR Clinician Scientist Award FREE and POPPI are funded by the NIHR Health Services and Delivery Research (HS&DR) programme The views expressed are those of the author and do not necessarily reflect those of the MRC, Wellcome Trust, the NIHR, the HTA and HS&DR programmes, the NHS or the Department of Health Critical care research in the UK and the recent trials | David Harrison Funding acknowledgements