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PINCER - Hot Topics March 2016
- 1. Academic Department of Critical Care Queen Alexandra Hospital Portsmouth Hot Topics in ICM @stevemathieu75 Consultant in Intensive Care Medicine Queen Alexandra Hospital, Portsmouth 18th March 2016
- 3. Academic Department of Critical Care Queen Alexandra Hospital Portsmouth 2016
- 4. Sepsis 3 • Sepsis should be defined as life-threatening organ dysfunction caused by a dysregulated host response to infection – Infection – Sepsis (‘Red Flag’ Sepsis) – Septic Shock • Screening: quickSOFA (qSOFA): – 2 of the following – RR 22/min or more – altered mentation – SBP 100 mm Hg or less – Simple, lactate? validated? Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 5. • French multicentre RCT • 383 patients • Acetazolamide vs placebo for up to 28d • Duration of invasive ventilation • Weaning • No of days of metabolic alkalosis in acetazolamide group Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 6. VANISH Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 7. Academic Department of Critical Care Queen Alexandra Hospital Portsmouth 2015
- 8. • RCT 23 ICU’s in Oz/Nz. 700 patients • 1g paracetamol 6 hourly vs placebo up to 28 days • ?immunomodulatory • Median ICU-free days (23 vs 22) • Mortality at 28 and 90 days; organ support free days • Early administration of paracetamol to ICU patients to treat fever due to probable infection results in a moderate reduction in temperature but does not effect mortality at 28 or 90 days Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 9. • In critically ill patients, does the use of a balanced crystalloid solution compared to normal saline effect the incidence of acute kidney injury? • Cluster RCT • RCT 4 ICU’s in Oz/Nz. 2278 patients • 0.9% NaCL vs Plasmalyte (median 2000mls each) • AKI Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 10. • 652 cardiac arrest survivors from TTM • Survival until 6/12 52% - invited to follow up - about half had psychometric testing - compared with a control group (STEMI & PCI but no cardiac arrest) • About 50% had cognitive impairment • 33 vs. 36 vs. control group similar • Attention & mental speed more affected in cardiac arrest patients • Memory & executive functioning similar Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 11. • In organ donors, following diagnosis of BSD, does TH decrease delayed graft function in kidney recipients? • 2 organ procurement centres in US • RCT 394 donors • Mild hypothermia (Target 34 – 35C) vs Normothermia (Target 36.5 – 37.5C) • Delayed graft function (the recipient’s requirement for dialysis during the 1st week post-transplantation) – 28.2% vs 39.2%, P=0.008 Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 12. • In paediatric patients with septic shock, does adrenaline compared with dopamine reduce 28 day mortality? • RCT; single centre Brazil • 120 patients • Adrenaline vs dopamine after 20mls/kg bolus • Once 60mls/kg fluid given, if still shocked, clinician choice of vasoactive drug • 28 day mortality in adrenaline group (0.7% vs 20.6%) Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 13. • In patients with severe pancreatitis, does early enteral feeding compared with on-demand feeding reduce death or major infection? • RCT; Netherlands; 208 patients • Early NJ within 24 hours vs IV fluids + ‘on demand’ • Composite outcome of death or major infection within 6 months Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 14. • In critically ill adults, does restriction of non-protein calories (permissive underfeeding) compared to standard feeding reduce mortality at 90 days? • RCT; Saudi Arabia and Canada; 894 patients • Permissive enteral underfeeding (40-60%) vs standard (70-100%) for up to 14 days • ? Moderate survival benefit from permissive underfeeding with moderate caloric intake (around 50% of target calories) and maintenance of full protein requirement (1.2-1.5g per kg per day) Academic Department of Critical Care Queen Alexandra Hospital Portsmouth PERMIT
- 15. • In patients with TBI, does hypothermia (32-35C) and standard care compared to standard care alone reduce death and major disability at 6 months after injury? • RCT, 18 countries > 50% UK • Composite outcomes measure • In patients with elevated intracranial pressure after TBI, therapeutic hypothermia, in addition to standard treatment, results in a greater risk of death and worse neurological outcomes in survivors compared to standard measures Academic Department of Critical Care Queen Alexandra Hospital Portsmouth PERMIT
- 16. • In moderate or severe TBI does EPO improve neurological outcome EPO? • Neuroprotective effects ? Reduce apoptosis • RCT, 29 countries; 606 patients • 40000 IU of EPO x 3 vs. placebo • Neurological disability at 6/12 or mortality – GOS-E 1-4: 44% vs 45% – 6/12 mortality 11% vs 16% – DVT 16% vs 18% Academic Department of Critical Care Queen Alexandra Hospital Portsmouth PERMIT
- 17. • In ICU patients who require a CVC, does the choice of insertion site affect the complication rates? • 10 ICUs in France (4 university hospitals and 5 general hospitals) • SC, IJ or femoral (>1000 lines in each group) • Composite measure of CRBSI and DVT • SC = lower infection; higher PTX Academic Department of Critical Care Queen Alexandra Hospital Portsmouth PERMIT
- 18. The Sepsis Studies Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 19. • In ICU patients undergoing intubation does apnoeic oxygenation during laryngoscopy increase the lowest arterial oxygen saturation experienced by patients • Single centre • HFNC + other NRBM/BiPAP/BVM/standard nasal vs. NRBM/BiPAP/standard nasal cannulae • Median lowest SpO2 Academic Department of Critical Care Queen Alexandra Hospital Portsmouth PERMIT
- 20. • 12 French ICU’s; 310 patients • ‘ALI’ • NRB vs HFNC vs NIV • Proportion of patients who required endotracheal intubation within 28 days after randomisation: • High-Flow oxygen: 40 patients (38%) • Non-invasive ventilation: 55 patients (50%) • Standard oxygen: 44 patients (47%) • p = 0.18 Academic Department of Critical Care Queen Alexandra Hospital Portsmouth PERMIT
- 21. • Is “fresh” blood (stored for 8 days or less) better than old (stored 2-42 days)? • RCT 64 ICUs in Canada and France; 2430 patients • RBCS: 6 days vs 22 days • 90 day mortality (37% vs. 35%) • Transfusion triggers and processes for safe administration of blood are probably more important Academic Department of Critical Care Queen Alexandra Hospital Portsmouth PERMIT
- 22. TITRe2 • In adults undergoing cardiac surgery, does a restrictive transfusion strategy vs liberal one lead to fewer infections and ischaemic events within 3 months? • RCT 17 cardiac ICUs in UK • Trigger Hb 75 vs 90g/dl • Composite outcome of serious infections or ischaemic events within 3/12 – 35% vs 33% TRICC, TRISS, Villanueva Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 23. PROPPR • RCT in 12 N. American Level 1 trauma centres • 680 patients • 1:1:1 vs. 1:1:2 FFP / plt / PRBCs • 24 hour and 30d mortality no different • Time of haemostasis; Any of 23 pre- defined complications; Hospital, ventilator & ICU free days • Post- hoc analysis: - Death by exasanguination in 1st 24 hrs much less in 1:1:1 group Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 24. • In adult patients with alcoholic hepatitis, does prednisolone and / or pentoxifylline compared to placebo reduce mortality? • RCT 65 UK hospitals • Pentoxyfylline + placebo vs. Prednisilone + placebo vs. both vs placebo x 2 • ICUs in Canada and France; 2510 patients • 28d mortality no statistical difference Academic Department of Critical Care Queen Alexandra Hospital Portsmouth PERMIT
- 25. Academic Department of Critical Care Queen Alexandra Hospital Portsmouth 2014
- 26. ALBIOS • RCT, 100 ICUs in Italy • 1795 patients with severe sepsis • 300mls 20% HAS daily + CSL vs. CSL • Target serum albumin 30g/dl • 287 mortality: no different – HAS + CSL: 31.8% – CSL: 32% • Secondary outcomes: 90 d mortality – No difference Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 27. ARISE • Randomised, controlled, multicentre, • 51 hospitals 1,600 patients with septic shock • EGDT vs. Usual Care • No difference in: – All cause mortality at 90d (18%) – ICU & Hospital LOS Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 28. ProCESS • RCT 31 ICUs in US • 03/2008 – 05/2013 • 1351 patients with septic shock • 3 groups – EGDT – Protocol based standard therapy – Usual care – No difference in 60 d mortality between groups Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 29. TRISS • RCT 32 general ICUs in Scandinavia • 998 patients with septic shock & Hb <9 • Transfusion threshold <7 vs. <9 • Excluded patients with ACS • Mortality at 90 days (43% vs 45%) • Secondary outcomes • Vasoactive drugs • Ventilation • RRT • % of days alive & out of hospital • Ischaemic events Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 30. CALORIES • Open, multicentre, RCT • 2400 patients in 33 ICUs in UK • PN vs. EN within 36 hours for 5/7 • Primary outcome: – All cause mortality 33.1% (PN) vs. 34% (EN) • Secondary outcome: – Vomiting more in EN – No difference on other 16 outcomes including ‘serious’ hypoglycaemia – NB daily calorific targets achieved in <40% in both groups Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 31. PEITHO • RCT; 13 countries; 1006 patients • Tenecteplase vs placebo • Death or haemodynamic decompensation within 7 days – Significantly lower in thrombolysis group – 2.6% vs. 5.6% in placebo group (NNT 34) • Mortality at 7 days and 30 days – 7 days: 1.2% vs. 1.8%; 30 days: 2.4% vs. 3.2% • Major extracranial bleeding - higher in thrombolysis group – 6.3% vs. 1.2% (NNH 19) • Haemorrhagic stroke – higher in thrombolysis group – 2% vs 0.2% (NNH 55) Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 32. HARP 2 • 540 patients ARDS; 40 UK ICUs • ARDSnet +/- statin for 28 days (80mg od simvastatin) • Primary outcome – No difference in ventilator free days at 28d • Secondary outcome – No difference in SOFA, oxygenation – Elevated CK or ALT/AST > in statin group Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 33. CATIS • 4,071 patients • Within 48 hrs ischaemic stroke • nonthrombolysed and ↑BP • Hypertension therapy vs no BP Rx • BP control effective • No difference – death and major disability • 14 days / hospital discharge • 3 months Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 34. CRISTAL Study • Stratified open label RCT • Recruitment over 9 years • Any colloid vs any CSL • 2857 patients with hypovolaemic shock • 28 day mortality • Colloids favoured: – 90 day mortality (30% vs 34%) – More days alive without MV – More days alive without vasopressors – Less RRT - Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 35. Academic Department of Critical Care Queen Alexandra Hospital Portsmouth Guidelines
- 36. Standards - quality • Staffing – Consultant presence • 24/7 & within 30 minutes – Consultant: patient 1:8 – 1:15; ICU resident/patient 1:8 – Designated CD – Ward rounds x2 daily – Training / FICM / Board Tutors – Nursing 1:1 (level 3); 1:2 (level 2) – MDT e.g. physio, pharmacy, dieticians • Operational – Large ICUs divided into pods of 8-15 patients – Admit within 4 hrs of decision to admit – Avoid non-clinical transfers – Transfer to ward – clear and formalised – Out of hours transfers – Readmission within 48 hours bad – Assessment of rehab for each patient • Equipment – Training • Data Collection – ICNARC – Risk register Academic Department of Critical Care Queen Alexandra Hospital Portsmouth Quality Indicators SMR Scoring Systems
- 37. Academic Department of Critical Care Queen Alexandra Hospital Portsmouth http://www.britishinfection.org/files/5614/5674/2938/McGill_meningitis_guidelines_Final_published_proof.pdf
- 38. Academic Department of Critical Care Queen Alexandra Hospital Portsmouth Themes
- 40. NAP 4 - 2011 • All NHS hospitals for 1 year ’08-’09 • 184 reports 133 anaesthesia 36 ICU 15 ED • Inclusion criteria death, brain damage emergency surgical airway unanticipated ICU admission Prolongation ICU stay Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 41. Summary of NAP 4 25% of major airway events in a hospital occur in ICU or the ED 46% of ICU events and 53% of ED events occurred out of hours 50% of ICU events were due to tracheostomy related events 50% events in ICU and 27% events in ED resulted in death 61% events in ICU resulted in death or severe neurological harm Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 42. Recommendations Capnography Airway equipment Back up planning Staffing Patient transfers Education/training Tracheostomy tube design Team working Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 43. TracMan - 2013 •Early tracheostomy (by d 4) or late (>10/7) – 455 patients – Mortality the same 31% – LOS the same 13 d – Complications slightly higher in late group 6% vs. 5% Young et al. JAMA 2013 May 22;309(20):2121-9 Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 44. ARDS
- 45. ARDS - Incidence • 1 yr prospective observational study; 255 patients • Incidence 7.2/100,000/year (? US 75/100,000) • Despite use of lung protective ventilation overall ICU mortality >40% Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 46. ARDS - lots of trials
- 47. OSCAR • 795 patients with moderate - severe ARDS (<26.7kPa / 200mmHg) • CMV vs. HFOV (MV <7 days) • No difference in – 30/7 mortality (41%) – Duration antimicrobial agents (2/3 chest sepsis) – Vasoactive support duration – ICU LOS – Hospital LOS Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 48. OSCILLATE • 548 patients with moderate - severe ARDS • HFOV vs low Vt/High PEEP CV (MV < 3d) • Trial stopped early as harm with HFOV • HFOV – Hospital mortality 47% vs 35% – More sedation – More NMBA’s – More vasopressors Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 49. Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 50. PROSEVA • 466 patients with severe ARDS • Prone position vs supine position • Prone position was associated with – Improved mortality • 28 day: 16% vs 33% • 90 day: 24% vs 41% – Less cardiac arrests – No difference in complications Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 51. PROSEVA Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 52. Statins in ARDS • Multicentre, RCT • Rosuvastatin vs. placebo in ARDS • Statin may modulate inflammatory response • 745 patients (trial stopped early because of futility) • Primary outcome: • 60d mortality: 28.5% vs. 24.9% (statin vs. placebo) • Ventilator free days: 15.1 vs. 15.1 Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 53. Statin & VAP • 300 patients with suspected VAP (CPIS ≥ 5) • Simvastatin 60mg vs placebo • No difference in – 28d survival – ICU or hospital mortality – Duration MV – Delta SOFA • Increased mortality in statin naieve Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 54. BALTI - 2012 • 162 patients; 46 UK ICU’s • ARDS & MV - salbutamol 15mcg/kg/hr or placebo - Treatment for up to 7 d • Mortality greater in those given salbutamol 34% vs 23% at 28d Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 55. Steroids in ARDS • 9 studies (4 RCT’s & 5 cohort) • 648 patients • Trend to reduced mortality but only ss when result pooled • Trials vary ++ 1. Dose 2. Initiation of treatment 3. Course length 4. Not all studies report adverse events Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 56. Functional disability 5 years after ARDS 109 survivors from ’98 - ’01 Interview, PFT’s, 6 min walk test, resting & exercise oximetry, chest imaging, QOL survey PFT’s normalish BUT 6 min walk test 76% predicted, physical/psychological problems Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 57. Nitric oxide – just say No • Potent pulmonary vasodilator which when inhaled = selective vasodilation in well ventilated lung units • Improved V/Q mismatch and PVR & PAP • Also anti-inflammatory effects • Systematic review of 12 trials with 1200 patients = improved oxygenation d1, no improvement in mortality • AKI and methaemaglobinaemia intracranial bleeding in children Afshari Cochrane review 2007 - adults Barrington Cochrane review 2010 – children Afshari – systematic review 2011 Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 58. Magnesium in asthma • 1200 patients 2008-2012 • Neb vs. IV Mg vs. placebo • No role for neb Mg • Limited role at best for IV Mg • Not life threatening asthma Intravenous or nebulised magnesium sulphate versus standard therapy for severe acute asthma (3Mg trial): a double- blind, randomised controlled trial Goodacre et al Lancet 2013 Vol 1 (4) 293-300 Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 59. Guidelines Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 60. NCEPOD 2014: Tracheostomy • Documentation & consent – Indications, type, inner tube, reasons for failed extubation/why no trial of extubation • Different types of tubes • Rapidly available difficult airway trolley • Training programmes in blocked/displaced tubes • Capnography • Discharge of patients with tracheostomy • MDT – physio & SALT Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 61. Tracheostomy standards • Indications for tracheostomy • Cautions and contraindications • Consent • Equipment • Ultrasound • Anaesthesia • Staffing • Types of tracheostomy tubes • Inner cannulae • Complication – Early – Late – Airway emergencies T R A C H E O S T O M Y C A R E I N T E N S I V E C A R E S O C I E T Y S T A N D A R D S © 2 0 1 4
- 62. MCA & DoLS DoLS • 3 cases in 2014 Academic Department of Critical Care Queen Alexandra Hospital Portsmouth MUST READ….
- 63. Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 64. INTERACT 2 • 2,839 pts with early spontaneous intracerebral haemorrhage & ↑SBP • Compared SBP <140 mmHg vs <180 • Aggressive BP control associated with – Trend for less adverse events (p=0.06) – Lower modified Rankin scores • No difference in mortality Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 65. Magnesium for aneurysmal SAH (MASH-2): a randomised placebo-controlled trial Mees S et al. 2012 The Lancet. Vol 380 9834:44-49 • 8 ICU’s in Europe and S America • 1204 patients • The question: does Mg reduce poor outcome by reducing vasospasm and delayed cerebral ischaemia (DCI) • Magnesium 64mmol/day for 20/7 or placebo • Primary outcome of poor outcomes as defined by score 4-5 on modified Rankin Scale at 3/12, or death • NO DIFFERENCE Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 66. Delirium HOPE ICU • 142 patients with delirium • CAM-ICU assessment • Double blinded • Haloperidol vs. placebo • No change in duration of delirium in critically ill patients • Haloperidol should be reserved for short term management on acute agitation Effect of intravenous haloperidol on the duration of delirium and coma in critically ill patients (Hope-ICU): a randomised, double-blind, placebo-controlled trial Valeirie Page. The Lancet Respiratory Medicine, Volume 1, Issue 7, Pages 515 - 523, September 2013 Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 67. Treating Delirium Academic Department of Critical Care Queen Alexandra Hospital Portsmouth 101 MV patients RCT haloperidol vs. ziprasidone vs placebo 21/7 study period No difference in any of the groups!
- 68. The beginning; Kress NEJM 2000 Reduction in LOS Girard Lancet 2008 Decreased ICU stay, time on ventilator and mortality Strom Lancet 2010 Reduction in LOS and ventilator days No sedation group - boluses of morphine, well established in institution, more agitated delerium in no sedation group Jacob JAMA 2012 PRODEX/MIDEX No better than midaz or propofol at maintaining light to mod sedation and more adverse effects. Increased patient interactions. Less vent days than midazolam Ryker JAMA 2009 Reduction in ventilator days and delirium Mehta 2013 For MV patients managed with protocolised sedation, the additon of daily sedation interruption did not reduce duration MV or ICU LOS
- 69. Don’t forget the simple things…. Academic Department of Critical Care Queen Alexandra Hospital Portsmouth • Small RCT 136 patients • Used NEECHAM score • Delirium (20%) similar but less mild confusion with ear plugs and good night sleep <50% vs. 25%
- 70. Guidelines for managing delirium Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 71. Neuro-ICU ICP Monitoring • Multicentre RCT of 324 patients Bolivia and Ecuador • Intraparenchymal ICP monitoring vs. clinical & imaging • No difference in mortality or neuropsycholoigcal status at 6/12 Academic Department of Critical Care Queen Alexandra Hospital Portsmouth A Trial of Intracranial-Pressure Monitoring in Traumatic Brain Injury Randall M. Chesnut et al N Engl J Med 2012; 367:2471-2481
- 72. Neuro Academic Department of Critical Care Queen Alexandra Hospital Portsmouth http://www.wessexics.com/WICS_Guidelines/ The SAH section definitely worth a read for the exam The SAH section definitely worth a read for the exam
- 73. VAP Academic Department of Critical Care Queen Alexandra Hospital Portsmouth What is VAP? What are the common organisms (early vs. late? Scoring systems e.g. CPIS, HELICS What antibiotics would you use? How can you reduce incidence
- 75. TTM • 950 unconscious adults; 36 ICU’s • 33°C (n=473) with 36°C (n=466) • No difference in – All cause mortality 33°C (50%) with 36°C (48%) – poor neurological function at 180 days 33°C (54%) with 36°C (52%) Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 76. Pre-hospital hypothermia • Prehospital cooling vs. standard care • 2L of cold normal saline once ROSC • 1,359 OOHCA patients • Cooling effective (reduced temp) • No difference – Survival to hospital discharge • VF 63% vs 64% • nonVF 19% vs 16% – Good neurological recovery • VF 57% vs 62% • nonVF 14% vs 13% Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 77. CO Monitoring – COMET-UK • Survey to all UK ICUs • Respondents – Majority used CO monitoring • Oesophageal doppler 57% • LiDCO 43% • PiCCO 42% Academic Department of Critical Care Queen Alexandra Hospital Portsmouth How does doppler work? Thermodilution?Pulse contour analysis ? How does doppler work? Thermodilution?Pulse contour analysis ?
- 78. OPTIMISE • RCT, multicentre, 17 UK ICUs • 734 patients • > 50y undergoing GI surgery with one or more ‘high risk’ risk factors • Algorithm-directed care dictating colloid and dopexamine administration using vs. clinician directed care without use of CO monitoring • Primary outcome: composite of 30d mortality and mod/major complications – Intervention: 36.6% – Control arm: 43.4% • No SS difference in secondary outcomes – POMS, infectious complications, critical care free days at 30d, mortality at 30d and 180d, hospital LOS Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 79. IVOIRE Study • Randomised, open study • 18 ICU’s in France, Belgium and Netherlands 2005-2010 • 140 pts with septic shock & AKI • HVHF 70mls/kg/hr v 35mls/kg/hr • Slow recruitment • No difference in mortality = 40% 28/7 • HVHF not recommended Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 80. IABP – SHOCK II • 600 patients with cardiogenic shock secondary to AMI • IABP vs no IABP • All received early revascularisation and best medical therapy • No difference – 30/7 mortality (40%) – ICU LOS, catecholamine, bleeding • Lancet 2013 Sept – 12/12 results = no difference in mortality or reinfarction rate Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 81. VSE in cardiac arrest • 268 patients in hospital cardiac arrest • Vasopressin(20IU/CPR cycle) + epinephrine (1mg/CPR cycle) + methylprednisilone (40mg) vs placebo + epinephrine (1mg/CPR cycle) • VSE group – ROSC at 20 mins higher 84% vs 66% – Improved survival to hospital discharge with CPC 1 or 2 – Improved haemodynamics & cvSpO2 – Less organ dysfunction • andAcademic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 82. Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 83. CHEER • Refractory cardiac arrest treated with mechanical CPR, hypothermia, ECMO and early reperfusion • 26 patients (11 OHCA; 15 IHCA) • Primary outcome – Survival with good neurological recovery (CPC 1-2) 14/26 (54%) • Secondary outcomes – ROSC achieved in 25/26 (92%) of patients – Survival to hospital discharge 14/26 (54%) Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 84. Academic Department of Critical Care Queen Alexandra Hospital Portsmouth The oxygenator in veno-venous ECMO
- 85. ECMO Study type Year pub N (ECM O) N (non ECMO) % H1N1 ECMO mortalit y Non- ECMO mortality p RCT 200 9 90 90 0 37% 50% 0.07 RCT 199 4 21 19 0 67% 58% 0.8 RCT 197 9 48 42 0 90% 92% 0.84 Cohort 200 6 32 118 0 47% 29% 0.06 Cohort 200 0 62 183 0 45% 39% NS Cohort 199 7 49 73 0 45% 11% <0.001 Case series 200 9 68 133 100% 23% 13% 0.06 Case series 201 1 69 11 100% 27.5% ?52% ***
- 86. ECMO for H1N1 • 2009-2010 • 80 patients referred for ECMO • 69 received ECMO • 22 of these died (27.5%) • Matching cohort = 52% • For patients with H1N1 related ARDS, mortality reduced with ECMO Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 88. Academic Department of Critical Care Queen Alexandra Hospital Portsmouth • Meta-analysis • 16 trials inc PEITHO, MAPPETT, MOPETT, TOPCOT • Thrombolysis + anticoagulation vs. anticoagulation alone • All cause mortality less in thrombolysis group but major bleeding & ICH higher
- 89. Academic Department of Critical Care Queen Alexandra Hospital Portsmouth SEPSIS
- 90. Ferrer: Empiric antibiotics in sepsis • Retrospective observational cohort study • 165 ICUs – Europe, US & S America • Jan 2005- Feb 2010 • 18,000 patients with septic shock • Delay in antibiotics administration over first 6 hours after identification of SS or septic shock -> increased mortality • < 1 hr 24.6%; 1-2h 25.9% > 6h 33% Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 91. SEPSISPAM • RCT, multicentre, 29 French ICUs • March 2010 – Dec 2011 • Septic shock • Target MAP 80-85 vs. 65-70 • No difference in – 28 day mortality (high MAP 36.6% vs. 34%) • New AF 6.7% in higher MAP group vs. 2.8% P=0.02 • In chronic hypertension group, worsening creatinine and need for RRT was lower in higher MAP group Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 92. PROWESS SHOCK • Randomised, controlled, multicentre, parallel group study • 1,697 patients with septic shock • No difference in – 28 day mortality (APC 26.4% vs 24.2%) – 90 day mortality (34.1% vs 32.7%) • No subgroup effect seen in protein C deficient group • Serious bleeding n = 10 APC vs 8 placebo Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 93. B blockers in septic shock • Open label, single unit • Septic shock + HR ≥ 95 + NADR • 77 patients – esmolol infusion (HR 80- 94) vs 77 patients standard treatment • Esmolol group – 28d Mortality 50% vs 81% in placebo – Improved SV index, LVSWI, lactate – Less NADR requirement – Less fluid requirement Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 94. Esmolol in refractory VF • Single centre, non randomised • 25 patients with refractory (>3 defib attempts) VF or pulseless VT • Esmolol vs. placebo • Primary outcome – Survival with good neurological recovery – 50% esmolol vs 11% control group – No difference in rates of ROSC or survival to hospital discharge Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 95. Steroids in Sepsis Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 96. ADRENAL Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 97. The evidence…..let’s give it Academic Department of Critical Care Queen Alexandra Hospital Portsmouth 8 trials published before ’89 - No mortality benefit (some worse) - Decreased time for shock resolution - More secondary infections - Higher doses and for shorter periods 19 ICU’s 300 patients - 50mg hydrocortisone + fludrocorisone vs. placebo by 8hrs of onset of septic shock. - ‘Non responders’ (adrenal suppression) better ICU (53% vs. 63%) and hospital mortality (61% vs. 72%). - Increase secondary bacterial infections - NNT = 7 (Annane JAMA 2002)
- 98. The evidence…..perhaps don’t give Academic Department of Critical Care Queen Alexandra Hospital Portsmouth CORTICUS - 52 ICU’s, 499 patients - 50mg hydrocortisone QDS vs. placebo 6/7 - 28/7 mortality no different between groups and subset of non- responders Quicker shock resolution, catecholamine sparing, more secondary infections Sprung et al. NEJM 2008: 358; 111-24 - Etomidate used in 1/5th of patients - Only 35% power to detect a 20% mortality reduction - High variability between laboratories in cortisol assays
- 99. VASST Academic Department of Critical Care Queen Alexandra Hospital Portsmouth - RCT 778 pts with septic shock - Noradrenaline vs. Norad & Vaso (0.03 units/min) - No mortality benefit - Higher doses associated with ischaemia “Possible use if other vasopressors failed” Less severe shock associated with reduced mortality when vasopressin used Russell et al. NEJM 2008: 358: 877-87
- 100. ABLE Multicentre UK RBC transfusion (7d vs. 15-25d) Transfusion triggers – TRICC, TRISS & Villaneuva, TITRe2 PROPPR: Plasma, Platelets & PRBC’s 1:1:1 vs. 1:1:2 Guidelines on the management of anemia and RBC transfusion in adult critically ill patients (BCSH Guidelines 2012) Serious Hazards of Transfusion (SHOT) – JICS July 2013
- 101. Acute UGI Bleed • Randomised, parallel group study • 921 pts with severe upper GI bleeding • Compared restrictive (Hb <7g/dL) vs liberal transfusion strategy (Hb<9g/dL) • Restrictive strategy associated with – Reduced number of pts receiving transfusion (15% vs 51%) – Increased probability survival (HR 0.55) – Less rebleeding (10% vs 16%) – Less adverse events (40% vs 48%) Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 102. TXA CRASH - 2 Lancet 2010 • tranexamic acid in reducing transfusion requirements and death from significant haemorrhage following injury • 20,000 patients • Risk of haemorrhage reduced by 0.8% • No reduction in transfusion usage • Only 50% received blood and average only 3 (? ‘significant haemorrhage’) CRASH - 2 subanalysis Lancet 2011 • Mortality directly related to haemorrhage • Tranexamic acid only effective if within first 3 hours. Beyond this time mortality increases Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 103. TXA CRASH – 2 Does TXA reduce the risk of intracranial bleeding in patients with TBI? BMJ 2011 • 250 of the 20,000 patients eligible. • Brain haemorrhage growth 5mm vs. 8mm (TXA vs. placebo) • Not SS • No mention of extent of extracranial injuries in either group making mortality comparisons difficult • Not well matched as there were more pts with SAH (61% vs 43%) • No increase is focal cerebral ischaemia • Conclusion “it is probable that benefits of tranexamic acid outweigh risks’ Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 104. Trauma Haemorrhage 1. Coagulation monitoring and measures to support coagulation should be implemented early 2. Damage control surgery 3. Physiological targets, suggested use & dosing of fluids, blood products and TXA 4. Patients on antiplatelet agents and/or oral anticoagulants require special attention 5. Mutlidisciplinary approach & evidence based protocols adapted to local circumstances need to be developed and implemented Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 105. Fluids • Don’t give too much • Don’t give too little • Make sure you give the right amount • Starches bad…very bad Association of HES administration with mortality and AKI in critically ill patients requiring volume resuscitation. Meta- analysis. JAMA 2013 vol 309 (7) • Albumin back in? SAFE subgroup analysis 1200 pts with severe sepsis - 28/7 mortality lower in albumin group (30% vs. 35% OR 0.87) Finfer S et al 2011 Intensive Care Med 37:86–96 Delayney metaanalysis. Role of albumin as a resuscitation fluid for patients with sepsis. 17 studies, 1977 patients. Crit Care Med 2011 Albios Study – Gattinoni (video ion ESICM website) Academic Department of Critical Care Queen Alexandra Hospital Portsmouth “lets talk about fluid responsiveness” NO!
- 106. ESICM statement on colloids 1. Recommend not to use HES with mw ≥ 200kDa in patients with severe sepsis or risk of AKI 2. Suggest avoid 6% HES or gelatin in these groups 3. Recommend not to use colloids in patients with head injury and not to administer gelatins and HES in orhan donors 4. Suggest avoid hyperoncotic solutions for fluid resuscitation Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 107. Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 108. 6S Study • 804 ICU pts with severe sepsis • Compared fluid resuscitation – 130/0.4 hydroxyethyl starch (tetraspan) vs Ringer's acetate • HES associated with – Increased 90 day mortality 51% vs 43% – Increased RRT requirement 22% vs 16% – Trend for increased bleeding 10% vs 6% Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 109. CHEST Study • 7000 ICU pts • Fluid resuscitation with 6% HES 130/0.4 (Voluven) or 0.9% saline • No differences in – Mortality (HES 18% vs 17%) – LOS – ICU / Hospital • HES associated with increased – RRT (7% vs 5.8%; RR 1.21) – Pruritus / Rash / Hepatic failure -Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 110. Gastrointenstinal
- 111. Need a nice summary? Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 112. The SuDDICU study SDD 12 meta-analyses of 28 RCT’s. 10 show reduced pneumonia rate; 6 show morality benefit • Why have clinicians avoided implementing it in UK? • What are the barriers? • What further evidence is required before full scale clinical implementation Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 113. VITdAL-ICU • RCT, Single Centre with 5 ICUs in Austria, 475 patients • Vit D or placebo • Primary outcome: – Hospital LOS no different • Secondary outcome. No difference: – ICU LOS – ICU-, 28d- , hospital- & 6 month- mortality • Subgroup analysis – If severe vit D def and given Vit D3 -> improvement in 28d- hospital- and 6 month- mortality Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 114. Systematic review: CCM 2010 In those patients receiving enteral nutrition, stress ulcer prophylaxis may not be required and may actually increase VAP Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 115. H2R antagonists vs PPI • Cohort Study of 35,000 pts • MV > 24 hours and either H2R antagonist or PPI • H2R antagonist group had – Less GI haemorrhage 2.1 vs 5.9% – Pneumonia 27% vs 39% – C.Diff 2.2% vs 3.8% Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 116. Hepatology • ALD Alcohol related illness costs NHS £1.7 billion/year Systematic review of 21 articles Overall ICU mortality 40-50% Mackle study only one to provide data on GI haemorrhage - mortality 48%, 62%, 67%,68% for unit, hospital, 6/12 and one yr - if get out of hospital most will survive Organ support - 3 papers (ventilation, vasoactive drugs, RRT) Mackle - - if MV and vasoactive drugs hospital mortality 86% - If MV, vasoactive drugs and RRT > 90% - If just MV 31% Saliba RRT 90% Rye 100% mortality if require RRT Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 118. Microbiology • 96 ICU’s • Data from 60,000 admissions ’09-’11 • Invasive fungal disease defined as BC or sample from normally sterile site showing yeast/mould cells in a microbiological or histopathological report • 383 (0.6%) were admitted with or developed IFD • Conclusion: Incidence of IFD in non- neutropenic, critically ill patients is low Academic Department of Critical Care Queen Alexandra Hospital Portsmouth
- 119. Academic Department of Critical Care Queen Alexandra Hospital Portsmouth Best of Luck! @WICSBottomLine @stevemathieu75
Editor's Notes
- Full text here http://www.nejm.org/doi/pdf/10.1056/NEJMoa1215716 OSCAR trial 2013 http://lifeinthefastlane.com/education/ccc/high-frequency-oscillation-ventilation-hfov/ non-blinded intention-to-treat MC RCT 795 patients HFOV versus usual care control group outcomes:-&gt; all cause mortality at 28 days was 41.7% vs 41.1% (P=0.85 chi-square test) Commentary and criticisms:— less hemodynamic compromise, lower airway pressures than OSCILLATE and more protocol variation, possibly due to physician judgement limiting the harm from HFOV settings— HFOV groups received more sedatives and muscle relaxants Conclusion: no mortality difference at 1 month
- Full text here http://www.nejm.org/doi/pdf/10.1056/NEJMoa1215716 OSCAR trial 2013 http://lifeinthefastlane.com/education/ccc/high-frequency-oscillation-ventilation-hfov/ non-blinded intention-to-treat MC RCT 795 patients HFOV versus usual care control group outcomes:-&gt; all cause mortality at 28 days was 41.7% vs 41.1% (P=0.85 chi-square test) Commentary and criticisms:— less hemodynamic compromise, lower airway pressures than OSCILLATE and more protocol variation, possibly due to physician judgement limiting the harm from HFOV settings— HFOV groups received more sedatives and muscle relaxants Conclusion: no mortality difference at 1 month
- The Interaction of Vasopressin and Corticosteroids in Septic Shock: A Pilot Randomized Controlled Trial. OBJECTIVES:: Vasopressin and corticosteroids are both commonly used adjunctive therapies in septic shock. Retrospective analyses have suggested that there may be an interaction between these drugs, with higher circulating vasopressin levels and improved outcomes in patients treated with both vasopressin and corticosteroids. We aimed to test for an interaction between vasopressin and corticosteroids in septic shock. DESIGN:: Prospective open-label randomized controlled pilot trial. SETTING:: Four adult ICUs in London teaching hospitals. PATIENTS:: Sixty-one adult patients who had septic shock. INTERVENTIONS:: Initial vasopressin IV infusion titrated up to 0.06 U/min and then IV hydrocortisone (50 mg 6 hourly) or placebo. Plasma vasopressin levels were measured at 6-12 and 24-36 hours after hydrocortisone/placebo administration. MEASUREMENTS AND MAIN RESULTS:: Thirty-one patients were allocated to vasopressin + hydrocortisone and 30 patients to vasopressin + placebo. The hydrocortisone group required a shorter duration of vasopressin therapy (3.1 d; 95% CI, 1.1-5.1; shorter in hydrocortisone group) and required a lower total dose of vasopressin (ratio, 0.47; 95% CI, 0.32-0.71) compared with the placebo group. Plasma vasopressin levels were not higher in the hydrocortisone group compared with the placebo group (64 pmol/L difference at 6- to 12-hour time point; 95% CI, -32 to 160 pmol/L). Early vasopressin use was well tolerated with only one serious adverse event possibly related to study drug administration reported. There were no differences in mortality rates (23% 28-day mortality in both groups) or organ failure assessments between the two treatment groups. CONCLUSIONS:: Hydrocortisone spared vasopressin requirements, reduced duration, and reduced dose, when used together in the treatment of septic shock, but it did not alter plasma vasopressin levels. Further trials are needed to assess the clinical effectiveness of vasopressin as the initial vasopressor therapy with or without corticosteroids.
- Full text here http://www.nejm.org/doi/pdf/10.1056/NEJMoa1215716 OSCAR trial 2013 http://lifeinthefastlane.com/education/ccc/high-frequency-oscillation-ventilation-hfov/ non-blinded intention-to-treat MC RCT 795 patients HFOV versus usual care control group outcomes:-&gt; all cause mortality at 28 days was 41.7% vs 41.1% (P=0.85 chi-square test) Commentary and criticisms:— less hemodynamic compromise, lower airway pressures than OSCILLATE and more protocol variation, possibly due to physician judgement limiting the harm from HFOV settings— HFOV groups received more sedatives and muscle relaxants Conclusion: no mortality difference at 1 month
- Full text here http://www.nejm.org/doi/pdf/10.1056/NEJMoa1215716 OSCAR trial 2013 http://lifeinthefastlane.com/education/ccc/high-frequency-oscillation-ventilation-hfov/ non-blinded intention-to-treat MC RCT 795 patients HFOV versus usual care control group outcomes:-&gt; all cause mortality at 28 days was 41.7% vs 41.1% (P=0.85 chi-square test) Commentary and criticisms:— less hemodynamic compromise, lower airway pressures than OSCILLATE and more protocol variation, possibly due to physician judgement limiting the harm from HFOV settings— HFOV groups received more sedatives and muscle relaxants Conclusion: no mortality difference at 1 month
- BACKGROUND: There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock. METHODS: In this randomized, double-blind, placebo-controlled, multicenter trial, we assigned 1697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours to receive either DrotAA (at a dose of 24 μg per kilogram of body weight per hour) or placebo for 96 hours. The primary outcome was death from any cause 28 days after randomization. RESULTS: At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval [CI], 0.92 to 1.28; P=0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P=0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P=0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P=0.81). CONCLUSIONS: DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock.
- Full text here http://www.nejm.org/doi/pdf/10.1056/NEJMoa1215716 OSCAR trial 2013 http://lifeinthefastlane.com/education/ccc/high-frequency-oscillation-ventilation-hfov/ non-blinded intention-to-treat MC RCT 795 patients HFOV versus usual care control group outcomes:-&gt; all cause mortality at 28 days was 41.7% vs 41.1% (P=0.85 chi-square test) Commentary and criticisms:— less hemodynamic compromise, lower airway pressures than OSCILLATE and more protocol variation, possibly due to physician judgement limiting the harm from HFOV settings— HFOV groups received more sedatives and muscle relaxants Conclusion: no mortality difference at 1 month
- Full text here http://www.nejm.org/doi/pdf/10.1056/NEJMoa1215716 OSCAR trial 2013 http://lifeinthefastlane.com/education/ccc/high-frequency-oscillation-ventilation-hfov/ non-blinded intention-to-treat MC RCT 795 patients HFOV versus usual care control group outcomes:-&gt; all cause mortality at 28 days was 41.7% vs 41.1% (P=0.85 chi-square test) Commentary and criticisms:— less hemodynamic compromise, lower airway pressures than OSCILLATE and more protocol variation, possibly due to physician judgement limiting the harm from HFOV settings— HFOV groups received more sedatives and muscle relaxants Conclusion: no mortality difference at 1 month
- Full text here http://www.nejm.org/doi/pdf/10.1056/NEJMoa1215716 OSCAR trial 2013 http://lifeinthefastlane.com/education/ccc/high-frequency-oscillation-ventilation-hfov/ non-blinded intention-to-treat MC RCT 795 patients HFOV versus usual care control group outcomes:-&gt; all cause mortality at 28 days was 41.7% vs 41.1% (P=0.85 chi-square test) Commentary and criticisms:— less hemodynamic compromise, lower airway pressures than OSCILLATE and more protocol variation, possibly due to physician judgement limiting the harm from HFOV settings— HFOV groups received more sedatives and muscle relaxants Conclusion: no mortality difference at 1 month
- Full text here http://www.nejm.org/doi/pdf/10.1056/NEJMoa1215716 OSCAR trial 2013 http://lifeinthefastlane.com/education/ccc/high-frequency-oscillation-ventilation-hfov/ non-blinded intention-to-treat MC RCT 795 patients HFOV versus usual care control group outcomes:-&gt; all cause mortality at 28 days was 41.7% vs 41.1% (P=0.85 chi-square test) Commentary and criticisms:— less hemodynamic compromise, lower airway pressures than OSCILLATE and more protocol variation, possibly due to physician judgement limiting the harm from HFOV settings— HFOV groups received more sedatives and muscle relaxants Conclusion: no mortality difference at 1 month
- Full text here http://www.nejm.org/doi/pdf/10.1056/NEJMoa1215716 OSCAR trial 2013 http://lifeinthefastlane.com/education/ccc/high-frequency-oscillation-ventilation-hfov/ non-blinded intention-to-treat MC RCT 795 patients HFOV versus usual care control group outcomes:-&gt; all cause mortality at 28 days was 41.7% vs 41.1% (P=0.85 chi-square test) Commentary and criticisms:— less hemodynamic compromise, lower airway pressures than OSCILLATE and more protocol variation, possibly due to physician judgement limiting the harm from HFOV settings— HFOV groups received more sedatives and muscle relaxants Conclusion: no mortality difference at 1 month
- Full text here http://www.nejm.org/doi/pdf/10.1056/NEJMoa1215716 OSCAR trial 2013 http://lifeinthefastlane.com/education/ccc/high-frequency-oscillation-ventilation-hfov/ non-blinded intention-to-treat MC RCT 795 patients HFOV versus usual care control group outcomes:-&gt; all cause mortality at 28 days was 41.7% vs 41.1% (P=0.85 chi-square test) Commentary and criticisms:— less hemodynamic compromise, lower airway pressures than OSCILLATE and more protocol variation, possibly due to physician judgement limiting the harm from HFOV settings— HFOV groups received more sedatives and muscle relaxants Conclusion: no mortality difference at 1 month
- Full text here http://www.nejm.org/doi/pdf/10.1056/NEJMoa1215716 OSCAR trial 2013 http://lifeinthefastlane.com/education/ccc/high-frequency-oscillation-ventilation-hfov/ non-blinded intention-to-treat MC RCT 795 patients HFOV versus usual care control group outcomes:-&gt; all cause mortality at 28 days was 41.7% vs 41.1% (P=0.85 chi-square test) Commentary and criticisms:— less hemodynamic compromise, lower airway pressures than OSCILLATE and more protocol variation, possibly due to physician judgement limiting the harm from HFOV settings— HFOV groups received more sedatives and muscle relaxants Conclusion: no mortality difference at 1 month
- BACKGROUND: There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock. METHODS: In this randomized, double-blind, placebo-controlled, multicenter trial, we assigned 1697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours to receive either DrotAA (at a dose of 24 μg per kilogram of body weight per hour) or placebo for 96 hours. The primary outcome was death from any cause 28 days after randomization. RESULTS: At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval [CI], 0.92 to 1.28; P=0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P=0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P=0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P=0.81). CONCLUSIONS: DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock.
- Full text here http://www.nejm.org/doi/pdf/10.1056/NEJMoa1215716 OSCAR trial 2013 http://lifeinthefastlane.com/education/ccc/high-frequency-oscillation-ventilation-hfov/ non-blinded intention-to-treat MC RCT 795 patients HFOV versus usual care control group outcomes:-&gt; all cause mortality at 28 days was 41.7% vs 41.1% (P=0.85 chi-square test) Commentary and criticisms:— less hemodynamic compromise, lower airway pressures than OSCILLATE and more protocol variation, possibly due to physician judgement limiting the harm from HFOV settings— HFOV groups received more sedatives and muscle relaxants Conclusion: no mortality difference at 1 month
- Full text here http://www.nejm.org/doi/pdf/10.1056/NEJMoa1215716 OSCAR trial 2013 http://lifeinthefastlane.com/education/ccc/high-frequency-oscillation-ventilation-hfov/ non-blinded intention-to-treat MC RCT 795 patients HFOV versus usual care control group outcomes:-&gt; all cause mortality at 28 days was 41.7% vs 41.1% (P=0.85 chi-square test) Commentary and criticisms:— less hemodynamic compromise, lower airway pressures than OSCILLATE and more protocol variation, possibly due to physician judgement limiting the harm from HFOV settings— HFOV groups received more sedatives and muscle relaxants Conclusion: no mortality difference at 1 month
- Full text here http://www.nejm.org/doi/pdf/10.1056/NEJMoa1215716 OSCAR trial 2013 http://lifeinthefastlane.com/education/ccc/high-frequency-oscillation-ventilation-hfov/ non-blinded intention-to-treat MC RCT 795 patients HFOV versus usual care control group outcomes:-&gt; all cause mortality at 28 days was 41.7% vs 41.1% (P=0.85 chi-square test) Commentary and criticisms:— less hemodynamic compromise, lower airway pressures than OSCILLATE and more protocol variation, possibly due to physician judgement limiting the harm from HFOV settings— HFOV groups received more sedatives and muscle relaxants Conclusion: no mortality difference at 1 month
- BACKGROUND: There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock. METHODS: In this randomized, double-blind, placebo-controlled, multicenter trial, we assigned 1697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours to receive either DrotAA (at a dose of 24 μg per kilogram of body weight per hour) or placebo for 96 hours. The primary outcome was death from any cause 28 days after randomization. RESULTS: At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval [CI], 0.92 to 1.28; P=0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P=0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P=0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P=0.81). CONCLUSIONS: DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock.
- Full text here http://www.nejm.org/doi/pdf/10.1056/NEJMoa1215716 OSCAR trial 2013 http://lifeinthefastlane.com/education/ccc/high-frequency-oscillation-ventilation-hfov/ non-blinded intention-to-treat MC RCT 795 patients HFOV versus usual care control group outcomes:-&gt; all cause mortality at 28 days was 41.7% vs 41.1% (P=0.85 chi-square test) Commentary and criticisms:— less hemodynamic compromise, lower airway pressures than OSCILLATE and more protocol variation, possibly due to physician judgement limiting the harm from HFOV settings— HFOV groups received more sedatives and muscle relaxants Conclusion: no mortality difference at 1 month
- BACKGROUND: There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock. METHODS: In this randomized, double-blind, placebo-controlled, multicenter trial, we assigned 1697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours to receive either DrotAA (at a dose of 24 μg per kilogram of body weight per hour) or placebo for 96 hours. The primary outcome was death from any cause 28 days after randomization. RESULTS: At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval [CI], 0.92 to 1.28; P=0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P=0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P=0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P=0.81). CONCLUSIONS: DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock.
- BACKGROUND: There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock. METHODS: In this randomized, double-blind, placebo-controlled, multicenter trial, we assigned 1697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours to receive either DrotAA (at a dose of 24 μg per kilogram of body weight per hour) or placebo for 96 hours. The primary outcome was death from any cause 28 days after randomization. RESULTS: At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval [CI], 0.92 to 1.28; P=0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P=0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P=0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P=0.81). CONCLUSIONS: DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock.
- BACKGROUND: There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock. METHODS: In this randomized, double-blind, placebo-controlled, multicenter trial, we assigned 1697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours to receive either DrotAA (at a dose of 24 μg per kilogram of body weight per hour) or placebo for 96 hours. The primary outcome was death from any cause 28 days after randomization. RESULTS: At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval [CI], 0.92 to 1.28; P=0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P=0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P=0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P=0.81). CONCLUSIONS: DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock.
- BACKGROUND: There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock. METHODS: In this randomized, double-blind, placebo-controlled, multicenter trial, we assigned 1697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours to receive either DrotAA (at a dose of 24 μg per kilogram of body weight per hour) or placebo for 96 hours. The primary outcome was death from any cause 28 days after randomization. RESULTS: At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval [CI], 0.92 to 1.28; P=0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P=0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P=0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P=0.81). CONCLUSIONS: DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock.
- BACKGROUND: There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock. METHODS: In this randomized, double-blind, placebo-controlled, multicenter trial, we assigned 1697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours to receive either DrotAA (at a dose of 24 μg per kilogram of body weight per hour) or placebo for 96 hours. The primary outcome was death from any cause 28 days after randomization. RESULTS: At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval [CI], 0.92 to 1.28; P=0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P=0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P=0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P=0.81). CONCLUSIONS: DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock.
- BACKGROUND: There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock. METHODS: In this randomized, double-blind, placebo-controlled, multicenter trial, we assigned 1697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours to receive either DrotAA (at a dose of 24 μg per kilogram of body weight per hour) or placebo for 96 hours. The primary outcome was death from any cause 28 days after randomization. RESULTS: At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval [CI], 0.92 to 1.28; P=0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P=0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P=0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P=0.81). CONCLUSIONS: DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock.
- BACKGROUND: In a previous randomised controlled phase 2 trial, intravenous infusion of salbutamol for up to 7 days in patients with acute respiratory distress syndrome (ARDS) reduced extravascular lung water and plateau airway pressure. We assessed the effects of this intervention on mortality in patients with ARDS. METHODS: We did a multicentre, placebo-controlled, parallel-group, randomised trial at 46 UK intensive-care units between December, 2006, and March, 2010. Intubated and mechanically ventilated patients (aged ≥16 years) within 72 h of ARDS onset were randomly assigned to receive either salbutamol (15 μg/kg ideal bodyweight per h) or placebo for up to 7 days. Randomisation was done by a central telephone or web-based randomisation service with minmisation by centre, pressure of arterial oxygen to fractional inspired oxygen concentration (PaO(2)/F(I)O(2)) ratio, and age. All participants, caregivers, and investigators were masked to group allocation. The primary outcome was death within 28 days of randomisation. Analysis was by intention-to-treat. This trial is registered, ISRCTN38366450 and EudraCT number 2006-002647-86. FINDINGS: We randomly assigned 162 patients to the salbutamol group and 164 to the placebo group. One patient in each group withdrew consent. Recruitment was stopped after the second interim analysis because of safety concerns. Salbutamol increased 28-day mortality (55 [34%] of 161 patients died in the salbutamol group vs 38 (23%) of 163 in the placebo group; risk ratio [RR] 1·47, 95% CI 1·03-2·08). INTERPRETATION: Treatment with intravenous salbutamol early in the course of ARDS was poorly tolerated. Treatment is unlikely to be beneficial, and could worsen outcomes. Routine use of β-2 agonist treatment in ventilated patients with this disorder cannot be recommended.
- MPORTANCE: Although the benefit of reducing blood pressure for primary and secondary prevention of stroke has been established, the effect of antihypertensive treatment in patients with acute ischemic stroke is uncertain. OBJECTIVE: To evaluate whether immediate blood pressure reduction in patients with acute ischemic stroke would reduce death and major disability at 14 days or hospital discharge. DESIGN, SETTING, AND PARTICIPANTS: The China Antihypertensive Trial in Acute Ischemic Stroke, a single-blind, blinded end-points randomized clinical trial, conducted among 4071 patients with nonthrombolysed ischemic stroke within 48 hours of onset and elevated systolic blood pressure. Patients were recruited from 26 hospitals across China between August 2009 and May 2013. INTERVENTIONS: Patients (n = 2038) were randomly assigned to receive antihypertensive treatment (aimed at lowering systolic blood pressure by 10% to 25% within the first 24 hours after randomization, achieving blood pressure less than 140/90 mm Hg within 7 days, and maintaining this level during hospitalization) or to discontinue all antihypertensive medications (control) during hospitalization (n = 2033). MAIN OUTCOMES AND MEASURES: Primary outcome was a combination of death and major disability (modified Rankin Scale score ≥3) at 14 days or hospital discharge. RESULTS: Mean systolic blood pressure was reduced from 166.7 mm Hg to 144.7 mm Hg (-12.7%) within 24 hours in the antihypertensive treatment group and from 165.6 mm Hg to 152.9 mm Hg (-7.2%) in the control group within 24 hours after randomization (difference, -5.5% [95% CI, -4.9 to -6.1%]; absolute difference, -9.1 mm Hg [95% CI, -10.2 to -8.1]; P &lt; .001). Mean systolic blood pressure was 137.3 mm Hg in the antihypertensive treatment group and 146.5 mm Hg in the control group at day 7 after randomization (difference, -9.3 mm Hg [95% CI, -10.1 to -8.4]; P &lt; .001). The primary outcome did not differ between treatment groups (683 events [antihypertensive treatment] vs 681 events [control]; odds ratio, 1.00 [95% CI, 0.88 to 1.14]; P = .98) at 14 days or hospital discharge. The secondary composite outcome of death and major disability at 3-month posttreatment follow-up did not differ between treatment groups (500 events [antihypertensive treatment] vs 502 events [control]; odds ratio, 0.99 [95% CI, 0.86 to 1.15]; P = .93). CONCLUSION AND RELEVANCE: Among patients with acute ischemic stroke, blood pressure reduction with antihypertensive medications, compared with the absence of hypertensive medication, did not reduce the li
- IMPORTANCE: Evidence supporting the choice of intravenous colloid vs crystalloid solutions for management of hypovolemic shock remains unclear. OBJECTIVE: To test whether use of colloids compared with crystalloids for fluid resuscitation alters mortality in patients admitted to the intensive care unit (ICU) with hypovolemic shock. DESIGN, SETTING, AND PARTICIPANTS: A multicenter, randomized clinical trial stratified by case mix (sepsis, trauma, or hypovolemic shock without sepsis or trauma). Therapy in the Colloids Versus Crystalloids for the Resuscitation of the Critically Ill (CRISTAL) trial was open label but outcome assessment was blinded to treatment assignment. Recruitment began in February 2003 and ended in August 2012 of 2857 sequential ICU patients treated at 57 ICUs in France, Belgium, North Africa, and Canada; follow-up ended in November 2012. INTERVENTIONS: Colloids (n = 1414; gelatins, dextrans, hydroxyethyl starches, or 4% or 20% of albumin) or crystalloids (n = 1443; isotonic or hypertonic saline or Ringer lactate solution) for all fluid interventions other than fluid maintenance throughout the ICU stay. MAIN OUTCOMES AND MEASURES: The primary outcome was death within 28 days. Secondary outcomes included 90-day mortality; and days alive and not receiving renal replacement therapy, mechanical ventilation, or vasopressor therapy. RESULTS: Within 28 days, there were 359 deaths (25.4%) in colloids group vs 390 deaths (27.0%) in crystalloids group (relative risk [RR], 0.96 [95% CI, 0.88 to 1.04]; P = .26). Within 90 days, there were 434 deaths (30.7%) in colloids group vs 493 deaths (34.2%) in crystalloids group (RR, 0.92 [95% CI, 0.86 to 0.99]; P = .03). Renal replacement therapy was used in 156 (11.0%) in colloids group vs 181 (12.5%) in crystalloids group (RR, 0.93 [95% CI, 0.83 to 1.03]; P = .19). There were more days alive without mechanical ventilation in the colloids group vs the crystalloids group by 7 days (mean: 2.1 vs 1.8 days, respectively; mean difference, 0.30 [95% CI, 0.09 to 0.48] days; P = .01) and by 28 days (mean: 14.6 vs 13.5 days; mean difference, 1.10 [95% CI, 0.14 to 2.06] days; P = .01) and alive without vasopressor therapy by 7 days (mean: 5.0 vs 4.7 days; mean difference, 0.30 [95% CI, -0.03 to 0.50] days; P = .04) and by 28 days (mean: 16.2 vs 15.2 days; mean difference, 1.04 [95% CI, -0.04 to 2.10] days; P = .03). CONCLUSIONS AND RELEVANCE: Among ICU patients with hypovolemia, the use of colloids vs crystalloids did not result in a significant difference in 28-day mortality. Although 90-day mortality was lower among patients receiving colloids, this finding should be considered exploratory and requires further study before reaching conclusions about efficacy.
- MPORTANCE: Tracheostomy is a widely used intervention in adult critical care units. There is little evidence to guide clinicians regarding the optimal timing for this procedure. OBJECTIVE: To test whether early vs late tracheostomy would be associated with lower mortality in adult patients requiring mechanical ventilation in critical care units. DESIGN AND SETTING: An open multicentered randomized clinical trial conducted between 2004 and 2011 involving 70 adult general and 2 cardiothoracic critical care units in 13 university and 59 nonuniversity hospitals in the United Kingdom. PARTICIPANTS: Of 1032 eligible patients, 909 adult patients breathing with the aid of mechanical ventilation for less than 4 days and identified by the treating physician as likely to require at least 7 more days of mechanical ventilation. INTERVENTIONS: Patients were randomized 1:1 to early tracheostomy (within 4 days) or late tracheostomy (after 10 days if still indicated). MAIN OUTCOMES AND MEASURES: The primary outcome measure was 30-day mortality and the analysis was by intention to treat. RESULTS: Of the 455 patients assigned to early tracheostomy, 91.9% (95% CI, 89.0%-94.1%) received a tracheostomy and of 454 assigned to late tracheostomy, 44.9% (95% CI, 40.4%-49.5%) received a tracheostomy. All-cause mortality 30 days after randomization was 30.8% (95% CI, 26.7%-35.2%) in the early and 31.5% (95% CI, 27.3%-35.9%) in the late group (absolute risk reduction for early vs late, 0.7%; 95% CI, -5.4% to 6.7%). Two-year mortality was 51.0% (95% CI, 46.4%-55.6%) in the early and 53.7% (95% CI, 49.1%-58.3%) in the late group (P = .74). Median critical care unit length of stay in survivors was 13.0 days in the early and 13.1 days in the late group (P = .74). Tracheostomy-related complications were reported for 6.3% (95% CI, 4.6%-8.5%) of patients (5.5% in the early group, 7.8% in the late group). CONCLUSIONS AND RELEVANCE: For patients breathing with the aid of mechanical ventilation treated in adult critical care units in the United Kingdom, tracheostomy within 4 days of critical care admission was not associated with an improvement in 30-day mortality or other important secondary outcomes. The ability of clinicians to predict which patients required extended ventilatory support was limited.
- Full text here http://www.nejm.org/doi/pdf/10.1056/NEJMoa1215716 OSCAR trial 2013 http://lifeinthefastlane.com/education/ccc/high-frequency-oscillation-ventilation-hfov/ non-blinded intention-to-treat MC RCT 795 patients HFOV versus usual care control group outcomes:-&gt; all cause mortality at 28 days was 41.7% vs 41.1% (P=0.85 chi-square test) Commentary and criticisms:— less hemodynamic compromise, lower airway pressures than OSCILLATE and more protocol variation, possibly due to physician judgement limiting the harm from HFOV settings— HFOV groups received more sedatives and muscle relaxants Conclusion: no mortality difference at 1 month
- BACKGROUND: Previous trials involving patients with the acute respiratory distress syndrome (ARDS) have failed to show a beneficial effect of prone positioning during mechanical ventilatory support on outcomes. We evaluated the effect of early application of prone positioning on outcomes in patients with severe ARDS. METHODS: In this multicenter, prospective, randomized, controlled trial, we randomly assigned 466 patients with severe ARDS to undergo prone-positioning sessions of at least 16 hours or to be left in the supine position. Severe ARDS was defined as a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (FiO2) of less than 150 mm Hg (20Kpa), with an FiO2 of at least 0.6, a positive end-expiratory pressure of at least 5 cm of water, and a tidal volume close to 6 ml per kilogram of predicted body weight. The primary outcome was the proportion of patients who died from any cause within 28 days after inclusion. RESULTS: A total of 237 patients were assigned to the prone group, and 229 patients were assigned to the supine group. The 28-day mortality was 16.0% in the prone group and 32.8% in the supine group (P&lt;0.001). The hazard ratio for death with prone positioning was 0.39 (95% confidence interval [CI], 0.25 to 0.63). Unadjusted 90-day mortality was 23.6% in the prone group versus 41.0% in the supine group (P&lt;0.001), with a hazard ratio of 0.44 (95% CI, 0.29 to 0.67). The incidence of complications did not differ significantly between the groups, except for the incidence of cardiac arrests, which was higher in the supine group. CONCLUSIONS: In patients with severe ARDS, early application of prolonged prone-positioning sessions significantly decreased 28-day and 90-day mortality.
- Full text here http://www.nejm.org/doi/pdf/10.1056/NEJMoa1215716 OSCAR trial 2013 http://lifeinthefastlane.com/education/ccc/high-frequency-oscillation-ventilation-hfov/ non-blinded intention-to-treat MC RCT 795 patients HFOV versus usual care control group outcomes:-&gt; all cause mortality at 28 days was 41.7% vs 41.1% (P=0.85 chi-square test) Commentary and criticisms:— less hemodynamic compromise, lower airway pressures than OSCILLATE and more protocol variation, possibly due to physician judgement limiting the harm from HFOV settings— HFOV groups received more sedatives and muscle relaxants Conclusion: no mortality difference at 1 month
- BACKGROUND: Previous trials suggesting that high-frequency oscillatory ventilation (HFOV) reduced mortality among adults with the acute respiratory distress syndrome (ARDS) were limited by the use of outdated comparator ventilation strategies and small sample sizes. METHODS: In a multicenter, randomized, controlled trial conducted at 39 intensive care units in five countries, we randomly assigned adults with new-onset, moderate-to-severe ARDS to HFOV targeting lung recruitment or to a control ventilation strategy targeting lung recruitment with the use of low tidal volumes and high positive end-expiratory pressure. The primary outcome was the rate of in-hospital death from any cause. RESULTS: On the recommendation of the data monitoring committee, we stopped the trial after 548 of a planned 1200 patients had undergone randomization. The two study groups were well matched at baseline. The HFOV group underwent HFOV for a median of 3 days (interquartile range, 2 to 8); in addition, 34 of 273 patients (12%) in the control group received HFOV for refractory hypoxemia. In-hospital mortality was 47% in the HFOV group, as compared with 35% in the control group (relative risk of death with HFOV, 1.33; 95% confidence interval, 1.09 to 1.64; P=0.005). This finding was independent of baseline abnormalities in oxygenation or respiratory compliance. Patients in the HFOV group received higher doses of midazolam than did patients in the control group (199 mg per day [interquartile range, 100 to 382] vs. 141 mg per day [interquartile range, 68 to 240], P&lt;0.001), and more patients in the HFOV group than in the control group received neuromuscular blockers (83% vs. 68%, P&lt;0.001). In addition, more patients in the HFOV group received vasoactive drugs (91% vs. 84%, P=0.01) and received them for a longer period than did patients in the control group (5 days vs. 3 days, P=0.01). CONCLUSIONS: In adults with moderate-to-severe ARDS, early application of HFOV, as compared with a ventilation strategy of low tidal volume and high positive end-expiratory pressure, does not reduce, and may increase, in-hospital mortality. http://lifeinthefastlane.com/education/ccc/high-frequency-oscillation-ventilation-hfov/ non-blinded intention-to-treat MCRCT 548 new-onset, moderate-to-severe ARDS patients HFOV vs low TV high PEEP controlled ventilation strategy outcomes:-&gt; 47% vs 35% in-hospital mortality (RR 1.33, 95% CI 1.09 to 1.64)-&gt; were given more midazolam, more NMBs, more vasopressors Commentary and criticisms:— stopped early due to harm from HFOV— HFOV strategy had high mean airway pressures – would a lower mean airway pressure strategy make a difference?— groups similar at baseline, both had baseline recruitment manoeuvre to improve lung homogeneity Conclusion: Increased mortality in ARDS patients treated with HFOV
- OSCAR = sensor medics (care fusion) ventilators
- BACKGROUND: Previous trials involving patients with the acute respiratory distress syndrome (ARDS) have failed to show a beneficial effect of prone positioning during mechanical ventilatory support on outcomes. We evaluated the effect of early application of prone positioning on outcomes in patients with severe ARDS. METHODS: In this multicenter, prospective, randomized, controlled trial, we randomly assigned 466 patients with severe ARDS to undergo prone-positioning sessions of at least 16 hours or to be left in the supine position. Severe ARDS was defined as a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (FiO2) of less than 150 mm Hg (20Kpa), with an FiO2 of at least 0.6, a positive end-expiratory pressure of at least 5 cm of water, and a tidal volume close to 6 ml per kilogram of predicted body weight. The primary outcome was the proportion of patients who died from any cause within 28 days after inclusion. RESULTS: A total of 237 patients were assigned to the prone group, and 229 patients were assigned to the supine group. The 28-day mortality was 16.0% in the prone group and 32.8% in the supine group (P&lt;0.001). The hazard ratio for death with prone positioning was 0.39 (95% confidence interval [CI], 0.25 to 0.63). Unadjusted 90-day mortality was 23.6% in the prone group versus 41.0% in the supine group (P&lt;0.001), with a hazard ratio of 0.44 (95% CI, 0.29 to 0.67). The incidence of complications did not differ significantly between the groups, except for the incidence of cardiac arrests, which was higher in the supine group. CONCLUSIONS: In patients with severe ARDS, early application of prolonged prone-positioning sessions significantly decreased 28-day and 90-day mortality.
- BACKGROUND: In a previous randomised controlled phase 2 trial, intravenous infusion of salbutamol for up to 7 days in patients with acute respiratory distress syndrome (ARDS) reduced extravascular lung water and plateau airway pressure. We assessed the effects of this intervention on mortality in patients with ARDS. METHODS: We did a multicentre, placebo-controlled, parallel-group, randomised trial at 46 UK intensive-care units between December, 2006, and March, 2010. Intubated and mechanically ventilated patients (aged ≥16 years) within 72 h of ARDS onset were randomly assigned to receive either salbutamol (15 μg/kg ideal bodyweight per h) or placebo for up to 7 days. Randomisation was done by a central telephone or web-based randomisation service with minmisation by centre, pressure of arterial oxygen to fractional inspired oxygen concentration (PaO(2)/F(I)O(2)) ratio, and age. All participants, caregivers, and investigators were masked to group allocation. The primary outcome was death within 28 days of randomisation. Analysis was by intention-to-treat. This trial is registered, ISRCTN38366450 and EudraCT number 2006-002647-86. FINDINGS: We randomly assigned 162 patients to the salbutamol group and 164 to the placebo group. One patient in each group withdrew consent. Recruitment was stopped after the second interim analysis because of safety concerns. Salbutamol increased 28-day mortality (55 [34%] of 161 patients died in the salbutamol group vs 38 (23%) of 163 in the placebo group; risk ratio [RR] 1·47, 95% CI 1·03-2·08). INTERPRETATION: Treatment with intravenous salbutamol early in the course of ARDS was poorly tolerated. Treatment is unlikely to be beneficial, and could worsen outcomes. Routine use of β-2 agonist treatment in ventilated patients with this disorder cannot be recommended.
- Importance Observational studies have reported that statin use may be associated with improved outcomes of various infections. Ventilator-associated pneumonia (VAP) is the most common infection in the intensive care unit (ICU) and is associated with substantial mortality. Objective To determine whether statin therapy can decrease day-28 mortality in patients with VAP. Design, Setting, and Participants Randomized, placebo-controlled, double-blind, parallel-group, multicenter trial performed in 26 intensive care units in France from January 2010 to March 2013. For power to detect an 8% absolute reduction in the day-28 mortality rate, we planned to enroll 1002 patients requiring invasive mechanical ventilation for more than 2 days and having suspected VAP, defined as a modified Clinical Pulmonary Infection Score of 5 or greater. The futility stopping rules were an absolute increase in day-28 mortality of at least 2.7% with simvastatin compared with placebo after enrollment of the first 251 patients. Interventions Participants were randomized to receive simvastatin (60 mg) or placebo, started on the same day as antibiotic therapy and given until ICU discharge, death, or day 28, whichever occurred first. Main Outcomes and Measures Primary outcome was day-28 mortality. Day-14, ICU, and hospital mortality rates were determined, as well as duration of mechanical ventilation and Sequential Organ Failure Assessment (SOFA) scores on days 3, 7, and 14. Results The study was stopped for futility at the first scheduled interim analysis after enrollment of 300 patients, of whom all but 7% in the simvastatin group and 11% in the placebo group were naive to statin therapy at ICU admission. Day-28 mortality was not lower in the simvastatin group (21.2% [95% CI, 15.4% to 28.6%) than in the placebo group (15.2% [95% CI, 10.2% to 22.1%]; P = .10; hazard ratio, 1.45 [95% CI, 0.83 to 2.51]); the between-group difference was 6.0% (95% CI, −3.0% to 14.9%). In statin-naive patients, day-28 mortality was 21.5% (95% CI, 15.4% to 29.1%) with simvastatin and 13.8% (95% CI, 8.8% to 21.0%) with placebo (P = .054) (between-group difference, 7.7% [95%CI, −1.8% to 16.8%). There were no significant differences regarding day-14, ICU, or hospital mortality rates; duration of mechanical ventilation; or changes in SOFA score. Conclusions and Relevance In adults with suspected VAP, adjunctive simvastatin therapy compared with placebo did not improve day-28 survival. These findings do not support the use of statins with the goal of improving VAP outcomes.
- BACKGROUND: In a previous randomised controlled phase 2 trial, intravenous infusion of salbutamol for up to 7 days in patients with acute respiratory distress syndrome (ARDS) reduced extravascular lung water and plateau airway pressure. We assessed the effects of this intervention on mortality in patients with ARDS. METHODS: We did a multicentre, placebo-controlled, parallel-group, randomised trial at 46 UK intensive-care units between December, 2006, and March, 2010. Intubated and mechanically ventilated patients (aged ≥16 years) within 72 h of ARDS onset were randomly assigned to receive either salbutamol (15 μg/kg ideal bodyweight per h) or placebo for up to 7 days. Randomisation was done by a central telephone or web-based randomisation service with minmisation by centre, pressure of arterial oxygen to fractional inspired oxygen concentration (PaO(2)/F(I)O(2)) ratio, and age. All participants, caregivers, and investigators were masked to group allocation. The primary outcome was death within 28 days of randomisation. Analysis was by intention-to-treat. This trial is registered, ISRCTN38366450 and EudraCT number 2006-002647-86. FINDINGS: We randomly assigned 162 patients to the salbutamol group and 164 to the placebo group. One patient in each group withdrew consent. Recruitment was stopped after the second interim analysis because of safety concerns. Salbutamol increased 28-day mortality (55 [34%] of 161 patients died in the salbutamol group vs 38 (23%) of 163 in the placebo group; risk ratio [RR] 1·47, 95% CI 1·03-2·08). INTERPRETATION: Treatment with intravenous salbutamol early in the course of ARDS was poorly tolerated. Treatment is unlikely to be beneficial, and could worsen outcomes. Routine use of β-2 agonist treatment in ventilated patients with this disorder cannot be recommended.
- BACKGROUND: In a previous randomised controlled phase 2 trial, intravenous infusion of salbutamol for up to 7 days in patients with acute respiratory distress syndrome (ARDS) reduced extravascular lung water and plateau airway pressure. We assessed the effects of this intervention on mortality in patients with ARDS. METHODS: We did a multicentre, placebo-controlled, parallel-group, randomised trial at 46 UK intensive-care units between December, 2006, and March, 2010. Intubated and mechanically ventilated patients (aged ≥16 years) within 72 h of ARDS onset were randomly assigned to receive either salbutamol (15 μg/kg ideal bodyweight per h) or placebo for up to 7 days. Randomisation was done by a central telephone or web-based randomisation service with minmisation by centre, pressure of arterial oxygen to fractional inspired oxygen concentration (PaO(2)/F(I)O(2)) ratio, and age. All participants, caregivers, and investigators were masked to group allocation. The primary outcome was death within 28 days of randomisation. Analysis was by intention-to-treat. This trial is registered, ISRCTN38366450 and EudraCT number 2006-002647-86. FINDINGS: We randomly assigned 162 patients to the salbutamol group and 164 to the placebo group. One patient in each group withdrew consent. Recruitment was stopped after the second interim analysis because of safety concerns. Salbutamol increased 28-day mortality (55 [34%] of 161 patients died in the salbutamol group vs 38 (23%) of 163 in the placebo group; risk ratio [RR] 1·47, 95% CI 1·03-2·08). INTERPRETATION: Treatment with intravenous salbutamol early in the course of ARDS was poorly tolerated. Treatment is unlikely to be beneficial, and could worsen outcomes. Routine use of β-2 agonist treatment in ventilated patients with this disorder cannot be recommended.
- BACKGROUND: In a previous randomised controlled phase 2 trial, intravenous infusion of salbutamol for up to 7 days in patients with acute respiratory distress syndrome (ARDS) reduced extravascular lung water and plateau airway pressure. We assessed the effects of this intervention on mortality in patients with ARDS. METHODS: We did a multicentre, placebo-controlled, parallel-group, randomised trial at 46 UK intensive-care units between December, 2006, and March, 2010. Intubated and mechanically ventilated patients (aged ≥16 years) within 72 h of ARDS onset were randomly assigned to receive either salbutamol (15 μg/kg ideal bodyweight per h) or placebo for up to 7 days. Randomisation was done by a central telephone or web-based randomisation service with minmisation by centre, pressure of arterial oxygen to fractional inspired oxygen concentration (PaO(2)/F(I)O(2)) ratio, and age. All participants, caregivers, and investigators were masked to group allocation. The primary outcome was death within 28 days of randomisation. Analysis was by intention-to-treat. This trial is registered, ISRCTN38366450 and EudraCT number 2006-002647-86. FINDINGS: We randomly assigned 162 patients to the salbutamol group and 164 to the placebo group. One patient in each group withdrew consent. Recruitment was stopped after the second interim analysis because of safety concerns. Salbutamol increased 28-day mortality (55 [34%] of 161 patients died in the salbutamol group vs 38 (23%) of 163 in the placebo group; risk ratio [RR] 1·47, 95% CI 1·03-2·08). INTERPRETATION: Treatment with intravenous salbutamol early in the course of ARDS was poorly tolerated. Treatment is unlikely to be beneficial, and could worsen outcomes. Routine use of β-2 agonist treatment in ventilated patients with this disorder cannot be recommended.
- Strom 2010 Some limitations of this study to consider are:1) The ‘no sedation’ group did in fact receive 2.5-5mg boluses of morphine which may have caused some sedation2) The ‘continuous sedation’ group received propofol for 48 hours and then it was switched to midazolam – longer clearance time especially if underlying hepatic/renal impairment3) The ‘no sedation’ approach has been used by Strom in his institution since 19994) Patient comforters were used in addition to 1:1 nurses. This suggests that the ‘no sedation’ protocol requires more staff presence which is not always available. Any deviation from this staffing level may compromise patient safety and may defeat the intended purpose of the study5) The intervention group (‘no sedation’) had more reported agitated delerium – as Paul mentions, perhaps not surprising and may well have been a justifiable response. Unfortunately DSM IV criteria used to determine this rather than the well validated CAM-ICU system. Still, an innovative study which should challenge our current practice. We often have a tendency to oversedate patients on ICU and perhaps we should be trying to ensure adequate analgesia before instituting continuous sedation. Protocolised sedation +/ - daily sedation interruption CONTEXT: Protocolized sedation and daily sedation interruption are 2 strategies to minimize sedation and reduce the duration of mechanical ventilation and intensive care unit (ICU) stay. We hypothesized that combining these strategies would augment the benefits. OBJECTIVE: To compare protocolized sedation with protocolized sedation plus daily sedation interruption in critically ill patients. DESIGN, SETTING, AND PATIENTS: Randomized controlled trial of 430 critically ill, mechanically ventilated adults conducted in 16 tertiary care medical and surgical ICUs in Canada and the United States between January 2008 and July 2011. INTERVENTION: Continuous opioid and/or benzodiazepine infusions and random allocation to protocolized sedation (n = 209) (control) or to protocolized sedation plus daily sedation interruption (n = 214). Using validated scales, nurses titrated infusions to achieve light sedation. For patients receiving daily interruption, nurses resumed infusions, if indicated, at half of previous doses. Patients were assessed for delirium and for readiness for unassisted breathing. MAIN OUTCOME MEASURE: Time to successful extubation. Secondary outcomes included duration of stay, doses of sedatives and opioids, unintentional device removal, delirium, and nurse and respiratory therapist clinical workload (on a 10-point visual analog scale [VAS]). RESULTS: Median time to successful extubation was 7 days in both the interruption and control groups (median [IQR], 7 [4-13] vs 7 [3-12]; interruption group hazard ratio, 1.08; 95% CI, 0.86-1.35; P = .52). Duration of ICU stay (median [IQR], 10 [5-17] days vs 10 [6-20] days; P = .36) and hospital stay (median [IQR], 20 [10-36] days vs 20 [10-48] days; P = .42) did not differ between the daily interruption and control groups, respectively. Daily interruption was associated with higher mean daily doses of midazolam (102 mg/d vs 82 mg/d; P = .04) and fentanyl (median [IQR], 550 [50-1850] vs 260 [0-1400]; P &lt; .001) and more daily boluses of benzodiazepines (mean, 0.253 vs 0.177; P = .007) and opiates (mean, 2.18 vs 1.79; P &lt; .001). Unintentional endotracheal tube removal occurred in 10 of 214 (4.7%) vs 12 of 207 patients (5.8%) in the interruption and control groups, respectively (relative risk, 0.82; 95% CI, 0.36-1.84; P = .64). Rates of delirium were not significantly different between groups (53.3% vs 54.1%; relative risk, 0.98; 95% CI, 0.82-1.17; P = .83). Nurse workload was greater in the interruption group (VAS score, 4.22 vs 3.80; mean difference, 0.41; 95% CI, 0.17-0.66; P = .001). CONCLUSION: For mechanically ventilated adults managed with protocolized sedation, the addition of daily sedation interruption did not reduce the duration of mechanical ventilation or ICU stay. Mehta. Daily Sedation Interruption in Mechanically Ventilated Critically Ill Patients Cared for With a Sedation Protocol. A Randomized Controlled Trial (SLEAP study). JAMA 2012; epublished ahead of print MCRCT, 16 ICUs using protocolised sedation, sedation holiday vs usual care no difference in time to extubation, ICU LOS, hospital LOS no difference in self extubations or delirium nurses perceived themselves as working harder and higher total doses of fentanyl and midazolam were needed in the ‘sedation holiday’ arm Jakob. Dexmedetomidine vs Midazolam or Propofol for Sedation During Prolonged Mechanical Ventilation: Two Randomized Controlled Trials. JAMA 2012;307(11):1151-1160 European, multi-centre, randomized, doubleblind studies conducted in 2007 - 2010 midazolam vs. dexmedetomidine (MIDEX trial; 44 centers in 9 European countries) propofol vs. dexmedetomidine (PRODEX trial; 31 centers in 6 European countries and 2 in Russia) Outcomes primary end point = proportion of time in target sedation range (RASS score, 0 to -3) without use of rescue therapy duration of mechanical ventilation from randomization. Secondary efficacy outcomes were length of ICU stay from randomization until medically fit for discharge and nurses’ assessment of arousal, ability to cooperate with care, and ability to communicate pain using visual analogue scales (VAS). Summary Shorter MV compared with midazolam ICU LOS - no difference Better cooperation/comm. of pain Significant CV complications with Dex More polyneuropathy in propofol group More neuro-cognitive adverse events in propofol group (but not midazolam) Some confounding
- Targeted Temperature Management (TTM) is an inexpensive, noninvasive therapy that offers hope of benefit for a condition with potentially devastating consequences Following the publication of two randomised controlled trials in 2002, by the Bernard et al and the HACA group — and despite their inherent flaws — the use of therapeutic hypothermia protocols targeting T32-34C became widespread From Life in the Fast Lane http://lifeinthefastlane.com/education/ccc/therapeutic-hypothermia-after-cardiac-arrest/ MCRCT, stratified according to site, no allocation concealment, 36 ICUs in Europe and Australia modified intention-to-treat analysis n= 939 (T33C: 473 vs T36C: 466 patients in the primary analysis)— inclusion criteria: Age ≥18y, OOHCA of presumed cardiac cause, sustained ROSC for 20 minutes, GCS &lt;8 after sustained ROSC— exclusion criteria: . pregnancy, known bleeding diathesis (other than medically induced coagulopathy, e.g. warfarin), suspected or confirmed acute intracranial bleeding or acute stroke, unwitnessed cardiac arrest with initial rhythm asystole, known limitations in therapy and Do Not Resuscitate-order, known disease making 180 days survival unlikely, known pre-arrest Cerebral Performance Category 3 or 4, &gt;4 hours from ROSC to screening, SBP &lt;80 mm Hg in spite of fluid loading/vasopressor and/or inotropic medication/intra aortic balloon pump, temperature on admission &lt;30°C Intervention: TTM at T33C: cooled my various means to target &lt;6hours, maintained T33C for 36h, then rewarmed at 0.25C per hour; fever actively managed until at least 72 hours after cardiac arrest. Comparison: TTM at T36C (otherwise similar treatment to the intervention group) Outcomes:— Primary: mortality at 180 days— Secondary: composite of poor neurologic function or death, defined as a Cerebral Performance Category (CPC) of 3 to 5 and a score of 4 to 6 on the modified Rankin scale, at or around 180 days Results:— no difference in mortality: 50% of the T33C (235 of 473 patients) had died, as compared with 48% of the patients in the 36°C group (225 of 466 patients) (hazard ratio with a T33°C, 1.06; 95%CI 0.89-1.28; P=0.51)— no difference in neurological outcomes: 54% of the T33C group versus 52% of the 36C group died or had poor neurologic function according to the CPC (RR, 1.02; 95% CI 0.88 to 1.16; P=0.78). Using the modified Rankin scale, the comparable rate was 52% in both groups (RR 1.01; 95% CI 0.89 to 1.14; P=0.87).— shorter duration of mechanical ventilation in the T36C group: T33C = 0.83 versus T33C = 0.76 median days receiving mechanical ventilation/days in ICU (P=0.006)— serious adverse effects were common and marginally higher (with borderline significance) in the T33C group (93%) compared with the T36C (90%) (RR 1.03; 95% CI 1.00 to 1.08; P=0.09)— higher rates of hypokalemia in T33C group (19%) than the T36C group (13%) P=0.02)— no differences found in subgroup analyses: age &gt; 65 years, presence of initial shockable rhythm, time from cardiac arrest to ROSC &gt;25 min, and presence of shock at admission— no differences in shivering— during the first 7 days of hospitalization, life-sustaining therapy was withdrawn in 247 patients (132 in the 33°C group and 115 in the 36°C group) Commentary and criticisms— this study is a methodological masterpiece!— unlike Bernard 2002 and HACA 2002, not just VT/VF OOHCA were included (~80% were VF/VT)— a useful standardised protocol for neurological prognostication and treatment withdrawal was used— the study was powered to detect a RRR of 20% or an ARR of ~11%, thus the study was not powered to detect a smaller treatment effect (this may be more realistic due to the lower ‘separation effect’ between T33C and T36C)— less than 50% of T33C patients had reached target at 6 hours, but there was good separation between T33C and T36C groups— Baseline balance: higher rates of previous MI and IHD in the T33C group, but no difference in the rates of interventions for these conditions— the true patient-orientated outcome that matters is neurologically intact survival, the authors didn’t use this as the primary outcome because mortality is a ‘harder endpoint’ and less subject to bias— staff caring for the patients could not be blinded; however the doctors who perform neurological prognostication and data interpretation for the study were— TTM differs to the Bernard 2002 and HACA 2002 trials: larger MCRCT with excellent methodology, not limited to VT/VF, control group still received TTM (but at T36C)— patients in TTM had short times to CPR (e.g. ~1 minute), could T33C be more beneficial in patients with more anoxic injury?— is prognostication of the T33C group at 72h too soon, could ‘late wakers’ have been missed? Bottom line: No difference found between targeted temperature management with a target of T36C compared to T33C Controversies and uncertainties remain regarding patient selection optimum target temperature timing of initiation of cooling duration of therapy rate of rewarming the impact of fever in the control groups of the Bernard et al ,2002 and HAC 2002 studies in versus out-of-hospital VT/VF versus non-VT/VF
- Objective To determine whether prehospital cooling improves outcomes after resuscitation from cardiac arrest in patients with ventricular fibrillation (VF) and without VF. Design, Setting, and Participants A randomized clinical trial that assigned adults with prehospital cardiac arrest to standard care with or without prehospital cooling, accomplished by infusing up to 2 L of 4°C normal saline as soon as possible following return of spontaneous circulation. Adults in King County, Washington, with prehospital cardiac arrest and resuscitated by paramedics were eligible and 1359 patients (583 with VF and 776 without VF) were randomized between December 15, 2007, and December 7, 2012. Patient follow-up was completed by May 1, 2013. Nearly all of the patients resuscitated from VF and admitted to the hospital received hospital cooling regardless of their randomization. Main Outcomes and Measures The primary outcomes were survival to hospital discharge and neurological status at discharge. Results The intervention decreased mean core temperature by 1.20°C (95% CI, −1.33°C to −1.07°C) in patients with VF and by 1.30°C (95% CI, −1.40°C to −1.20°C) in patients without VF by hospital arrival and reduced the time to achieve a temperature of less than 34°C by about 1 hour compared with the control group. However, survival to hospital discharge was similar among the intervention and control groups among patients with VF (62.7% [95% CI, 57.0%-68.0%] vs 64.3% [95% CI, 58.6%-69.5%], respectively; P = .69) and among patients without VF (19.2% [95% CI, 15.6%-23.4%] vs 16.3% [95% CI, 12.9%-20.4%], respectively; P = .30). The intervention was also not associated with improved neurological status of full recovery or mild impairment at discharge for either patients with VF (57.5% [95% CI, 51.8%-63.1%] of cases had full recovery or mild impairment vs 61.9% [95% CI, 56.2%-67.2%] of controls; P = .69) or those without VF (14.4% [95% CI, 11.3%-18.2%] of cases vs 13.4% [95% CI,10.4%-17.2%] of controls; P = .30). Overall, the intervention group experienced rearrest in the field more than the control group (26% [95% CI, 22%-29%] vs 21% [95% CI, 18%-24%], respectively; P = .008), as well as increased diuretic use and pulmonary edema on first chest x-ray, which resolved within 24 hours after admission. Conclusion and Relevance Although use of prehospital cooling reduced core temperature by hospital arrival and reduced the time to reach a temperature of 34°C, it did not improve survival or neurological status among patients resuscitated from prehospital VF or those without VF.
- BACKGROUND: There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock. METHODS: In this randomized, double-blind, placebo-controlled, multicenter trial, we assigned 1697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours to receive either DrotAA (at a dose of 24 μg per kilogram of body weight per hour) or placebo for 96 hours. The primary outcome was death from any cause 28 days after randomization. RESULTS: At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval [CI], 0.92 to 1.28; P=0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P=0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P=0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P=0.81). CONCLUSIONS: DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock.
- BACKGROUND: There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock. METHODS: In this randomized, double-blind, placebo-controlled, multicenter trial, we assigned 1697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours to receive either DrotAA (at a dose of 24 μg per kilogram of body weight per hour) or placebo for 96 hours. The primary outcome was death from any cause 28 days after randomization. RESULTS: At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval [CI], 0.92 to 1.28; P=0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P=0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P=0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P=0.81). CONCLUSIONS: DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock.
- PURPOSE: Septic shock is a leading cause of death among critically ill patients, in particular when complicated by acute kidney injury (AKI). Small experimental and human clinical studies have suggested that high-volume haemofiltration (HVHF) may improve haemodynamic profile and mortality. We sought to determine the impact of HVHF on 28-day mortality in critically ill patients with septic shock and AKI. METHODS: This was a prospective, randomized, open, multicentre clinical trial conducted at 18 intensive care units in France, Belgium and the Netherlands. A total of 140 critically ill patients with septic shock and AKI for less than 24 h were enrolled from October 2005 through March 2010. Patients were randomized to either HVHF at 70 mL/kg/h or standard-volume haemofiltration (SVHF) at 35 mL/kg/h, for a 96-h period. RESULTS: Primary endpoint was 28-day mortality. The trial was stopped prematurely after enrolment of 140 patients because of slow patient accrual and resources no longer being available. A total of 137 patients were analysed (two withdrew consent, one was excluded); 66 patients in the HVHF group and 71 in the SVHF group. Mortality at 28 days was lower than expected but not different between groups (HVHF 37.9 % vs. SVHF 40.8 %, log-rank test p = 0.94). There were no statistically significant differences in any of the secondary endpoints between treatment groups. CONCLUSIONS: In the IVOIRE trial, there was no evidence that HVHF at 70 mL/kg/h, when compared with contemporary SVHF at 35 mL/kg/h, leads to a reduction of 28-day mortality or contributes to early improvements in haemodynamic profile or organ function. HVHF, as applied in this trial, cannot be recommended for treatment of septic shock complicated by AKI.
- BACKGROUND: In current international guidelines the recommendation for intra-aortic balloon pump (IABP) use has been downgraded in cardiogenic shock complicating acute myocardial infarction on the basis of registry data. In the largest randomised trial (IABP-SHOCK II), IABP support did not reduce 30 day mortality compared with control. However, previous trials in cardiogenic shock showed a mortality benefit only at extended follow-up. The present analysis therefore reports 6 and 12 month results. METHODS: The IABP-SHOCK II trial was a randomised, open-label, multicentre trial. Patients with cardiogenic shock complicating acute myocardial infarction who were undergoing early revascularisation and optimum medical therapy were randomly assigned (1:1) to IABP versus control via a central web-based system. The primary efficacy endpoint was 30 day all-cause mortality, but 6 and 12 month follow-up was done in addition to quality-of-life assessment for all survivors with the Euroqol-5D questionnaire. A masked central committee adjudicated clinical outcomes. Patients and investigators were not masked to treatment allocation. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00491036. FINDINGS: Between June 16, 2009, and March 3, 2012, 600 patients were assigned to IABP (n=301) or control (n=299). Of 595 patients completing 12 month follow-up, 155 (52%) of 299 patients in the IABP group and 152 (51%) of 296 patients in the control group had died (relative risk [RR] 1·01, 95% CI 0·86-1·18, p=0·91). There were no significant differences in reinfarction (RR 2·60, 95% CI 0·95-7·10, p=0·05), recurrent revascularisation (0·91, 0·58-1·41, p=0·77), or stroke (1·50, 0·25-8·84, p=1·00). For survivors, quality-of-life measures including mobility, self-care, usual activities, pain or discomfort, and anxiety or depression did not differ significantly between study groups. INTERPRETATION: In patients undergoing early revascularisation for myocardial infarction complicated by cardiogenic shock, IABP did not reduce 12 month all-cause mortality.
- http://jama.jamanetwork.com/article.aspx?articleid=1713589 IMPORTANCE: Among patients with cardiac arrest, preliminary data have shown improved return of spontaneous circulation and survival to hospital discharge with the vasopressin-steroids-epinephrine (VSE) combination. OBJECTIVE: To determine whether combined vasopressin-epinephrine during cardiopulmonary resuscitation (CPR) and corticosteroid supplementation during and after CPR improve survival to hospital discharge with a Cerebral Performance Category (CPC) score of 1 or 2 in vasopressor-requiring, in-hospital cardiac arrest. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled, parallel-group trial performed from September 1, 2008, to October 1, 2010, in 3 Greek tertiary care centers (2400 beds) with 268 consecutive patients with cardiac arrest requiring epinephrine according to resuscitation guidelines (from 364 patients assessed for eligibility). INTERVENTIONS: Patients received either vasopressin (20 IU/CPR cycle) plus epinephrine (1 mg/CPR cycle; cycle duration approximately 3 minutes) (VSE group, n = 130) or saline placebo plus epinephrine (1 mg/CPR cycle; cycle duration approximately 3 minutes) (control group, n = 138) for the first 5 CPR cycles after randomization, followed by additional epinephrine if needed. During the first CPR cycle after randomization, patients in the VSE group received methylprednisolone (40 mg) and patients in the control group received saline placebo. Shock after resuscitation was treated with stress-dose hydrocortisone (300 mg daily for 7 days maximum and gradual taper) (VSE group, n = 76) or saline placebo (control group, n = 73). MAIN OUTCOMES AND MEASURES: Return of spontaneous circulation (ROSC) for 20 minutes or longer and survival to hospital discharge with a CPC score of 1 or 2. RESULTS: Follow-up was completed in all resuscitated patients. Patients in the VSE group vs patients in the control group had higher probability for ROSC of 20 minutes or longer (109/130 [83.9%] vs 91/138 [65.9%]; odds ratio [OR], 2.98; 95% CI, 1.39-6.40; P = .005) and survival to hospital discharge with CPC score of 1 or 2 (18/130 [13.9%] vs 7/138 [5.1%]; OR, 3.28; 95% CI, 1.17-9.20; P = .02). Patients in the VSE group with postresuscitation shock vs corresponding patients in the control group had higher probability for survival to hospital discharge with CPC scores of 1 or 2 (16/76 [21.1%] vs 6/73 [8.2%]; OR, 3.74; 95% CI, 1.20-11.62; P = .02), improved hemodynamics and central venous oxygen saturation, and less organ dysfunction. Adverse event rates were similar in the 2 groups. CONCLUSION AND RELEVANCE: Among patients with cardiac arrest requiring vasopressors, combined vasopressin-epinephrine and methylprednisolone during CPR and stress-dose hydrocortisone in postresuscitation shock, compared with epinephrine/saline placebo, resulted in improved survival to hospital discharge with favorable neurological status.
- BACKGROUND: There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock. METHODS: In this randomized, double-blind, placebo-controlled, multicenter trial, we assigned 1697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours to receive either DrotAA (at a dose of 24 μg per kilogram of body weight per hour) or placebo for 96 hours. The primary outcome was death from any cause 28 days after randomization. RESULTS: At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval [CI], 0.92 to 1.28; P=0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P=0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P=0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P=0.81). CONCLUSIONS: DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock.
- BACKGROUND: There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock. METHODS: In this randomized, double-blind, placebo-controlled, multicenter trial, we assigned 1697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours to receive either DrotAA (at a dose of 24 μg per kilogram of body weight per hour) or placebo for 96 hours. The primary outcome was death from any cause 28 days after randomization. RESULTS: At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval [CI], 0.92 to 1.28; P=0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P=0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P=0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P=0.81). CONCLUSIONS: DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock.
- BACKGROUND: There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock. METHODS: In this randomized, double-blind, placebo-controlled, multicenter trial, we assigned 1697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours to receive either DrotAA (at a dose of 24 μg per kilogram of body weight per hour) or placebo for 96 hours. The primary outcome was death from any cause 28 days after randomization. RESULTS: At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval [CI], 0.92 to 1.28; P=0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P=0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P=0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P=0.81). CONCLUSIONS: DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock.
- BACKGROUND: There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock. METHODS: In this randomized, double-blind, placebo-controlled, multicenter trial, we assigned 1697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours to receive either DrotAA (at a dose of 24 μg per kilogram of body weight per hour) or placebo for 96 hours. The primary outcome was death from any cause 28 days after randomization. RESULTS: At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval [CI], 0.92 to 1.28; P=0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P=0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P=0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P=0.81). CONCLUSIONS: DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock.
- BACKGROUND: There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock. METHODS: In this randomized, double-blind, placebo-controlled, multicenter trial, we assigned 1697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours to receive either DrotAA (at a dose of 24 μg per kilogram of body weight per hour) or placebo for 96 hours. The primary outcome was death from any cause 28 days after randomization. RESULTS: At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval [CI], 0.92 to 1.28; P=0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P=0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P=0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P=0.81). CONCLUSIONS: DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock.
- BACKGROUND: There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock. METHODS: In this randomized, double-blind, placebo-controlled, multicenter trial, we assigned 1697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours to receive either DrotAA (at a dose of 24 μg per kilogram of body weight per hour) or placebo for 96 hours. The primary outcome was death from any cause 28 days after randomization. RESULTS: At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval [CI], 0.92 to 1.28; P=0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P=0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P=0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P=0.81). CONCLUSIONS: DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock.
- BACKGROUND: There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock. METHODS: In this randomized, double-blind, placebo-controlled, multicenter trial, we assigned 1697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours to receive either DrotAA (at a dose of 24 μg per kilogram of body weight per hour) or placebo for 96 hours. The primary outcome was death from any cause 28 days after randomization. RESULTS: At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval [CI], 0.92 to 1.28; P=0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P=0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P=0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P=0.81). CONCLUSIONS: DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock.
- IMPORTANCE: β-Blocker therapy may control heart rate and attenuate the deleterious effects of β-adrenergic receptor stimulation in septic shock. However, β-Blockers are not traditionally used for this condition and may worsen cardiovascular decompensation related through negative inotropic and hypotensive effects. OBJECTIVE: To investigate the effect of the short-acting β-blocker esmolol in patients with severe septic shock. DESIGN, SETTING, AND PATIENTS: Open-label, randomized phase 2 study, conducted in a university hospital intensive care unit (ICU) between November 2010 and July 2012, involving patients in septic shock with a heart rate of 95/min or higher requiring high-dose norepinephrine to maintain a mean arterial pressure of 65 mm Hg or higher. INTERVENTIONS: We randomly assigned 77 patients to receive a continuous infusion of esmolol titrated to maintain heart rate between 80/min and 94/min for their ICU stay and 77 patients to standard treatment. MAIN OUTCOMES AND MEASURES: Our primary outcome was a reduction in heart rate below the predefined threshold of 95/min and to maintain heart rate between 80/min and 94/min by esmolol treatment over a 96-hour period. Secondary outcomes included hemodynamic and organ function measures; norepinephrine dosages at 24, 48, 72, and 96 hours; and adverse events and mortality occurring within 28 days after randomization. RESULTS: Targeted heart rates were achieved in all patients in the esmolol group compared with those in the control group. The median AUC for heart rate during the first 96 hours was -28/min (IQR, -37 to -21) for the esmolol group vs -6/min (95% CI, -14 to 0) for the control group with a mean reduction of 18/min (P &lt; .001). For stroke volume index, the median AUC for esmolol was 4 mL/m2 (IQR, -1 to 10) vs 1 mL/m2 for the control group (IQR, -3 to 5; P = .02), whereas the left ventricular stroke work index for esmolol was 3 mL/m2 (IQR, 0 to 8) vs 1 mL/m2 for the control group (IQR, -2 to 5; P = .03). For arterial lactatemia, median AUC for esmolol was -0.1 mmol/L (IQR, -0.6 to 0.2) vs 0.1 mmol/L for the control group (IQR, -0.3 for 0.6; P = .007); for norepinephrine, -0.11 μg/kg/min (IQR, -0.46 to 0.02) for the esmolol group vs -0.01 μg/kg/min (IQR, -0.2 to 0.44) for the control group (P = .003). Fluid requirements were reduced in the esmolol group: median AUC was 3975 mL/24 h (IQR, 3663 to 4200) vs 4425 mL/24 h(IQR, 4038 to 4775) for the control group (P &lt; .001). We found no clinically relevant differences between groups in other cardiopulmonary variables nor in rescue therapy requirements. Twenty-eight day mortality was 49.4% in the esmolol group vs 80.5% in the control group (adjusted hazard ratio, 0.39; 95% CI, 0.26 to 0.59; P &lt; .001). CONCLUSIONS AND RELEVANCE: For patients in septic shock, open-label use of esmolol vs standard care was associated with reductions in heart rates to achieve target levels, without increased adverse events. The observed improvement in mortality and other secondary clinical outcomes warrants further investigation.
- IMPORTANCE: β-Blocker therapy may control heart rate and attenuate the deleterious effects of β-adrenergic receptor stimulation in septic shock. However, β-Blockers are not traditionally used for this condition and may worsen cardiovascular decompensation related through negative inotropic and hypotensive effects. OBJECTIVE: To investigate the effect of the short-acting β-blocker esmolol in patients with severe septic shock. DESIGN, SETTING, AND PATIENTS: Open-label, randomized phase 2 study, conducted in a university hospital intensive care unit (ICU) between November 2010 and July 2012, involving patients in septic shock with a heart rate of 95/min or higher requiring high-dose norepinephrine to maintain a mean arterial pressure of 65 mm Hg or higher. INTERVENTIONS: We randomly assigned 77 patients to receive a continuous infusion of esmolol titrated to maintain heart rate between 80/min and 94/min for their ICU stay and 77 patients to standard treatment. MAIN OUTCOMES AND MEASURES: Our primary outcome was a reduction in heart rate below the predefined threshold of 95/min and to maintain heart rate between 80/min and 94/min by esmolol treatment over a 96-hour period. Secondary outcomes included hemodynamic and organ function measures; norepinephrine dosages at 24, 48, 72, and 96 hours; and adverse events and mortality occurring within 28 days after randomization. RESULTS: Targeted heart rates were achieved in all patients in the esmolol group compared with those in the control group. The median AUC for heart rate during the first 96 hours was -28/min (IQR, -37 to -21) for the esmolol group vs -6/min (95% CI, -14 to 0) for the control group with a mean reduction of 18/min (P &lt; .001). For stroke volume index, the median AUC for esmolol was 4 mL/m2 (IQR, -1 to 10) vs 1 mL/m2 for the control group (IQR, -3 to 5; P = .02), whereas the left ventricular stroke work index for esmolol was 3 mL/m2 (IQR, 0 to 8) vs 1 mL/m2 for the control group (IQR, -2 to 5; P = .03). For arterial lactatemia, median AUC for esmolol was -0.1 mmol/L (IQR, -0.6 to 0.2) vs 0.1 mmol/L for the control group (IQR, -0.3 for 0.6; P = .007); for norepinephrine, -0.11 μg/kg/min (IQR, -0.46 to 0.02) for the esmolol group vs -0.01 μg/kg/min (IQR, -0.2 to 0.44) for the control group (P = .003). Fluid requirements were reduced in the esmolol group: median AUC was 3975 mL/24 h (IQR, 3663 to 4200) vs 4425 mL/24 h(IQR, 4038 to 4775) for the control group (P &lt; .001). We found no clinically relevant differences between groups in other cardiopulmonary variables nor in rescue therapy requirements. Twenty-eight day mortality was 49.4% in the esmolol group vs 80.5% in the control group (adjusted hazard ratio, 0.39; 95% CI, 0.26 to 0.59; P &lt; .001). CONCLUSIONS AND RELEVANCE: For patients in septic shock, open-label use of esmolol vs standard care was associated with reductions in heart rates to achieve target levels, without increased adverse events. The observed improvement in mortality and other secondary clinical outcomes warrants further investigation.
- IMPORTANCE: β-Blocker therapy may control heart rate and attenuate the deleterious effects of β-adrenergic receptor stimulation in septic shock. However, β-Blockers are not traditionally used for this condition and may worsen cardiovascular decompensation related through negative inotropic and hypotensive effects. OBJECTIVE: To investigate the effect of the short-acting β-blocker esmolol in patients with severe septic shock. DESIGN, SETTING, AND PATIENTS: Open-label, randomized phase 2 study, conducted in a university hospital intensive care unit (ICU) between November 2010 and July 2012, involving patients in septic shock with a heart rate of 95/min or higher requiring high-dose norepinephrine to maintain a mean arterial pressure of 65 mm Hg or higher. INTERVENTIONS: We randomly assigned 77 patients to receive a continuous infusion of esmolol titrated to maintain heart rate between 80/min and 94/min for their ICU stay and 77 patients to standard treatment. MAIN OUTCOMES AND MEASURES: Our primary outcome was a reduction in heart rate below the predefined threshold of 95/min and to maintain heart rate between 80/min and 94/min by esmolol treatment over a 96-hour period. Secondary outcomes included hemodynamic and organ function measures; norepinephrine dosages at 24, 48, 72, and 96 hours; and adverse events and mortality occurring within 28 days after randomization. RESULTS: Targeted heart rates were achieved in all patients in the esmolol group compared with those in the control group. The median AUC for heart rate during the first 96 hours was -28/min (IQR, -37 to -21) for the esmolol group vs -6/min (95% CI, -14 to 0) for the control group with a mean reduction of 18/min (P &lt; .001). For stroke volume index, the median AUC for esmolol was 4 mL/m2 (IQR, -1 to 10) vs 1 mL/m2 for the control group (IQR, -3 to 5; P = .02), whereas the left ventricular stroke work index for esmolol was 3 mL/m2 (IQR, 0 to 8) vs 1 mL/m2 for the control group (IQR, -2 to 5; P = .03). For arterial lactatemia, median AUC for esmolol was -0.1 mmol/L (IQR, -0.6 to 0.2) vs 0.1 mmol/L for the control group (IQR, -0.3 for 0.6; P = .007); for norepinephrine, -0.11 μg/kg/min (IQR, -0.46 to 0.02) for the esmolol group vs -0.01 μg/kg/min (IQR, -0.2 to 0.44) for the control group (P = .003). Fluid requirements were reduced in the esmolol group: median AUC was 3975 mL/24 h (IQR, 3663 to 4200) vs 4425 mL/24 h(IQR, 4038 to 4775) for the control group (P &lt; .001). We found no clinically relevant differences between groups in other cardiopulmonary variables nor in rescue therapy requirements. Twenty-eight day mortality was 49.4% in the esmolol group vs 80.5% in the control group (adjusted hazard ratio, 0.39; 95% CI, 0.26 to 0.59; P &lt; .001). CONCLUSIONS AND RELEVANCE: For patients in septic shock, open-label use of esmolol vs standard care was associated with reductions in heart rates to achieve target levels, without increased adverse events. The observed improvement in mortality and other secondary clinical outcomes warrants further investigation.
- IMPORTANCE: β-Blocker therapy may control heart rate and attenuate the deleterious effects of β-adrenergic receptor stimulation in septic shock. However, β-Blockers are not traditionally used for this condition and may worsen cardiovascular decompensation related through negative inotropic and hypotensive effects. OBJECTIVE: To investigate the effect of the short-acting β-blocker esmolol in patients with severe septic shock. DESIGN, SETTING, AND PATIENTS: Open-label, randomized phase 2 study, conducted in a university hospital intensive care unit (ICU) between November 2010 and July 2012, involving patients in septic shock with a heart rate of 95/min or higher requiring high-dose norepinephrine to maintain a mean arterial pressure of 65 mm Hg or higher. INTERVENTIONS: We randomly assigned 77 patients to receive a continuous infusion of esmolol titrated to maintain heart rate between 80/min and 94/min for their ICU stay and 77 patients to standard treatment. MAIN OUTCOMES AND MEASURES: Our primary outcome was a reduction in heart rate below the predefined threshold of 95/min and to maintain heart rate between 80/min and 94/min by esmolol treatment over a 96-hour period. Secondary outcomes included hemodynamic and organ function measures; norepinephrine dosages at 24, 48, 72, and 96 hours; and adverse events and mortality occurring within 28 days after randomization. RESULTS: Targeted heart rates were achieved in all patients in the esmolol group compared with those in the control group. The median AUC for heart rate during the first 96 hours was -28/min (IQR, -37 to -21) for the esmolol group vs -6/min (95% CI, -14 to 0) for the control group with a mean reduction of 18/min (P &lt; .001). For stroke volume index, the median AUC for esmolol was 4 mL/m2 (IQR, -1 to 10) vs 1 mL/m2 for the control group (IQR, -3 to 5; P = .02), whereas the left ventricular stroke work index for esmolol was 3 mL/m2 (IQR, 0 to 8) vs 1 mL/m2 for the control group (IQR, -2 to 5; P = .03). For arterial lactatemia, median AUC for esmolol was -0.1 mmol/L (IQR, -0.6 to 0.2) vs 0.1 mmol/L for the control group (IQR, -0.3 for 0.6; P = .007); for norepinephrine, -0.11 μg/kg/min (IQR, -0.46 to 0.02) for the esmolol group vs -0.01 μg/kg/min (IQR, -0.2 to 0.44) for the control group (P = .003). Fluid requirements were reduced in the esmolol group: median AUC was 3975 mL/24 h (IQR, 3663 to 4200) vs 4425 mL/24 h(IQR, 4038 to 4775) for the control group (P &lt; .001). We found no clinically relevant differences between groups in other cardiopulmonary variables nor in rescue therapy requirements. Twenty-eight day mortality was 49.4% in the esmolol group vs 80.5% in the control group (adjusted hazard ratio, 0.39; 95% CI, 0.26 to 0.59; P &lt; .001). CONCLUSIONS AND RELEVANCE: For patients in septic shock, open-label use of esmolol vs standard care was associated with reductions in heart rates to achieve target levels, without increased adverse events. The observed improvement in mortality and other secondary clinical outcomes warrants further investigation.
- IMPORTANCE: β-Blocker therapy may control heart rate and attenuate the deleterious effects of β-adrenergic receptor stimulation in septic shock. However, β-Blockers are not traditionally used for this condition and may worsen cardiovascular decompensation related through negative inotropic and hypotensive effects. OBJECTIVE: To investigate the effect of the short-acting β-blocker esmolol in patients with severe septic shock. DESIGN, SETTING, AND PATIENTS: Open-label, randomized phase 2 study, conducted in a university hospital intensive care unit (ICU) between November 2010 and July 2012, involving patients in septic shock with a heart rate of 95/min or higher requiring high-dose norepinephrine to maintain a mean arterial pressure of 65 mm Hg or higher. INTERVENTIONS: We randomly assigned 77 patients to receive a continuous infusion of esmolol titrated to maintain heart rate between 80/min and 94/min for their ICU stay and 77 patients to standard treatment. MAIN OUTCOMES AND MEASURES: Our primary outcome was a reduction in heart rate below the predefined threshold of 95/min and to maintain heart rate between 80/min and 94/min by esmolol treatment over a 96-hour period. Secondary outcomes included hemodynamic and organ function measures; norepinephrine dosages at 24, 48, 72, and 96 hours; and adverse events and mortality occurring within 28 days after randomization. RESULTS: Targeted heart rates were achieved in all patients in the esmolol group compared with those in the control group. The median AUC for heart rate during the first 96 hours was -28/min (IQR, -37 to -21) for the esmolol group vs -6/min (95% CI, -14 to 0) for the control group with a mean reduction of 18/min (P &lt; .001). For stroke volume index, the median AUC for esmolol was 4 mL/m2 (IQR, -1 to 10) vs 1 mL/m2 for the control group (IQR, -3 to 5; P = .02), whereas the left ventricular stroke work index for esmolol was 3 mL/m2 (IQR, 0 to 8) vs 1 mL/m2 for the control group (IQR, -2 to 5; P = .03). For arterial lactatemia, median AUC for esmolol was -0.1 mmol/L (IQR, -0.6 to 0.2) vs 0.1 mmol/L for the control group (IQR, -0.3 for 0.6; P = .007); for norepinephrine, -0.11 μg/kg/min (IQR, -0.46 to 0.02) for the esmolol group vs -0.01 μg/kg/min (IQR, -0.2 to 0.44) for the control group (P = .003). Fluid requirements were reduced in the esmolol group: median AUC was 3975 mL/24 h (IQR, 3663 to 4200) vs 4425 mL/24 h(IQR, 4038 to 4775) for the control group (P &lt; .001). We found no clinically relevant differences between groups in other cardiopulmonary variables nor in rescue therapy requirements. Twenty-eight day mortality was 49.4% in the esmolol group vs 80.5% in the control group (adjusted hazard ratio, 0.39; 95% CI, 0.26 to 0.59; P &lt; .001). CONCLUSIONS AND RELEVANCE: For patients in septic shock, open-label use of esmolol vs standard care was associated with reductions in heart rates to achieve target levels, without increased adverse events. The observed improvement in mortality and other secondary clinical outcomes warrants further investigation.
- IMPORTANCE: β-Blocker therapy may control heart rate and attenuate the deleterious effects of β-adrenergic receptor stimulation in septic shock. However, β-Blockers are not traditionally used for this condition and may worsen cardiovascular decompensation related through negative inotropic and hypotensive effects. OBJECTIVE: To investigate the effect of the short-acting β-blocker esmolol in patients with severe septic shock. DESIGN, SETTING, AND PATIENTS: Open-label, randomized phase 2 study, conducted in a university hospital intensive care unit (ICU) between November 2010 and July 2012, involving patients in septic shock with a heart rate of 95/min or higher requiring high-dose norepinephrine to maintain a mean arterial pressure of 65 mm Hg or higher. INTERVENTIONS: We randomly assigned 77 patients to receive a continuous infusion of esmolol titrated to maintain heart rate between 80/min and 94/min for their ICU stay and 77 patients to standard treatment. MAIN OUTCOMES AND MEASURES: Our primary outcome was a reduction in heart rate below the predefined threshold of 95/min and to maintain heart rate between 80/min and 94/min by esmolol treatment over a 96-hour period. Secondary outcomes included hemodynamic and organ function measures; norepinephrine dosages at 24, 48, 72, and 96 hours; and adverse events and mortality occurring within 28 days after randomization. RESULTS: Targeted heart rates were achieved in all patients in the esmolol group compared with those in the control group. The median AUC for heart rate during the first 96 hours was -28/min (IQR, -37 to -21) for the esmolol group vs -6/min (95% CI, -14 to 0) for the control group with a mean reduction of 18/min (P &lt; .001). For stroke volume index, the median AUC for esmolol was 4 mL/m2 (IQR, -1 to 10) vs 1 mL/m2 for the control group (IQR, -3 to 5; P = .02), whereas the left ventricular stroke work index for esmolol was 3 mL/m2 (IQR, 0 to 8) vs 1 mL/m2 for the control group (IQR, -2 to 5; P = .03). For arterial lactatemia, median AUC for esmolol was -0.1 mmol/L (IQR, -0.6 to 0.2) vs 0.1 mmol/L for the control group (IQR, -0.3 for 0.6; P = .007); for norepinephrine, -0.11 μg/kg/min (IQR, -0.46 to 0.02) for the esmolol group vs -0.01 μg/kg/min (IQR, -0.2 to 0.44) for the control group (P = .003). Fluid requirements were reduced in the esmolol group: median AUC was 3975 mL/24 h (IQR, 3663 to 4200) vs 4425 mL/24 h(IQR, 4038 to 4775) for the control group (P &lt; .001). We found no clinically relevant differences between groups in other cardiopulmonary variables nor in rescue therapy requirements. Twenty-eight day mortality was 49.4% in the esmolol group vs 80.5% in the control group (adjusted hazard ratio, 0.39; 95% CI, 0.26 to 0.59; P &lt; .001). CONCLUSIONS AND RELEVANCE: For patients in septic shock, open-label use of esmolol vs standard care was associated with reductions in heart rates to achieve target levels, without increased adverse events. The observed improvement in mortality and other secondary clinical outcomes warrants further investigation.
- Purpose Colloids are administered to more patients than crystalloids, although recent evidence suggests that colloids may possibly be harmful in some patients. The European Society of Intensive Care Medicine therefore assembled a task force to compile consensus recommendations based on the current best evidence for the safety and efficacy of the currently most frequently used colloids—hydroxyethyl starches (HES), gelatins and human albumin. Methods Meta-analyses, systematic reviews and clinical studies of colloid use were evaluated for the treatment of volume depletion in mixed intensive care unit (ICU), cardiac surgery, head injury, sepsis and organ donor patients. Clinical endpoints included mortality, kidney function and bleeding. The relevance of concentration and dosage was also assessed. Publications from 1960 until May 2011 were included. The quality of available evidence and strength of recommendations were based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Recommendations and conclusions We recommend not to use HES with molecular weight ≥200 kDa and/or degree of substitution &gt;0.4 in patients with severe sepsis or risk of acute kidney injury and suggest not to use 6% HES 130/0.4 or gelatin in these populations. We recommend not to use colloids in patients with head injury and not to administer gelatins and HES in organ donors. We suggest not to use hyperoncotic solutions for fluid resuscitation. We conclude and recommend that any new colloid should be introduced into clinical practice only after its patient-important safety parameters are established.
- BACKGROUND: Hydroxyethyl starch (HES) [corrected] is widely used for fluid resuscitation in intensive care units (ICUs), but its safety and efficacy have not been established in patients with severe sepsis. METHODS: In this multicenter, parallel-group, blinded trial, we randomly assigned patients with severe sepsis to fluid resuscitation in the ICU with either 6% HES 130/0.42 (Tetraspan) or Ringer&apos;s acetate at a dose of up to 33 ml per kilogram of ideal body weight per day. The primary outcome measure was either death or end-stage kidney failure (dependence on dialysis) at 90 days after randomization. RESULTS: Of the 804 patients who underwent randomization, 798 were included in the modified intention-to-treat population. The two intervention groups had similar baseline characteristics. At 90 days after randomization, 201 of 398 patients (51%) assigned to HES 130/0.42 had died, as compared with 172 of 400 patients (43%) assigned to Ringer&apos;s acetate (relative risk, 1.17; 95% confidence interval [CI], 1.01 to 1.36; P=0.03); 1 patient in each group had end-stage kidney failure. In the 90-day period, 87 patients (22%) assigned to HES 130/0.42 were treated with renal-replacement therapy versus 65 patients (16%) assigned to Ringer&apos;s acetate (relative risk, 1.35; 95% CI, 1.01 to 1.80; P=0.04), and 38 patients (10%) and 25 patients (6%), respectively, had severe bleeding (relative risk, 1.52; 95% CI, 0.94 to 2.48; P=0.09). The results were supported by multivariate analyses, with adjustment for known risk factors for death or acute kidney injury at baseline. CONCLUSIONS: Patients with severe sepsis assigned to fluid resuscitation with HES 130/0.42 had an increased risk of death at day 90 and were more likely to require renal-replacement therapy, as compared with those receiving Ringer&apos;s acetate.
- BACKGROUND: The safety and efficacy of hydroxyethyl starch (HES) for fluid resuscitation have not been fully evaluated, and adverse effects of HES on survival and renal function have been reported. METHODS: We randomly assigned 7000 patients who had been admitted to an intensive care unit (ICU) in a 1:1 ratio to receive either 6% HES with a molecular weight of 130 kD and a molar substitution ratio of 0.4 (130/0.4, Voluven) in 0.9% sodium chloride or 0.9% sodium chloride (saline) for all fluid resuscitation until ICU discharge, death, or 90 days after randomization. The primary outcome was death within 90 days. Secondary outcomes included acute kidney injury and failure and treatment with renal-replacement therapy. RESULTS: A total of 597 of 3315 patients (18.0%) in the HES group and 566 of 3336 (17.0%) in the saline group died (relative risk in the HES group, 1.06; 95% confidence interval [CI], 0.96 to 1.18; P=0.26). There was no significant difference in mortality in six predefined subgroups. Renal-replacement therapy was used in 235 of 3352 patients (7.0%) in the HES group and 196 of 3375 (5.8%) in the saline group (relative risk, 1.21; 95% CI, 1.00 to 1.45; P=0.04). In the HES and saline groups, renal injury occurred in 34.6% and 38.0% of patients, respectively (P=0.005), and renal failure occurred in 10.4% and 9.2% of patients, respectively (P=0.12). HES was associated with significantly more adverse events (5.3% vs. 2.8%, P&lt;0.001). CONCLUSIONS: In patients in the ICU, there was no significant difference in 90-day mortality between patients resuscitated with 6% HES (130/0.4) or saline. However, more patients who received resuscitation with HES were treated with renal-replacement therapy.
- Trophic vs Full Enteral Feeding 1000 within 48 hrs of ALI requiring MV 80% ALI from pneumonia Trophic vs. full* enteral feed Unblinded; 44 sites Hypothesis – considerably lower feed (25% of target full feed) during first 6/7 increases ventilator free dys *25-30kcal/kg/d Although this is just one study, it appears to refute those studies that have suggested benefits of hypocaloric feeding over full feeding, but also suggests there is a wide window of nutritional intake that has little effect on patient outcomes, at least up to 6 days into the intensive care course. It needs to be remembered that this study was carried out in a very specific group of patients with ALI, so extrapolation to other groups of critically ill patients, for example those with severe sepsis or septic shock, is not necessarily warranted. It is also important to note that hypocaloric feeding stopped after 6 days with reversion to nutritional targets. No difference in ventilator dys or infection (VAP/c.diff/bacteraemia) or 60 d mortality More gastroparesis despite increase prokinetics in full feed group 1/3 pts also in OMEGA study – fatty acids supplementsand antixodiant – did not improve ventilator free days REDOX Randomised, blinded, 2x2 factorial study 1,223 critically ill pts with MOF Glutamine, antioxidants & placebo Glutamine associated with harm Increased mortality Trend at 28 days (34% vs 27%; p=0.05) Increased at 90 days (44% vs 37%; p=0.02) Antioxidants ineffective Mortality Other endoints Residual gastric volume Randomized, noninferiority, open-label, multicenter study 452 pts receiving Mechanical ventilation &gt; 2 days Enteral nutrition within 36 hours of MV Monitoring gastric volume or not No difference in VAP (15.8% vs 16.7%) Other ICU-acquired infections Duration MV / ICU LOS / Hospital LOS Higher proportion reached calorific goal (OR 1.77)
- IMPORTANCE: Evidence supporting the choice of intravenous colloid vs crystalloid solutions for management of hypovolemic shock remains unclear. OBJECTIVE: To test whether use of colloids compared with crystalloids for fluid resuscitation alters mortality in patients admitted to the intensive care unit (ICU) with hypovolemic shock. DESIGN, SETTING, AND PARTICIPANTS: A multicenter, randomized clinical trial stratified by case mix (sepsis, trauma, or hypovolemic shock without sepsis or trauma). Therapy in the Colloids Versus Crystalloids for the Resuscitation of the Critically Ill (CRISTAL) trial was open label but outcome assessment was blinded to treatment assignment. Recruitment began in February 2003 and ended in August 2012 of 2857 sequential ICU patients treated at 57 ICUs in France, Belgium, North Africa, and Canada; follow-up ended in November 2012. INTERVENTIONS: Colloids (n = 1414; gelatins, dextrans, hydroxyethyl starches, or 4% or 20% of albumin) or crystalloids (n = 1443; isotonic or hypertonic saline or Ringer lactate solution) for all fluid interventions other than fluid maintenance throughout the ICU stay. MAIN OUTCOMES AND MEASURES: The primary outcome was death within 28 days. Secondary outcomes included 90-day mortality; and days alive and not receiving renal replacement therapy, mechanical ventilation, or vasopressor therapy. RESULTS: Within 28 days, there were 359 deaths (25.4%) in colloids group vs 390 deaths (27.0%) in crystalloids group (relative risk [RR], 0.96 [95% CI, 0.88 to 1.04]; P = .26). Within 90 days, there were 434 deaths (30.7%) in colloids group vs 493 deaths (34.2%) in crystalloids group (RR, 0.92 [95% CI, 0.86 to 0.99]; P = .03). Renal replacement therapy was used in 156 (11.0%) in colloids group vs 181 (12.5%) in crystalloids group (RR, 0.93 [95% CI, 0.83 to 1.03]; P = .19). There were more days alive without mechanical ventilation in the colloids group vs the crystalloids group by 7 days (mean: 2.1 vs 1.8 days, respectively; mean difference, 0.30 [95% CI, 0.09 to 0.48] days; P = .01) and by 28 days (mean: 14.6 vs 13.5 days; mean difference, 1.10 [95% CI, 0.14 to 2.06] days; P = .01) and alive without vasopressor therapy by 7 days (mean: 5.0 vs 4.7 days; mean difference, 0.30 [95% CI, -0.03 to 0.50] days; P = .04) and by 28 days (mean: 16.2 vs 15.2 days; mean difference, 1.04 [95% CI, -0.04 to 2.10] days; P = .03). CONCLUSIONS AND RELEVANCE: Among ICU patients with hypovolemia, the use of colloids vs crystalloids did not result in a significant difference in 28-day mortality. Although 90-day mortality was lower among patients receiving colloids, this finding should be considered exploratory and requires further study before reaching conclusions about efficacy.
- BACKGROUND: There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock. METHODS: In this randomized, double-blind, placebo-controlled, multicenter trial, we assigned 1697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours to receive either DrotAA (at a dose of 24 μg per kilogram of body weight per hour) or placebo for 96 hours. The primary outcome was death from any cause 28 days after randomization. RESULTS: At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval [CI], 0.92 to 1.28; P=0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P=0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P=0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P=0.81). CONCLUSIONS: DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock.
- BACKGROUND: There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock. METHODS: In this randomized, double-blind, placebo-controlled, multicenter trial, we assigned 1697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours to receive either DrotAA (at a dose of 24 μg per kilogram of body weight per hour) or placebo for 96 hours. The primary outcome was death from any cause 28 days after randomization. RESULTS: At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval [CI], 0.92 to 1.28; P=0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P=0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P=0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P=0.81). CONCLUSIONS: DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock.
- Importance Histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) are commonly used to prevent gastrointestinal tract (GI) hemorrhage in critically ill patients. The stronger acid suppression of PPIs may reduce the rate of bleeding but enhance infectious complications, specifically pneumonia and Clostridium difficile infection (CDI). Objective To evaluate the occurrence and risk factors for GI hemorrhage, pneumonia, and CDI in critically ill patients. Design, Setting, and Participants A pharmacoepidemiological cohort study was conducted of adult patients requiring mechanical ventilation for 24 hours or more and administered either an H2RA or PPI for 48 hours or more while intubated across 71 hospitals between January 1, 2003, and December 31, 2008. Propensity score–adjusted and propensity-matched multivariate regression models were used to control for confounders. Main Outcomes and Measures Primary outcomes were secondary diagnoses of International Classification of Diseases, Ninth Revision (ICD-9)–coded GI hemorrhage, pneumonia, and CDI occurring 48 hours or more after initiating invasive ventilation. Results Of 35 312 patients, 13 439 (38.1%) received H2RAs and 21 873 (61.9%) received PPIs. Gastrointestinal hemorrhage (2.1% vs 5.9%; P &lt; .001), pneumonia (27% vs 38.6%; P &lt; .001), and CDI (2.2% vs 3.8%; P &lt; .001) occurred less frequently in the H2RA group. After adjusting for propensity score and covariates, odds ratios of GI hemorrhage (2.24; 95% CI, 1.81-2.76), pneumonia (1.2; 95% CI, 1.03-1.41), and CDI (1.29; 95% CI, 1.04-1.64) were greater with PPIs. Similar results were obtained in the propensity-matched models of 8799 patients in each cohort. Conclusions and Relevance Proton pump inhibitors are associated with greater risks of GI hemorrhage, pneumonia, and CDI than H2RAs in mechanically ventilated patients. Numerous other risk factors are apparent. These data warrant confirmation in comparative prospective studies.
- APP (abdominal perfusion pressure) = mean arterial pressure - IAP