‘The Critical Care Evidence Base that is Critical For Exams lan Seppelt, Dept of Intensive Care Medicine, Nepean Hospital ian.seppelt@sydney.edu.au Advice for the FCICM exam 1 You must know at least the key evidence that informs modern intensive care: Practice ~ don’t worry about quoting the reference exactly but atleast be able to quote the major findings and know the implications of the findings. ‘You must know about the major multicentre RCTs that have led to Aust and [NZ's international reputation for this sort of clinical research in the last two decades [Dopamine, SAFE, CHEST, NICE, RENAL, MERIT, ARISE... and know the strengths and weaknesses ofthese studies. You must also know about the major ANZ trials recently completed (eg ADRENAL, SPICE, TARGET, POLAR] and important trials currently underway or about to startin your ICUs (eg PLUS, SUDDICU, REVISE) ‘You must know about major current controversies, including synthetic colloids Uoachim Boldt scandal in HES research), steroids in sepsis / ARDS, different approaches to nutrition, management of HIE/OHCA, and now ECMO/ECLS. Its worth atleast looking at the program of meetings such the ANZICS Clinical Trials Group ASM ~ many examiners will be there. You must know the major international guidelines [Surviving Sepsis, Brain Trauma Foundation, International Liaison Committee on Resuscitation) and the strengths and weaknesses of these guidelines. You must know atleast the basics of how to sensibly evaluate a paper’. This includes as a minimum a working knowledge of how to assess internal and external validity. The CONSORT (Consolidated Standards of Reporting Trials) statement will help you with internal validity (ie was the study well done). You must appraise external validity yourself ("how does this study apply to MY patient population in my environment”) and understand how to rationally evaluate subgroups and secondary endpoints in the context of a large pragmatic trial. Also think about the validity of post hoc as opposed to preplanned analyses and why these can lead us astray. My approach toa ‘Critically Evaluate...” question (often poorly done in the ‘exam) sno different to how | write a protocol for my department, (1) Outline the issue, (2) Summarise the current evidence, including strengths and weaknesses, (3} Here isthe bottom line, (4) Based on the above, this is what! recommend (5) So do what | say, please Regardless of how strong or weak the evidence is you must ultimately have a statement of what YOU will do. “The EBM / statistics / clinical research questions in the written paper are a ‘very good bet (there's almost always one there) and are basicaly designed to test the question ‘have you been going to journal club’? ‘do you take an interest in the literature’? ‘do you stay up to date’? (not by reading UpToDate HIN}. You do NOT have to know how to evaluate complex statistics, but ais one question ik Beneral understanding ofthe princilsis expected, There sone question ike this in every written paper, so take the time to understand the basi Useful Resources 1. The local internet sites [CrtlQ wonw.critia.com (great journal club) and Intensive Care Network ICN intensivecarenetwork.com], and an excellent Liternational review site www.criticalcarereviews.com. Good information in blogs lke LifeintheFastLane (ITF), The FOAMed stuffis growing xonentially, but beware the line where critique turns in to opinion. The JAMA User's Guides to the Medical Literature. Links availabe from many sites, or buy the book from AMPCo. Gordon Doig’s website. ‘ wovnw.evidencebased.net which includes a number of Vidence Based links and a lot of reviews The journal Critical Core and Resuscitation. Read all the editorials and {eviews for the last few years ~ these are written by prominent Australian intensivists, many of whom are examiners, Likewise many of the chapter authors in T.£.0h’s intensive Care Medicine are examiners Zo small books: Greenhalgh T How to Read a Paper, 3rd ed, BM books and Keech A, Gebski V and Pike R, Interpreting and Reporting Clinical Trials A ‘uide to the CONSORT statement and the principles of randomised controlled trials, AMPCO Fink M, Hayes M and Soni N (eds) Clossic Papers in Critical Care, Bladon Medical Publishing. A collection of all those older papers which are really Important and led to the development of how we now practice, Theres also an iPad app entitled “ICU Clinical Trials ClinCale” which lists 127 key critical care articles and is reasonably up to date. My personal list of ‘Must Knows’ | have pdf copies of all the papers below which | am happy to send to anyone having difficulty finding a particular paper (most are easy to get) 1. The Users Guide Papers, even though they are getting abit old. These Provided the basis for everything that followed. Cook DJ, Hebert PC, Heyland DK, Guyatt GH, Brun-Buisson Cet al How to use an article on therapy or prevention: pneumonia prevention Using subglottic secretion drainage. Critical Care Medicine 1997; 25: 1502-1513 b. Jaeschke RZ, Meade MO, Guyatt GH, Keenan $P, Cook Di, How to use diagnostic test articles in the intensive care unit: diagnosing weanability using f/Vt. Critical Care Medicine 1997; 25: 1514-1521, Meade MO, Cook DJ, Kernerman P, Bernard G. How to use articlesabout harm: the relationship between high tidal volumes, ventilating, Pressures, and ventilator-induced lung injury. Critical Care Medicine 1997; 25: 1915-1922 4. Cook DJ, Levy MM, Heyland DK. How to use a review article’ Prophylactic endoscopic sclerotherapy for esophageal varices. Critical Care Medicine 1998; 26: 692-700. ©. Keenan SP, Guyatt GH, Sibbald WJ, Cook DJ, Heyland DK, Jaeschke RZ. How to use articles about diagnostic technology: gastric tonometry, Critical Care Medicine 1999; 27: 1726-1731, Fluid Resuscitation: Start with The SAFE Study Investigators, A comparison Of saline and albumin for fluid resuscitation in the intensive care unit, New Engl Med, 2004, 350: 2247-2256, See also The SAFE Study Investigators, Saline or Albumin for Fluid Resuscitation in Patients with Traumatic Brain Injury, New Engl J Med, 2007, 357:874-884, and Saline versus Albumin Fluid Evaluation Investigators, Effect of baseline serum albumin concentration con outcome of resuscitation with albumin or saline in patients in intensive care "nits: analysis of data from the SAFE study, Br Med J, 2006, 333:1044-1049 Al this of course was prompted by Cochrane Injuries Group Albumin Reviewers, Human albumin administration in critically il patients: systematic review of randomised controlled tials, BMJ. 1998 Jul 25;317(7153}:235-40 ~ certainly the most controversial paper in intensive care in along time, and the stimulus for SAFE, Fluid Resuscitation 2: Ongoing controversies, such as the place of synthetic colloids such a hydroxyethy/ starch (HES). The most prolific researcher in the area has been convicted of academic fraud with over 80 papers (a large part of the HES literaturel] retracted. Know about the HES controversy and the (CHEST and 65 trials (both New Engl J Med, 2012). Also know about FEAST (K. Maitland, New Engl J Med, 2011) and work which has flowed from this which are likely to radically change fluid resuscitation practices in paediatrics, And now extemely topical, the possible association between hyperchloraemia and renal failure (Yunos, JAMA 2012:308:1566-1572). Be ‘aware of the results of SPLIT (Young P, JAMA Oct 2015) and future studies Of high vs restricted chloride resuscitation fluids (particularly PLUS which is ‘now recruiting in many of our ICUs). Know about the SMART and SALTED cluster trials from Vanderbilt (NEJM, 2018) and the strengths and weaknesses of this approach to pragmatic trials. Fluid Resuscitation 3: Related to allthis is the restriction of intraoperative fluids, led by the colorectal surgeons, the concept of ‘ERAS’ and the RELIEF trial (NEJM 2018) which brings some balance back into the discussion. ‘The NICE-SUGAR Study Investigators, Intensive versus Conventional Glucose Contral in Critically Il Patients, New Engl J Med, 2003, 360:1283- 1297, a large pragmatic multicentre PRCT in response to van den Berghe G, Wouters P, Weekers F, etal, Intensive insulin therapy in critically ill patients. 1N Engl J Med, 2001 Nov 8;345(19):1359-67. Make sure you have thought ‘about the pros and cons of IIT and the external validity of van den Berghe’s paper. Renal: ANZICS CTG, Low-dose dopamine in patients with early renatSysuncion a laceb controle randomised al tne, 2000 Dec 23.3 356(8248):2139.43. Definitvely pus this one to rest—the place for intravenous dopamine isin the medical museum ‘The RENAL Study Investigators, The randomised evaluation of Normal versus Augmented Level Regleement Therapy (RENAL) Ta High Dose - \ersus Standard Dose Hemofitration in Acute Renal Failure, New Eng J Med, 2008, 361:1627-1638. Compare that to Ronco’s previous single centre study oF CVVHD with post dilution and again think about external validity. Also, whys the VA ~ NIH study so different? Ang have a think about longer term pakcomes of acute kidney injury. Now what about the timing of initiation of ART, and trials such as STARRT-AKI (currently recruiting). Ventilation: AROSNET, N Engl/ Med, 2000 May 4;342(18):1301-8. Low ‘volume ventilation improves survival in acute lung injury / ARDS. And see also the subsequent AROSNet studies (ALVEOLI Higher vs lower PEEP). Higher versus lower positive end-expiratory pressures in patients with the Fe iesbitatory distress syndrome, N Engl J Med. 2004 Jul 22;36(4):327- 36. The only ‘positive’ interventions are neuromuscular blockade (the ACURASYS rial of cisatracurium, NEJM 2020, 363(12):1107) ***, and prone ventlation (PROSEVA, NEIM 2013, 368(23}:2159) but why? The big Problem of course is that none of these trials describe how we vemilate Patients in Australia and New Zealand, and there is a clear need for an {OUNET” trial, One phase 2 tral PHARLAP) which compored conventional ‘Ventilation with ‘lung protective ventilation’ including staircase recruitment TraTOuNTeS was terminated in 2017 in ight ofa large predominantly Braziian Wal (ART tral, JAMA 2017). And don’t forget the Berlin definition for, ‘ARDS (JAMA, 2012, 307:2526).. £2 Bedits The recent ROSE trial of cisatracurium (NEIM 2018, 380:1997) refutes the penefit of early paralysis in ARDS. ROSE was a larger multicentre study compared to ACCURASYS, and used strategies more in keeping with usual pracice (higher PEEP in both tours, lighter sedation inthe contol group) ROSE was stopped early due to fut. 8. What about oscilation and ECMO. Know about OSCILLATE and OSCAR {oth New Engl Med 2013) and know what they say {and do not say) about HFOV as both an early and as a rescue therapy, Likewise CESAR (Peck, {ancet 2008). And now, to keep the controversy going, we have the EOLA {rial (MEIM, 2028) - have a think about the role of the DSMB in ths trial and whether it was appropriate to terminate it early. 10- NIV in COPD, Celikel Chest 1998, 110:1636-42 or the classic study by Esteban NEJM 1995, Without doubt conscious COPD patients do better with non invasive facemask ventilation rather than endotracheal intubation, But 100. But think about the generalisability. This study done before universal leucodepletion and includes significant biases, Compare this to more recent restrictive transfusion trials ike in upper Gl bleeding (NEI 2013, 368(1):11-21), More modern issues include the 3660 blood (is fresher’ blood better) and the use of erythropoietin. Know about AN2 TRANSFUSE trial (NEJM, 2018). ‘Steroids in shock: CORTICUS: Sprung CL, Annane D, Keh D et ol Hydrocortisone therapy for patients with septic shock, N Eng! J Med, 2008, 398:111-124, and COIITSS, Corticosteroid treatment and intensive insulin therapy for septic shock in adults: an RCT, JAMA, 2010, 303:341-348. This 2Fgument aint over yet! The original was Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troche G, Chaumet-Riffaut P, Bellissant E., Effect of treatment with low Boses of hydrocortisone and fludracortisone on mortality in patients with Septic shock, JAMA. 2002 Aug 21;288(7):862-71. The ANZ ADRENAL trial (NE1M, Jan 19th, 2028) and the French APROCCHSS TRIAL (NEJM 2028). While we hoped ADRENAL would be definitive, it still leaves Guestions open and you must read it closely and understand the endpoints (Brimary and secondary) and have an opinion of what the results mean for Your practice, Steroids appear to never die ~and coming shortly, @ Combination of hydrocortisone, vitamin C and thiamine (depserately awaiting an RCT), “*UP edit: And now we have a HAT (hydrocort, ascorbic aci, thiamine) RCT ~ VITAMINS (AMA 2020). No difference to duration of time alive and free of ‘vasopressors, Also see ATESS (ICM 2020) and CITRIS-ALI (AMA 2019) Ibrahim EH, Sherman G, Ward S, Fraser VI, Kollef MH. The influence of inadequate antimicrobial treatment of bloodstream infections on patient ‘Outcomes in the ICU setting, Chest. 2000 Jul;118(1):146-55. and Roberts D, Kumar A and Sharma, Time to Appropriate Antibiotic Administration is 3 critical determinant in pneumonia-associated septic shock, Chest, 2004, 126, 7245, interesting current work looking at kinetics of antibiotic infusions (BLISS and BLING groups). BLING? (Dulhunty ), AIRCCM, July 2015) is. 2 phase 2 study. BLING3 has started recruiting in 2018. CRASH and CRASH2. Both really well done mega-trals with significant ‘results ina truma population, but again have a serious thought about the external validity, ‘Traumatic brain injury: As well asthe Brain Trauma Foundation Guidelines, know DECRA (N Engl Med 2011) and some of the ‘controversies eg Chesnut (NV Engl J Med 2012:367:2471-81). How does DECRA compare with RESCUE-ICP (NEJM 2016) and why? Sedation: Topical at present. Know the SCCM 2013 guidelines for sedation (PAD) ***. Look at the SLEAP study (Mehta, JAMA, 2012, 308:1985-1992} which partly refutes the passion for ‘sedation vacation’ and the dexmedetomidine studies (PRODEX and MIDEX, JAMA, 2012,307(11):1151-1160) ch has fishery si tte scene forthe current ANZ SPICE tal ‘ecruiting and will be published in early 2019. *** “** BPedit: SCCM 2013, delta, immoaity ang esenes now updated to PADIS (pain, gtation/sedation, and sleep disrupt bttps://iournals.h poy: event pe cemiournal/Fulitext/2018/09000/Clinical Practice Guidelines for the Prevention 29cco-emlournal ules 2016/09000/clnical Practice Guidelines “"" Pedit: Use of dexm ae ae (NEJM 2019, doi: 10.1056/NEJMoa1904710), showing that the 2082) moray Poe pay outometo i) ut di showsinceneinavese thnk se atv 2rd, hypotension, asystole)~ particularly n the younger patients. Have a DahLia (AMA 2016, 315(14):1460) which showed increased vent-free hours, quicker time 21. Nutrition: To me one of the most confusing but also topical parts of the current literature. Start with the Canadian Crtcal Care Nutrition Guidelines http://www.crticalcarenutrtion.com/ and make sure you know and have some pinion on EPaNIC (Casaer, N Engl J Med, 2011;365:506-517), EarlyPN (Doig, sana, 2013, 309(20):2130), CALORIES (NEJM 2014, 371(18):1673 and Glutamine supplementation (Heyland). Know what they DON'T say as well as what they say. Make sure you have an opinion on the Permit trial of permissive underfeeding (Arabi, NEJM, May 2015) -is it valid to compare deliberate (46% of target calories) to accidental (71%) underfeeding? And the ANZ TARGET trial has just reported (NEJM , Oct 2018). TARGET isthe only adequately powered, blinded RCT of two nutrition strategies in intesive care medicine. ** pedit: For your convenience. EPONIC: Early (day 3) vs late (day 8) PN Late > earlier ICU discharge, more likely to be discharged alive, no difference in mortality (hospital, 90 day). Early PW: Early PN (day 0-1) vs standard care. No difference in 60 day mortality, less ventilation days in early PN group, no difference in complications. (“PN is safe!” ‘CALORIES: Early PN neither beneficial nor harmful compared to EN. EN gives more vomiting ‘and hypoglycaemia, but no harm. Both groups under-fed. TARGET: Targeting rate of 1mU/kg using either 1.Skcal/mL or 1kcal/mL feed. No difference in 90 day mortality, or any other outcomes. Awaiting 6mo QOL data PermiT: Permissive underfeeding (with full protein supplementation) is likely safe, but trial underpowered to detect survival benefit Good luck, lan Seppelt Jan.seppelt@sydney.edu.au Dept of Intensive Care Medicine, Nepean Hospital Nov Sth, 2018Resources in the Social Media era ~The Bottom Line (thebottomline.org.uk) © Fantastic summaries of landmark papers International contributors Has a dedicated “Intensive Care Medicine” section Has a Twitter presence for those who are savvy Critical Care Reviews (crticalcarereviews,com) © Rob Mac Sweeney's masterpiece © Get yourself on the mailing list for the newsletter, which highlights the important papersin the Critical Care world, and is sent to your email address EVERY WEEK (effort free!) © Beware the guilt associated with unread emails from “rob” ‘Wellington ICU (@WellingtoniCu) © These guys have started a fantastic initiative where the papers being covered | their Journal Club are summarised in a series of punchy tweets on Twitter © Again, a low-effort way to keep on top of things Other more recent notable areas of study: covip-19: Steroids (RECOVERY), antivirals (remdesivir vs others), hydroxychloroquine, tocilizumab (IL-6 receptor antag), etc. Oxygen: ICU-ROX (NEJM 2019) > Megarox Dialysis/RRT: STARRT-AKI (NEJM 2020) 1 ulcer prophylaxis: PEPTIC UAMA 2020)‘oy pue (Sewoayne But yanaeee | ___ex0u ‘sropiosd are ‘suedoned ‘aidwexe 10) suonuanqu oy wowublse Joye pap a supuia ] \ _ 01 stuedionsed pauBisse oym pue ‘sjuedionied payoiua oym ‘aouenbas uoneDo|Ie WopUeL au) pare/sUEB OUNA onewewaydust | | areas ae - ni een oe ~~~ usueypeur | pPauBisse avom suonuaneyutinun esuenbes ey) je20U00 oj uaye) sdais Aue Bulquosap quawyesouc0 jk yoo parequny fyenuenbes se Yons) eouanbas UoNedo|e Wopues ayy juOWe;dwu! oj pasn WILEY | 6 uoneooiy (@2is oIg pue Bun|pc|g se YDNs) 1 Kue 40 Si/e\8p ‘UOI 8 uojesaueb | spa 7s ‘Souanbss uojeooje wopUeT ay) aje/8U86 oF DASA PON | eB eouendes os a) = ‘Seuyapin6 Buiddoys pue sesXjeue wiuayui Aue jo uoneueidxe “siqeaidde usu | az ote ~__ paURLUaIE St er azis ajdweg f= : are UST oe “ ou) vaya pue moy Buipnjout 'sainseaw swo2\no KJepuoDas pue Aewud payloads-eud pauyap Aiorsidulog | eg s2.wo2ino pelaisqulupe Kienive ___| vam Kou uayin pue moy Suyprjour uoneaidos moje 0} ste.ap WareWINS Wm dnosB YoeE JO} SuOMYaRIeIUI UL |S suoquanauy a us S| __semener = = cm suedioueg ae Joie spoujew oi sabueqs Tueyodu! | ae Soa jezed Se Wons) uBsep eu 0 uondioseq | ec ubisap eu as Spowain Se SiBUOTET To Woeuexe pue pURDIB DER ue punosByoea = vonanponuy 7a) UOEHOD 3s BURA DIENT) SUOISTIBUCD Hue “SINGEI "SPOeIU UBIESP TEU) jo KEW 7 = : “senSGe PUR AIL oa . 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