A summary of studies discussed at the Critical care reviews meeting held on Friday (23/1/2015) in Northern Ireland – attended by oxicm POCUS fellow Adrian WongFollow @avkwong with further notes by Wessex’s Emma FitzgeraldFollow @emma_zcharm6and wessex / the bottom line’s Duncan ChamblerFollow @DuncanChambler
edited by Jamie strachan Follow @strachanjamie
Albumin In Sepsis: Albios Trial
Caironi et al. Albumin Replacement in Patients with Severe Sepsis or Septic Shock (ALBIOS study)- N Engl J Med 2014; 370(15):1412–21.
- No difference between the groups
- Target of 30g/L probably is not representative of what we would normally see in these patients
- Albumin is safe, but we probably don’t need it
- The haemodynamic benefit is not clinically significant (only a difference of 2-3mmHg)
Raised ICP in paediatric patients with meningitis: RCT ICP v CPP target
Kumar et al. Randomized Controlled Trial Comparing Cerebral Perfusion Pressure-Targeted Therapy Versus Intracranial Pressure-Targeted Therapy for Raised Intracranial Pressure due to Acute CNS Infections in Children. Critical Care Med 2014;42(8):1775-1787
- Huge improvement in outcome in children with bacterial meningitis when CPP target is used compared with ICP target
- There seemed to be a benefit related CPPs in the survivors in the ICP group, i.e. the CPP is the thing that matters
- Target a higher MAP
- ICP monitoring may not be necessary
Pick Your Pressure: Optimise trial
Pearse et al. Effect of a Perioperative, Cardiac Output–Guided Hemodynamic Therapy Algorithm on Outcomes Following Major Gastrointestinal Surgery. A Randomized Clinical Trial and Systematic Review (OPTIMISE) JAMA 2014;311(21):2181-2190
- Trial failed to enroll emergency patients, large proportion were elective GI patients, mostly ASA2-3
- Control group received less fluid
- High use of inotropes both groups
- High number of epidurals (70%)
- Very low mortality (3%) ?representative study
- Difference in outcomes when looking at the interim analysis ?was there a learning curve
- Didn’t really answer the questions that we wanted it to – as the risk of the patient went up, the benefits of the cardiac monitor algorithm was increased
- Unclear which monitor should be used
- BUT it is the largest algorithm trial to date
- Dopexamine – probably no real benefit over dobutamine
- Where next? Optimise II…
- Colloids may have had an effect on the outcomes, but the colloid trials in the peri-op setting may not be as harmful as in the critical care setting
Blood Pressure targets in sepsis
High versus Low Blood-Pressure Target in Patients with Septic Shock (SEPSISPAM study). New Engl J Med 2014; epublished March 18th
- SCC recommends MAP >65mmHg, in the studies that look at septic shock, most actually use >75mmHg
- Some evidence that aiming for higher MAP targets may be reno-protective (Badin et al Crit Care 2011)
- Rationale: which target is best? 65-70mmHg versus 80-85mmHg
- Difference in frequency of RRT in patients with chronic hypertension
- Otherwise no differences between the groups BUT the lower target group had higher than intended MAPs, which may compromise the interpretation of the results
- Hard to know which patients had chronic hypertension – not all had been diagnosed prior to enrollment
- Higher MAP is safe with no increase in adverse incidence such as mesenteric ischaemia
Pulmonary Embolus and Fibrinolysis – Does Size Matter?
Meyer et al. Fibrinolysis for Patients with Intermediate-Risk Pulmonary Embolism (PEITHO study). N Engl J Med 2014;370:1402-1411
- RCT – Included RV dysfunction, no CVS instability
- Use of a composite outcome has been criticized
- In patients with intermediate-risk pulmonary embolism, fibrinolytic therapy prevented hemodynamic decompensation but increased the risk of major hemorrhage and stroke
- Study details: See The Bottom Line review…
Fragility Index – Robustness of RCTs, ie statistically significant but clinically fragile.
Walsh et al. The Statistical Significance of Randomized Controlled Trial Results is Frequently Fragile: a Case for a Fragility Index. Journal of Clinical Epidemiology 2014;67(6):622-628
- Evidence-Based Medicine – Need to gather information and then need to interpret it.
- Ioannidis in JAMA 2005 294(2) showed 1/3 clinical studies are later found to be incorrect, smaller or insignificant. Is an open acknowledgement of why studies are inconsistent. Subsequent studies are not being conducted because people are putting too much value on the negative outcome in one study
- Hypothesis testing versus Estimation
- P values are NOT an error rate – Estimated error rate of at least 23% (typically closer to 50%) using a p value of 0.05.
- P<0.05 =some evidence, but is NOT equal to conclusive evidence, i.e. it is “worth another look”
- This study, looked at the impact of this phenomenon – used PubMed RCTs. Used a fragility index – added an event until p became compromised, i.e. one study needed only 1 more event to compromise the statistical significance in outcome, some needed NO events, which is worrying! Also those lost to follow up exceeded the number of events required, i.e. the fragility index.
- Good paper – simple idea, it raises the profile of over-interpreting statistical significance. RCTs are often statistically fragile
Mechanical CPR devices in Resuscitation OHCA
Manual vs. integrated automatic load-distributing band CPR with equal survival after out of hospital cardiac arrest. The randomized CIRC trial. Resuscitation 2014;epublished March 15th
Rubertsson et al. Mechanical Chest Compressions and Simultaneous Defibrillation vs Conventional Cardiopulmonary Resuscitation in Out-of-Hospital Cardiac Arrest. The LINC Randomized Trial. JAMA 2013;311(1):53-61
CRIC Trial and LINC Trial both presented
- Use of mechanical devices versus standard manual CPR
- Only included patients with a likely CARDIAC cause for arrest
- LINC Trial – got DCCV regardless of the initial rhythm
- CIRC – equivalent survival at hospital discharge regardless of which one
- LINC – more defibrillations in mechanical group and despite this, there is no difference between the two groups (primary OR secondary outcomes)
- More adverse incidents with mechanical CPR devices
- No benefit in outcome in either study
- Post resus care not standardised
- Unable to assess manual CPR quality – it may be better than normal standard care (Hawthorn effect)
- Marked difference in presenting rhythms
- There are some advantages to the mechanical devices e.g. in the cath lab, mountain rescues etc. or to prevent fatigue, but no evidence to suggest a benefit otherwise
Is it Worth Waiting on a ProMISE?
- 3 studies, but methodology harmonized so that the results could be pooled into a meta-analysis – ProCESS, ARISE, ProMISE trials
- 31 centres in the USA.
- All academic hospitals? Are they like NHS hospitals?
- Not all of SCC were adhered to in the protocol
- Fluid challenge changed mid-trial
- Sample size was reduced… preserved the ARR, but lost power in the RRR
- No difference in 60d outcome, but use of long-term facilities is different to UK
- Not powered on 90d mortality, but similar to UK
- 51 centres
- Actual 90d mortality was also lower than the 38% expected and so the results are not as sound as they could have been
- Both trials do not discount the possibility that there could be a 20% Relative risk Reduction
- Interim analysis – base line mortality assessed and it was not advised that the sample size required changing
- ICNARC data shows an improvement in mortality from severe sepsis in patients coming from the ED, but higher than that in Australasia
- Questions around the definition of severe sepsis – in ProCESS and ARISE, mean lactate was 4. Few had BOTH hypotension and a high lactate
- Fluids: Rivers, ProCESS and ARISE: Less fluids, less ventilation, less blood in these two new studies suggesting better care now with regards to resuscitation
- ProMISE has good spread of hospitals – better generalizability. Is the only one of the 3 trials that adhered to the pre-specified stats anaylsis plan
- Interpretation: All are different to Rivers study – earlier recognition of sepsis, timing and design are both different. Resuscitation has changed a lot, but probably because of the Rivers Study
- The idea of a harmonized study could take off as a model… i.e. a lot of Phase 2 studies that use an intermediary outcomes, but collect what a large RCT would for a primary outcome and then combine them using a meta-analysis. This would have lots of benefits, including having very big sub-groups that could be pooled to get a big sample size
- Of note – there is no big USA database that could give them accurate mortality estimates… they had to look at some databases and previous studies etc., they chose an increment that was too much. ProMISE could use the data from the ones that came to ICU from ED, but acknowledge that they may have missed some as the ED data was missing – may have missed the ones that improved to not need ICU.
ProMISE Links: Results due to be released in Brussels this year. Trial info here
Sepsis Reconsidered: On behalf of the SCCM/ESICM Taskforce
- Defining sepsis has been very difficult. SIRS is very sensitive but not specific. This had big implications for tying to establish the incidence and prevalence of sepsis
- Why is it hard to define? Our definitions aren’t really “definitions”, they are just clinical and epidemiologic surrogates for this underlying pathobiology
- Need a clinical description that is useful for clinicians and also a “lay” definition for the public
- The old description of:
Infection -> Sepsis -> Severe sepsis -> Septic shock
- … Is not helpful… New idea:
Infection -> Badness -> Sepsis (includes Septic shock)
Badness is hard to define
- Large database interrogated (university of Pittsburgh) – SIRS and SOFA were not useful at identifying the patients we are interested in
- A new collection of variables needed to identify risk of developing sepsis / mortality / ICU stay etc.
- The next stage is to use this discovery set of data from University of Pittsburgh and to validate it using other databases around the world. However, the baseline variables that will predict outcome are still yet to be identified!
- Organ dysfunction – difficult to define. SOFA is the most popular, it is internationally accepted and is robust in predicting mortality.
- Septic shock – Large databases have been interrogated to try to get a definition to approximate septic shock
- Lots of variability in mortality and incidence as a consequence of the inconsistencies in the definitions
- Reflects more than CVS dysfunction – cellular abnormalities are of prime importance
- The large databases will be used to try to establish more information
- Septic shock new definition likely to included– persistent hypotension (?what threshold and ? normalized with support) and/or an elevated lactate
- The SSC will try to establish new definitions, but think that it is likely to keep evolving
ECMO for ARDS
- Berlin definition of ARDS
- Concept of VV ECMO
- History of ECMO – Hill NEJM 1972 286:620-634 – Case report of the first case of VA-ECMO outside of theatre. RCT in the 1970s showed a 10% SURVIVAL in ECMO and the control group!
- The reports during the H1N1 pandemic changed the view about ECMO. Survival had improved a lot since the 1970s – survival in the 70% range. ICNARC trial highlighted that if you go to an ECMO centre, your mortality is lower…all added to the idea that ECMO is worth looking at more
- CESAR – first RCT, but heavily criticized as most didn’t actually get ECMO. Also a pragmatic trial – MV was not protocolised. The fragility index was also high – only few more in one group reduced the statistical significance.
- Case series – ECMO and H1N1 in JAMA vs similar cohort – mortality the same… so, is it really is it the ECMO?!?
- MA by Munshi: May be a signal, but needs confirmation in a better trial
- Review of ECCO2R device Terragni P Anaes 2009; 111: 826
- Brodie editorial (NEJM 2011 365: 1905-14) highlights the indications and contraindications for ECMO in ARDS in adults
- Now – Idea of using ECMO in facilitating lung protection.
- Lots of evidence to suggest that reduced TV (i.e. a dose response curve) leads to better outcomes. ECMO could be the “ultimate” lung protection strategy
- The SOLVE ARDS Study Program: A physiological study, in progress.. To look at the physiological consequences of ventilation
- The SUPERNOVA Trial – ESICM Trial ). International pilot about to start – feasibility of “respiratory dialysis”
- The EOLIA trial – Rescue VV-ECMO for severe ARDS..is it ECMO, rather than the centre
- Position paper – suggests a minimum standard for anyone to call themselves an ECMO centre. The more cases you do, the better the mortality (data from Ann Arbor)
Amrein et al. Effect of High-Dose Vitamin D3 on Hospital Length of Stay in Critically Ill Patients With Vitamin D Deficiency. The VITdAL-ICU Randomized Clinical Trial. JAMA 2014;312(15):1520-1530
- Vitamin D is a steroid hormone that regulates about 200 genes and there appears to be a threshold below which skeletal health is impaired (<20ng/ml)
- Suggestions in the literature that vitamin D deficiency in ICU is common and associated with a higher mortality…Is vitamin D a marker or a contributor?
- There are a multitude of potential mechanisms of vitamin D e.g. infection / lung/ heart muscle
- Plasma vitamin D levels are associated with longer duration of mechanical ventilation in patients with sepsis
- Pilot study showed that the administration of vitamin D increased the serum levels, but not as much as the equivalent dose would have in healthy volunteers.
- RCT study
- Primary end-point = hospital LOS. Study cost per patient was 5-10 euros…
- Almost half of the patients had severe vitamin D deficiency.
- No difference in the LOS (hospital or ICU). Only corrected vitamin D levels in 52% of the patients (in contrast to the pilot study)
- There were 4 patients who had fractures in the first six months ?reason for this? Consistent with a study that showed post-menopausal women had a higher incidence of falls and fractures after administration of vitamin D
- Six month follow up – better functional outcome with vitamin D in the less severely deficient group
- A recommendation of 600IU-800IU for general population, but 200IU in TPN!!
- Endocrine society say 1500IU-2000IU for at risk patients.
Statins in ARDS: HARP-2
McAuley et al. Simvastatin in ARDS (HARP 2). New Engl J Med 2014;epublished September 30th
- Based on the evidence that simvastatin appeared to attenuate inflammatory response in animals, healthy volunteers and was associated with a reduction in systemic inflammation in a phase II study
- RCT: 80mg simvastatin given in ICU vs placebo (ARDS, 48 hours of mechanical ventilation)
- No statistically significant difference between the groups (outcomes or physiological variables)
- There was an improvement in outcome in those patients already established on statins, but not in those who were started de novo
- Statins are safe… increase in CK and transaminases but no difference in serious adverse events
- No difference in CRP: ?Anti-inflammatory effect not achieved
- SAILS study – rosuvastatin vs placebo: no difference between the groups, but a trend the other way, with a non-significant improvement in outcome in the placebo group
- Where next?
- Was the dose right? Probably – adverse events happened and so probably couldn’t use a higher dose
- Prevention may be a more effective strategy
- May just be an under-powered study – maybe should be powered for mortality
Nielsen et al. Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest (TTM study). N Engl J Med 2013;369:2197-2206
- Overview of TTM trial and background to cooling cardiac arrest patients
- RCT 33°C versus 36°C
- All patients had feedback controlled cooling devices (intravascular or surface)
- Target temperature was achieved in each group
- No survival difference between the 2 groups, nor any difference in neurological outcome. Trend towards higher complications in the cold arm
- How can this be so different from previous trials?
- Fever was not allowed to develop
- Groups were not comparable
- High attention to post arrest care
- Strict rules for prognostication
- Short time of no-flow and high bystander CPR rate
- Not as severely ill as in previous trials
- Support and criticisms both followed the trial
- Imbalances between groups – if the variables were adjusted for, mortality is even more in favour of the non-cooled arm (still not significant)
- Higher “ICU” support in the cold group (i.e. inotropes etc.)
- Criticized for long time to cooling, but was consistent with previous work AND it reflects actual clinical practice
- Suggestion that hypothermia is more effective when the “no flow” time is longer – In TTM trial – high number of patients had no flow for >8 minutes, but no difference at all between the 2 groups
- Subgroups – no signal seen in any of the groups, but a tendency towards worse outcome in the hypothermia group in some groups
- ILCOR and other guidelines are still to come… BUT remember the hazard ratio is 1.1, with adjusted favouring not cooling
- To come..
- Is fever dangerous?
- Does hypothermia work and we are doing it too late?
- Should we go cooler?
- Tailored therapy – are sub groups important?
- Take home message – Target a temperature, could use either one
- Question about sedation – cooling and sedation and prognostication – TTM used 72 hours after warming. They are collecting this data retrospectively now
- Harvey et al. Trial of the Route of Early Nutritional Support in Critically Ill Adults (CALORIES Study). N Engl J Med 2014;epublished October 1st
- Trial was commissioned
- Pragmatic and “real life” in nature and used local feeding protocols
- Balanced groups
- Only a small proportion were malnourished at enrollment
- Large number of TPN patients stopped at 119 hours and so look like non-adherence to protocol, probably reflects not wanting to site another line etc.
- Route and dose were not confounded
- Slightly higher use of insulin in TPN group, but glucose levels were similar
- Baseline mortality was as predicted (34%).
- No significant difference between groups.
- No difference in organ support requirements.
- No difference in new infectious complications, including CVC infections
- Episodes of hypoglycaemia and vomiting less in TPN group
- LOS – no difference
- Adverse events – no difference (5% each group)
- No sub-group differences
- No adherence differences
- Interpretation / thoughts from the study from Kathy Rowan and why no differences were seen…
- The management of CVC BSI is much better
- VAP prevention is better these days
- Developments in feed technology
- Caloric targets were not met in either group – ?lack of availability of nutritional products
- Maybe increasing dose of TPN is associated with increasing infection?
ECMO – Early Mobilisation
Importance of early mobilization comes from the functional recovery work undertaken by Margaret Herridge et al. NEJM 2003
- ICU acquired weakness is a form of neuromuscular organ failure
- Risk factors are controversial, but there is a strong signal that corticosteroids are significantly associated (e.g. study in JAMA in early 2000’s: OR 14.9 with >7d of mechanical ventilation)
- Need to recognize it early and prevent it
- New ATS guideline – highlighted the importance of it being a clinical diagnosis
- Bed rest duration is the single most important risk factor in development of ICU acquired weakness Hermanns et al
- Interventions post hospital had no effect (Cuthbertson et al) – need to act early (e.g. Vasilevskis et al Reducing iatrogenic risks: ICU-acquired delirium and weakness–crossing the quality chasm )
- Early mobilisation is safe, e.g. Bailey et al Crit Care Med 2007; 35:139-145
- Review of early mobilization – http://ccforum.com/content/17/1/207
- Early Physical Medicine and rehab QI project (Needham, Fan et al) at Johns Hopkins – Significant reduction in LOS (3 days) with increased mobilization etc. – financially v valuable
- Best RCT – Schweickert et al Lancet 2009; 1874-1882: Significant improvement and a drop in delirium rates
- Why aren’t we doing it?
- Need to transform the culture (Hopkins Crit Care Clinics 2007; 23:S1-96)
- Need to MEASURE YOUR SUCCESS – to help local change
- Electrical stimulation of muscles and cycle if need to be sedated etc.
Too much choice for airway devices and not much evidence for it
- Poor practice, poor planning, poor performance
- The psychology: Lots of the evidence is faith-based! People tend to reject the evidence, we think we are better than we are and we always think we can get away with it!!
- Solution? Need to match the right device to the right patient with the right practitioner
- There are controllable and uncontrollable factors in difficult airway management
- A review of NAP4 (very cynical!!!). Need to plan for failure.
- Airway management in critical care
- Right preparation
- Right equipment
- Right location
- Right practitioner
- Right technique
- Right CAPNOGRAPHY
- DAS Guidelines – http://www.das.uk.com/guidelines/downloads.html
- NAP4 – https://www.rcoa.ac.uk/system/files/CSQ-NAP4-ES.pdf
- Is it affected by target temperature? Do we need separate guidelines for those who are cooled and those who are not?
- Purpose is to inform decisions but also to inform relatives and avoid futile care.
- 50% of resuscitated die, but brain death is rare (5-10%)…withdrawal is based on the assumption of our neuroprognostication
- But prognostication does not have to mean withdrawal of care
- Cardiac deaths are uncommon cause of deaths, brain damage is the common cause, but cardiac deaths occur in the early phase
- 72 hours after normothermia seemed to appropriate (Cronberg, Neurology. 2012)
- Late awakening with good neurological recovery is still possible – favorable outcome occurred in 8/10 of these (Gold et al Resuscitation 2013)…how can we identify this group?
- Are we pulling the plug too early?
- Is there a window of opportunity for withdrawal of care? In the early stages, relatives are prepared for the worst, but get more hope as things improve slightly
- AAN guidelines 2006 – each part has been shown to be not so secure
- Low false positive rates: Pupillary reflexes, SSEP, corneal reflexes BUT motor score has a high false positive rate. Same number in both pre and post hypothermia studies
- Exactly the same after cooling
- Other modalities? CT/MRI work being done. Biomarkers are coming. EEG (continuous) is useful and will be more common. Standard EEG useful
- Most important – multi-modal approach
- New recommendations are underway e.g. ESICM and ERC
- 3 groups: awake / severe damage / somewhere in the middle
- Friberg and Cronberg 2013 have a great approach to this
- ERC and ESICM guidelines
- Day 3-5 after rewarming
- If motor score >1-2 then can wait.
- Suggestion to wait between tests.
- The reliability of tools probably not affected by temp
- Don’t need separate guidelines when Hypothermia used
- Can’t use 2006 AAN guidelines anymore, but new ones are coming.
Many thanks to the Critical Care Reviews team – see you in Belfast next year?