Mar 15, 10 03:28AM
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Dopamine has been the vasopressor of choice in septic patients in continental europe historically, although this may be changing. Dopamine has theoretically beneficial effects in maintaining splancnic and renal perfusion although in the SOAP trial (observational) suggested that there was an excess of mortality of dopamine treated patients. The old story of “renal dose dopamine” [...]
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Sign in nowI am most impressed by this site Dan.
I am grateful that you highlighted a paper which would have passed me by.
I think that this paper highlights one of the problems with ICU research and EBM. The problem is we want to know the answers, but we don’t really know what the question is.
ICU is the land of syndromes. Diseases like ARDS, sepsis, AKI are at best a spectum of diseases and at worse a group of many distict pathophysiological conditions that just happen to give us respiratory or cardiovascular dysfunction. The assumption that an 80 year old with multiple comorbidities, abdominal sepsis and ARDS is the same as an 18 year old with meningococal sepsis, is at best naive. The belief that you can account for these variances by recruiting 10 000 patients is just brainless.
I think the first thing we need to do is define our patients more clearly. One way this could be done is to recuit responders only. A simple example is in a vasopressor trial to give everyone a drug like dopamine and only recruit responders to a vasopressin/norad trial and not anyone with multifactorial hypotension.
I believe responder (or at least better trial candidate selection trials) could still be undertaken in single centre units. This will allow us to recruit quality and not quantity to RCT’s.
Finally, if we need to recruit 10 000 patients to discover a statistically significant benefit to treatment X then is it clinically relevant?
Keep up the good work
An interesting paper. There is still much uncertainty about the timing and dosing of RRT in AKI – Mehta has just sent out a questionnaire to intensivists and nephrologists to try and ascertain worldwide practice. Obviously in ICU we practice something similar to the intensive arm whereas on a renal unit we usually do a more less intensive strategy – we review the renal chemistry and urine output on a daily basis (obviously looking for signs of renal recovery) and in practice dialyse most people on alternate days – it is rare that we dialyse people daily for AKI, but then again our patients usually have only single organ dysfunction, unlike the patients in this study who had failure of 1 or more non-renal systems. I cannot see where they have stated clearly at which point in terms of renal chemistry or other critieria they chose to initiate RRT (is it in the appendix?) – Dr Sharman states it was when the GFR was approximately 60mls/minute which if it is indeed the case would probably mean they didn’t need any RRT at all! All I can find is the level of BUN at initiation of RRT. Am I missing something? I can only find where they state that they chose to continue RRT if the creatinine clearance was <12mls/min.
In reply to your comment Dan, I don’t think isolated UF should be of particular concern. We often UF patients (albeit usually our fluid-overloaded patients with ESRF on chronic HD)inbetween HD sessions if necessary, and I can’t see why it should be any different for those with AKI.
Given that RRT is expensive, requires intensive nursing input and is not without complications it is interesting to see that no survival benefit was demonstrated in the intensive therapy group, and that it did not improve recovery in renal function.
This study has now been discussed at QMC’s journal club. A presentation (by Dr. Joy Abbott) of the paper can be found in the blue box, and the summary points from the discussion were….
1. Initiation of treatment unspecified
2. Still predominantly USA based study
3. Suggests intensive treatment in sepsis is
unlikely to be beneficial
4. Should audit to ensure we are achieving the less intensive regime of 20mls/kg/hr
5. Potential cost saving of moving to a less intensive regime (? Increase filter longevity)
The Denver experience in heart transplantation from DCD / NHBD donors was presented to the 4th International Meeting on Transplantation from Non-Heart Beating Donors: London 15-16 May 2008. See for a report: http://journal.ics.ac.uk/pdf/0902206.pdf
There the speaker from Denver during question time defended the chosen time frame for declaring death by claiming that such a short time was “in the best interests of the recipient”. There I think we have perfectly phrased the ethical divide between DCD (donation after cardiac death) and DBD (donation after brain death).
These ethical differences between DCD, concentrating on Maastricht III DCD (withdrawal on ICU) v DBD may be summarised in point form as:
1. Historical differences
a. DCD donation was the first form of solid organ necro-donation but was abandoned due to the warm ischaemia inherent to DCD.
b. Although it is often claimed that the diagnosis of brain death was linked to the first cardiac transplantation by Christian Barnard it is more appropriate to see the recognition of the phenomenon and development of criteria to diagnose brain death as arising in parallel with solid organ donation. Thus there was a need for diagnostic criteria of brain death independent of the need for organ donation.
c. The re-emergence of the debate of when cardiac death can be certified is driven entirely by the need for solid organ transplantation. Indeed I can remember being told as a junior doctor not to rush to certify the newly dead but to allow extra time to pass to ensure that the dead stay dead. In DCD such time luxury is impossible.
2. Conflict of interest
a. Diagnosis v decision: Brain death or brain stem death rests on a diagnosis; DCD rests on a decision to withdraw. This decision can be debated.
b. The compacted timeframe to diagnose death in DCD can lead to pressure to declare death prematurely to minimise organ ischaemia. In DBD there is no such necessity to rush.
c. The manipulation of medications during the dying process following withdrawal in DCD allows for great conflict of interest between the interests of the patient (donor) and the recipient. Dr Roozrokh is a San Franciscan transplant surgeon standing charges in a DCD case highlights the potential for conflict of interest.
3. Dead Donor Rule: Is is my belief that ALL DCD violates the Dead Donor Rule (DDR)
a. DBD and the provisions leading up to DBD can all wait until after death has been certified. Therefore the DDR is not violated. Moves to involve organ donor co-ordinators early in potential DBD risk violation.
b. DCD requires alterations of the dying process even in conservative programs like the UK of – timing of withdrawal, extubation (near 100% in DCD but not in usual ICU practice) and a change of attitude to the patient whereby they are treated as a donor before death is certified – that violates the DDR. (awaiting publication in the Cambridge Quarterly of Healthcare Ethics)
c. It is possible that such changes to the treatment of the dying is illegal in the UK.
d. The practice in the USA of pre-morbid cannulation and heparinisation makes this violation even more dramatic.
e. The certification of death in DCD depends on a definition of irreversible that, as noted in the NEJM perspective articles, is difficult to defend in heart transplantation from DCD.
f. Auto-resuscitation and the Lazarus Phenomenon
i. Despite the claim that no auto-resuscitation is possible after ~60 seconds (of PEA NOT asystole) this is inconsistent with the case reports of Lazarus Phenomenon
ii. Although not spontaneous an auto-resuscitation during lung DCD (greater than five minute asystole) was presented to the 4th International Meeting on Transplantation from Non-Heart Beating Donors (see above link)
g. The use of extracorporeal circulation whilst awaiting DCD has the potential to resuscitate both the heart and brain. Prevention requires the use of a thoracic balloon blocker which in one USA institute was no longer routine and the heart was often seen to restart. (see link)
h. There have been calls to abandon the DDR but this should be seen as a radical departure from the ethical norm.
4. Consent
a. If the DDR rule is abandoned than the primacy of informed consent should be emphasised.
b. The current UK Organ Donor Register has minimal mention of DCD and certainly does not meet the requirement for informed consent. Under the Human Tissue Act (2004) families have no legal right of veto and if their loved one was on the ODR they have therefore legally consented to the manipulation of their death for the purposes of facilitating DCD. It is difficult to sustain this position and neither can UK Transplant (for a discussion on the HTA see page 42-44: http://journal.ics.ac.uk/pdf/07_02.pdf
c. Even surrogate consent as practiced in the USA is suspect when Mrs Navarro the mother of Ruben Navarro (the DCD case involved in the Dr Roozrokh case) says “They mistreated him and they abused him and they took advantage of him and me.” And “He didn’t die with dignity, and I didn’t have the chance to really say goodbye to him. I don’t think it’s right. These people need to pay for what they did to him.”
Dr D Gardiner
Thanks for a great post Dale. This paper has also been discussed at QMC ICU journal club – a copy of a ppt presentation by Dr. Lizzie Robinson can be found in the blue box labelled “nmbd nejm 2008 presentation”.
A very topical issue. As Hina says CAOS study certainly raised the profile of COPD in ICU circle.
I used to be nihilistic about ventilating COPD patients till i looked up the evidence.
I would like to know what people think about mortality (ICU and hospital), duration of mechanical ventilation and length of stay.
There’s are 2 ppt presentations of the some of the evidence I have summarised available from the blue box – They are called “NIV in pneumonia presentation – Sovani” and “Mechanical Ventilation & COPD – Sovani”.
New guidelines for ventilating COPD patients are going to be published soon.
milind
checked out bmjupdates.com. good website. for all those who are waiting to rubbish another study here is one for you
They compared standard care with (std care + cpap) for pts with severe respiratory distress in COMMUNITY.
71 pts in total, CPAP reduced intubation rate and mortality. Alright then- over to you now- go for it
Does anybody have access to Ann Emerg Med?
Thompson J. Out-of-hospital continuous positive airway pressure ventilation versus usual care in acute respiratory failure: a randomized controlled trial. Ann Emerg Med. 2008 Sep;52(3):232-41, 241.e1. Epub 2008 Apr 3
Link to pubmed abstract here
Milind
PS I’ve changed this to comment from an original post by Milind, as at present we can’t get to the original article, which makes critical appraisal of it tricky! Hope that’s OK. Thanks for highlighting it – cheers Ed (Dan)
I noticed that IVIG is recommended by the DOH for the treatment of MRSA PVL necrotising pneumonia (in this useful review). I guess the basis for this will be grade D or at best C evidence. So treatments remain in the guidelines on the basis of case series or uncontrolled trial evidence for specific rare sub types of conditions, but are rejected for broader condition definitions. This appears to me to be a double standard.
The above papers are making waves outside of the medical establishment (as they should), see this article from the Economist which discusses the legal position, and upcoming religious discussion over non-heart beating donation.
Although I wasn’t at the meeting (sorry to have missed it), I would add that determining adequate power for ROC curve generation is tricky. They presumably included all those who died in the negative outcome group as well James ?
This is a provacative paper that’s for sure. The mortality benefit probably reflects decreased barotrauma in the paralysed group — the rates of pneumothorax in the 2 arms was 11% for control and 4% for neuromuscular bloackade.
However there are alot of questions to answer:
- could increased analgesia/ sedation have reduced the rates of pneumothorax in the control group?
- how plausible is it that 2 days of paralysis would result in such marked survival benefits? What is the mechanism?
- although 90d survival was measured, muscle weakness was only assessed up to 28d – are there delayed cases of critical illness polynuropathy being missed?
- How was the adequacy of blockade assured in the absence of train-of-four testing?
- could the benefit be a property of cis- atracurium rather than neuromuscular blockade?
- is the blinding of this study suspect? If the NMB group is fully paralysed only the control group would trigger ventilations, thus breaking randomisation.
- How was ventilator dyssynchrony dealt with? This is not described in the paper – could this be killing patients?
- Was volume-control ventilation appropriate? The patients in this study were sick – PaO2:FiO2 of 100, compared with about 150 in the ARDSNet study where they got their ventilation protocol from. Patients were excluded if they had refractory hypoxemia in the ARDSnet study. The low-volume ventilation protocol may not suitable for these severely-effective patients. Although, similar rates of barotrauma were seen in the ARDSnet study.
- how does this apply to other ventilation modes like APRV that tend to be used in severe ARDS these days?
Cheers,
Chris Nickson
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Thanks for great comments Chris. I aggree the paper poses more questions than answers. It’s interesting that despite pneumothorax rates being different, plateaux pressures were equal in both groups. Are we using the wrong parameter when assessing the applied pressure?
Has this paper changed your practise? It has changed mine, starting paralysis now means an infusion (ideally 48hours) rather than bolts dose.
Hi Dan,
Interesting point on the plateau pressure – will be interesting to see if it’s borne out in other studies. Don’t have a great answer!
Don’t think this changes practice – in severe ARDS I wouldn’t be using volume-controlled ventilation – more likely to use APRV. Was using NMBs anyway if absolutely required – though not so much as an infusion, though its clearly an option if needed (not routine).
It seems to offer some reassurance that it is OK to use NMBs if needed, given the unchanged rates of polyneuropathy at 28d.
Cheers,
Chris
We commonly leave on pressure control, but inverse I:E ratios (which is therefore essentially APRV) or oscillate, so take you point that the trial may not be applicable.
The reason for moving to an infusion over a bolus is that the control arm in the trial were allowed open label bolus atricurium (which mirrors my previous practise) and did worse. We’ve stopped short of making a 48hour infusion routine, although we are considering it on the basis of this trial.
I wonder if ANZICS will do us the usual service of running a properly powered RCT and disproving the initial positive european study!
The link doesn’t seem to work…. bear in mind that I am on a trust PC!!
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Link should work now James, seems pubmed have yet to catch up and give this a full slot.
I know it’s been a while since the last post, it’s been a very busy few months! Hopefully will be able to post more frequently on Critical Insight over the next few months.
Dan, very thoughtful analysis. Death within 48hrs is pretty heavyweight endpoint. Clearly this was a very ill cohort. I do think is worrying that an intervention that would “normally” be expected to improve a physiological derangement doesnt necessarily help. The use of norepinephrine appears to have lasted longer than most, but many rapid interventions do seem to cause trouble…i hastened the demise of a few people with mechanical ventilation, correction of electrolyte and pH
This is a wonderful demonstration of the harm of volume controlled ventilation, and how paralysing patients allows you to use this mode fractionally more safely – the mortality and pneumothorax rates are horrifying and unacceptable, especially considering that the average P/F ratios and FiO2 and PO2 averages demonstrate generous (over) oxygenation, underPEEPing and really not very sick lungs, despite the high mortality rate!
The fascinating piece of information is the HEAVIER use of sedatives, and in particular Ketamine in the NMBA group!
Morale of this study – don’t use volume controlled ventilation strategies (note no mention of use of PRVC/VC+/Autoflow, which would be a lot better)
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