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Should we buy the LiDCOrapid for theatres?

26/6/2014

7 Comments

 
Does the use of cardiac output monitoring make a difference?  NICE seem to think so, the Cochrane group are less certain.  What we needed was a large, well conducted trial and this is what we got...
optimise.pdf
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The study compared two groups undergoing surgery of the gut.  The control group did not have a cardiac output monitor, the intervention group had stroke volume guided fluid therapy and low dose Dopexamine intra-op and 6 hours postoperatively.  The patients were 'high risk'.  The primary outcome was composite.  To cut a long story short this trial was NEGATIVE - there were no differences in primary or secondary outcomes between the groups.  It's worth taking a closer look however...

First off the addition of Dopexamine may seem odd.  To explain this some background may be useful.  Rupert Pearse, the first author, is a fan of Dopexamine.  He has received honoraria from the company that makes it* and in 2009 he published in Critical Care Medicine a meta-analysis reporting a halving of mortality with low dose Dopexamine (CI 0.3-0.9).  This sounds almost too good to be true?   Well maybe it was, at the same time another group were doing the same meta-analysis looking at the same papers and they reported no benefit to Dopexamine! Their paper can be found here, (you may recognise the name of one of the authors).  So how can this be explained, is meta-analysis not the gold standard for EBM?  Well no, it's not, it depends on the quality of the papers in the first place.  The reasons for the differing results are explained in this editorial, and Pearse's reply to the paper is here.  So whether Dopexamine makes a difference is still unclear, but Pearse it would seem thinks so.  The addition of Dopexamine also makes the study original, and would (if you agree with Pearse) increase the likelihood of a positive result.

The outcome measure was a composite.  I think we've discussed on a previous post how composite outcomes may be more relevant to the patient (e.g. a stroke, MI or loosing a limb are all bad and I don't want any of them), account for outcomes with low frequencies etc. but that they also may combine to a false negative (Outcome A occurs more frequently with intervention, outcome B less frequently, the composite of A&B is no difference, or worse benefit).  A secondary outcome was all-cause mortality at 180 days, on the basis that post-operative complications, even minor ones, seem to affect long term outcome - my own bias however is that this is an association rather than causation (which we've also previously discussed).  Do you agree?

The latter bit of the paper was interesting.  By adding their (negative) results to a meta-analysis, the intervention becomes more positive.  I admit I haven't looked at this in detail, but I wonder if this is a demonstration of the Simpson Paradox which is (honestly) an interesting bit of statistics.

I won't go on; this is another paper that I could talk about for ages, but I just want to highlight some other points:

Colloid was the bolus fluid in the intervention group - the patients didn't all die of renal failure but the dose wasn't massive.

'Dynamic CVP targeting' was recommended in the control group - I find it hard to put into words how I feel about this but  I'm not quite as angered by it as I am by  the accompanying editorial that claims "Another factor that may have lowered the occurrence of the primary outcome rate in the control group was the protocol recommendation that patients in the usual care group receive dynamic CVP guided fluid administration"!!!  For anyone who wants a reference for the lack of usefulness of CVP, there are many out there but here's a meta-analysis.

There is no mention in the discussion about the conflicting pre-existing evidence re Dopexamine.

I'm amazed how many of these patients went to critical care, particularly as level 3 - Hawthorne effect?

If you want to hear what the author has to say about his (negative) results click here.  Do you agree with his interpretation?

I look forward to reading what you think........


*Which is fine, but I commend you to always look at people's conflicts of interest





7 Comments
David Laws
26/6/2014 07:37:43 am

Interesting publication for a variety of reasons. The use of goal-directed therapy was originally proposed to prevent avoidable non-vital organ hypoperfusion (liver, spleen, gut, kidneys) in patients who presented for major surgery in a dehydrated and hypovolaemic state secondary to bowel prep and prolonged fasting. Hypoperfusion of these organs can lead to SIRS and associated clinical complications. Benefit of this intervention wasn't so much based on the overall volume of intravenous fluid used perioperatively, but on the timing of the fluid. i.e. The cardiac output monitor enabled an assessment of the intravascular fluid status of the patient immediately post-induction and gave a means to correct this quickly and safely prior to the surgical insult. For example, Noblett's study mentioned in the meta-analysis demonstrated this phenomenon well (and demonstrated significant benefit from goal directed therapy).

Sadly in this latest study there is no mention of the proportion of patients found to be hypovolaemic post-induction, nor whether fasting times and use of prep were equivalent in each group.

I'm therefore not surprised that no difference was found - the fundamental reason for performing this intervention has not been measured. The CVP issue and high use of Level 3 care post-op has been highlighted already. In addition, over the last 10 years, encouraging patients to drink prior to surgery and selective use of bowel prep has probably reduced the potential incidence of patients that need to be rescued by GDT. This does not mean that cardiac output monitors are no longer valuable as a method of checking and ensuring appropriate fluid volume status prior to and during a major surgical insult.

Reply
Deva
28/6/2014 06:05:53 pm

Greetings from Toronto!
I would like to group my comments into two.

Methodology:

- Minimisation was done with stratification based on site, urgency of surgery and type. This is an extremely clever and well-accepted way of avoiding imbalance between the groups.

- Sample size was calculated based on an ARR of 12.5%, but the observed ARR was 6.8%. If the sample size was calculated for 6.8% , they might have achieved statistical significance (they would have needed more than twice the number they have recruited). So technically, this study is an underpowered study.

- As Pete mentioned, we all know about the pitfalls of composite outcomes in clinical research.

- If you combine similar, small studies with a trend towards an outcome into a meta-analysis, you are likely to get a positive result. Remember Streptokinase Forest plot? There is no trend in this plot, but statistically it is possible. It is interesting to note that Optimise is the only study with higher weight age in the first plot.

- Sandham and Polonen papers skew the results in the other plots (you don’t need optimise to get a positive result for infection and LOS)


Clinical:

- Inclusion criteria – Oesophagectomy, gastrectomy, Whipples and hemicolectomy are in the same pot here! Not sure whether AR and APR are included as well!

- AT of 14 or less and METS 6 or less were used as high risk criteria. Will leave this point to the experts in pre-assessment and CPEX.

- Table 1 – As Dr Laws mentions in the post above, I would like to see the number of laparoscopic cases here. Sophie’s (Noblett) paper done at the Freeman was a great small RCT. It is very relevant if you starve your patients, administer prep, give an epidural and do an open procedure. It is probably not relevant for ERAS cases done laparoscopically. It is not known how many of the Optimise patients had a diagnosis of cancer (or is it hidden somewhere in the paper?)

- 70% received an epidural!

- Why 5% Dextrose maintenance? I don’t care what they used as long as it doesn’t affect the sugar levels and cause bowel oedema, but this is not a standard practice (atleast in the North East)

- Only about 20% went to the ward or PACU. Considering 45% were lower GI procedures and 60% were ASA 1 or 2, I don’t know why so many of them needed level 3 and 2 care.

- Impressive mortality figures 3.3% at 30 days, 7 and 11% at 6 months (were they all actually low risk!). Impressive SSI figures too (emergencies included).

Over all, a good attempt. CO monitors do have their place in the OR, but I am not convinced that a meta-analysis combining studies done over 3 decades, even with a mild statistical heterogeneity at 31%, is the right way to answer this question. In my opinion, the clinical heterogeneity amongst the studies is very important in this case.

Apples ≠ oranges.

Sorry for the really long post.

Reply
Peter Hersey
30/6/2014 11:55:37 am

I think the high rates of admission to crit care are because despite what Pearse claims, no other ward would accept a Dobutamine infusion (or have anyone to look at a lidco). I think local arrangements may have been to just admit them all to crit care. Was anyone in JCUH when they were recruiting?

I'm not sure these patients were all high risk. I didn't look for a supplementary appendix but I'd be interested how many met each 'high risk criterion' some of which were softer than others.

Reply
Mark Carpenter
30/6/2014 01:44:40 pm

I have a 3 points to make.

Firstly there is an issue of whether the treatment burden (my new favourite expression) outweighs the benefit. The benefit would seem to be modest if anything and the burden might be significant. If you put an arterial line in an otherwise fit 50 yr-old man having emergency right hemicolectomy, and they lost their hand as a consequence.....
Secondly the heterogeneity of the treatment group makes this very difficult to make firm recommendations on your (single) patient....always a problem with EBM, but this seems particularly diverse
Thirdly colorectal surgery has changed massively in the last 10 years and I can only assume that other surgery has change simiarly, so combining Sophie's results (Noblett) with others is bound to be difficult. 10 years ago, an APR was a major day long undertaking, 1000ml blood loss was absolutely par, art line, CVC and epidural were standard care and I would give up to 5000ml of intra-operative fluid (even some colloid in those days) without being worried.....this year, and APR might take 3-4 hours but no longer, only laparascopic port holes in the abdomen, big drip (x2), 1000ml fluid max, 50 ml blood loss the norm. Very different.
Finally: what intervention are 70% of these patients having to make them level 3 patients or are they defining level 3 care differently perhaps simply by location? If this is the case then this is not very "pragmatic" if all of these patients with 3.3% mortality need to come to the ICU afterwards

Reply
Caroline MacFie
3/7/2014 07:59:45 am

It seems unlikely that this will change local management given the choice of dopexamine and the concerns regarding non-standard fluid and CVP practices; plus the overall negative result in contrast to the altered conclusion of the meta-analysis once this study is added.

Reply
Deva
12/7/2014 03:52:36 am

In the July A&A's published ahead of print, the results of another study called POEMAS (Perioperative Goal-Directed Hemodynamic Optimization Using Noninvasive Cardiac Output Monitoring in Major Abdominal Surgery) have been published. Unfortunately there is an embargo for 1 month before Ovid access, so I couldn't access the full text. It is a smaller study compared to Optimise, but the results are worth a look.

Reply
Pete Hersey
14/7/2014 03:47:14 am

Courtesy of Rob MacSweeny (www.criticalcarereviews.com) here's a summary:

CPestaña and colleagues completed a pragmatic, multi-centre study in 142 patients undergoing general surgery, comparing a noninvasive cardiac output monitor guided hemodynamic protocol, including fluid administration and vasoactive drugs, with standard practice, and found:

the interventional protocol was associated with

an increase in

the number of colloid boluses (2.4 ± 1.8 vs 1.3 ± 1.4; P < 0.001), packed red blood cell units (0.6 ± 1.3 vs 0.2 ± 0.6; P = 0.019), dobutamine use (p < 0.001) intraoperatively: 25% vs 1.4%
postoperatively: 19.4% vs 0%

reduced

reoperations (5.6% vs 15.7%; P = 0.049)

no statistically significant differences in

overall fluid administration,
overall complications (40% vs 41%) relative risk 0.99; 95% CI 0.67 to 1.44; P = 0.397
length of stay (11.5 [8-15] vs 10.5 [8-16]; P = 0.874)
time to first flatus (62 hours [40-76] vs 72 hours [48-96]; P = 0.180)
wound infection (7 vs 14; P = 0.085)
anastomotic leaks (2 vs 5; P = 0.23)
mortality (4.2% vs 5.7%; P = 0.67)

Conclusion: The use of a perioperative goal-directed haemodynamic protocol in major abdominal surgery was not associated with reductions in overall complications, length of hospital stay, or mortality.

Abstract: Pestaña. Perioperative Goal-Directed Hemodynamic Optimization Using Noninvasive Cardiac Output Monitoring in Major Abdominal Surgery: A Prospective, Randomized, Multicenter, Pragmatic Trial: POEMAS Study (PeriOperative goal-directed thErapy in Major Abdominal Surgery). Anesth Analg 2014;epublished July 9th

With the caveat that I HAVEN'T READ THE PAPER I wonder if the increase in Dobutamine, RBS, Colloid is due to the protocol of the intervention i.e. inevitable. I'd also make the point that a monitor never changes outcome, it's the actions taken in response to the monitored variable (obvious but clearly not that obvious to those debating PACMAN for years and years!), so the results here and in optimise may well be due to Dopexamine, that we don't yet understand the role of fluid, and in this case Dobutamine, blood etc.

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