normal saline or balanced crystalloid?

balanced_crystalloids_vs_saline_in_critically_ill.pdf
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balanced_crystalloids_vs_saline_in_noncritically_ill.pdf
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In 2019's relaunched journal club, we'll go after answers to clinical queries, interspersed with 'classic' or recommended papers.  Recently, the above question has been raised regarding treatment of ED patients.  My practice habit is to use balanced crystalloid (Plasma-Lyte in our ED) for sick patients, and normal saline for the less sick patients.  Based on having seen large volume fluid resuscitation with saline cause hyperchloraemic metabolic acidosis.  
The question has recently been raised again due to a shortage of Plasma-Lyte in our trust.
So two papers for you to peruse and consider, recommended by one of our intensivists.  There's significant ED experience/expertise on this topic - please add your thoughts &  other references via the comments!
~Lou Mitchell~

My appraisal & thoughts:
critically ill patients paper
Strenths and weaknesses
- Big (15000 patients) study, in a single big academic centre (probably the only avoidable weakness of this study).  Lightly patient - relevant primary outcomes stated prior to the study  (death from any cause, initiation of renal replacement therapy (RRT), or persisting renal dysfunction at discharge or 30 days post ICU admission).
- Secondary outcomes were also stated prior to the study.
- Randomised by month, including ED stay prior to ICU admission.  Not blinded, but results extraction from patient records was.
- Power calculations were done, then adjusted pre-study, seem appropriate.
- 'Off protocol' permitted for patients with hyperkalaemia (as balanced crystalloids contain K+) and traumatic brain injury (where balanced crystalloids may worsen cerebral oedema).  Intention to treat analysis.
- No industry involvement declared, and 2 types of balanced crystalloid used.  Would be good to have more specific results, study approach maybe means greater generalisability of results, as apply to more than one 'brand' balanced crystalloid.
- Really readable & clear paper.  Authors should be commended.  I recommend you read it as an example of a well constructed study.

Key findings
Approx. 10% less hyperchloraemia and 10% less bicarb drop in the balanced crystalloid group, with the effect increasing as the amount of fluid given increased.  Interesting but not a patient-oriented outcome.  However...
- Study found an odds ratio of 0.9 in reduction of primary outcomes listed (95% CI 0.84-0.99) giving balanced crystalloid instead of normal saline.  
- Breaking this down a bit further it's 0.8% mortality reduction, 0.4% reduction in RRT, and 0.2% reduction in persistant renal dysfunction.  All statistically significant.  One patient per 94 admitted could avoid these outcomes if balanced crystalloid were used in all patients. 
- Very similar outcomes using various predetermined sensitivity analyses.  Authors excluded various groups from analysis who could affect result validity - for example those patients in ICU in a 'crossover month' where they were exposed to both crystalloids. 
- The NNT seems high, and 0.8% mortality reduction sounds a small effect.  But the outcomes are so important - death obviously, but RRT and persistent renal dysfunction are highly resource consuming, invasive, and quality of life reducing, that this result matters.
- A litre of normal saline costs £3.59 according to the BNF - but the price your trust pays may be very different as it's all negotiated...
- A litre of Plasmalyte cost is not in the BNF/ on medicines.org/on the manufacturer website.
- A conversation with a pharmacist at our trust clarified that the trust negotiated price for Plasma-Lyte is comparable to that of the trust price for normal saline. 

- In sepsis - the outcomes were more marked.  There was a 4% difference between in hospital mortalities, favouring balanced crystalloid.  This was a secondary outcome, so don't hang on to hard to that figure, but it was predetermined (i.e. there was no data-mining looking for positive correlation in this study).

non critically ill patients paper - the ED paper
Strengths & weaknesses - are essentially the same as above.  Single centre is key weakness here. 13,000 patients - who were then admitted, but not to ICU, hence not 'critically ill'  
- primary outcome was hospital free days (alive after discharge before day 28).
- secondary outcomes were essentially the same as the primary ones in the study above.
- median fluids given in ED was 1 litre.  Excluded those who received less than 500mls in the ED stay.  That's quite a lot for 'noncritically ill' patients.  They may have just reached their ceiling of care, but I think this is less likely in US practice than the UK.
- was 95% Ringer's lactate used in this study, 5% Plasma-Lyte.  We don't have Ringer's lactate in our ED.  This may matter... but probably doesn't.
​ 
Key findings 
- no difference in length of hospital admission.
- Similar, perhaps slightly greater effect, on the secondary outcomes - death/RRT/persistent renal dysfunction - OR 0.82, 95% CI 0.7-0.95.  NNT of 111.

Bottom line - I'll continue use balanced resuscitation fluids in adult resuscitation, excepting hyperkalaemia and traumatic brain injury, and DKA till the protocol changes.  I think I'll start using them in majors too, as there appears to be a mortality benefit, once availability is no longer an issue.