This issue has never come up in the fellowship exam, but merits some attention from the preparing candidate because studies have been published and words have been written on this topic, most notably by local experts who also happen to be examiners. So, one might ask – why have the Myburghs and Bellomos of this world not written any SAQs asking for us to “critically evaluate the use of balanced crystalloid” etc? Well, perhaps because it would be hard work marking such a thing, or because there is equipoise, or because the question does not discriminate safe intensivists from unsafe ones. Either way, no past paper “model answers” exist to help us divine what the college officially thinks on this issue. As such, the topic is probably of little importance to the person who is one week before exam. Its relevance in this section is largely theoretical, to protect trainees from the possibility that they might come across an examiner at a viva who happens to have some strong unbalanced views about saline.

As far as published evidence and opinion go, there is much in the literature. The exam candidate can safely limit their reading to virtually any top Google result for a search string where “saline” and “balanced” figure prominently. Of the saline-bashing, the most violent prison-shower-like attacks happen in articles by Dileep Lobo (see here, here, here here and here, as well as here and a little bit here). The man has strong opinions and has infiltrated various organisations giving rise to anti-saline guidelines (more on that later). Of balanced views, there are many of notable quality, but one which stands out is a paper by Cortez Bonor and Vincent from 2014. The time-poor candidate can limit their reading to this single resource. An updated alternative is the 2016 review by Reddy et al. LITFL also has a great one-stop resource. For a good review of the reasons as to why saline should not be dismissed as toxic pickle brine, Thomas Woodcock's 2014 critique of the NICE fluid guidelines and Chris Palmer's ACEP 2014 editorial are also worth reading.

## Rationale and boundaries for this discussion

To be clear, the specific question is whether there is any realistic benefit to the use of  balanced crystalloid solutions (such as Plasmalyte or Hartmanns) instead of normal saline for maintenance or resuscitation in the undifferentiated cohort of “critically ill” patients.

## Arguments against the use of saline

One can make an argument that saline has physiological effects which are detrimental, and which are exaggerated in the ICU where the volume of resuscitation fluid is greatest. These are discussed in some detail in a recent article by Santi et al (2015). Although the discussion has a somewhat paediatric inclination, the arguments they offer remain interesting, and are summarised below. Wherever possible, the evidence supporting or dismissing the argument is offered.

### Normal anion gap metabolic acidosis

Though this is usually well tolerated in the healthy patient (eg. Lobo’s surgical registrars) the ICU population is rather less likely to shoulder it effortlessly. Without reproducing the entire list of consequence of acidosis, it will suffice for us all to agree that it has negative physiological effects on the nearly dead ICU patient. Negative inotropy, impaired response to catecholamines, increased respiratory drive and so forth.

Whether this theoretical concern translates into real-life dead patients is difficult to ascertain. Taken as a homogeneous group, the mortality of all-comer ICU patients is probably unaffected. In undifferentiated ICU patients, Gunnerson et al (2006) were unable to find a strong association between normal anion gap metabolic acidosis and increased mortality (29% dead vs. 26% in the non-acidotic group, vs. 56% for lactic acidosis). However, some patient groups are probably going to be worst affected, for example patients with trauma (Ho et al, 2001) – acidosis is part of the “lethal triad” which is a widely acknowledged Bad Thing. Similarly, Neyra et al (2015) were able to demonstrate increased mortality from hyperchloraemia in critically ill septic patients (with an OR of death around 1.37 associated with a 5mmol/L increase in chloride).

### Acute kidney injury

Hyperchloraemia seems to be associated with decreased renal blood flow velocity and decreased renal cortical perfusion among healthy volunteers (Choudhury et al, 2012). In their article, Santi et al theorise that this may arise from afferent arteriolar vasoconstriction in reaction to increased chloride delivery to the macula densa. Surely, ICU patients do not need any extra reasons to have renal impairment. Does this really affect ICU-relevant outcomes? Prospective non-RCT data (eg. Bellomo et al, 2012) has supported the idea that chloride does some sort of renal damage; of the linked study cohort at Austin Hospital, the chloride-enriched group had almost twice the incidence of requiring dialysis (10% vs. 6.3%). Thus far, no association with increased mortality has been found, in spite of the fact that acute kidney injury is traditionally supposed to increase ICU mortality.

### Proinflammatory effects

Contrary to hypertonic saline (which is supposed to have some sort of anti-inflammatory effects) normal saline is suspected of activating the release of inflammatory mediators. This, however, comes from either animal studies or small scale human data. For instance, Wu et al (2011) reported substantially worsened SIRS variables in patients with pancreatitis who were resuscitated with normal saline. However, this was a study using the now-defunct (and widely derided) SIRS definitions, and they used CRP to measure inflammation (which may not be the best-ever biomarker of such things).

### Anti-haemostatic properties

Normal saline is thought to have some sort of negative influence on perioperative haemostasis and blood transfusion requirements. Cortez et al (2014) summarise the data and conclude that probably there is no such effect in the majority of patients. By massaging the data through post-hoc subgroup analysis of other people’s findings, these authors were able to identify a high risk group of surgical patients who had increased transfusion requirements associated with the use of normal saline.

### Nausea and vomiting

Though Heidari et al (2011) found an increase in the risk of post-operative nausea and vomiting with normal saline among ninety Pakistani elective surgical patients, no such increase was found by Karaca et al (2006) among  sixty Turkish patients undergoing spinal anaesthesia. Is this for real? Who knows. Certainly this has little bearing on the overall experience of a “proper” ICU patient, i.e. somebody who is sedated and ventilated with multiple organ problems. The nausea signal is lost in the mess of the overall unhappy state of critical illness.

### The adverse effects of balanced crystalloids

All those expensive fluids are themselves not benign. The following observations can be made about them:

• They are not biologically equivalent, and none approach the concentration of human body fluids very closely.
• Hartmann’s is hypotonic, which is counterproductive if you want to avoid oedema.
• Hypotonic fluids, when used in liberal volumes, may give rise to cerebral oedema (i.e. the uncritical use of such fluid can produce a blood-brain osmotic gradient)
• Calcium in Hartmanns can react with blood products and inactivate antibiotics (eg. ceftriaxone)
• Little is known about gluconate (a component of Plasmalyte), which is worrying.
• Acetate has a recognised cardio-depressant effect (Kirkendol et al, 1979)
• Alkalosis arises from the overuse of balanced crystalloid, and this is not a benign process (at leats no more benign than the normal anion gap acidosis due to saline).

## Saline versus balanced crystalloid in big randomised trials

Up to 2014, Cortez Bonor and Vincent identifed 28 studies, which were all small and the meta-analysis of which had led to no firm conclusions about anything. Since then a few more developments have taken place, of which a few were run by ANZICS CTG and therefore have exam relevance (as one might run afoul of a primary investigator in the vivas).

### SPLIT (Young et al, 2015)

This was a double-crossover RCT conducted in 4 ICUs from New Zealand. 2278 patients were enrolled. The hypothesis was that the use of Plasmalyte would be protective against acute kidney injury. It was not. However, of the 1100-something patients in each group, only 38 went on to have dialysis, which begs the question - how sick were they, really? Were these “real” ICU patients? On average, they all received only about 2000ml of resuscitation fluid. Overall in-hospital mortality was around 7-8%, suggesting that the population was perhaps too well to benefit from elegant biochemical manipulation. Indeed, a subgroup analysis which excluded short-stayers and elective post-op patients found a statistically insignificant (but interesting) trend towards increased mortality (19% vs 15%).

### PLUS (Finfer, Bellomo et al)

This is still in its “set up phase”, and will compare Plasmalyte with saline in a gargantuan cohort of 8800 patients.  With Finfer and Bellomo at the helm, one can expect it to appear in NEJM (if not on a platinum tablet launched into interstellar space).

## Support for balanced crystalloid in society guidelines

Apart from NICE, the various societies do not seem to have specific guidelines.  The unfortunately abbreviated British GIFTASUP and the even more unfortunate 2014 GIFTAHo update favoured the use of lactate or acetate-balanced solutions for everything except for replacement of chloride-rich nasogastric losses (but that was virtually guaranteed with the presence of Lobo among the authors).  These recommendations were not met with uniform agreement. There are both opponents (Woodcock, 2014) and defenders (Stroud Nolan and Soni, 2014).

## “Own Practice” statement

Generally, the examiners like to see an answer to “what would you do in this situation?” as a means of determining whether the candidate is likely to have well-formed opinions (rather than just memorised trial results). However, a good exam result is favoured by a well-formed opinion which falls in line with the examiner’s opinion. Locally, there appears to be a pro-balanced sentiment. Glassford et al published a 2016 retrospective study of “fluid ecology” in Australia and New Zealand demonstrating that balanced crystalloid use is on the rise (“widespread bi-national preference” is how they described it).

Thus, for exam purposes, basic statements can be made:

• The aim of ICU management at its most fundamental level is to normalise the physiological homeostasis of the patient.
• The use of balanced crystalloids is as valid as the use of saline when it is used to achieve this aim. Acidotic patients should receive “alkalinising” balanced crystalloid, and alkalotic hypochloraemic patients should receive saline.
• In patients with unimpaired acid-base balance, the fluid choice should aim to maintain that balance. Thus, these patients should be resuscitated with balanced crystalloid. This is not because there might be some sort mortality or renal perfusion benefit. Rather, the pursuit of physiological normality is the goal. This separates a “reasonable” fluid choice from the ideal fluid choice.
• The mindless use of any specific fluid choice will result in adverse effects, regardless of which fluid one chooses. The user of resuscitation fluid must be familiar with the physiological consequences of administering normal saline (or Hartmanns, or Plasmalyte), as it would be insanely irresponsible to infuse a patient with 8000ml of a substance which one does not fully understand.

### References

Many thanks to Tom Woodcock whose correspondence helped fortify my arguments in defense of saline.

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Lobo, D. N., et al. "Problems with solutions: drowning in the brine of an inadequate knowledge base." Clinical Nutrition 20.2 (2001): 125-130.

Lobo, Dileep N. "Intravenous 0.9% saline and general surgical patients: a problem, not a solution." Annals of surgery 255.5 (2012): 830-832.

Palmer, Christopher M., Michael C. Scott, and Michael E. Winters. "The Use of Saline as a Resuscitation Fluid in ED." ACEP (www.acep.org)

Powell-Tuck, Jeremy, et al. "Summary of the British Consensus Guidelines on Intravenous Fluid Therapy for Adult Surgical Patients (GIFTASUP)–For Comment." Journal of the Intensive Care Society 10.1 (2009): 13-15.

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KIRKENDOL, PAUL L., et al. "Myocardial depressant effects of sodium acetate." Cardiovascular research 12.2 (1978): 127-136.

Lobo, Dileep N. Physiological aspects of fluid and electrolyte balance. Diss. University of Nottingham, 2003.

Lobo, Dileep N., and Sherif Awad. "Should chloride-rich crystalloids remain the mainstay of fluid resuscitation to prevent ‘pre-renal’acute kidney injury?" Kidney international 86.6 (2014): 1096-1105.

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Chowdhury, Abeed H., et al. "A randomized, controlled, double-blind crossover study on the effects of 2-L infusions of 0.9% saline and plasma-lyte® 148 on renal blood flow velocity and renal cortical tissue perfusion in healthy volunteers." Annals of surgery 256.1 (2012): 18-24.

Heidari, Sayyed Morteza, et al. "Comparison of the effect of preoperative administration of Ringer’s solution, normal saline and hypertonic saline 5% on postoperative nausea and vomiting: a randomized, double blinded clinical study." Pak J Med 27 (2011): 771-774.

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Young, Paul, et al. "Effect of a buffered crystalloid solution vs saline on acute kidney injury among patients in the intensive care unit: the SPLIT randomized clinical trial." Jama 314.16 (2015): 1701-1710.

Woodcock, T. "GIFTAHo; an improvement on GIFTASuP? New NICE guidelines on intravenous fluids." Anaesthesia 69.5 (2014): 410-415.

Stroud, M. A., J. Nolan, and N. Soni. "A defence of the NICE guidelines on intravenous fluids." Anaesthesia 69.5 (2014): 416-419.

Glassford, Neil J., Paul Myles, and Rinaldo Bellomo. "The Australian approach to peri-operative fluid balance." Current Opinion in Anesthesiology 25.1 (2012): 102-110.

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Glassford, N. J., et al. "Changes in intravenous fluid use patterns in Australia and New Zealand: evidence of research translating into practice." Critical care and resuscitation: journal of the Australasian Academy of Critical Care Medicine 18.2 (2016): 88-88.