Hypertonic saline in critical care

Hypertonic saline is a tool with numerous uses, among which is the replacement of sodium (and not water) to correct hypervolemic hypoosmolar hyponatremia, osmotherapy for raised intracranial pressure, resuscitation of hypotensive patients where a small fluid volume is desirable, and increased sputum clearance when given via a nebuliser. Unfortunately, for many of these indications there is either poor quality evidence to support them, or good quality evidence to demonstrate a lack of benefit.

Hypertonic saline has been a reasonably popular topic in the Part II exam papers. Question 5 from the second paper of 2017 expected the candidates to produce a list of  "indications, mechanisms of action ...supporting evidence ...as well as the potential adverse effects" of hypertonic saline. This question can be rephrased as "How many legitimate uses for hypertonic saline can you think of?" Prior to that, its appearance in the exams had been limited to discussions of osmotherapy for raised intracranial pressure (eg. Question 4 from the first paper of 2007 and Question 8 from the first paper of 2001).  

As osmotherapy is discussed in greater detail elsewhere, this chapter will focus more on the non-intracranial uses of hypertonic saline, and is structured as a list of indications. The time-poor exam candidate may limit their reading to the excellent 2013 article by Jeffrey Holmes, which covers all the major indications and discuss the evidence behind them comprehensively. A good paywalled article from 2017 was also published by Pfortmueller & Schefold. Also, this 2009 review by Gustav Strandvik offers a reasonable overview of the the use of hypertonic saline in the management of hypotension and raised ICP; it also contains a long discussion of the various physiological consequences of infusing somebody with it. 

Positive effects of hypertonic saline therapy

Hypertonic saline has advantages and disadvantages which are specific for each indications (i.e. it might have advantages in comparison to another thing which even more toxic). However, there also some supposed benefits which it has intrinsically. Pfortmueller & Schefold (2017) list these in their article:

Positive volume-expanding effects of hypertonic saline

• Increased intravascular volume (as demonstrated by a fall in haematocrit)
• Increased cardiac output as the result of this

Other positive haemodynamic effects of hypertonic saline

• As compared to an equal volume of isotonic saline, hypertonic saline produces improved cardiac output.
• This is not totally due to the increase in preload. 
• Increased systemic vascular resistance is observed.
• Decreased pulmonary vascular resistance is also seen.
• Generally speaking, the studies which measure total sodium load do not show much of a difference, i.e. one ends up giving 150mmol of NaCl as 0.9% or as 20% either way.

Positive effects of hypertonic saline on organ and tissue blood flow

• Hypertonicity has the effect of producing vascular smooth muscle relaxation
• Hypertonic saline is thought to improve renal blood flow 
• There is some supposed rheological effect on the blood cells, which increases their deformability and therefore should improve the microcirculation by decreasing blood viscosity.

Positive immunomodulatory effects of hypertonic saline

• Decreased neutrophil activation
• Modified cytokine production
• Augmented T-cell function
• "To date, no clinical studies have been conducted that demonstrate a patient-oriented benefit from these immunomodulation properties" - Holmes, 2011

Complications of hypertonic saline therapy

A review of 3% saline among neuroICU patients has a nice table (Table 1) which lists the potential adverse effects of hypertonic saline administration, which is reproduced here with minimal modifications: 

• Hyperosmolarity
• Overshoot hypernatremia
• Congestive heart failure and pulmonary oedema
• Hypokalemia
• Normal anion gap metabolic acidosis
• Coagulopathy
• Phlebitis (hypertonic saline is a sclerosant)
• Renal failure 
• Decreased level of consciousness
• Rebound intracranial hypertension
• Seizures
• Central pontine myelinolysis
• Subdural and intraparenchymal hemorrhage

Hypertonic saline as sodium replacement

Hypertonic saline is indicated as a means of sodium replacement for hypoosomolar hyponatremia. In their answer to Question 24 from the first paper of 2016, the college recommend to raise the sodium level by 2-4% over 30 minutes if the patient is symptomatic, i.e. confused or having seizures. This is consistent with the recent European guidelines (Spasovski et al, 2014). 

Advantages:

• Ideal when fluid restriction is needed, eg. in SIADH.

Disadvantages:

• Not ideal in situations where hypovolemia accompanies hyponatremia, i.e. when volume as well as sodium need to be replaced. The logical choice there would be isotonic saline.

The recent overview of published guidelines by Verbalis et al (2014) and the college answer to Question 24 from the first paper of 2016 both recommend to raise the sodium level by 2-4% over 30 minutes if the patient is symptomatic, i.e. confused or having seizures. 

Hypertonic saline as a resuscitation fluid

Advantages

• Hypotensive patients will usually require some sort of fluid resuscitation
• Use of hypertonic saline instead of isotonic fluids in hypotensive states should make use of its haemodynamic advantages while protecting the patient from fluid overload
• Smaller volume means less haemodilution (in trauma for example)
• Small volume also means a more neutral fluid balance
• All the haemodynamic and immunomodulatory benefits should be helpful

Disadvantages

• There is a theoretical coagulopathy associated with its use
• Hypernatremia is not benign
• Hypokalemia and normal anion gap metabolic acidosis may cause problems
• Volume may actually be desirable (eg. the patient may be genuinely dehydrated)

Evidence for hypertonic saline in burns

There is little evidence to support this practice; some centres (eg. the Allfred) routinely use this fluid as a means of reducing the total fluid balance of the notoriously overload-prone burns patients.  Not all agree that this is a reasonable thing to do. For instance, a small study from 1989 (Gunn et al) found that hypertonic sodium lactate had no effect on total fluid balance.

Evidence for hypertonic saline in sepsis

A review by Oliveira et al (2002) found numerous encouraging animal studies but nothing in humans that was looking at hard outcomes. More recently, it was not associated with any improvement in mortality in the HYPERS2S trial (Ashfar et al, 2017) although it is not clear whether the saline or the 100% hyperoxia were responsible.

Evidence for hypertonic saline in severe trauma

Strandvik (2009) mainly complains about the poor methodological qualities of all the studies which investigate this aspect. Little has changed in subsequent years: de Crescenzo et al (2017) also concluded that "the quality of some of the included studies is not optimal" in their meta-analysis. Ultimately, meta-analysis of all these sub-optimal studies shows that there is probably no benefit.

Hypertonic saline as osmotherapy for raised intracranial pressure 

An entire chapter is dedicated to this topic, so it will only be treated briefly here.

In short, the advantages of hypertonic saline for this purpose:

• Cheap
• Stable in storage
• Very rapid effect
• Seems to have some sort of intrinsic anti-inflammatory effect
• May also have some rheological benefits
• At least as potent as mannitol when it comes to reducing intracranial pressure
• Less potential for hypovolemia than with mannitol- the diuretic effect is less potent
• May have a better effect on cerebral blood flow for a given reduction in ICP.
• Safe endpoint (serum sodium around 145-155) is easily monitored with serial ABGs.

The disadvantages:

• Need for central venous access
• No standards for which concentration to use, or how to give it
• Hypokalaemia
• Hyperchloraemic acidosis
• Should not be used if the patient is chronically hyponatremic
• Possible seizures due to wild fluctuations in serum sodium
• Increase in circulating volume with risk of fluid overload.
• Coagulopathy (APTT and INR)
• Altered platelet aggregation.
• May affect normal brain more that injured brain which theoretically may worsen herniation

The evidence:

• The (2016)  publication of the BTF Guidelines was  unable to make a firm recommendation in favour of hypertonic saline.
• A reasonably recent review (Lazarides et al, 2013) found a small statistically significant benefit for its use, as compared to mannitol.

Hypertonic saline as management for tissue oedema

Historically, people have thought about using hypertonic saline as a means of improving the diuresis of high NYHA-grade congestive heart failure patients, which is counterintuitive given that typically these people are put on low-salt diets. Paterna et al (2011) gave their patients both  a massive 250mg dose of frusemide (twice a day) and 150ml of hypertonic saline. Urine output increased, TTE findings improved and hospital length of stay was better. So, hypertonic saline can improve diuresis, and it is not clear whether there is any advantage in this approach in all massively oedematous patients.

Hypertonic saline as an expectorant for cystic fibrosis

Advantages

• Given as a nebulised fluid (i.e.no need for IV access)
• Hypertonic saline decreases the viscosity of respiratory mucus by multiple mechanisms, which include osmotic hydration of the mucus layer (i.e. attracting water into it) and disruption of mucus proteins 
• It is also irritant, which promotes cough

Disadvantages

• It's irritant, which the patients will not appreciate.
• Routine frequent use may result in systemic absorption of sodim and chloride, which might not be desirable

Evidence

• Elkins and Bye (2011) reviewed the evidence for the use of hypertonic saline in cystic fibrosis and found that it has positive effects on "most people with CF who find it tolerable"