This article aims to provide some explanation of the basic concepts of fluid therapy and an introduction to the various fluid
Rob Shulman DHC (Pharm) MRPharmS
Lead Pharmacist – Critical Care
University College Hospital,
University College London Hospitals NHS Foundation Trust, London, UK
Honorary Associate Professor in Clinical Pharmacy Practice,
UCL School of Pharmacy
Honorary Lecturer, Department of Medicine, University College London, UK
The spotlight is currently shining brightly on intravenous (IV) fluid therapy following the publication of a number of trial reports which has led to a significant international regulatory response. This is a therapy that is widely used, as all hospitalised patients are routinely assessed for electrolytes needs, in addition to fluid requirements. IV fluids are necessary only when the patient’s requirements cannot be met by oral or enteral routes. This article aims to provide some explanation of the basic concepts of fluid therapy and an introduction to the various fluid classes.
Physiology of fluid compartments
The intravascular space is relatively small and contains higher concentration of protein and other blood components, compared to the other compartments.
Its purpose is to supply oxygen within the blood, other essential substrates and immunomediators around the body and removal of metabolites. Importantly, it needs a working pressure to operate and hence it needs to have sufficient fluid. Plasma is the fluid medium that fills the space, enabling oxygen delivery, thus it is a key to survival.
The interstitial space is a large space, which has a different electrolyte balance to the intravascular space, with a dominance of sodium, proteins and other macromolecules. Membranes and pores separate it from the intravascular space. It is clinically observed when oedema is noted but is usually inaccessible for measurement. It is drained by the lymphatics and transports substrates and metabolites between the circulation and the cell. During stress or injury, the barrier between the intravascular space and the interstitium becomes leaky, causing local oedema to occur, thought to be due to loss or damage to the endothelial glycocalyx.
The intracellular compartment has a membrane that maintains electrolyte disequilibrium between the intracellular and the interstitial compartment, secondary to Na+/K+– ATPase. This large compartment is important for cellular function and is not usually accessible to clinical measurement.
The 5 Rs
Patients may need IV fluids for the first four of the above indications. Each is now discussed in turn.
Fluid resuscitation is required when the circulating volume is needed to be restored quickly in order to maintain perfusion to the vital organs. This may be required due to blood or plasma loss, severe internal losses (for example, from sepsis), or from external fluid and electrolyte loss. The principle goal in the management of hypovolaemia is to stop volume loss (if possible) and restore the circulating volume. A fluid challenge is used in many intensive care units. A small increment of blood volume is achieved (such as 200ml) and the impact of this is judged by measuring the central venous pressure and/or cardiac stroke volume. Other vital signs are usually taken into account as well. This challenge is repeated until there is no further improvement in blood volume increment. This process provides the right amount of fluid, individualised to the patient, and fluid overload is rare. The fluid challenge can be met with 200ml of a crystalloid or colloid. Previously, it was thought that a bigger volume of crystalloid would be necessary, that is, 500ml (see Figure 1), but the SAFE study(1) showed that this was not the case in practice.
This describes the need to give fluid replacement in patients who cannot meet the fluid or electrolyte needs by the oral or enteral route alone.
Fluid replacement is required for patients with non-urgent losses from intravascular or other fluid compartments. Typically these are necessary for patients with burns, pyrexia, GI or urinary losses.
This describes significant internal fluid distribution changes or abnormal fluid handling. This is seen in septic, critically ill, post-major operative patients or those with severe cardiac, liver or renal co-morbidities. These patients may develop oedema from sodium and water excess.
Typically for routine maintenance, patients require 25–30ml/kg water per day and approximately 1mmol/kg of Na+, Cl- and K+ and approximately 50–100g/day of glucose to limit starvation ketosis. All IV fluid prescriptions should add enough fluid and/or electrolytes to correct any existing deficits and meet abnormal ongoing losses.
The typical maximum rate is 30ml/kg/day for routine fluid maintenance, but patients who are older or frail may have renal impairment or cardiac failure and so require less, for example, 25ml/kg/day of fluid.
In acute respiratory distress syndrome, the FACTT study reported better outcomes (lung injury scores and oxygenation indices as well as lower plateau pressures and positive end-expiratory pressures) for a ‘conservative’ fluid strategy compared to ‘liberal’. This has been interpreted as support of ‘running these patients dry’. However, it is worth noting that these approaches did not start until after the initial resuscitation over 48 hours had already occurred.(2)
Regular reassessment is important in order to review how the patient responds to the fluid strategy, so that the therapy can be changed if necessary and stopped as soon as possible.
The choice of fluid therapy
The key types of fluid that have been used in practice are crystalloids, colloids (including gelatins and synthetic starches) and albumin.
This term refers to solutions of inorganic ions and small organic molecules for IV therapy. They are based on either glucose or sodium and may be iso-, hypo- or hypertonic. Hypertonic solutions have a high osmolarity, are irritant to veins and need to be given either centrally or into a large vein. The isotonic solutions are sodium chloride 0.9% and Hartmann’s (lactated Ringer’s) solution. When infused, glucose 5% becomes hypotonic due to rapid cell metabolism despite being isosmolar in the bag. Though normal saline 0.9% is the prototype crystalloid used historically, there is a concern that the chloride content is too high and thus may predispose to cause hyperchloraemia and associated adverse effects. Hence there is a movement towards using Hartmann’s for standard replacement, as its constituents are more ‘balanced’ and similar to plasma.
Whilst balanced solutions have theoretical advantages, the benefits have not been comprehensively demonstrated in clinical trials, although one study3 demonstrated a chloride-restrictive strategy was associated with a decrease in acute kidney injury and renal replacement therapy. Glucose solutions have specific roles in hypoglycaemia rescue, with insulin in hyperkalaemia and for energy replacement when other forms of nutrition are unavailable or unsuitable. Glucose 5% and glucose saline are not suitable for resuscitation because they distribute rapidly across all the fluid compartments (see Figure 1).
Another crystalloid often overlooked is sodium bicarbonate 1.26%. This is an isotonic concentration and can be useful in situations where sodium replacement is required without any chloride, that is, in the hyponatraemic/hyperchloraemic patient.
Synthetic colloids contain non-crystalline large molecules or ultramicroscopic particles dispersed through a fluid. The colloidal particles are large enough to be retained within the circulation and so exert an oncotic pressure across capillary membranes. This should result in greater and more persistent intravascular volume expansion and less interstitial oedema than the infusion of a similar volume of crystalloid (see Figure 1). Thus, colloids should be superior to crystalloids for resuscitation or oedematous redistribution. In addition to albumin, the two broad groups are gelatins and starches. Several recent studies have thrown into question the safety of starch use as a product class(4–6) and this has led several countries to review their product licenses and availability. While the FDA and several European countries have stated these drugs should not be used in sepsis, the critical care setting or cardiac surgery, the UK has suspended their marketing authorisation entirely, at the time of writing (though this is under review, see below).
These are prepared by the hydrolysis of bovine collagen. Gelatins have a molecular weight of around 30 kDa. Trials similar to those suggesting renal problems with starches have not been conducted with gelatins, with the exception partially of the CRISTAL study (see below).
Hydroxyethyl starches (HES) are synthesised from amylopectin, a waxy starch derived from maize or sorghum. A series of recent high-quality, prospective, double-blind studies have reported that starches were associated with harm in severely septic and septic shock patients, and in critically ill patients, particularly in terms of new-onset renal failure, need for renal replacement therapy and 90-day mortality. This has been confirmed by a series of meta-analyses that found that there is no clinical benefit for HES and no subgroup that benefits.(7,8) However, the newly published CRISTAL study contradicts these conclusions so the controversy will remain.(9)
The international licensing authorities have acted to limit the use of these products, confirming that HES should no longer be used in patients with sepsis or burn injuries or in critically ill patients because of an increased risk of kidney injury and mortality, but that it will be available for patients to treat hypovolaemia caused by acute blood loss “where treatment with alternative infusions solutions (crystalloids) alone are not considered to be sufficient. In order to minimise potential risks in these patients, HES solutions should not be used for more than 24 hours and patients’ kidney function should be monitored after HES administration. In addition to updating the product information, further studies should be carried out on the use of these medicines in elective surgery and trauma patients”.(10) These recommendations, issued in the Coordination Group for Mutual Recognition and Decentralised Procedures – Human endorsement by the majority of the PRAC recommendation, are based on a review of all available safety and efficacy data, including recent data from clinical studies, meta-analyses and post-marketing experience.(9)
Albumin in a naturally occurring monodisperse colloid. Albumin has a higher cost compared to colloids and crystalloids in many countries. Albumin is available as isotonic 4–5% solutions and hypertonic 20–25% solutions. The latter have been used in oedematous patients, aiming to draw fluid from the interstitial space into the intravascular space to promote renal perfusion and excretion of the excess sodium and water.
The SAFE study1 in ICU adult patients compared albumin 4% with saline. It reported no difference in the 28 day rate of death or development of new organ failure. In a post-hoc analysis, albumin use was associated with better outcomes in septic patients. This finding was not confirmed by the recent, as yet unpublished, ALBIOS study; however, it should be noted that this was an albumin supplementation, rather than resuscitation, trial.
In the SAFE trauma subgroup, albumin use was associated with an increase in mortality at two years. In a meta-analysis, albumin use was associated with improved outcome.(11) The recent withdrawal and restriction of starches have led many to reconsider the role of albumin in therapy.
Fluid therapy is fundamental to patient management, and yet there is still substantial controversy in the field.
There are several ways to manage patients effectively. Choice of fluids for resuscitation have to be re-evaluated in light of the latest data on safety.
Increasingly balanced crystalloids are considered ideal for maintenance therapy, and some centres also use these fluids for resuscitation. Albumin is recommended by the Surviving Sepsis Campaign for fluid resuscitation in sepsis, particularly in those requiring large volumes of crystalloids.(12) The safety of gelatins has not been studied adequately, in contrast to starches, where the use is in sharp decline, at least in critical care and sepsis.
- Hartmann’s solution is an ideal crystalloid for maintainance therapy and resuscitation.
- The high chloride content of ‘normal saline’ may be problematic for routine use.
- Hydroxyethylstarch should be avoided in sepsis and burns due to kidney injury.
- Safety trials of gelatins have not been conducted, but some units continue to use them for resuscitation.
- Albumin may have a role in septic patients requiring high volume resuscitation or in oedema/ascites.
- Finfer S et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004;350:2247–56.
- The National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 2006;354:2564–75.
- Yunos NM et al. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. J Am Med Assoc 2012;308:1566–72.
- Brunkhorst FM et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008;358:125–39.
- Perner A et al. Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med. 2012;367:124–34.
- Myburgh JA et al. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med 2012;367:1901–11.
- Mutter TC, Ruth CA, Dart AB. Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function (Review). The Cochrane Collaboration;013:7.
- Zarychanski R et al. Association of hydroxyethyl starch administration with mortality and acute kidney injury in critically ill patients requiring volume resuscitation. A systematic review and meta-analysis. JAMA 2013;309:678–88.
- Annane D et al. Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock. The CRISTAL randomized trial. 2013;http://jama.jamanetwork.com/.
- PRAC confirms that hydroxyethyl-starch solutions (HES) should no longer be used in patients with sepsis or burn injuries or in critically ill patients (11/10/2013); Hydroxyethyl-starch solutions (HES) should no longer be used in patients with sepsis or burn injuries or in critically ill patients – CMDh endorses PRAC recommendations (25/10/2013). www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/ (accessed 9 January 2014).
- Delaney AP et al. The role of albumin as a resuscitation fluid for patients with sepsis: a systematic review and meta-analysis. Crit Care Med 2011;39:386–91.
- Dellinger RP et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013;41:580–637.
I wish to thank Dr D Brealey for his insightful comments on this paper.