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Table 2 Key themes in critical illness fluid research

From: Fluid therapy in critical illness

Patient group Research question Early trial evidence Subsequent developments and ongoing research questions
Sepsis Does early goal-directed bolus fluid therapy improve survival from severe sepsis? Key single-centre study by Rivers showing reduced mortality when bolus fluid therapy targeting central venous pressure and mixed venous saturations was used at presentation of septic patients to hospital [14]. Further developments in sepsis care through treatment ‘bundles’ and the need to test the intervention have led to a re-appraisal of the benefits of this intervention. The ProCESS trial recently published comparing protocol-driven goal-directed therapy with protocol (but not goal-directed) therapy and with standard care in 1,341 patients. No differences in mortality at 60, 90 or 365 days [15]. Further multicentre trials based on River's original protocol are nearing completion in the UK (ProMISe) and Australasia (ARiSE).
Mixed critical care populations Is fluid composition used for resuscitation associated with acute kidney injury and increased mortality? Early starch-based colloids with high molecular weight were associated with renal dysfunction [16]. Lower molecular weight starches were brought to market based on efficacy data but without trials large enough to detect possible harm. A number of large trials have demonstrated an increase in the need for renal replacement therapy with modern starches, when compared to isotonic crystalloids. This has been shown in both septic [17, 18] and mixed critical care [13] populations. Despite concerns over trial methods, for example that some patients had been partially resuscitated before trial entry, use of starches has now been restricted (USA, Europe) or stopped (UK). A recent network meta-analysis has suggested that renal replacement requirement is highest in association with starches, followed by isotonic saline then balanced crystalloids [19] .
Surgery Does goal-directed haemodynamic therapy improve outcomes for patients undergoing major surgery? Survivors of high-risk surgery were found to achieve higher global oxygen delivery levels than non-survivors. These ‘survivor values’ were then used as therapeutic targets in subsequent interventional trials, with benefit shown [20, 21]. Reduced popularity of the pulmonary artery catheter followed by minimally invasive cardiac output monitors and an evolution of fluid administration protocols. Single-centre trials from the 1990s onwards showed reduction in hospital length of stay and postoperative morbidity in goal-directed therapy intervention groups. A recent Cochrane review points to no harm and probably morbidity benefit from goal-directed therapy, although studies span over 30 years of trials [22]. A large contemporary multicentre trial also involving an inotrope in the intervention group (OPTIMISE) again suggested benefit but lacked statistical significance. The accompanying update to the meta-analysis strengthens the evidence for a reduction in postoperative morbidity [23]. Studies in emergency surgery are lacking.
Surgery Can targeting a fluid ‘dose’ lead to improved outcomes in patients undergoing major surgery? Patients receiving ‘standard’ volumes of fluid in the peri-operative phase were shown to have more postoperative morbidity than those receiving ‘restrictive’ volumes [24]. This research theme has been hampered by varying definitions of what constitutes liberal and restrictive volumes of fluid. Subsequent trials have therefore shown contrasting results. A common theme though is the association between a positive fluid balance in the immediate peri-operative period (>3,500–5,000 ml) and worse postoperative outcomes. Giving larger volumes of fluid without robust physiological monitoring appears to be associated with worse outcomes, even when overall quantities given may be similar to those used in goal-directed therapy interventions [25]. A large and hopefully definitive multicentre trial (RELIEF) is underway in Australasia and the UK.
Surgery Does isotonic saline cause harm to patients undergoing surgery when compared with balanced solutions? Concerns that isotonic saline is unphysiological in composition and may cause harm through reduction in renal blood flow and hyperchloraemic acidosis. These have never been backed up by trials with adequate statistical power. Observational studies suggest harm with saline as compared to balanced solutions [26, 27]. A Cochrane review suggests an increase in postoperative acidosis and need for compensatory hyperventilation with saline used in the peri-operative setting [28]. No increase in postoperative renal morbidity. However, there is a lack of high-quality large trials, and this remains an important topic for ongoing research.
Trauma Does limiting volumes of early resuscitation fluid improve outcomes from trauma? Early suggestions from battlefield that fluid resuscitation may be harmful in ‘wound shock’ [29]. Renewed interest following pre-hospital randomised trial in penetrating trauma showing reduced mortality in limited vs. standard resuscitation [30]. Permissive hypotension with limited volumes of clear fluid given prior to achieving haemostasis is proposed as a part of ‘damage control resuscitation’ [31]. This also includes early surgical or radiological control of haemorrhage and steps to limit coagulopathy, including tranexamic acid and high ratios of plasma and platelets to red blood cell units transfused [32]. Controversy remains about the place of limited volume early resuscitation, as follow-up trials have not shown in-hospital or 30-day mortality benefit when blunt trauma patients are included [33, 34]. Hypotension may also worsen co-existing brain injury [35].
Trauma Does hypertonic saline improve outcomes from trauma? Hypertonic solutions may have the ability to draw water from the intracellular to the extracellular compartment, achieving plasma volume expansion with minimal volume of fluid administered. Limited human studies examining hypertonic saline used early in trauma resuscitation. One large trial stopped early as interim analysis demonstrated futility [36]. Hypertonic solutions not routinely recommended in trauma resuscitation. Although hypertonic saline is effective at reducing raised intracranial pressure [37], there is no benefit in early traumatic brain injury when intracranial pressure is not monitored [38].