Fluid Resuscitation in Sepsis

Early Goal Directed Therapy

Early work by Rivers et al sought to optimise oxygen delivery in an attempt to improve outcomes in sepsis.1 It focused on management of five key parameters to optimise oxygen delivery: CVP (8-12mmHg), MAP (65-90mmHg), urine output (>0.5ml/kg/hr), mixed venous oxygen saturation (>65%) or ScvO2 (>70%), and haematocrit (>30%). It did this through early use of mechanical ventilation to reduce work of breathing, fluid resuscitation, use of vasoactive agents, and transfusion. This work demonstrated a 19% decrease in mortality when comparing early goal directed therapy (EGDT) to standard care in sepsis.

Despite these impressive results, there were a number of criticisms of the study. It was a study population limited to a single ED. The control group had an above-average mortality rate and high rate of comorbidities. The patients were not blinded and the intervention arm benefitted from the undivided attention of a critical care trained doctor.

Indeed, subsequent trials in the 15 years following Rivers’ workcomparing EGDT vs standard care (the ARISE, ProMISe, ProCESS trials) have not demonstrated any mortality benefit. A subsequent metanalysis of all 3 of these trials incorporated 3723 patients at 138 hospitals across seven countries showed 90 day mortality was similar for EGDT vs usual care (24.9% for EGDT compared to 25.4% for usual care, with an adjusted odds ratio of 0.97 (95% CI 0.82-1.14)).2

This focus on the early aspects of care, inspired in large part by the Rivers study has created a number of quality assurance initiatives such as the Surviving Sepsis Campaign which have reinforced the concept of early, meticulous care in septic shock.4 The EGDT protocol encouraged physicians to be diligent in their surveillance of septic patients, aggressive in the early resuscitation of these patients, and to reassess the effect of their interventions leading to a higher quality of standard of care.3 Indeed, despite the problems with the Rivers study, a meta-analysis of resuscitation targeting haemodynamic end points has shown a demonstrable reduction in mortality.5

What is ‘the right’ amount of fluid?

The current Surviving Sepsis Guidelines recommends 30ml/kg of IV balanced crystalloid within the first 3 hours. There is low quality evidence to support this recommendation.6,7 They suggest using serial serum lactate measurements to guide resuscitation.

A study by Wang et al.7, a multicentre prospective observational study of 302 patients, found patients who received 30 mL/kg initial fluid resuscitation in the first 1-2 h had the lowest 28-day mortality rate (22.8%, P < 0.05).

A retrospective cohort study by Kuttab et al.8 in 208 patients  showed failure to meet 30ml/kg by 3 hours had greater odds of mortality (odds ratio 1.52; 95% CI 1.03-2.24), delayed hypotension (odds ratio 1.42; 95% CI 1.02-1.99), and increased ICU stay (by 2 d) (β = 2.0; 95% CI 0.5-3.6), without differential effects for “at-risk” groups. Higher fluid volumes administered by 3 hours correlated with decreased mortality, with a plateau effect between 35 and 45 mL/kg (p < 0.05).8

Despite this national guidance, compliance to the 30ml/kg target in 3 hours is affected by multiple factors. A study by Kabil et al.9 looked at compliance to the 30ml/kg target. This systematic review included 31 studies of which 21 were included in the meta-analysis and 11 in the narrative synthesis. The study concluded that performance improvement interventions improve compliance, reduced time to delivery of fluids, and volume of fluids administered to patients with sepsis in the emergency department. While patient-related factors such as advanced age, co-morbidities, cryptic shock were associated with poor compliance, important organisational factors such as inexperience of clinicians, overcrowding and inter-hospital transfers were also identified.

However, a balance must be struck. A recent metanalysis by Messmer et al in Critical Care10 showed that cumulative fluid balance was linked to mortality in patients with sepsis (adjusted relative risk 1.66; 95% CI 1.39-1.98), acute kidney injury (adjusted relative risk 2.63; 95% CI 1.30-5.30), and respiratory failure (adjusted relative risk 1.19; 95% CI 1.03-1.43). The risk of mortality increased by a factor of 1.19 (95% CI, 1.11-1.28) per litre increase in positive fluid balance.

The Conservative vs Liberal Approach to fluid therapy of septic shock in Intensive Care Trial (CLASSIC) is a large Multicentre RCT designed to assess the benefits and harms of the two approaches.11

Is assessing fluid responsiveness useful?

ANDROMEDA-SHOCK is a multicentre RCT of 424 patients which compared the effect of peripheral perfusion vs. lactate-targeted resuscitation on 28-day mortality. It concluded that was no difference in 28 day mortality between the two strategies. A secondary analysis showed systematic assessment allowed determination of fluid responsiveness status in more than 80% of patients with early septic shock. It was a safe strategy, and fluid boluses could be stopped in non-fluid responsive patients without any negative impact on relevant clinical outcomes.12

What is the best fluid?

Current Surviving Sepsis guidelines advises balanced crystalloid as the resuscitation fluid of choice. A metanalysis by Tseung et al.13 compared the survival benefits and adverse effects of seven fluid types with network meta-analysis in sepsis, surgical, trauma, and traumatic brain injury patients.

Fifty-eight trials (n=26,351 patients) were identified. Seven fluid types were evaluated. In those with sepsis, balanced crystalloids significantly reduced mortality more than saline (OR 0.84; 95% CI 0.74-0.95) and low molecular weight hydryoxethyl starch (L-HES) (OR 0.81; 95% CI 0.69-0.95) and reduced acute kidney injury more than L-HES (OR 0.80; 95% CI 0.65-0.99).

ABC Sepsis is an ongoing UK Trial comparing 5% albumin vs balanced crystalloid in the resuscitation of sepsis.14

What about peripheral vasopressors?

A recent metanalysis by Li et al. looking at the timing of noradrenaline showed early initiation of norepinephrine in patients with septic shock was associated with decreased short-term mortality, shorter time to achieved target MAP, and less volume of intravenous fluids within 6 h. However, it concludes further large-scale RCTs are still required to confirm these results.15

The CLOVERS study aimed to compare a restrictive fluids strategy (vasopressors first followed by rescue fluids) with a liberal fluid strategy (fluids first followed by rescue vasopressors) on 90-day in-hospital mortality in patients with sepsis-induced hypotension. This study concluded early following interim analysis which showed that there was no difference in 90 day mortality between the two strategies, with further recruitment was unlikely to change this. EVIS is a UK based study comparing the two approaches, which is ongoing.16,17

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