This meta-analysis pooled data from three large randomised controlled trials to determine whether early goal-directed therapy (EGDT) was an effective intervention for managing septic shock. The data were collected prospectively through collaboration between the investigators of the ProCESS, ARISE and ProMISe trials. The final analysis studied 3,723 patients across seven countries and multiple centres; it did not demonstrate a mortality benefit for EGDT in this setting, and suggested that it was not a cost-effective intervention. Subgroup analysis showed a mortality benefit for the patient group with severe chronic lung disease, and a negative effect on the survival of patients with chronic liver disease.
The initial report on EGDT in septic shock was published in 2001 by Rivers et al. EGDT is a 6-hour resuscitation protocol that focusses on the administration of intravenous fluids, vasopressors, ionotropes and packed red cells to meet defined ‘optimal’ physiological targets for arterial pressure, central venous pressure, central venous oxygen saturation and haemoglobin levels. The initial randomised control trial showed a reduced mortality, dropping from 46.5% to 30.5% with EGDT. This promising result provoked further investigation, and three large, multicentre trials were conducted: ProCESS, ARISE and ProMISe. These studies failed to show improved mortality with EGDT, and this meta-analysis was planned to increase the statistical power of those three trials by pooling data to establish whether a subtler effect could be elicited.
The three trials all investigated the same EGDT protocol, and the design for a meta-analysis was published prior to unblinding the data, allowing for a prospective analysis. In the both the usual treatment group and the EGDT group, early recognition of sepsis and prompt delivery of IV antibiotics and fluids were emphasised. The data were analysed on an intent-to-treat basis, with subgroups prespecified to explore the impact of EGDT on certain subgroups – such as those with more severe disease, or certain pre-existing conditions. Other subgroups were created to account for demographic differences.
After exclusions, 3,723 patients were included in the final analysis (1,852 in the EGDT group, 1,871 in the usual care group), and included data from 138 hospitals across the USA, Australia, New Zealand, Finland, Hong Kong, Ireland and the UK. Mortality within 90 days did not vary significantly (24.9% in the EGDT group versus 25.4% in the usual management group; adjusted odds ratio (OR) 0.97 [95% CI: 0.82–1.14] p=0.68). Secondary outcomes showed that 1-year mortality also did not vary significantly, while EGDT patients experienced a longer ITU/ICU stay and more frequent and longer duration cardiovascular support. Subgroup analysis also failed to show a mortality benefit in even those with the most severe disease. There was a mortality benefit from EGDT in the 370 patients with severe chronic lung disease (OR 0.54 [95% CI: 0.34–0.85] p=0.01), and higher mortality in patients receiving EGDT with severe chronic liver disease (n=117; OR 2.51 [95% CI: 1.12–5.63] p=0.01). The cost analysis demonstrated a higher cost up to 90 days with EGDT than with usual care; quality of life and quality-adjusted life year outcomes were similar, leading the analysis to suggest that the probability that EGDT is cost effective is 0.25 for realistic thresholds.
In their discussion, the authors highlight that there was no evidence to suggest EGDT resulted in improved mortality – an effect that persisted across a variety of healthcare systems. There was no evidence from the analysis that patients who were more unwell benefit, and the authors do not believe that the difference in disease severity is sufficient to explain the different outcomes found by Rivers et al. and this study. They concede that the intervention may have increased the standard of usual care, but subgroup analyses sought to establish whether there was inter-departmental variation, and did not find it to be so; highlighting that even those departments with the least aggressive usual care protocols did not demonstrate an EGDT benefit. Most of the evidence supporting EGDT thus far has been observational, and this study has potentially avoided some of the biases that may persist through an observational design. The authors point to the early harmonisation of research methodologies and alignment of key objectives as an example of how richer data can be generated – potentially leading to better practice.
The limitations to the study include: the relatively small size of some potentially important subgroups, the fact that the underlying trials were unblinded, and that the results may not be suitable for extrapolation to lower-income healthcare systems.
This study goes a long way towards demonstrating that a blanket approach to septic shock using EGDT is neither beneficial in terms of mortality nor cost-effective. It does however leave the door open for utilisation of some of the aspects of EGDT in clinically-relevant situations.
Catch-up on the debate surrounding hydroxyethyl starch use as we take you on an interactive journey through its changing fortunes. Do you think current restrictions will be enough to change clinical practice?
This position paper from the Italian Association for the Study of the Liver (AISF) and the Italian Society of Transfusion Medicine and Immunohaematology (SIMTI) reviews the evidence for the use of albumin in several settings related to liver cirrhosis.
This paper presents a meta-analysis to determine the impact of resuscitation with albumin on the morbidity and mortality of adult burn patients.
This meta-analysis examines whether the dosing of albumin affects outcomes in type 1 hepatorenal syndrome (HRS).
This review article explores the relationship between low albumin levels and acute kidney injury (AKI).
This meta-analysis pooled data from three large randomised controlled trials to determine whether early goal-directed therapy (EGDT) was an effective intervention for managing septic shock.
This systematic review and meta-analysis looked at the different mortality rates of various intravenous fluids and fluid protocols when used for resuscitation in sepsis.
This Chinese randomised controlled study explores the impact that a goal-directed fluid restriction (GDFR) protocol had on outcomes during anaesthesia for brain surgery.
This review paper examines the role of albumin in chronic liver disease, assessing the evidence for its use in several key clinical areas.
This matched cohort study aimed to determine whether a goal-directed fluid therapy (GDFT) intervention, delivered intraoperatively, would reduce post-operative morbidity in patients undergoing hip revision surgery.
This study explored fluid prescribing practices in intensive care – providing a picture of how fluid resuscitation is being managed internationally.
This multicentre audit reviewed the records of 431 patients who had undergone major elective surgery. The authors sought to determine how well IV fluids were prescribed both intraoperatively and perioperatively when compared with current guidance.
This double-blinded, randomised controlled trial examined whether pre-operative administration of exogenous albumin affected rates of acute kidney injury (AKI).
This article is a review and summary of the current opinion of albumin in fluid management.
This retrospective, observational study used a propensity scoring system to match patients treated with saline with those given a balanced, calcium-free fluid.
A recent PRAC review has recommended suspension of marketing authorisations for HES solutions for infusion across the EU.
Following the European Medicines Agency’s (EMA) suspension of the marketing authorisations of hydroxyethyl starch (HES) solutions across the European Union (EMA, 2018), Roberts et al., have written an open letter addressed to the World Health Organization (WHO) Director General seeking support for the suspension of HES solutions and expanding it to a worldwide ban.
The Coordination Group for Mutual Recognition and Decentralised Procedures (CMDh) endorse the suspension of hydroxyethyl-starch (HES) solutions, due to serious risks of kidney injury and death in certain patient populations.
The hypothesis that hypertonic fluid has a dual physiological role, increasing circulatory volume while administering minimal volumes and muting the pro-inflammatory response to injury and illness, may be appealing, but is it superior to isotonic fluids in practice?
In this post-hoc, subgroup analysis (study 1) and prospective, single-centre nested cohort (study 2) from the SPLIT (0.9% saline vs. PL-148 for ICU fluid therapy) trial, the investigators hypothesised that patients receiving Plasma-Lyte 148 would require fewer blood products and have less post-operative bleeding than those receiving saline.
Acute kidney injury (AKI) affects one-fifth of major surgery patients, increasing the risk of long-term mortality. This review paper discusses recent study data, discussing the best methods for preventing postoperative AKI.
Guidelines to promote the early recovery of patients undergoing major surgery recommend a restrictive intravenous-fluid strategy for abdominal surgery. However, the supporting evidence is limited, and there is concern about impaired organ perfusion.
Cirrhosis of the liver is a leading cause of mortality. For patients with decompensated cirrhosis, long-term weekly human albumin administration can act as an effective disease-modifying treatment.
In 1896 Ernest Starling published his hypothesis for fluid exchange, whereby fluid exchange exists mainly in the capillaries through a process of plasma ultrafiltration across semipermeable membranes (Starling, 1896). But is this 19th century theory something of the past?
Long-term albumin treatment for ascites associated with cirrhosis has been debated in recent years, with mixed results reported for the treatment’s efficacy. In this non-randomised prospective study, Di Pascoli and colleagues question the benefits of long-term albumin in patients with liver cirrhosis and refractory ascites, focussing on survival and emergent hospitalisations. Could this be part of the solution to the ongoing challenge of ascites in cirrhosis?
The choice of fluid administered during cardiac surgery remains a debated topic, often focussed around colloid solutions containing albumin. Conflicting results from numerous studies have left questions over albumin safety and potential to be superior to crystalloids during surgery. Kingeter et al. hoped to achieve clarity on this controversial topic in a retrospective study of cardiac surgery outcomes over a 12-year period.
Patients admitted to intensive care are often haemodynamically unstable with fluid resuscitation therapy regularly used to overcome this. The use of small volume resuscitation with 20% albumin has historically been limited compared to standard fluid resuscitation with 4–5% albumin due to safety concerns, but could those concerns be misplaced? Read more about how the SWIPE trial has provided new insights into the possibilities of using small volume resuscitation within the ICU.
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