No one is likely to argue with the belief that prompt and appropriate treatment is effective and should be the standard of care. Back in 2001, Emmanuel Rivers and colleagues published their landmark study of Early Goal Directed Therapy (EGDT) [1]. Perhaps the central concept behind EGDT is that of oxygen debt and the secondary inflammatory insult inflicted by tissue hypoxia, which is modifiable with timely and aggressive cardiovascular support. A series of recently published papers emphasise and further elucidate this idea.
Firstly, Rivers and colleagues have published the results of a study of serum biomarkers of systemic inflammation from the majority of patients from their original study [2]. Patients had multiple biomarkers measured periodically over the first 72 hours of their illness. Two separate comparative analyses were performed. First, the protocol group are considered against the standard care group. Second, the whole patient population has been stratified into three groups by severity of admission global dysoxia (serum lactate and central venous oxygen saturations) and compared. Unfortunately, no third analysis of these three groups separated into those in the protocol and standard care groups was performed. Although this post hoc separation would have yielded statistically small groups, the results may well have provided useful hypothesis generation rather than statistically significant results. The results of the treatment comparison analysis demonstrate a statistically significant reduction in the level of all markers in the protocol group. However, the time course and magnitude of this difference is markedly different between the substrates. EGDT appears to obtund the early peak in interleukin 1 receptor antagonist and tumour necrosis factor alpha (although the baseline level was significantly higher in the protocol group). Perhaps the most striking difference however was in caspase-3, a marker of cellular apoptosis, the level of which fell dramatically in the protocol group and remained at a much lower level throughout the 72 hours, suggesting that EGDT reduced the secondary insult of oxygen debt. In the second analysis, unsurprisingly, the most dysoxic group at baseline had the highest and most persistently elevated levels of all the markers. Also noteworthy is the late (after 24 hours) but dramatic rise in caspase-3 in the middle group. Overall, this study provides additional and valuable biological plausibility to the oxygen debt hypothesis. I hope the third analysis suggested above is forthcoming.
Since the original EGDT trial, and following the advent of the Surviving Sepsis Campaign, there have been a number of published studies demonstrating the benefits of early protocolised care in patients with severe sepsis and septic shock. However, none have prospectively tested the EGDT protocol in a real world setting. Jones and colleagues have now done so [3]. Using a before and after design, they collected data for one year, on patients with septic shock attending their emergency department, then instituted EGDT and collected data for a further year. They observed 79 patients in the data capture group and 77 in the EGDT group. Their patient population differed significantly from the original study, being not as sick at presentation, but despite this, they found a mortality reduction from 27% to 18%. Protocolising care resulted in earlier administration of antibiotics, nearly twice as much crystalloid administration, a four times increase in the intubation rate and a doubling of vasopressor use in the first six hours. Of note, 40% of the EGDT group also received corticosteroids as compared to just 6% of the non EGDT group. Though no doubt, the criticism will be levelled at this study that the observed group received suboptimal care, what this, and all of the other studies in this area have demonstrated, is that raising the profile of sepsis and implementing a time critical approach to care improves outcomes. Arguments about the elements of the protocol will no doubt continue as well, however, those with strong pro or con views would be best served by expending their time and energy designing and conducting clinical trials to provide an evidence base upon which to base future guidelines.