“The Case of the Dying Detective Continues…”

A picture of Florence Nightingale (1820-1910), "The Lady with the lamp", the English nurse, famous for her work during the Crimean War, is seen here in the hospital at Scutari, Turkey.

Survivors of the Armageddon in any of its many forms, zombie, alien, or otherwise, are often left in a state of emotional turmoil. They face an uncertain future, the loss of loved ones, and the constant stress of imminent danger. Underneath the obvious anguish lies a deeper more subtle but equally distressing sentiment, uncertainty. Now faced with a world completely devoid of the values they once held dear, they are often incapable of finding meaning in this post-apocalyptic wasteland. On March 18th 2014, the publication of the ProCESS trial has ushered in a new era of sepsis management (1). And yet despite being the largest and highest quality trial thus far to examine the efficacy of various strategies for managing the septic patient, it has done very little to illuminate what this post-Early Goal Directed Therapy (EGDT) era will entail.

In 2001 Rivers et al published the findings of a single center 263 subject RCT examining the efficacy of an Emergency Department based protocol consisting of reaching stepwise goals meant to optimize hemodynamics and tissue perfusion (2). Comparing this protocol to “standard care” the authors reported astounding results, with an absolute mortality benefit of 16% in favor of the protocol based strategy. Initial trials of Goal Directed Therapy which failed to demonstrate benefit when applied to ICU patients, now obtained incredible results when implemented in the Emergency Department (11,12). And thus the era of EGDT was born. This acronym was the battle cry for Emergency Physicians near and far.  Enforced, in some cases, in a militaristic fashion it became the standard of care in Emergency Departments internationally.

However there was unease among the troops, in the form of a number of those opposed to accepting EGDT in its entirety. After all was it a wise decision to globally adopt a protocol based off a single center study with so few participants? They challenged the wisdom of the unquestioning application of EGDT as a bundled therapy. Though components of EGDT undoubtedly benefit patients in septic shock (fluids, early antibiotics and supportive care), others have proven to be of no benefit and in some cases harmful (dobutamine use and CVP monitoring)(3). These subtleties required further examination before adopting the bundle universally.

ProCESS sought to address these very concerns, and in a sense it was a success. In a 1:1:1 RCT design, Yealy et al compared the Rivers EGDT protocol, to both a less invasive but still protocol-based strategy, and a “usual care” group(care as determined by the attending physician).  The authors found no difference in any of the endpoints measured. Most importantly, the primary endpoint, 60-day mortality was found to be 21.0%, 18.2%, and 18.9% respectively. Although there were small differences in the total amount of fluid given within the first 6 hours, the main differences in the 3 groups were the use of vasopressors (significantly higher in the two protocol-based groups) and dobutamine (only used with any consistency in the EGDT group).

ProCESS exposes many important aspects of the management of sepsis. First the importance of EGDT is not in the execution of the bundle in its entirety, but rather the value of early and aggressive fluid resuscitation and the necessity of early administration of broad-spectrum antibiotics. ProCESS also establishes that there is more than one way to manage the septic patient. Providing evidence that the unstructured judgment of physicians is as effective in determining fluid status, hemodynamics and tissue perfusion as a standardized protocol.

What the ProCESS trial fails to divulge is the most effective strategy to guide fluid therapy. The authors compared unstructured clinician judgment (not specifically defined) of fluid responsiveness to either CVP or SBP plus shock index, neither of which are reliable indicators of true fluid responsiveness. We have known for some time now that from a physiological standpoint CVP is a poor marker of fluid responsiveness(4). Since the publication of the Rivers EGDT bundle many more elegant and intrinsically accurate methods of assessing fluid responsiveness have been proposed.

Bedside ECHO, IVC ultrasound, and non-invasive CO monitors have all been suggested as alternatives to CVP monitoring (each found to be more reliable predictors of fluid responsiveness). The trials that examine the accuracy of these methods in assessing fluid responsiveness have used the surrogate endpoint of CO, measured by pulmonary artery catheter (PAC) (5,6,7,8,9). PAC has generally been viewed as the gold standard for measuring cardiac output (CO), and yet in the case of assessing fluid responsiveness in the septic patient it should be viewed as a surrogate endpoint. When treating a patient in septic shock it is not critical to know their specific CO or how our fluid challenge affects it. What is important is how our fluid challenge affects this patient’s morbidity and mortality. Though we assume that cardiac output and direct assessment of fluid responsiveness with a PAC are ideal metrics to follow, we have no real proof supporting this concept. In fact the only real evidence we have has demonstrated just the opposite. A large multi-center RCT published by Richards et al in JAMA in 2003, examined this very question (10). 681 ICU patients in shock (86% septic in origin) were randomized to have their treatment facilitated by PAC measurements or solely based on the clinical judgment of the treating physician. This trial failed to demonstrate any added clinical benefit to the addition of direct monitoring of a patient’s cardiac output and fluid responsiveness. Thus using the accuracy with which ECHO, IVC ultrasound, or non-invasive CO monitors predict PAC findings to decide the ideal strategy to guide fluid resuscitation, when direct measurements of these metrics via PAC were of no benefit to clinical outcomes, seems logically flawed.

It is necessary to examine how ECHO, IVC ultrasound and non-invasive CO monitors affect patient oriented, clinically relevant endpoints. Rivers et al proposed CVP, and up until the publication of the ProCESS trial, it was the only metric that when used to guide fluid resuscitation in a clinically trial improves mortality. The ProCESS trial has demonstrated that CVP is not superior to unstructured clinician judgment. Unfortunately, ProCESS fails to provide us with a better option. ECHO, IVC ultrasound, or non-invasive CO monitors may be more accurate guides, but until they are tested against clinician judgment, using patient oriented endpoints, it is hard to truly quantify their utility. In the ProCESS trial mortality was unaffected between groups despite the fact that there was over a liter difference in the quantity of fluid administered (5,059 mL, 5,511 mL, 4,362 mL respectively).  This may suggest a precise measurement of fluid responsiveness is not necessary (1). Merely assessing for fluid tolerance rather than responsiveness and using IVC ultrasound may be the simplest and most effective method to guide fluid administration.

ProCESS has ushered in a new era for the management of sepsis in the Emergency Department. Though this trial was able to clarify the importance of fluid and early antibiotics as key components in the septic bundle, it has yielded little assistance on how best to guide the administration of said fluid. In this post-EGDT dystopia, it may be that a single metric will never be as powerful a tool as the flawed mind of the physician caring for the patient. The human brain, with all its beautiful imperfections may prove to be superior to any single objective measurement. A new era indeed…


Sources Cited:

1. The ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. N Engl J Med.  2014 March.

2. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med.  2001;345:1368-1377.

3. Marik et al. Early goal-directed therapy: on terminal life support? Am J Emerg Med. 2010 Feb;28(2):243-5.

4. Marik et al. Does the central venous pressure predict fluid responsiveness? An updated meta-analysis and a plea for some common sense. Crit Care Med. 2013 Jul;41(7):1774-81.

5. Marik et al.Noninvasive cardiac output monitors: a state-of the-art review. J Cardiothorac Vasc Anesth. 2013 Feb;27(1):121-34.

6. Marik et al. Hemodynamic parameters to guide fluid therapy. Annals of Intensive Care. 2011, 1:1.

7. Barbier et al. Respiratory changes in inferior vena cava diameter are helpful in predicting fluid responsiveness in ventilated septic patients. Intensive Care Med 2004, 30:1740-1746.

8. Feissel et al. The respiratory variation in inferior vena cava diameter as a guide to fluid therapy. Intensive Care Med 2004, 30:1834-1837.

9. Biais et al. Changes in stroke volume induced by passive leg raising in spontaneously breathing patients: comparison between echocardiography and Vigileo/FloTrac device. Crit Care 2009, 13.

10. Richard et al. Early Use of the Pulmonary Artery Catheter and Outcomes in Patients With Shock and Acute Respiratory Distress Syndrome: A Randomized Controlled Trial. JAMA. 2003;290(20):2713-2720.

11. Hayes et al. Elevation of Systemic Oxygen Delivery in the Treatment of Critically Ill Patients. N Engl J Med. 1994 Jun;330(24):1717-22.

12. Gattinoni et al. A Trial of Goal-Oriented Hemodynamic Therapy in Critically Ill Patients. N Engl J Med. 1995 Oct;333(16):1025-32.

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