Infectious disease/concepts
Liberal Versus Restrictive Intravenous Fluid Therapy for Early Septic Shock: Rationale for a Randomized Trial

https://doi.org/10.1016/j.annemergmed.2018.03.039Get rights and content

Prompt intravenous fluid therapy is a fundamental treatment for patients with septic shock. However, the optimal approach for administering intravenous fluid in septic shock resuscitation is unknown. Two competing strategies are emerging: a liberal fluids approach, consisting of a larger volume of initial fluid (50 to 75 mL/kg [4 to 6 L in an 80-kg adult] during the first 6 hours) and later use of vasopressors, versus a restrictive fluids approach, consisting of a smaller volume of initial fluid (≤30 mL/kg [≤2 to 3 L]), with earlier reliance on vasopressor infusions to maintain blood pressure and perfusion. Early fluid therapy may enhance or maintain tissue perfusion by increasing venous return and cardiac output. However, fluid administration may also have deleterious effects by causing edema within vital organs, leading to organ dysfunction and impairment of oxygen delivery. Conversely, a restrictive fluids approach primarily relies on vasopressors to reverse hypotension and maintain perfusion while limiting the administration of fluid. Both strategies have some evidence to support their use but lack robust data to confirm the benefit of one strategy over the other, creating clinical and scientific equipoise. As part of the National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Network, we designed a randomized clinical trial to compare the liberal and restrictive fluids strategies, the Crystalloid Liberal or Vasopressor Early Resuscitation in Sepsis trial. The purpose of this article is to review the current literature on approaches to early fluid resuscitation in adults with septic shock and outline the rationale for the upcoming trial.

Introduction

For the past 2 decades, clinicians in the emergency department (ED) and ICU have routinely administered large volumes of intravenous fluid to patients with septic shock, often totaling greater than 5 L in the first several hours of resuscitation.1, 2, 3, 4, 5 However, an improved mechanistic understanding of potential harm from excessive fluid administration6, 7, 8 and emerging observational data associating positive fluid balance with higher mortality9, 10, 11, 12, 13, 14, 15 have recently challenged the paradigm of large-volume fluid resuscitation.

Because of inadequate evidence to support a specific intravenous fluid strategy for the management of early septic shock, 2 alternative approaches have emerged: a liberal fluids approach that relies on a larger volume of initial intravenous fluid administration (often 50 to 75 mL/kg [4 to 6 L in an 80-kg adult]); and a restrictive fluids approach consisting of a smaller volume of initial intravenous fluid (often ≤30 mL/kg [≤2 to 3 L]) and earlier use of vasopressors. Because of the equipoise surrounding these competing treatment strategies, we designed a randomized clinical trial to compare a liberal versus restrictive approach to intravenous fluid resuscitation, the Crystalloid Liberal or Vasopressor Early Resuscitation in Sepsis (CLOVERS) trial. The goal of this article is to describe the current state of the literature in regard to intravenous fluid resuscitation in early septic shock and the rationale for the upcoming CLOVERS trial.

Section snippets

Liberal Fluids Approach

A “liberal” fluids approach to septic shock management is characterized by the administration of several liters (typically 50 to 75 mL/kg) of intravenous fluid during the first several hours of treatment.1, 16, 17 Vasopressor infusions are added immediately if the patient is profoundly hypotensive (eg, systolic blood pressure <70 mm Hg) or remains hypotensive despite large-volume fluid resuscitation. This liberal fluids strategy dominates current ED care in the United States, based in part on

Restrictive Fluids Approach

A “restrictive” fluids approach to septic shock management is characterized by the administration of smaller fluid volumes (often ≤30 mL/kg) and earlier use of vasopressors to reduce vasodilation and improve tissue perfusion.17 With a restrictive fluids approach, the primary method of maintaining blood pressure and systemic perfusion is through vasopressor titration, with fluid boluses added when there is evidence of extreme hypovolemia or when tissue hypoperfusion is suspected despite high

CLOVERS: An Upcoming Trial

Recognizing the equipoise around intravenous fluid management during early sepsis resuscitation and the critical importance of high-quality data in this area to promote continued improvement in sepsis outcomes, the National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Clinical Trials Network (http://www.petalnet.org) developed the CLOVERS trial. The network consists of emergency medicine and critical care researchers at more than 40 enrolling centers

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    Supervising editor: David A. Talan, MD

    Authorship: All authors attest to meeting the four ICMJE.org authorship criteria: (1) Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; AND (2) Drafting the work or revising it critically for important intellectual content; AND (3) Final approval of the version to be published; AND (4) Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

    Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). This work was supported by National Heart, Lung, and Blood Institute U01 grants HL123009, HL123010, HL123004, HL123022, HL122989, HL123008, HL123027, HL123020, HL123018, HL123031, HL123033, HL122998, and HL123023. Dr. Self was supported in part by K23GM110469 from the National Institute of General Medical Sciences. All authors are supported by the National Heart, Lung, and Blood Institute within the National Institutes of Health (NIH) for participation in the Prevention and Early Treatment of Acute Lung Injury Clinical Trials Network. Dr. Self reports receiving grants from Cheetah Medical; consultant fees from Abbott Point of Care, Cempra Pharmaceuticals, Ferring Pharmaceuticals, and BioTest AG; and travel funds from Gilead Sciences and Pfizer. Dr. Brown reports receiving fees from Faron Pharmaceuticals for serving on a steering committee for a clinical trial in acute respiratory distress syndrome. Dr. Ginde reports receiving consulting fees from the Coalition for Sepsis Survival (a nonprofit foundation) to develop sepsis-related algorithms. Dr. Liu reports stock ownership with Amgen; receiving consultant fees from Achaogen, Durect, Z S Pharma, Theravance, Quark, and Potrero Medical; receiving travel funds from the American Society of Nephrology and National Policy Forum on Critical Care and Acute Renal Failure; and receiving compensation for an editorial position from the National Kidney Foundation. Dr. Miller reports receiving grants from Abbott, Ferring, Siemens, as well as software from Siemens. Dr. Rice reports receiving consultant fees from Cumberland Pharmaceuticals, Inc, and personal fees from Avisa Pharma, LLC. Dr. Douglas reports a relationship with Cheetah Medical in which he is principal investigator for an industry-sponsored sepsis trial; payments for his principal investigator role and study-site enrollment are to his employer, an academic hospital. Dr. Shapiro reports receiving research funding from the NIH, Siemens, Lajolla Pharmaceuticals, and ThermoFisher, as well as advisory board income from Baxter.

    Trial registration number: NCT03434028

    The opinions expressed in this article are those of the authors and do not necessarily represent those of the US Department of Health and Human Services, the National Institutes of Health, or the National Heart, Lung, and Blood Institute.

    A podcast for this article is available at www.annemergmed.com.

    A list of PETAL Network Investigators is included in Appendix E1, available online at http://www.annemergmed.com.

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