Infectious disease/conceptsLiberal Versus Restrictive Intravenous Fluid Therapy for Early Septic Shock: Rationale for a Randomized 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
References (61)
- et al.
Positive fluid balance as a prognostic factor for mortality and acute kidney injury in severe sepsis and septic shock
J Crit Care
(2015) - et al.
Accountability for sepsis treatment: the SEP-1 Core Measure
Chest
(2017) - et al.
Translating research to clinical practice: a 1-year experience with implementing early goal-directed therapy for septic shock in the emergency department
Chest
(2006) Unbundling early sepsis resuscitation
Ann Emerg Med
(2014)- et al.
Central venous pressure and shock index predict lack of hemodynamic response to volume expansion in septic shock: a prospective observational study
J Crit Care
(2012) - et al.
The importance of fluid management in acute lung injury secondary to septic shock
Chest
(2009) - et al.
Fluid balance in sepsis and septic shock as a determining factor of mortality
Am J Emerg Med
(2015) - et al.
A most stubborn bias: no adjustment method fully resolves confounding by indication in observational studies
J Clin Epidemiol
(2010) - et al.
Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016
Crit Care Med
(2017) - et al.
A randomized trial of protocol-based care for early septic shock
N Engl J Med
(2014)
Goal-directed resuscitation for patients with early septic shock
N Engl J Med
Trial of early, goal-directed resuscitation for septic shock
N Engl J Med
Early goal directed therapy in severe sepsis and septic shock: insights and comparisons to ProCESS, ProMISe and ARISE
Crit Care
Iatrogenic salt water drowning and the hazards of a high central venous pressure
Ann Intensive Care
Physiologic changes after fluid bolus therapy in sepsis: a systematic review of contemporary data
Crit Care
Exploring mechanisms of excess mortality with early fluid resuscitation: insights from the FEAST trial
BMC Med
Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality
Crit Care Med
Fluid balance and cardiac function in septic shock as predictors of hospital mortality
Crit Care
Fluid resuscitation in septic shock: the effect of increasing fluid balance on mortality
J Intensive Care Med
A positive fluid balance is an independent prognostic factor in patients with sepsis
Crit Care
Fluid overload in patients with severe sepsis and septic shock treated with early goal directed therapy is associated with increased acute need for fluid-related medical interventions and hospital death
Shock
Higher fluid balance increases the risk of death from sepsis: results from a large international audit
Crit Care Med
Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock:2012
Crit Care Med
Restricting volumes of resuscitation fluid in septic shock after the initial management: the CLASSIC randomised, parallel-group, multicenter feasibility trial
Intensive Care Med
Effects of fluids on microvascular perfusion in patients with severe sepsis
Intensive Care Med
Serious adverse events associated with vasopressin and norepinephrine infusion for septic shock
Crit Care Med
Early goal directed therapy in severe sepsis and septic shock
N Engl J Med
Implementation and outcomes of the Multiple Urgent Sepsis Therapies (MUST) protocol
Crit Care Med
Before-after study of a standardized hospital order set for the management of septic shock
Crit Care Med
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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.
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A list of PETAL Network Investigators is included in Appendix E1, available online at http://www.annemergmed.com.