Restrictive Intravenous Fluids Trial in Sepsis

NCT03137446 | Completed DMC

• 1 other identifier: 409916
• Study Type: interventional
• Target: 113
• Locations: 1 country
• Sites: 1

Brief Summary

IV fluid resuscitation has long been recognized to be an important treatment for patients with severe sepsis and septic shock. While under-resuscitation is known to increase morbidity and mortality, contemporary data suggests that overly aggressive fluid resuscitation may also be harmful. Currently, following an initial IVF resuscitation of 30 ml/kg, there is no standard of care and a lack of evidence to support a fluid restrictive or more liberal strategy. The investigators seek to determine if a fluid restrictive strategy reduces morbidity and mortality among patients with severe sepsis and septic shock.

Conditions

Septic Shock; Severe Sepsis

Keywords

Intravenous fluid resuscitation; Septic shock; Severe sepsis; Fluid restriction

Outcome Measures

Primary Outcomes (1)

• Discharge Mortality and Persistent Organ Dysfunction (POD) a composite outcome

  Persistent Organ Dysfunction is defined as the ongoing need for vasopressor agents such as norepinephrine, epinephrine, vasopressin or dopamine for more than two hours in a given day; persistent renal failure as defined by the need for any ongoing renal replacement therapy; or persistent respiratory failure as defined by the ongoing need for mechanical ventilation at least 2 hours a day. The composite outcome will be defined as having at least one of the 4 possible composite outcomes (death, vasopressor support, persistent renal failure, or persistent respiratory failure). If a patient has one or more of these outcomes they will be classified as having the primary composite outcome. If the patient has 0 of 4 outcomes they will be classified as not having the composite outcome.

  At participant hospital discharge or up to 60 days

Secondary Outcomes (9)

• 7 day Mortality and Persistent Organ Dysfunction

  Day 7

• 30 day Mortality and Persistent Organ Dysfunction

  Day 30

• 60 day Mortality and Persistent Organ Dysfunction

  Day 60

• Intensive Care Unit length of stay

  up to 60 days

• Length of Shock

  up to 60 days

Study Arms (2)

Usual Care

NO INTERVENTION

Participants randomized to the usual care resuscitation strategy will receive an initial 30 ml/kg bolus and then IV fluids as needed and without limit as well as IV vasopressors to maintain a MAP\>65, determined by the primary care team for the duration of the study.

Restrictive Care

EXPERIMENTAL

Participants randomized to the restrictive fluid resuscitation strategy will be LIMITED to 60 ml/kg (up to 6000 ml) of IV fluids as initial resuscitation followed by administration of IV vasopressors to maintain a MAP\>65 mm Hg for the first 72 hours of care. The intervention is defined as capping the total allowed IVF administered. After 72 hours the participants are eligible for IV fluids as determined by the primary care team.

Other: Intravenous Fluid Cap

Interventions

Intravenous Fluid Cap OTHER

Normal Saline or Ringers Lactate limited to 60ml/kg for first 72 hours

Restrictive Care

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• The patients must be suspected by the treating physician to have sepsis causing their acute illness as exhibited by 2 or more of the following Systemic Inflammatory Response Syndrome (SIRS) criteria was well as a known or suspected infection at the time of screening:
• Temperature of \> 38 C or \< 36 C
• Heart rate of \> 90/min
• Respiratory rate of \> 20/min or PaCO2 \< 32 mm Hg
• White blood cell count \> 12000/mm3 or \< 4000/mm3 or \>10% immature bands.
• Since approximately 12% of patients ultimately diagnosed with sepsis do not meet SIRS criteria , SIRS negative patients will be eligible for the study if the treating physician makes a clinical diagnosis of severe sepsis or septic shock.
• Patients must be suspected of having severe sepsis or septic shock defined as refractory hypotension or a lactic acid\>4 at the time of enrollment. Refractory hypotension is defined as having a SBP \<90 or MAP \<65, for 15 minutes, following 1000 mL of IV fluid or a blood pressure maintained by vasopressor administration.
• Patients must have received less than 60ml/kg of intravenous fluid at time of study enrollment.

You may not qualify if:

• Patients with a PRIMARY diagnosis of acute cerebral vascular event, acute coronary syndrome, acute pulmonary edema, status asthmaticus, active gastrointestinal bleeding, seizure, drug overdose, burn, trauma, requirement for immediate surgery, or undergoing extracorporeal membrane oxygenation.
• Patients who have a diagnosis of severe sepsis or septic shock and additionally have an active fluid wasting process such as extensive diarrhea, diabetes insipidus, cerebral salt wasting, or an osmotic diuresis.
• Patients who have a diagnosis of severe sepsis or septic shock who have a concurrent diagnosis of diabetic ketoacidosis, hyperosmolar non-ketotic hyperglycemia, or rhabdomyolysis.
• Patients who have received \>60 ml/kg of IVF resuscitation.
• Patient who are \<18 years old, pregnant, or incarcerated.

Sponsors & Collaborators

• Rhode Island Hospital: lead

Study Sites (1)

Rhode Island Hosptial

Providence, Rhode Island, 02903, United States

Location

Related Publications (25)

• Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001 Jul;29(7):1303-10. doi: 10.1097/00003246-200107000-00002.

  PMID: 11445675 BACKGROUND

• Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, Moreno R, Carlet J, Le Gall JR, Payen D; Sepsis Occurrence in Acutely Ill Patients Investigators. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med. 2006 Feb;34(2):344-53. doi: 10.1097/01.ccm.0000194725.48928.3a.

  PMID: 16424713 BACKGROUND

• Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M; Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001 Nov 8;345(19):1368-77. doi: 10.1056/NEJMoa010307.

  PMID: 11794169 BACKGROUND

• Holst LB, Haase N, Wetterslev J, Wernerman J, Guttormsen AB, Karlsson S, Johansson PI, Aneman A, Vang ML, Winding R, Nebrich L, Nibro HL, Rasmussen BS, Lauridsen JR, Nielsen JS, Oldner A, Pettila V, Cronhjort MB, Andersen LH, Pedersen UG, Reiter N, Wiis J, White JO, Russell L, Thornberg KJ, Hjortrup PB, Muller RG, Moller MH, Steensen M, Tjader I, Kilsand K, Odeberg-Wernerman S, Sjobo B, Bundgaard H, Thyo MA, Lodahl D, Maerkedahl R, Albeck C, Illum D, Kruse M, Winkel P, Perner A; TRISS Trial Group; Scandinavian Critical Care Trials Group. Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med. 2014 Oct 9;371(15):1381-91. doi: 10.1056/NEJMoa1406617. Epub 2014 Oct 1.

  PMID: 25270275 BACKGROUND

• Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA; Emergency Medicine Shock Research Network (EMShockNet) Investigators. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA. 2010 Feb 24;303(8):739-46. doi: 10.1001/jama.2010.158.

  PMID: 20179283 BACKGROUND

• ProCESS Investigators; Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA, Pike F, Terndrup T, Wang HE, Hou PC, LoVecchio F, Filbin MR, Shapiro NI, Angus DC. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014 May 1;370(18):1683-93. doi: 10.1056/NEJMoa1401602. Epub 2014 Mar 18.

  PMID: 24635773 BACKGROUND

• Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RD, Jahan R, Harvey SE, Bell D, Bion JF, Coats TJ, Singer M, Young JD, Rowan KM; ProMISe Trial Investigators. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med. 2015 Apr 2;372(14):1301-11. doi: 10.1056/NEJMoa1500896. Epub 2015 Mar 17.

  PMID: 25776532 BACKGROUND

• ARISE Investigators; ANZICS Clinical Trials Group; Peake SL, Delaney A, Bailey M, Bellomo R, Cameron PA, Cooper DJ, Higgins AM, Holdgate A, Howe BD, Webb SA, Williams P. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014 Oct 16;371(16):1496-506. doi: 10.1056/NEJMoa1404380. Epub 2014 Oct 1.

  PMID: 25272316 BACKGROUND

• Marik PE. Early management of severe sepsis: concepts and controversies. Chest. 2014 Jun;145(6):1407-1418. doi: 10.1378/chest.13-2104.

  PMID: 24889440 BACKGROUND

• Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb S, Beale RJ, Vincent JL, Moreno R; Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013 Feb;39(2):165-228. doi: 10.1007/s00134-012-2769-8. Epub 2013 Jan 30.

  PMID: 23361625 BACKGROUND

• Hilton AK, Bellomo R. A critique of fluid bolus resuscitation in severe sepsis. Crit Care. 2012 Jan 25;16(1):302. doi: 10.1186/cc11154.

  PMID: 22277834 BACKGROUND

• Hilton AK, Bellomo R. Totem and taboo: fluids in sepsis. Crit Care. 2011;15(3):164. doi: 10.1186/cc10247. Epub 2011 Jun 10.

  PMID: 21672278 BACKGROUND

• Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Engl J Med. 2001 Aug 23;345(8):588-95. doi: 10.1056/NEJMra002709. No abstract available.

  PMID: 11529214 BACKGROUND

• Ueda S, Nishio K, Akai Y, Fukushima H, Ueyama T, Kawai Y, Masui K, Yoshioka A, Okuchi K. Prognostic value of increased plasma levels of brain natriuretic peptide in patients with septic shock. Shock. 2006 Aug;26(2):134-9. doi: 10.1097/01.shk.0000226266.99960.d0.

  PMID: 16878020 BACKGROUND

• Zhang Z, Zhang Z, Xue Y, Xu X, Ni H. Prognostic value of B-type natriuretic peptide (BNP) and its potential role in guiding fluid therapy in critically ill septic patients. Scand J Trauma Resusc Emerg Med. 2012 Dec 31;20:86. doi: 10.1186/1757-7241-20-86.

  PMID: 23276277 BACKGROUND

• Bruegger D, Jacob M, Rehm M, Loetsch M, Welsch U, Conzen P, Becker BF. Atrial natriuretic peptide induces shedding of endothelial glycocalyx in coronary vascular bed of guinea pig hearts. Am J Physiol Heart Circ Physiol. 2005 Nov;289(5):H1993-9. doi: 10.1152/ajpheart.00218.2005. Epub 2005 Jun 17.

  PMID: 15964925 BACKGROUND

• Bruegger D, Schwartz L, Chappell D, Jacob M, Rehm M, Vogeser M, Christ F, Reichart B, Becker BF. Release of atrial natriuretic peptide precedes shedding of the endothelial glycocalyx equally in patients undergoing on- and off-pump coronary artery bypass surgery. Basic Res Cardiol. 2011 Nov;106(6):1111-21. doi: 10.1007/s00395-011-0203-y. Epub 2011 Jul 19.

  PMID: 21769675 BACKGROUND

• Alphonsus CS, Rodseth RN. The endothelial glycocalyx: a review of the vascular barrier. Anaesthesia. 2014 Jul;69(7):777-84. doi: 10.1111/anae.12661. Epub 2014 Apr 28.

  PMID: 24773303 BACKGROUND

• Bark BP, Persson J, Grande PO. Importance of the infusion rate for the plasma expanding effect of 5% albumin, 6% HES 130/0.4, 4% gelatin, and 0.9% NaCl in the septic rat. Crit Care Med. 2013 Mar;41(3):857-66. doi: 10.1097/CCM.0b013e318274157e.

  PMID: 23318490 BACKGROUND

• Micek ST, McEvoy C, McKenzie M, Hampton N, Doherty JA, Kollef MH. Fluid balance and cardiac function in septic shock as predictors of hospital mortality. Crit Care. 2013 Oct 20;17(5):R246. doi: 10.1186/cc13072.

  PMID: 24138869 BACKGROUND

• Boyd JH, Forbes J, Nakada TA, Walley KR, Russell JA. Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality. Crit Care Med. 2011 Feb;39(2):259-65. doi: 10.1097/CCM.0b013e3181feeb15.

  PMID: 20975548 BACKGROUND

• Kelm DJ, Perrin JT, Cartin-Ceba R, Gajic O, Schenck L, Kennedy CC. 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. 2015 Jan;43(1):68-73. doi: 10.1097/SHK.0000000000000268.

  PMID: 25247784 BACKGROUND

• Maitland K, Kiguli S, Opoka RO, Engoru C, Olupot-Olupot P, Akech SO, Nyeko R, Mtove G, Reyburn H, Lang T, Brent B, Evans JA, Tibenderana JK, Crawley J, Russell EC, Levin M, Babiker AG, Gibb DM; FEAST Trial Group. Mortality after fluid bolus in African children with severe infection. N Engl J Med. 2011 Jun 30;364(26):2483-95. doi: 10.1056/NEJMoa1101549. Epub 2011 May 26.

  PMID: 21615299 BACKGROUND

• Kaukonen KM, Bailey M, Pilcher D, Cooper DJ, Bellomo R. Systemic inflammatory response syndrome criteria in defining severe sepsis. N Engl J Med. 2015 Apr 23;372(17):1629-38. doi: 10.1056/NEJMoa1415236. Epub 2015 Mar 17.

  PMID: 25776936 BACKGROUND

• Heyland DK, Muscedere J, Drover J, Jiang X, Day AG; Canadian Critical Care Trials Group. Persistent organ dysfunction plus death: a novel, composite outcome measure for critical care trials. Crit Care. 2011;15(2):R98. doi: 10.1186/cc10110. Epub 2011 Mar 18.

  PMID: 21418560 BACKGROUND

MeSH Terms

Conditions

Shock, Septic; Sepsis

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock

Study Officials

• Keith Corl, MD

  Department of Pulmonary Critical Care Brown University

  PRINCIPAL INVESTIGATOR

• Mitchell Levy, MD

  Department of Pulmonary Critical Care Brown University

  STUDY CHAIR

• Amy Palmisciano, RN, BSN

  Department of Pulmonary Critical Care Brown University

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Randomized Trial

Study Record Dates

• First Submitted: April 10, 2017
• First Posted: May 2, 2017
• Study Start: April 20, 2017
• Primary Completion: March 30, 2018
• Study Completion: March 30, 2018
• Last Updated: August 31, 2018

Record last verified: 2018-06

Locations

US (1)