A trial to determine whether septic shock-reversal is quicker in pediatric patients randomized to an early goal-directed fluid-sparing strategy versus usual care (SQUEEZE): study protocol for a pilot randomized controlled trial

Melissa J Parker, Lehana Thabane, Alison Fox-Robichaud, Patricia Liaw, Karen Choong, Canadian Critical Care Trials Group and the Canadian Critical Care Translational Biology Group, Melissa J Parker, Lehana Thabane, Alison Fox-Robichaud, Patricia Liaw, Karen Choong, Canadian Critical Care Trials Group and the Canadian Critical Care Translational Biology Group

Abstract

Background: Current pediatric septic shock resuscitation guidelines from the American College of Critical Care Medicine focus on the early and goal-directed administration of intravascular fluid followed by vasoactive medication infusions for persistent and fluid-refractory shock. However, accumulating adult and pediatric data suggest that excessive fluid administration is associated with worse patient outcomes and even increased risk of death. The optimal amount of intravascular fluid required in early pediatric septic shock resuscitation prior to the initiation of vasoactive support remains unanswered.

Methods/design: The SQUEEZE Pilot Trial is a pragmatic, two-arm, parallel-group, open-label, prospective pilot randomized controlled trial. Participants are children aged 29 days to under 18 years with suspected or confirmed septic shock and a need for ongoing resuscitation. Eligible participants are enrolled under an exception to consent process and randomly assigned via concealed allocation to either the Usual Care (control) or Fluid Sparing (intervention) resuscitation strategy. The primary objective of this pilot trial is to determine feasibility, based on the ability to enroll participants and to adhere to the study protocol. The primary outcome measure by which success will be determined is participant enrollment rate ("pass" defined as at least two participants/site/month, recognizing that enrollment may be slower during the run-in phase). Secondary objectives include assessing (1) appropriateness of eligibility criteria, and (2) completeness of clinical outcomes to inform the endpoints for the planned multisite trial. To support the nested translational study, SQUEEZE-D, we will also evaluate the feasibility of describing cell-free DNA (a procoagulant molecule with prognostic utility) in blood samples obtained from children enrolled into the SQUEEZE Pilot Trial at baseline and at 24 h.

Discussion: The optimal degree of fluid resuscitation and the timing of initiation of vasoactive support in order to achieve recommended therapeutic targets in children with septic shock remains unanswered. No prospective study to date has examined this important question for children in developed countries including Canada. Recruitment for the SQUEEZE Pilot Trial opened on 6 January 2014. Findings will inform the feasibility of the planned multicenter trial to answer our overall research question.

Trial registration: ClinicalTrials.gov Identifier NCT01973907 , registered on 23 October 2013.

Keywords: Fluid therapy; Pediatrics; Resuscitation; Sepsis; Shock.

Figures

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Fig. 1
Flow of participants

References

    1. Goldstein B, Giroir B, Randolph A, Sepsis ICCoP International Pediatric Sepsis Consensus Conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med. 2005;6(1):2–8. doi: 10.1097/01.PCC.0000149131.72248.E6.
    1. Carcillo JA, Tasker RC. Fluid resuscitation of hypovolemic shock: acute medicine’s great triumph for children. Intensive Care Med. 2006;32(7):958–61. doi: 10.1007/s00134-006-0189-3.
    1. Brierley J, Carcillo JA, Choong K, Cornell T, Decaen A, Deymann A, et al. Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine. Crit Care Med. 2009;37(2):666–88. doi: 10.1097/CCM.0b013e31819323c6.
    1. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580–637. doi: 10.1097/CCM.0b013e31827e83af.
    1. Ranjit S, Kissoon N, Jayakumar I. Aggressive management of dengue shock syndrome may decrease mortality rate: a suggested protocol. Pediatr Crit Care Med. 2005;6(4):412–9. doi: 10.1097/.
    1. Han YY, Carcillo JA, Dragotta MA, Bills DM, Watson RS, Westerman ME, et al. Early reversal of pediatric-neonatal septic shock by community physicians is associated with improved outcome. Pediatrics. 2003;112(4):793–9. doi: 10.1542/peds.112.4.793.
    1. Carcillo JA, Davis AL, Zaritsky A. Role of early fluid resuscitation in pediatric septic shock. JAMA. 1991;266(9):1242–5. doi: 10.1001/jama.1991.03470090076035.
    1. Carcillo JA, Kuch BA, Han YY, Day S, Greenwald BM, McCloskey KA, et al. Mortality and functional morbidity after use of PALS/APLS by community physicians. Pediatrics. 2009;124(2):500–8. doi: 10.1542/peds.2008-1967.
    1. Oliveira CF, de Sa FRN, Oliveira DSF, Gottschald AFC, Moura JDG, Shibata ARO, et al. Time- and fluid-sensitive resuscitation for hemodynamic support of children in septic shock: barriers to the implementation of the American College of Critical Care Medicine/Pediatric Advanced Life Support Guidelines in a pediatric intensive care unit in a developing world. Pediatr Emerg Care. 2008;24(12):810–5. doi: 10.1097/PEC.0b013e31818e9f3a.
    1. Hilton AK, Bellomo R. Totem and taboo: fluids in sepsis. Crit Care. 2011;15(3):164. doi: 10.1186/cc10247.
    1. 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;39(2):259–65. doi: 10.1097/CCM.0b013e3181feeb15.
    1. Murphy CV, Schramm GE, Doherty JA, Reichley RM, Gajic O, Afessa B, et al. The importance of fluid management in acute lung injury secondary to septic shock. Chest. 2009;136(1):102–9. doi: 10.1378/chest.08-2706.
    1. Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, et al. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med. 2006;34(2):344–53. doi: 10.1097/01.CCM.0000194725.48928.3A.
    1. Payen D, de Pont AC, Sakr Y, Spies C, Reinhart K, Vincent JL, et al. A positive fluid balance is associated with a worse outcome in patients with acute renal failure. Crit Care. 2008;12(3):R74. doi: 10.1186/cc6916.
    1. Maitland K, Kiguli S, Opoka RO, Engoru C, Olupot-Olupot P, Akech SO, et al. Mortality after fluid bolus in African children with severe infection. N Engl J Med. 2011;364(26):2483–95. doi: 10.1056/NEJMoa1101549.
    1. Ford N, Hargreaves S, Shanks L. Mortality after fluid bolus in children with shock due to sepsis or severe infection: a systematic review and meta-analysis. PLoS One. 2012;7(8):e43953. doi: 10.1371/journal.pone.0043953.
    1. Arikan AA, Zappitelli M, Goldstein SL, Naipaul A, Jefferson LS, Loftis LL. Fluid overload is associated with impaired oxygenation and morbidity in critically ill children. Pediatr Crit Care Med. 2012;13(3):253–8. doi: 10.1097/PCC.0b013e31822882a3.
    1. van Paridon BM, Sheppard C, Garcia Guerra G, Joffe AR, Alberta Sepsis N Timing of antibiotics, volume, and vasoactive infusions in children with sepsis admitted to intensive care. Crit Care. 2015;19:293. doi: 10.1186/s13054-015-1010-x.
    1. Watson RS, Carcillo JA, Linde-Zwirble WT, Clermont G, Lidicker J, Angus DC. The epidemiology of severe sepsis in children in the United States. Am J Respir Crit Care Med. 2003;167(5):695–701. doi: 10.1164/rccm.200207-682OC.
    1. Inwald DP, Tasker RC, Peters MJ, Nadel S, Paediatric Intensive Care Society Study Group Emergency management of children with severe sepsis in the United Kingdom: the results of the Paediatric Intensive Care Society sepsis audit. Arch Dis Child. 2009;94(5):348–53. doi: 10.1136/adc.2008.153064.
    1. Carcillo JA, Fields AI, American College of Critical Care Medicine Task Force Committee Members Clinical practice parameters for hemodynamic support of pediatric and neonatal patients in septic shock. Crit Care Med. 2002;30(6):1365–78. doi: 10.1097/00003246-200206000-00040.
    1. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368–77. doi: 10.1056/NEJMoa010307.
    1. Kissoon N, Carcillo JA, Espinosa V, Argent A, Devictor D, Madden M, et al. World Federation of Pediatric Intensive Care and Critical Care Societies: Global Sepsis Initiative. Pediatr Crit Care Med. 2011;12(5):494–503. doi: 10.1097/PCC.0b013e318207096c.
    1. Ribeiro CT, Delgado AF, de Carvalho WB. Mortality after fluid bolus in African children with sepsis. N Engl J Med. 2011;365(14):1348–9. doi: 10.1056/NEJMc1108712.
    1. Scott H, Melendez E, Cruz AT, American Academy of Pediatrics SoEM, Septic Shock Collaborative Mortality after fluid bolus in African children with sepsis. N Engl J Med. 2011;365(14):1350–1.
    1. Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden D, deBoisblanc B, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006;354(24):2564–75. doi: 10.1056/NEJMoa062200.
    1. De Waele JJ, De Laet I, Kirkpatrick AW, Hoste E. Intra-abdominal hypertension and abdominal compartment syndrome. Am J Kidney Dis. 2011;57(1):159–69. doi: 10.1053/j.ajkd.2010.08.034.
    1. Regueira T, Hasbun P, Rebolledo R, Galindo J, Aguirre M, Romero C, et al. Intraabdominal hypertension in patients with septic shock. Am Surg. 2007;73(9):865–70.
    1. Ford SR, Visram A. Mortality after fluid bolus in African children with sepsis. N Engl J Med. 2011;365(14):1348. doi: 10.1056/NEJMc1108712.
    1. Gelbart B, Glassford N, Bellomo R. Fluid bolus therapy-based resuscitation for severe sepsis in hospitalized children: a systematic review. Pediatric Crit Care Med. 2015;16:e297–307. doi: 10.1097/PCC.0000000000000507.
    1. Koerber RK, Haven GT, Cohen SM, Fleming WH, Hofschire PJ. Peripheral gangrene associated with dopamine infusion in a child. Clin Pediatr (Phila) 1984;23(2):106–7. doi: 10.1177/000992288402300209.
    1. Golbranson FL, Lurie L, Vance RM, Vandell RF. Multiple extremity amputations in hypotensive patients treated with dopamine. JAMA. 1980;243(11):1145–6. doi: 10.1001/jama.1980.03300370019018.
    1. Dünser MW, Mayr AJ, Tür A, Pajk W, Barbara F, Knotzer H, et al. Ischemic skin lesions as a complication of continuous vasopressin infusion in catecholamine-resistant vasodilatory shock: incidence and risk factors. Crit Care Med. 2003;31(5):1394–8. doi: 10.1097/01.CCM.0000059722.94182.79.
    1. Arnold DM, Burns KE, Adhikari NK, Kho ME, Meade MO, Cook DJ, et al. The design and interpretation of pilot trials in clinical research in critical care. Crit Care Med. 2009;37(1 Suppl):S69–74. doi: 10.1097/CCM.0b013e3181920e33.
    1. Thabane L, Ma J, Chu R, Cheng J, Ismaila A, Rios L, et al. A tutorial on pilot studies: the what, why and how. BMC Med Res Methodol. 2010;10:1. doi: 10.1186/1471-2288-10-1.
    1. Dwivedi DJ, Toltl LJ, Swystun LL, Pogue J, Liaw KL, Weitz JI, et al. Prognostic utility and characterization of cell-free DNA in patients with severe sepsis. Crit Care. 2012;16(4):R151. doi: 10.1186/cc11466.
    1. Chan AW, Tetzlaff JM, Altman DG, Dickersin K, Moher D. SPIRIT 2013: new guidance for content of clinical trial protocols. Lancet. 2013;381(9861):91–2. doi: 10.1016/S0140-6736(12)62160-6.
    1. Chan AW, Tetzlaff JM, Gotzsche PC, Altman DG, Mann H, Berlin JA, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013;346:e7586. doi: 10.1136/bmj.e7586.
    1. Cocks K, Torgerson D. Sample size calculations for pilot randomized controlled trials: a confidence interval approach. J Clin Epidemiol. 2013;66:197–201. doi: 10.1016/j.jclinepi.2012.09.002.
    1. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377–81. doi: 10.1016/j.jbi.2008.08.010.
    1. Moher D, Hopewell S, Shulz KF, Montori V, Gotzsche PC, Deveraux PJ, et al. Consort 2010 Explanation and Elaboration: updated guidelines for reporting parallel group randomised trials. J Clin Epidemiol. 2010;63(8):e1–e37.
    1. Shulz KF, Altman DG, Moher D, Group C. Consort 2010 Statement: updated guidelines for reporting parallel group randomized trials. J Clin Epidemiol. 2010;63(8):834–40.
    1. U.S. Department of Health Center for Biologics Evaluation and Research (CBER). Guidance for Clinical Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees, OMB Control No. 0910–0581 (2006).
    1. Cook D, Lauzier F, Rocha MG, Sayles MJ, Finfer S. Serious adverse events in academic critical care research. CMAJ. 2008;178(9):1181–4. doi: 10.1503/cmaj.071366.
    1. McIntyre L, Fergusson DA, Rowe B, Cook DJ, Arabi Y, Bagshaw SM, et al. The PRECISE RCT: evolution of an early septic shock fluid resuscitation trial. Transfus Med Rev. 2012;26(4):333–41. doi: 10.1016/j.tmrv.2011.11.003.
    1. Cooper DJ, Myles PS, McDermott FT, Murray LJ, Laidlaw J, Cooper G, et al. Prehospital hypertonic saline resuscitation of patients with hypotension and severe traumatic brain injury: a randomized controlled trial. JAMA. 2004;291(11):1350–7. doi: 10.1001/jama.291.11.1350.
    1. The SAFE Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004;350(22):2247–56.
    1. Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, and Social Sciences and Humanities Research Council of Canada, Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans. 2014. Available from: . Accessed Nov 2016.
    1. International Committee of Medical Journal Editors. Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals; 2015. Available from: . Accessed Nov 2016.
    1. Process Investigators, Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014;370(18):1683–93.
    1. ARISE Investigators, ANZICS Clinical Trials Group, Peake SL, Delaney A, Bailey M, Bellomo R, et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014;371(16):1496–506.
    1. Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RD, et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med. 2015;372(14):1301–11. doi: 10.1056/NEJMoa1500896.
    1. Leteurtre S, Duhamel A, Salleron J, Grandbastien B, Lacroix J, Leclerc F, et al. PELOD-2: an update of the PEdiatric Logistic Organ Dysfunction score. Crit Care Med. 2013;41(7):1761–73. doi: 10.1097/CCM.0b013e31828a2bbd.
    1. Parker MJ, de Laat S, Schwartz L. Exploring the experiences of substitute decision-makers with an exception to consent in a paediatric resuscitation randomised controlled trial: study protocol for a qualitative research study. BMJ Open. 2016;6:e012931. doi: 10.1136/bmjopen-2016-012931.

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