Pilot Study for the SQUEEZE Trial

Septic Shock Clinical Trial

— SQUEEZE  

Official title:

Pilot Study for the SQUEEZE Trial: a Trial to Determine Whether Septic Shock Reversal is Quicker in Pediatric Patients Randomized to an Early Goal Directed Fluid-sparing Strategy vs. Usual Care (SQUEEZE)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01973907
• Other study ID #: 13-295
• Status: Completed
• Phase: Phase 3
• First received: October 27, 2013
• Last updated: August 16, 2016
• Start date: January 2014
• Est. completion date: June 2016

Study information

• Verified date: August 2016
• Source: McMaster Children's Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada: Health Canada
• Study type: Interventional

Clinical Trial Summary

The purpose of the SQUEEZE Trial is to determine which fluid resuscitation strategy results in the best outcomes for children treated for suspected or confirmed septic shock. In this study, eligible children will be randomized to either the 'Usual Care Arm' or the 'Fluid Sparing Arm'. Children will receive treatment according to current ACCM Septic Shock Resuscitation Guidelines, with the assigned resuscitation strategy used to guide administration of further fluid boluses as well as the timing of initiation and escalation of vasoactive medications to achieve ACCM recommended hemodynamic targets.

Description:

Current pediatric surviving sepsis guidelines from the American College of Critical Care Medicine (ACCM) emphasize an early and goal-directed approach to resuscitation. These guidelines suggest that fluid resuscitation should be aggressive with repeated intravenous (IV) fluid boluses of 20 mL/kg, such that some children may require as much as 200 mL/kg of fluid to achieve therapeutic endpoints. The guidelines also recommend the initiation of vasoactive agents at the stage of "fluid refractory shock", i.e. when there is persistent hypoperfusion despite at least 60 ml/kg IV fluid. Improvements in pediatric septic shock survival have been attributed to adherence to the first iteration of the ACCM septic shock guidelines, and the use of goal directed targets. However, the largest and most publicized pediatric trial of fluid resuscitation in children with suspected septic shock (FEAST Trial), published in NEJM in 2011, demonstrated an increased mortality among children treated with aggressive fluid resuscitation in comparison to the conservative fluid resuscitation arm. As a result, the pediatric critical care community clearly acknowledges that these results, while important, are not necessarily generalizable to developed countries such as Canada.

Emerging publications in the ICU literature suggest that excessive compared to conservative fluid administration in adults with septic shock worsens outcomes such as duration of mechanical ventilation, complications related to the third-spacing of fluids, length of ICU stay, and mortality. A systematic review published in August 2012 reveals a paucity of randomized controlled trial (RCT) evidence apart from the FEAST trial examining the impact of fluid resuscitation on mortality in children with septic shock. This raises the important question of whether children in developed countries would also benefit from a fluid sparing resuscitation strategy to achieve the ACCM goal-directed targets. Use of such a fluid sparing strategy would, by default, require earlier initiation and preferential escalation of vasoactive medications to meet ACCM hemodynamic goals. The optimal degree of fluid resuscitation and the timing of initiation of vasoactive support in order to achieve therapeutic targets in children with septic shock remains unanswered.

This Pilot Randomized Controlled Trial constitutes the first step in answering our research question of whether, in pediatric patients with septic shock, use of a fluid sparing strategy to achieve ACCM therapeutic goals, results in improved clinical outcomes without an increased risk of adverse events, compared to the usual care of aggressive fluid resuscitation as currently recommended by the ACCM guidelines. The purpose of the pilot study is to determine feasibility and inform the appropriate methodological design of the larger multi-centre RCT to fully answer our research question. The hypothesis of the pilot study is that the SQUEEZE Trial is feasible to conduct.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 53
• Est. completion date: June 2016
• Est. primary completion date: June 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 17 Years

Eligibility

Inclusion Criteria:

Inclusion Criteria for 1 and 3 must be answered YES to be eligible for study.

1. Age 29 days to less than 18 years of age

2a) Patient has Persistent Signs of Shock including one or more of the following: i) Vasoactive Medication Dependence ii) Hypotension (Systolic Blood Pressure and/or Mean Blood Pressure less than the 5th percentile for age) iii) Abnormal Perfusion (2 or more of: abnormal capillary refill, tachycardia, decreased level of consciousness, decreased urine output)

2b) Suspected or Confirmed Septic Shock (Shock due to Suspected or Confirmed Infectious Cause)

2c) Patient has received initial fluid resuscitation of: Minimum of 40 mL/kg of isotonic crystalloid (0.9% Normal Saline and/or Ringer's Lactate) and/or colloid (5% albumin) as fluid boluses within the previous 6 hours for patients weighing less than 50 kg, OR Minimum of 2 litres (2000 mL) of isotonic crystalloid (0.9% Normal Saline and/or Ringer's Lactate) and/or colloid (5% albumin) as fluid boluses within the previous 6 hours for patients weighing 50 kg or more

3. Patient has Fluid Refractory Septic Shock as defined by the Presence of all of 2a, 2b, and 2c.

Exclusion Criteria:

• Patient admitted to the Neonatal Intensive Care Unit (NICU)

• Patient requiring resuscitation in the Operating Room (OR) or Post-Anesthetic Care Unit (PACU)

• Full active resuscitative treatment not within the goals of care

• Shock Secondary to Cause other than Sepsis (i.e. obvious signs of cardiogenic shock, anaphylactic shock, hemorrhagic shock, spinal shock)

• Previous enrolment in this trial, where known by the research team

Study Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Septic Shock
• Shock
• Shock, Septic

Intervention

Other:
• Fluid Sparing Resuscitation Strategy
Tier 1: Initiate IV/IO vasoactive medication infusion support immediately. Further IV/IO isotonic fluid bolus therapy [crystalloid (0.9% Normal Saline or Ringers Lactate) or colloid (5% Albumin)] should be avoided; small volume isotonic fluid boluses [5-10 mL/kg (250-500 mL for participants = 50 kg)] may be provided if required due to A. Clinically unacceptable delay in ability to initiate vasoactive medication infusion(s) and/or 2. Documented intravascular hypovolemia. Tier 2: Vasoactive medication(s) should be preferentially titrated/escalated to achieve recommended ACCM hemodynamic goals. Further IV/IO isotonic fluid bolus therapy [crystalloid (0.9% Normal Saline or Ringers Lactate) or colloid (5% Albumin)] should be avoided; small volume isotonic fluid boluses [5-10 mL/kg (250-500 mL for participants = 50 kg)] may be provided if required due to A. Documented intravascular hypovolemia. Intervention end: Patient is free from vasoactive medication support and shock is reversed.

Locations

Country	Name	City	State
Canada	McMaster Children's Hospital	Hamilton	Ontario

Sponsors (4)

Lead Sponsor	Collaborator
McMaster Children's Hospital	Canadian Critical Care Trials Group, Hamilton Health Sciences Corporation, McMaster University

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Daily Fluids	We will record daily intake of fluids and blood products and fluid losses to characterize these and calculate daily fluid balance	Over the Duration of the Intervention Period, Defined as from the time of Randomization (Time zero) until 24 hours after Shock is Reversed	No
Other	Fluids Received in the 24 hours prior to study entry	We will record the intake of fluids and blood products in the 24 hours immediately prior to randomization to characterize these	24 hour period immediately prior to randomization (time zero)	No
Other	Positive Culture results from specimens obtained during the Intervention Period	We will record daily positive culture results from specimens obtained during the intervention period	Over the Duration of the Intervention Period, Defined as from the time of Randomization (Time zero) until 24 hours after Shock is Reversed	No
Other	Positive Culture Results from specimens obtained in the 24 hours immediately prior to study entry	We will record positive culture results from specimens obtained in the 24 hours immediately prior to Randomization (Time zero)	The 24 hour period immediately prior to Randomization (Time zero)	No
Primary	Feasibility of conducting the SQUEEZE Trial	The Primary Outcome of Feasibility of conducting the SQUEEZE Trial will be evaluated based on the following: Participant enrolment rate: We will define success as an enrolment rate of at least 2 patients/month (recognizing that enrolment may be slower during the study run-in phase).; Protocol adherence: the ability to execute the study procedures. We will assess our ability to initiate study procedures in enrolled patients within 1 hour of randomization.	The earliest of: 1. Recruitment of the planned 50 participants, or 2. 24 months following initiation of recruitment	No
Secondary	Appropriateness of eligibility criteria	We will determine our ability to enroll patients based on the current eligibility criteria, to inform the design of a future multi-centered RCT.	The earliest of: 1. Recruitment of the planned 50 participants, or 2. 24 months following initiation of recruitment	No
Secondary	Clinical outcomes	We will assess our ability to collect clinical outcome data of interest to determine the most appropriate outcomes, perform a sample size calculation, and inform the design of a definitive multi-centered RCT. Clinical outcomes include: i) PICU admission rate, PICU Length of Stay, Ventilator Free Days, Acuity Scores (PRISM III), Organ Dysfunction scores (PELOD, PELOD 2), Vasoactive Medication Score, Mortality (28-day, 60-day, and 90-day), Hospital Mortality; ii) Adverse Events- complications which may be attributable to third spacing of fluid, or inotrope/vasopressor use, including: Intrabdominal Hypertension, Abdominal Compartment Syndrome, Pulmonary Edema, Pleural Effusion requiring drainage, Signs of Digital Ischemia, Digital/Limb Revision amputation, Bowel Ischemia; iii) Short term hemodynamic outcomes- time to shock reversal determined by freedom from vasoactive medication(s), bedside hemodynamic measurements (HR, MAP, CVP, and non-invasive CO (CI) measurement (USCOM)	The earliest of: 1. Recruitment of the planned 50 participants, or 2. 24 months following initiation of recruitment	No
Secondary	Process Feasibility	We will collect descriptive data related to study Process feasibility to inform conduct of a multi-centred RCT	The earliest of: 1. Recruitment of the planned 50 participants, or 2. 24 months following initiation of recruitment	No
Secondary	Resource Feasibility	We will collect descriptive data related to study Resource feasibility to inform conduct of a multi-centred RCT.	The earliest of: 1. Recruitment of the planned 50 participants, or 2. 24 months following initiation of recruitment	No
Secondary	Management Feasibility	We will collect descriptive data related to study Management feasibility to inform conduct of a multi-centred RCT.	The earliest of: 1. Recruitment of the planned 50 participants, or 2. 24 months following initiation of recruitment	No