Pilot Study for the SQUEEZE Trial (SQUEEZE)

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)

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.

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.

Decisions regarding the IV/IO administration of isotonic fluid boluses and/or the initiation and escalation of vasoactive medication infusions are left to the discretion of the treating physician and medical team. We ask that vasoactive medications not be initiated until at least 60 mL/kg (3 litres for children ≥ 50 kg) of isotonic fluid bolus therapy has been administered. The treating physician and medical team are advised to follow ACCM guidelines for the resuscitation of neonatal and pediatric septic shock and to target ACCM recommended therapeutic endpoints.

The treating physician and medical team are advised to follow the assigned Fluid Sparing Resuscitation Strategy to guide decisions regarding the IV/IO administration of further isotonic fluid boluses, and the timing of initiation and escalation of vasoactive medication infusions to target the therapeutic endpoints recommended in the ACCM guidelines for the resuscitation of neonatal and pediatric septic shock.

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.

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

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

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

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

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

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

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

We will record the intake of fluids and blood products in the 24 hours immediately prior to randomization to characterize these

Over the Duration of the Intervention Period, Defined as from the time of Randomization (Time zero) until 24 hours after Shock is Reversed

We will record positive culture results from specimens obtained in the 24 hours immediately prior to Randomization (Time zero)

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

Parker MJ, Thabane L, Fox-Robichaud A, Liaw P, Choong K; Canadian Critical Care Trials Group and the Canadian Critical Care Translational Biology Group. 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. Trials. 2016 Nov 22;17(1):556. doi: 10.1186/s13063-016-1689-2.