Clinical trial NCT03340805
Conditions: Shock, Septic
Keywords: Sepsis Septic shock Pediatric Fluid resuscitation Saline Lactated Ringer's Crystalloid Mortality Pragmatic trial Feasibility
Sponsor: Children's Hospital of Philadelphia
Start date: 2018-01-24; Completion date: 2019-01-15
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this pilot study is to assess overall feasibility prior to embarking on a larger randomized pragmatic trial comparing the clinical effectiveness of fluid resuscitation with NS versus LR for pediatric patients with suspected septic shock. Necessary feasibility assessments include ensuring appropriate compliance with study fluid in each of the two arms, effectiveness of study enrollment using a pragmatic study design embedded within routine clinical practice, and acceptability of using Exception from Informed Consent (EFIC).

Detailed description:
Approximately 5,000 children die from septic shock each year in the US and thousands more die worldwide. Despite widespread implementation of resuscitation protocols, contemporary studies still report 2-6% mortality for children with septic shock treated in the pediatric emergency department (ED). In the investigators' recent survey of the Pediatric Emergency Care Applied Research Network (PECARN), 45% of physicians had treated a child for septic shock in the ED who subsequently died in the hospital in the past two years.

Fluid resuscitation is the cornerstone of resuscitation for hypovolemia and shock, and intravenous fluids are among the most commonly used therapies worldwide. Yet, there remains uncertainty as to the most appropriate fluid type to restore effective blood volume and optimize organ perfusion. In the absence of a clear role for the early use colloids, administration of crystalloid fluids is generally preferred (except in cases of hemorrhage). For septic shock, in particular, crystalloid fluids have long been the standard resuscitative fluid. Crystalloid fluids can be categorized as non-buffered (most commonly 0.9% normal saline \[NS\]) or buffered/balanced (in the US, this is most commonly lactated Ringer's \[LR\]) solutions. NS and LR are inexpensive, stable at room temperature, and nearly universally available with identical storage volumes and dosing strategies. Notably, both are also of proven clinical benefit in septic shock and have extensive clinical experience for use in fluid resuscitation of critically ill patients. However, while NS is currently used in 80-95% of cases of septic shock, an increasing body of data now suggest that LR resuscitation may have superior efficacy and safety. Buffered crystalloids, including LR, have demonstrated a 1-4% absolute mortality reduction and up to a 50% lower odds of dialysis compared to NS in observational and non-randomized interventional studies in adult sepsis. Nevertheless, because definitive conclusions have not been able to be drawn from existing observational and non-randomized studies, NS overwhelmingly remains the most commonly used fluid based on historical precedent while controversy remains.

To definitively test the comparative effectiveness of NS and LR, a well-powered randomized controlled trial (RCT) is necessary. A large pragmatic randomized trial embedded within everyday clinical practice provides a cost-efficient and generalizable approach to inform clinicians about best comparative effectiveness of common therapies. Unlike explanatory RCTs, pragmatic trials need heterogeneity in patients, non-study therapies, and settings. To accomplish this, these trials must be large enough to detect small effects and simple enough to incorporate into routine clinical practice. The characteristics of LR and NS provide the ideal scenario for a large pragmatic trial.18 An ED-based trial is necessary to enroll patients at initiation of resuscitation. While any benefit is expected to be small, even a 1-2% absolute reduction in mortality that is in line with prior adult studies would be a clinically important difference by saving the lives of 50-100 children in the US (and many more worldwide) each year. This overall public health impact is commensurate with changing from NS to LR because such a practice change is a simple, cost-neutral shift from largely using NS to largely using LR.

However, before embarking on a large, pragmatic randomized trial that will determine the comparative effectiveness and safety of NS and LR, several concerns regarding feasibility of such a trial need to be addressed including a) ensuring adequate compliance with study fluid administration within each randomized arm using the proposed pragmatic study design, b) determining that a sufficient proportion of patients can be enrolled using the proposed pragmatic study design that will be embedded within routine clinical practice rather than use of a dedicated study team, and c) demonstrating that the study can feasibly be performed using EFIC when enrolling critically ill infants, children, and adolescents into this clinical trial. Demonstrating these feasibility criteria at a single site will strongly support success in a larger, multicenter study that will enroll several thousand patients across the 18 sites comprising Pediatric Emergency Care Applied Research Network (PECARN) to test morbidity and mortality outcomes.

Arms: arm 1: Lactated Ringer's (LR) fluid will be administered to patients randomized to the experimental arm. LR will be used for all fluid boluses and maintenance fluids (supplemental electrolytes are allowed) from time immediately after randomization through 11:59 pm of the next calender day. The determination of when to give fluid, how much fluid to give, how fast to give fluid, and what access to use to administer fluid will remain at the discretion of the treating team. arm 2: 0.9% "normal" saline (NS) fluid will be administered to patients randomized to the active comparator (control) arm. NS will be used for all fluid boluses and maintenance fluids (supplemental electrolytes are allowed) from time immediately after randomization through 11:59 pm of the next calender day. The determination of when to give fluid, how much fluid to give, how fast to give fluid, and what access to use to administer fluid will remain at the discretion of the treating team.
Interventions: intervention 1: Lactated Ringer intervention 2: Normal saline
Intervention descriptions: intervention 1: LR is a sterile, nonpyrogenic "balanced" solution used for fluid and electrolyte replenishment via intravenous or intraosseous administration. Each 100 mL of LR contains 600 mg sodium chloride (NaCl), 310 mg of sodium lactate (C3H5NaO3), 30 mg of potassium chloride (KCl), and 20 mg of calcium chloride (CaCl2 · 2H20) with an approximate potential of hydrogen (pH) of 6.5 (6.0 to 7.5). intervention 2: Normal saline solution is an "unbalanced" crystalloid solution containing 154 mEq/L of sodium and 154 milliequivalent (mEq/L) of chloride.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
i
INTERVENTION STUDY (CLINICAL TRIALS) 
  
Title: 
Feasibility Study for the Randomized Pragmatic Pediatric 
Trial of Balanced versus Normal Saline Fluid in Sepsis 
Short Title 
PRoMPT BOLUS - Feasibility 
Drug or Device 
Name(s): 
0.9% Isotonic (“Normal”) Saline, Lactated Ringer’s 
FDA IND 
136978 
Regulatory Sponsor: 
FDA 
eIRB Number 
 17-013936 
Protocol Date: 
 November 6, 2017 
Amendment 1 Date:  
Amendment 3 Date:  
Amendment 2 Date: 
Amendment 4 Date: 
 
IND Sponsor  
Scott L. Weiss, MD MSCE 
Assistant Professor of Anesthesia, Critical Care, and Pediatrics 
Perelman School of Medicine at the University of Pennsylvania 
Attending Physician, Division of Critical Care 
Department of Anesthesia and Critical Care Medicine 
Children’s Hospital of Philadelphia 
3401 34th St., 7S Tower, Room 7C04 
Philadelphia, PA, 19104 
Phone:  215-590-2356 
Email: WeissS@email.chop.edu 
 
Study Principal Investigator: 
Fran Balamuth, MD PhD MSCE 
Assistant Professor of Pediatrics 
Perelman School of Medicine at the University of Pennsylvania 
Attending Physician, Division of Emergency Medicine 
Children’s Hospital of Philadelphia 
3535 Market St, Office 1516 
Phone: 215 590 7295 
Email: balamuthf@email.chop.edu 
 


 
 
 
 
 
 
 
ii
 
Table of Contents 
Abbreviations and Definitions of Terms.............................................................................. v 
Abstract ................................................................................................................................. vi 
Protocol Synopsis ................................................................................................................. vii 
Table 1: Schedule of Study Procedures ............................................................................. xii 
Figure 1:  Pilot Study Diagram .......................................................................................... xiii 
1 
BACKGROUND INFORMATION AND RATIONALE ....................................................................... 1 
1.1 
INTRODUCTION ..................................................................................................................................... 1 
1.2 
NAME AND DESCRIPTION OF INVESTIGATIONAL PRODUCT OR INTERVENTION ..................................... 2 
1.3 
FINDINGS FROM NON-CLINICAL AND CLINICAL STUDIES ..................................................................... 3 
1.3.1 
Pre-Clinical Studies ........................................................................................................................ 3 
1.3.2 
Clinical Studies ............................................................................................................................... 3 
1.4 
SELECTION OF DRUGS AND DOSAGES................................................................................................... 5 
1.5 
RELEVANT LITERATURE AND DATA ..................................................................................................... 7 
1.6 
COMPLIANCE STATEMENT .................................................................................................................... 8 
2 
STUDY OBJECTIVES ............................................................................................................................ 10 
2.1 
PRIMARY OBJECTIVE (OR AIM) .......................................................................................................... 10 
2.2 
SECONDARY OBJECTIVES (OR AIM) .................................................................................................... 10 
3 
INVESTIGATIONAL PLAN .................................................................................................................. 11 
3.1 
GENERAL SCHEMA OF STUDY DESIGN ............................................................................................... 11 
3.1.1 
Screening Phase ............................................................................................................................ 11 
3.1.2 
Intervention Phase ........................................................................................................................ 11 
3.1.3 
Follow-up Phase ........................................................................................................................... 12 
3.2 
ALLOCATION TO TREATMENT GROUPS AND BLINDING ...................................................................... 13 
3.3 
STUDY DURATION, ENROLLMENT AND NUMBER OF SITES ................................................................. 13 
3.3.1 
Duration of Study Participation .................................................................................................... 13 
3.3.2 
Total Number of Study Sites/Total Number of Subjects Projected ................................................ 13 
3.4 
STUDY POPULATION ........................................................................................................................... 13 
3.4.1 
Inclusion Criteria .......................................................................................................................... 14 
3.4.2 
Exclusion Criteria ......................................................................................................................... 15 
4 
STUDY PROCEDURES .......................................................................................................................... 18 
4.1 
SCREENING VISIT ............................................................................................................................... 18 
4.2 
INTERVENTION PHASE ........................................................................................................................ 18 
4.3 
FOLLOW-UP PHASE ............................................................................................................................. 18 
4.4 
CONCOMITANT MEDICATION ............................................................................................................. 19 
4.5 
RESCUE MEDICATION ADMINISTRATION ............................................................................................ 19 
4.6 
SUBJECT COMPLETION/WITHDRAWAL ............................................................................................... 19 
4.6.1 
Early Termination Point ................................................................................................................ 19 
5 
STUDY EVALUATIONS AND MEASUREMENTS ............................................................................ 22 
5.1 
SCREENING AND MONITORING EVALUATIONS AND MEASUREMENTS ................................................ 22 
5.1.1 
Medical Record Review ................................................................................................................. 22 
5.1.2 
Laboratory Evaluations................................................................................................................. 23 
5.1.3 
Radiographic Evaluations ............................................................................................................. 23 
5.2 
FEASIBILITY EVALUATIONS ................................................................................................................ 24 
5.2.1 
Aim 1 ............................................................................................................................................. 24 
5.2.2 
Aim 2 ............................................................................................................................................. 24 
5.2.3 
Aim 3 ............................................................................................................................................. 24 


 
 
 
 
 
 
 
iii
5.3 
EFFICACY EVALUATION ..................................................................................................................... 25 
5.4 
SAFETY EVALUATION ......................................................................................................................... 25 
6 
STATISTICAL CONSIDERATIONS .................................................................................................... 27 
6.1 
PRIMARY ENDPOINT ........................................................................................................................... 27 
6.2 
SECONDARY ENDPOINTS .................................................................................................................... 27 
6.3 
STATISTICAL METHODS...................................................................................................................... 27 
6.3.1 
Baseline Data ................................................................................................................................ 27 
6.3.2 
Feasibility Analysis ....................................................................................................................... 27 
6.3.3 
Efficacy Analysis ........................................................................................................................... 28 
6.3.4 
Safety Analysis .............................................................................................................................. 28 
6.4 
SAMPLE SIZE AND POWER .................................................................................................................. 28 
6.5 
INTERIM ANALYSIS ............................................................................................................................ 29 
7 
STUDY MEDICATION........................................................................................................................... 30 
7.1 
DESCRIPTION ...................................................................................................................................... 30 
7.1.1 
Packaging ...................................................................................................................................... 30 
7.1.2 
Labeling ........................................................................................................................................ 30 
7.1.3 
Dosing ........................................................................................................................................... 30 
7.1.4 
Treatment Compliance and Adherence ......................................................................................... 30 
7.1.5 
Drug Accountability ...................................................................................................................... 31 
8 
SAFETY MANAGEMENT ..................................................................................................................... 32 
8.1 
CLINICAL ADVERSE EVENTS .............................................................................................................. 32 
8.2 
ADVERSE EVENT REPORTING ............................................................................................................. 32 
8.3 
DEFINITION OF AN ADVERSE EVENT .................................................................................................. 33 
8.4 
DEFINITION OF A SERIOUS ADVERSE EVENT (SAE) ........................................................................... 33 
8.4.1 
Relationship of SAE to study drug or other intervention ............................................................... 34 
8.5 
IRB/IEC NOTIFICATION OF SAES AND OTHER UNANTICIPATED PROBLEMS ...................................... 34 
8.5.1 
Reporting procedures .................................................................................................................... 34 
8.5.2 
Follow-up report ........................................................................................................................... 36 
8.6 
INVESTIGATOR REPORTING OF A SERIOUS ADVERSE EVENT TO SPONSOR .......................................... 36 
8.7 
MEDICAL EMERGENCIES .................................................................................................................... 36 
9 
STUDY ADMINISTRATION ................................................................................................................. 37 
9.1 
TREATMENT ASSIGNMENT METHODS................................................................................................. 37 
9.1.1 
Randomization............................................................................................................................... 37 
9.1.2 
Blinding ......................................................................................................................................... 37 
9.2 
DATA COLLECTION AND MANAGEMENT ............................................................................................ 37 
9.3 
CONFIDENTIALITY .............................................................................................................................. 38 
9.4 
REGULATORY AND ETHICAL CONSIDERATIONS.................................................................................. 39 
9.4.1 
Data and Safety Monitoring Plan ................................................................................................. 39 
9.4.2 
Data Safety Monitoring Board (DSMB) ........................................................................................ 39 
9.4.3 
Risk Assessment ............................................................................................................................. 40 
9.4.4 
Potential Benefits of Trial Participation ....................................................................................... 42 
9.4.5 
Risk-Benefit Assessment ................................................................................................................ 42 
9.5 
RECRUITMENT STRATEGY .................................................................................................................. 43 
9.6 
INFORMED CONSENT/ASSENT AND HIPAA AUTHORIZATION ............................................................ 43 
9.6.1 
Informed Consent and HIPAA Authorization ................................................................................ 43 
9.6.2 
Waiver of Assent ............................................................................................................................ 44 
9.6.3 
Exception From Informed Consent (EFIC) ................................................................................... 44 
9.6.4 
Non-English Speakers ................................................................................................................... 47 
9.7 
PAYMENT TO SUBJECTS/FAMILIES ..................................................................................................... 48 
10 
PUBLICATION ........................................................................................................................................ 49 


 
 
 
 
 
 
 
iv
11 
REFERENCES ......................................................................................................................................... 50 
Appendix ............................................................................................................................... 54 
 
 
 


 
 
 
 
 
 
 
v
ABBREVIATIONS AND DEFINITIONS OF TERMS 
C 
95% CI 
ACCM 
 
Degrees centigrade 
95% confidence interval 
American College of Critical Care Medicine 
AE 
AKI 
CHOP 
CRF 
DCC 
DKA 
DSMB 
ED 
EFIC 
FDA 
HIPAA 
ICD-9 
ICH 
IND 
IO 
IRB 
IV 
kg 
LAR 
LR 
ml 
NaCl 
NS 
NSAID 
OR 
PECARN 
PHI 
PHIS 
PICU 
RCT 
RRT 
SAE 
SAN 
SID 
tPA 
 
Adverse Event 
Acute Kidney Injury 
Children’s Hospital of Philadelphia 
Case Report Form 
Data Coordinating Center 
Diabetic Ketoacidosis 
Data Safety and Monitoring Board 
Emergency Department 
Exception from Informed Consent 
Food and Drug Administration 
Health Insurance Portability and Accountability Act 
International Classification of Diseases, 9th edition 
International Conference on Harmonization 
Investigational New Drug 
Intraosseus 
Institutional Review Board 
Intravenous 
Kilogram 
Legally Authorized Representative 
Lactated Ringers 
Milliliter 
Sodium Chloride 
Normal Saline 
Non Steroidal Anti Inflammatory Drug 
Odds Ratio 
Pediatric Emergency Care Applied Research Network 
Personal Health Information 
Pediatric Health Information System 
Pediatric Intensive Care Unit 
Randomized Controlled Trial 
Renal Replacement Therapy 
Serious Adverse Event 
Storage Area Network 
Strong Ion Difference 
Tissue Plasminogen Activator 


 
 
 
 
 
 
 
vi
ABSTRACT 
Context:  Intravenous (IV) crystalloids are the standard resuscitative fluid for pediatric 
septic shock.  Despite proven clinical benefit for both non-buffered 0.9% “normal” saline 
(NS) and buffered/balanced lactated Ringer’s (LR) to restore effective circulation and 
increasing data supporting relative benefits and improved safety profile for LR over NS, the 
use of NS overwhelmingly remains the most commonly used crystalloid fluid in pediatric 
septic shock.  A cost-efficient approach to definitively determine the comparative 
effectiveness and safety of NS and LR is with a large pragmatic randomized trial, though 
concerns regarding feasibility need to be addressed prior to such a trial. 
Objectives: The objective of this study is to assess overall feasibility of this study at CHOP 
with the following specific aims: 
Aim 1:  To determine compliance with study fluid administration, throughout the 
intervention phase, within each randomized arm using a pragmatic study design 
Aim 2:  To estimate the proportion of eligible pediatric patients with suspected septic shock 
who may be enrolled into a randomized pragmatic trial of fluid resuscitation 
Aim 3:  To demonstrate feasibility of patient enrollment into a pragmatic fluid resuscitation 
trial using Exception from Informed Consent (EFIC) 
Study Design: Randomized, controlled, open-label pragmatic pilot trial 
Setting/Participants:  Eligible patients >6 months and <18 years with clinician concern for 
septic shock who require at least 20 ml/kg of fluid resuscitation will be enrolled in the 
Emergency Department of the Children’s Hospital of Philadelphia.  Patients will be enrolled 
prior to receipt of >40 mL/kg IV/IO crystalloid fluid.  Due to the life-threatening nature of 
septic shock and the narrow therapeutic window for fluid resuscitation, potential subjects 
will be enrolled through the federal “exception from informed consent” (EFIC) process, with 
prospective informed consent obtained as possible in rare circumstances.  
Study Interventions and Measures:  Seventy subjects will be randomized to receive either 
open-label NS or LR for all remaining fluid administration (bolus and maintenance) until 
11:59pm on the calendar day following randomization such that all patients receive at least 
24 hours of study fluid.  The primary feasibility outcome for this pilot study will be the 
proportion of total crystalloids administered as the correct study fluid within each 
randomized arm (Aim 1). Secondary outcomes will include mean proportion of total 
crystalloids administered as non-study fluid in each arm (Aim 1), percent 
enrollment/randomization/treatment of eligible patients (Aim 2), and successful EFIC 
approval with <10% subject withdrawal.  Specified safety outcomes will be monitored as 
they occur in the course of routine clinical practice but this pilot study will not be powered 
to assess safety given that both fluids are FDA-approved and have well-described efficacy 
and safety profiles. 


 
 
 
 
 
 
 
vii
PROTOCOL SYNOPSIS 
Study Title 
Feasibility Study for the Randomized Pragmatic Pediatric Trial 
of Balanced versus Normal Saline Fluid in Sepsis (PRoMPT 
BOLUS – Feasibility) 
Funder 
The Children’s Hospital of Philadelphia 
Clinical Phase 
Pilot/feasibility study 
Study Rationale 
Intravenous (IV) crystalloids are the standard resuscitative fluid for 
pediatric septic shock.  Despite proven clinical benefit for both non-
buffered 0.9% “normal” saline (NS) and buffered/balanced lactated 
Ringer’s (LR) to restore effective circulation and increasing data 
supporting relative benefits and improved safety profile for LR over 
NS, the use of NS overwhelmingly remains the most commonly 
used crystalloid fluid in pediatric septic shock.  A cost-efficient 
approach to definitively determine the comparative effectiveness 
and safety of NS and LR is with a large pragmatic randomized trial, 
though concerns regarding feasibility need to be addressed prior to 
such a trial.  The objective of this pilot study is to assess overall 
feasibility prior to embarking on a larger randomized pragmatic trial 
comparing the clinical effectiveness of fluid resuscitation with NS 
versus LR for pediatric patients with suspected septic shock.  
Necessary feasibility assessments include ensuring appropriate 
compliance with study fluid in each of the two arms, effectiveness 
of study enrollment using a pragmatic study design embedded 
within routine clinical practice, and acceptability of using Exception 
from Informed Consent (EFIC).  
Study Objective(s) 
Primary  
 To determine compliance with study fluid administration, 
throughout the intervention phase, within each randomized arm 
using a pragmatic study design. 
Secondary 
 To estimate the proportion of eligible pediatric patients with 
suspected septic shock who may be enrolled into a randomized 
pragmatic trial of fluid resuscitation. 
 To demonstrate feasibility of patient enrollment into a pragmatic 
fluid resuscitation trial using Exception from Informed Consent 
(EFIC). 
Test Article(s) 
 Study arm #1:  Fluid resuscitation with lactated Ringer’s (LR) 
 Study arm #2  Fluid resuscitation with 0.9% “normal” saline 
(NS) 


 
 
 
 
 
 
 
viii
Study Design 
 
Randomized, open-label pragmatic pilot trial to assess feasibility of 
comparing two different crystalloid fluids for resuscitation of 
pediatric septic shock. 
Subject Population 
key criteria for 
Inclusion and 
Exclusion: 
Inclusion Criteria 
1. Age >6 months to <18 years 
2. Clinician concern for septic shock, operationalized as: 
a. a “positive” ED sepsis alert confirmed at the 
physician led “sepsis huddle” OR 
b. a physician diagnosis of suspected septic shock 
requiring parenteral antibiotics and fluid resuscitation 
as per the ED sepsis management pathway 
Condition 2a above is met by: 
A. Tachycardia or hypotension for age AND 
B. Fever (home or ED >38 °F), hypothermia, or other 
signs/symptoms of infection AND  
 
At least one of C, D, or E 
 
C. Flash (< 1 second) or delayed (>3 seconds) capillary 
refill 
D. Altered mental status 
E. Existing high-risk condition, including: 
i. <56 days-old 
ii. Asplenia 
iii. Bone marrow or solid organ transplant 
iv. Central venous catheter 
v. Malignancy 
vi. Significant neurological dysfunction or 
technological dependence at baseline 
vii. Other immunodeficiency or 
immunocompromised 
3. Administration of at least 20 mL/kg IV/IO fluid resuscitation 
4. Receipt of ≤40 mL/kg IV/IO crystalloid fluid prior to 
randomization 
5. Additional fluid deemed likely to be necessary to treat poor 
perfusion, defined as either hypotension for age or abnormal 
capillary refill (as determined by clinician’s judgment) 
6. Parental/guardian permission (informed consent) if time 
permits; otherwise, EFIC criteria met 


 
 
 
 
 
 
 
ix
Exclusion Criteria:  
1.   Clinician judgement that patient’s condition deems it unsafe 
to administer either NS or LR (since patients will be equally 
likely to receive NS or LR at time of study enrollment), 
including (but not limited to): 
a) Clinical suspicion for impending brain herniation based on 
data available at or before patient meets criteria for study 
enrollment 
b) Known hyperkalemia, defined as non-hemolyzed whole 
blood or plasma/serum potassium > 6 mEq/L, based on data 
available at or before patient meets criteria for study 
enrollment 
c) Known hypercalcemia, defined as plasma/serum total 
calcium >12 mg/dL or whole blood ionized calcium > 1.35 
mmol/L, based on data available at or before patient meets 
criteria for study enrollment 
d) Known acute fulminant hepatic failure, defined as 
plasma/serum ALT >10,000 U/L or total bilirubin >12.0 
mg/dL, based on data available at or before patient meets 
criteria for study enrollment 
e) Known history of severe hepatic impairment, defined as 
diagnosis of cirrhosis, “liver failure”, or active listing for 
liver transplant 
f)  Known history of severe renal impairment, defined as current 
dependency on peritoneal dialysis or hemodialysis 
g) Known metabolic disorder, inborn error of metabolism, or 
primary mineralcorticoid deficiency (e.g., mitochondrial 
disorder, urea cycle disorder, amino acidemia, fatty acid 
oxidation disorder, glycogen storage disorder, congenital 
adrenal hypoplasia, Addison’s disease) as reported by 
subject, LAR or accompanying caregiver, or as listed in the 
medical record 
 
2.    Known pregnancy 
3. Known prisoner as determined by routine social history 
disclosed by patient and/or LAR (or other accompanying 
acquaintance) 
4. Known allergy to either normal saline or lactated Ringer’s as 
determined by routine allergy history disclosed by patient 
and/or LAR (or other accompanying acquaintance) or as 
indicated in the medical record 


 
 
 
 
 
 
 
x
5. Indication of prior declined consent to participate based on 
presence of a “PRoMPT BOLUS Opt-Out” bracelet with 
appropriate messaging embossed into the bracelet or opt-out 
letter that will be provided to the family to be presented to 
clinical team at time of care 
Number Of Subjects  
 
Total Number of Subjects = 80 
Total Number at CHOP = 80 
Total Number of Sites = 1 
Study Duration 
Each subject’s participation will last up to 90 days, including 1 day 
for screening, 1-2 days for study intervention, and up to 90 days for 
follow-up. 
 
Study Phases 
Screening 
Study Treatment 
Follow-Up   
(1) Screening: screening for eligibility and obtaining 
consent/EFIC 
(2) Intervention phase: use of randomized crystalloid fluid (NS 
or LR) for resuscitation and maintenance fluid  
(3) Follow-up: determination of study completion or subject 
withdrawal, including vital status and clinical outcome 
assessment at hospital discharge or 90 days following study 
enrollment, whichever comes first 
Efficacy Evaluations 
Feasibility will be assessed as part of each aim as follows: 
 Aim 1:  proportion of total crystalloids administered as 
saline in each arm (primary) and proportion of total 
crystalloids administered as non-study fluid (i.e., cross-over) 
in each arm (secondary) 
 Aim 2:  percent enrollment/randomization/treatment of 
eligible patients 
 Aim 3: successful EFIC approval with ≤10% subject 
withdrawal 
Efficacy outcomes, including mortality, hospital-free days, dialysis, 
and length of stay, will be collected in preparation for a subsequent 
multicenter trial, though this pilot feasibility study will not be 
powered to analyze these endpoints. 
Safety Evaluations 
For this single-site feasibility study, specified safety outcomes will 
be monitored as they occur in the course of routine clinical practice 
but this feasibility study will not be powered to assess safety given 
that both fluids are FDA-approved and have well-described efficacy 
and safety profiles. 
Statistical And 
Analytic Plan 
The statistical plan will be descriptive for this feasibility study. 


 
 
 
 
 
 
 
xi
For Aim 1, feasibility will be defined by either: 
1) an absolute difference in the mean use of NS between study 
arms of at least 65% with a lower 95% CI border of >60%, 
or 
2) at least 85% of subjects in the NS arm receiving ≥90% of 
study fluid as NS during the study window and at least 80% 
of subjects in the LR arm receiving ≥75% of study fluid as 
LR. 
The secondary endpoints will be defined as meeting feasibility 
criteria if: 
 The proportion of eligible patients treated in the pediatric 
ED who are enrolled, randomized, and treated with study 
fluid is >65%. 
 EFIC is approved by the IRB at CHOP 
 The proportion of eligible patients who meet criteria for 
EFIC who are not enrolled or who are enrolled but withdraw 
prior to completion of the follow-up phase is ≤10%.  
Data and Safety 
Monitoring Plan 
Data will be managed and stored by the University of Utah Data 
Coordinating Center.  In addition the PI, an independent Data Safety 
Monitoring Board (DSMB) will be convened to ensure data quality 
and patient safety. 


 
xii  
 
 
 
 
TABLE 1: SCHEDULE OF STUDY PROCEDURES  
Study Phase 
Screening 
Intervention 
Follow-Up1 
Study Day 
1 
1 
2 
2 to 902 
Informed Consent/Assent or EFIC 
X 
 
 
 
Review Inclusion/Exclusion Criteria 
X 
X 
X 
X 
Inform patient/LAR of study 
enrolment (if EFIC) 
 
X 
X 
X 
Demographics/Medical History 
X 
 
 
X 
Prior/Concomitant Medications 
X 
X 
X 
X 
Randomization  
X 
 
 
 
Dispense Study Drug 
 
X 
X 
 
Drug Compliance 
 
X 
X 
 
Open-label fluid treatment 
 
 
 
X 
Data collection  
 
X 
X 
X 
Outcome Assessment:  Aim 1 
 
 
X 
 
Outcome Assessment:  Aim 2 
X 
 
 
 
Outcome Assessment:  Aim 3 
 
 
 
X 
Adverse Event Assessment 
 
 
X 
X 
 
1Censured at 90 days from study enrollment 
2Follow-up will cease at 90 days from study enrolment or hospital discharge, whichever comes first 


 
page xiii 
  
FIGURE 1:  PILOT STUDY DIAGRAM  
 
 
 
 
.


 
  1
1 
BACKGROUND INFORMATION AND RATIONALE 
1.1 Introduction 
Approximately 5,000 children die from septic shock each year in the US and thousands 
more die worldwide.1,2  Despite widespread implementation of resuscitation protocols, 
contemporary studies still report 2-6% mortality for children with septic shock treated in the 
pediatric emergency department (ED).3-7  In our recent survey of the Pediatric Emergency 
Care Applied Research Network (PECARN), 45% of physicians had treated a child for 
septic shock in the ED who subsequently died in the hospital in the past two years 
(unpublished data). 
 
Fluid resuscitation is the cornerstone of resuscitation for hypovolemia and shock, and 
intravenous fluids are among the most commonly used therapies worldwide.8,9  Yet, there 
remains uncertainty as to the most appropriate fluid type to restore effective blood volume 
and optimize organ perfusion.  In the absence of a clear role for the early use colloids, 
administration of crystalloid fluids is generally preferred (except in cases of 
hemorrhage).10,11  For septic shock, in particular, crystalloid fluids have long been the 
standard resuscitative fluid.12  Crystalloid fluids can be categorized as non-buffered (most 
commonly 0.9% normal saline [NS]) or buffered/balanced (in the US, this is most 
commonly lactated Ringer’s [LR]) solutions.  NS and LR are inexpensive, stable at room 
temperature, and nearly universally available with identical storage volumes and dosing 
strategies. Notably, both are also of proven clinical benefit in septic shock and have 
extensive clinical experience for use in fluid resusciation of critically ill patients.8  However, 
while NS is currently used in 80-95% of cases of septic shock,13-15 an increasing body of 
data now suggest that LR resuscitation may have superior efficacy and safety.  Buffered 
crystalloids, including LR, have demonstrated a 1-4% absolute mortality reduction and up to 
a 50% lower odds of dialysis compared to NS in observational and non-randomized 
interventional studies in adult sepsis.16,17  Nevertheless, because definitive conclusions have 
not been able to be drawn from existing observational and non-randomized studies, NS 
overwhelmingly remains the most commonly used fluid based on historical precedent while 
controversy remains.18,19 
 
To definitively test the comparative effectiveness of NS and LR, a well-powered 
randomized controlled trial (RCT) is necessary.  A large pragmatic randomized trial 
embedded within everyday clinical practice provides a cost-efficient and generalizable 
approach to inform clinicians about best comparative effectiveness of common therapies.20  
Unlike explanatory RCTs, pragmatic trials need heterogeneity in patients, non-study 
therapies, and settings.21  To accomplish this, these trials must be large enough to detect 
small effects and simple enough to incorporate into routine clinical practice.  The 
characteristics of LR and NS provide the ideal scenario for a large pragmatic trial.18  An ED-
based trial is necessary to enroll patients at initiation of resuscitation.22,23  While any benefit 
is expected to be small, even a 1-2% absolute reduction in mortality that is in line with prior 
adult studies would be a clinically important difference by saving the lives of 50-100 
children in the US (and many more worldwide) each year.  This overall public health impact 
is commensurate with changing from NS to LR because such a practice change is a simple, 
cost-neutral shift from largely using NS to largely using LR. 


 
  2
 
However, before embarking on a large, pragmatic randomized trial that will determine the 
comparative effectiveness and safety of NS and LR, several concerns regarding feasibility of 
such a trial need to be addressed including a) ensuring adequate compliance with study fluid 
administration within each randomized arm using the proposed pragmatic study design, b) 
determining that a sufficient proportion of patients can be enrolled using the proposed 
pragmatic study design that will be embedded within routine clinical practice rather than use 
of a dedicated study team, and c) demonstrating that the study can feasibly be performed 
using EFIC when enrolling critically ill infants, children, and adolescents into this clinical 
trial.  If these feasibility criteria can be adequately demonstrated at CHOP as a single site, 
we will have established the necessary feasibility metrics to indicate a high likelihood of 
success in a larger, multicenter study that will enroll several thousand patients across the 18 
sites comprising Pediatric Emergency Care Applied Research Network (PECARN) to test 
morbidity and mortality outcomes. 
1.2 Name and Description of Investigational Product or Intervention 
The study intervention will be the use of lactated Ringer’s (LR), a balanced/buffered 
crystalloid fluid, for initial resuscitation of pediatric patients with suspected septic shock.  
The comparison group will be use of 0.9% “normal” saline (NS), a non-buffered isotonic 
crystalloid fluid that is most commonly used to resuscitate patients treated for suspected 
septic shock in pediatric emergency departments in the United States. For example, in the 
PECARN registry of three large, academic pediatric EDs, LR was used in only 0.2% of 
suspected cases of septic shock (personal communication, Elizabeth Alpern).  Therefore, 
although LR is commonly cited in the literature, recommended (along with NS) as an 
appropriate crystalloid fluid option for pediatric septic shock, and is used in approximately 
50% of septic shock cases treated in the CHOP PICU, use of LR as an alternative crystalloid 
resuscitative fluid to NS in the pediatric ED setting requires a specific interventional study. 
The package inserts for NS is included in Appendix 1 and for LR is included in Appendix 2.  
Table 1 shows the biochemical components of NS and LR. 
Table 1:  Composition of Human Plasma, Normal Saline, and Lactated Ringer’s 
Content1 
Human Plasma 
0.9% Normal 
Saline 
Lactated 
Ringer’s 
Sodium 
140 
154 
130 
Chloride 
100 
154 
109 
Potassium 
4 
0 
4 
Calcium 
5 
0 
2.7 
Magnesium 
1.0 
0 
0 
Lactate 
1-2 
0 
28 
Bicarbonate 
24 
0 
0 
Osmolality (mOsm/L) 
290 
308 
273 
Cost (US $ per liter) 
--  
$1.00 – 2.00 
$1.00 - $2.00 
1Units are mEq/L (unless indicated) 


 
  3
1.3 Findings from Non-Clinical and Clinical Studies  
1.3.1 Pre-Clinical Studies 
NS contains a supra-physiologic concentration of chloride (1.5X that of plasma) and a 
strong ion difference (SID) of zero but is isotonic compared to extracellular fluid.  LR has 
less chloride, small amounts of additional electrolytes, and a higher SID due to the presence 
of lactates as an anion buffer.8,24  The high chloride content and low SID of NS has been 
associated with acute kidney injury (AKI), acidemia, hyperkalemia, vascular permeability, 
inflammation, coagulopathy, fluid overload, and death.25  For example, infusion of NS 
reduced renal blood flow and the glomerular filtration rate in a dog model to a greater extent 
than more balanced fluids.26  In addition, hyperchloremic metabolic acidosis produces a 
more profund pro-inflammatory response in a cell model than other forms of acidemia, such 
as hyperlactatemia.27  In a rat model of sepsis, fluid resusication with NS resulted in higher 
blood chloride, lower arterial blood pH, a more severe pattern of acute kidney injury, and 
higher levels of the pro-inflammatory cytokine interleukin-6.28 
1.3.2 Clinical Studies 
1.3.2.1 Clinical Studies in Adults 
In healthy human volunteers, infusion of NS impairs renal blood flow compared to LR and 
has demonstrated impaired cognition that was not evident with similar volumes of balanced 
fluids.29  Moreover, the development of a hyperchloremic metabolic acidosis has been 
associated with mortality after surgery30, adult critical illness,31 and pediatric sepsis (Hector 
Wong, MD, personal communication, February 14, 2017). 
Several studies have compared the effects of infusions of NS and buffered crystalloids on 
outcomes for adults with sepsis and other critical illnesses.  In a sequential period study of 
critically-ill adults, use of chloride-restrictive fluids reduced AKI by almost 50%.17  
However, the SPLIT crossover trial in 2,278 critically-ill adults found no differences in AKI 
or mortality for chloride-restrictive versus NS fluid.32  Similarly, in the CRISTAL open-
label randomized trial of adult ICU patients with hypovolemic shock, 31% of 72 patients 
who received LR died compared to 27% of 1,035 who received NS (p=0.49).33  In contrast, 
in a propensity-matched observational study of 6,730 adults with vasopressor-dependent 
septic shock, resuscitation with at least some crystalloid fluid as LR was associated with a 
14% relative reduction in hospital mortality, with a dose-dependent decrease in mortality as 
proportion of total crystalloid infused as LR increased.16  In a meta-analysis, adult septic 
patients who received balanced fluids had a trend towards a lower mortality than those that 
received NS (OR 0.78, 95% CI 0.58, 1.05) although no trial directly compared NS to 
balanced fluids.34  In a randomized trial of 65 adults with trauma, resuscitation with 
balanced fluids improved acid-base status and decreased hyperchloremia.35  Finally, in 
adults undergoing abdominal surgery, use of balanced fluids has been associated with fewer 
post-operative infections.36 
 
Two ongoing trials are currently comparing balanced fluids to NS in adult shock (PLUS 
study in septic shock, ClinicalTrials.gov NCT02721654 and SaLT-ED study in all shock, 
ClinicalTrials.gov NCT02614040).  However, both trials specifically exclude patients <18 
years of age. 


 
  4
1.3.2.2 Clinical Studies in Children 
In pediatric sepsis, there are limited data comparing clinical outcomes following LR versus 
NS resuscitation.  While Carcillo et al. demonstrated the importance of early fluid 
resuscitation in pediatric septic shock, there was no differentiation between use of NS or LR 
in that landmark study.37  In a randomized trial of four fluid regimens in children with 
dengue fever in Vietnam, patients receiving LR required a median of 15 minutes longer to 
recover from shock compared to NS but this small study was not powered for morbidity or 
mortality outcomes and dengue shock syndrome has unique circulatory and vasogenic 
pathophysiology compared to the more typical septic shock syndromes treated in the U.S.38  
In a small randomized study of balanced fluid (sterofundin) versus NS during major surgery 
in children up to 3 years of age conducted in Germany, subjects randomized to NS had 
higher blood chloride and more acidemia, but no difference in clinical outcomes.  The theme 
of insufficient power to determine the comparative effectiveness of NS versus LR (or other 
balanced fluids) is common in the pediatric literature.  Unfortunately, the largest prospective 
study of fluid resuscitation conducted in children with severe infections to date restricted 
crystalloid fluids only to NS.39 
 
To our knowledge, only two observational studies comparing NS and LR have been 
conducted in pediatric septic shock.  The first was a propensity-matched analysis of 2,398 
patients in the Pediatric Health Information Systems (PHIS) database who received 
exclusive NS- or LR-based fluid resuscitation for septic shock and was presented in abstract 
form at the 2016 Society of Critical Care Medicine Annual Congress.  The authors reported 
a 2% lower mortality for children receiving LR versus NS.40  The second study, which we 
recently published in The Journal of Pediatrics, was a matched analysis of 4,234 children 
with septic shock resuscitated with at least some proportion of LR fluid from 382 hospitals 
in the Premier Healthcare Alliance.41  Patients were identified using International 
Classification of Disease-9-Clinical Modifications (ICD-9-CM) codes for either severe 
sepsis/septic shock or a combination of codes indicating infection with organ system 
dysfunction.  Overall, we found no differences in mortality, AKI, or use of renal 
replacement therapies for patients resuscitated with NS or LR, even when matched by fluid 
volume and proportion of total fluids given as LR.  But for the subset of patients identified 
using sepsis-specific ICD-9-CM codes (which we and others have previously shown to have 
more severe illness than patients identified using combination codes), 30-day hospital 
mortality trended lower in patients who received LR (13.8%) compared to only NS (16.4%; 
p=0.16), as did the proportion treated with renal replacement therapies (RRT): LR, 1.9% 
versus NS, 3.9%; p=0.07).  However, in our cohort, LR was preferentially used either as 
first-line fluid in patients with lower illness severity or as an adjunctive fluid in patients who 
received large amounts of fluid resuscitation, and the matching algorithm was least effective 
in the most severely ill patients who received the largest total fluid volumes.  Consequently, 
we concluded that the results of our study are best interpreted as establishing the need for 
and the equipoise to conduct a prospective randomized trial to definitely address the 
comparative effectiveness of balanced fluids and NS in pediatric sepsis. 
 
Of note, in our recent survey (data unpublished), 95% of PECARN investigators agreed that 
the existing adult and pediatric data are insufficient to reach consensus on the best 
crystalloid fluid to use for resuscitation in pediatric septic shock. 


 
  5
 
1.4 Selection of Drugs and Dosages 
Both NS and LR are available with identical storage volumes and dosing strategies. 
For this study, standard storage units of NS and LR will be used, including 250, 500, and 
1,000 mL units.  At the discretion of the care team, dextrose may be added to either NS or 
LR for resuscitation (uncommon) or maintenance (common) fluid therapy.  Commonly used 
dextrose preparations for pediatric septic shock include NS or LR with 5% or 10% dextrose 
which are also available in standard volumes of 250, 500, and 1,000 mL units.  Potassium or 
other electrolytes may be added to either NS or LR as clinically indicated. 
Volume for fluid resuscitation is typically 10-20 mL/kg per dose administered over 5-20 
minutes via the intravenous or intraosseous route, though children with sepsis often receive 
>100-200 mL/kg total crystalloid volume resuscitation within 24-48 hours.  Volume for 
maintenance fluids is typically determined by patient weight, assessment of intravascular 
volume status, and need for a specific glucose infusion rate.  However, for this study, only 
the type of base fluid (i.e., NS or LR) will be determined by study protocol, while the actual 
volume administered (per bolus dose, per hour, and in total), duration of administration, and 
need for electrolyte additives (i.e., dextrose, potassium, others) will be at the complete 
discretion of the treating care team. 
The costs for NS and LR are equivalent, with both fluids at approximately $1-2.00 per liter.  
Since the volume of fluid will be determined by the care team and use of both NS and LR 
are consistent with published guidelines for crystalloid resuscitation of pediatric septic 
shock, the randomized selection of fluid will not significantly alter health care costs for 
subjects enrolled in this study. 
Both NS and LR are FDA-approved crystalloid fluid solutions recommend for use10,12 and 
clinically used for resuscitation of patients with shock.13-15  NS was first approved for 
medical use by the FDA in 1970, and LR was first approved for medical use by the FDA in 
1971.  Both NS and LR are listed for use in pediatrics based on “clinical practice” and 
reference in the “medical literature”.  In the pediatric ED population, however, NS is 
overwhelmingly the more common fluid used for resuscitation of pediatric septic shock.15  
Therefore, we will consider NS to be the control fluid (since >98% of patients not enrolled 
in this study would initially receive NS) and LR, the less commonly utilized fluid, the 
intervention fluid in this study.  Specific cautions for use of LR in the pediatric and critically 
ill population are shown in Table 2: 
Table 2:  FDA Contraindications and Warnings to LR Administration to the Pediatric 
and Critically Ill Population 
Concern 
Type of Caution 
Relevance to Proposed Study 
Pediatric Population: 
 
LR and ceftriaxone must not 
be simultaneously 
Contraindication 
Not relevant, inclusion criteria are age 
>6 months to <18 years (see page 11, 
section 3.4.1) 


 
  6
administered (age ≤ 28 days) 
LR and ceftriaxone must not 
be simultaneously 
administered through the 
same infusion line (age >28 
days)  
Contraindication 
If both LR and ceftriaxone prescribed, 
usual, routine clinical practice will be 
followed (see page 10, section 3.1.2) 
Lactate-containing solutions 
should be administrated with 
caution to infants <6 months 
Warning 
Not relevant, inclusion criteria are age 
>6 months to <18 years (see page 11, 
section 3.4.1) 
Critically Ill Population: 
 
LR should not be 
simultaneously administered 
with citrate anticoagulated 
blood through same 
administration set 
Warning 
If both LR and blood products are 
administered, usual, routine clinical 
practice will be followed (see page 10, 
section 3.1.2) 
LR infusion must be stopped 
if suspected hypersensitivity 
develop 
Warning 
Usual, routine clinical practice will be 
followed (see page 10, section 3.1.2) 
Depending on volume and rate 
of infusion, infusion of LR can 
cause fluid overload and/or 
electrolyte abnormalities 
Warning 
Not relevant, volume and rate of 
infusion of both LR (and NS) are at the 
discretion of the clinical team and both 
fluid and electrolytes will be monitored 
as indicated as part of usual, routine 
clinical practice (see page 10-11, 
section 3.2.1) 
Cautious administration of LR 
to patients with hyperkalemia or 
cardiac disease 
Warning 
 Eligibility criteria require treating 
clinician to determine it is safe to 
administer both NS and LR (see page 
11, section 3.4.1), with known 
hyperkalemia a specified exclusion 
criteria. In addition, study fluid may be 
stopped at clinician’s discretion if new 
data changes this determination during 
intervention phase (page 11, section 
3.1.2) 
Cautious administration of LR 
to patients with metabolic 
alkalosis 
Warning 
Not relevant, metabolic alkalosis rare 
during resuscitation in septic shock and 
study fluid may be stopped at clinician’s 
discretion (page 11, section 3.1.2) 
Cautious administration of LR 
to patients with inability to 
metabolize lactate (e.g., 
fulminant hepatic failure) 
Precaution 
Although fulminant hepatic failure or 
complete inability to metabolize lactate 
is rare in septic shock, eligibility criteria 
require treating clinician to determine it 
is safe to administer both NS and LR 
with known fulminant hepatic failure a 
specified exclusion criteria (see page 
11, section 3.4.1). In addition, study 


 
  7
fluid may be stopped at clinician’s 
discretion if new data changes this 
determination during intervention phase 
(page 11, section 3.1.2) 
Cautious administration of LR 
to patients with hypercalcemia 
Precaution 
Although severe hypercalcemia is rare 
in pediatric septic shock, eligibility 
criteria require treating clinician to 
determine it is safe to administer both 
NS and LR (see page 11, section 3.4.1) 
with known hypercalcemia a specified 
exclusion criteria. In addition, study 
fluid may be stopped at clinician’s 
discretion if new data changes this 
determination during intervention phase 
(page 11, section 3.1.2) 
 
1.5 Relevant Literature and Data 
Infusion of saline to restore circulating blood volume was first attempted during the cholera 
outbreak of the 1830’s.  In a letter to the Lancet published on June 2, 1832, Thomas Latta 
noted with intravenous saline “improvement in the pulse and countenance is almost 
simultaneous, the cadaverous expression gradually gives place to appearances of returning 
animation, the livid hue disappears, the warmth of the body returns.”42  Fluids of various 
composition were subsequently described, with the first reference to a solution similar to 
that of NS in the 1880’s.  Hartog Joakob Hamburger recognized that erythrocytes did not 
lyse when placed in NS and concluded that “the blood of man was isotonic with a NaCl 
solution of 0.9%”.43  Although these observations conceivably led to the “normal” moniker 
for 0.9% NS (nobody knows for sure), human plasma is actually closer to 0.6% NaCl.  
Subsequent events leading to the widespread adoption of NS into clinical practice remain 
unclear.  LR was also born in the 1880’s when Sydney Ringer added calcium and potassium 
to saline after observing that inorganic constituents of pipe water better preserved frog heart 
muscle ex vivo than just salt dissolved in distilled water.44  In 1932, the pediatrician Alexis 
Hartmann modified Ringer’s original formula in order to reduce the acidosis observed in 
infants with diarrhea.43 
Although commonly used, an increasing body of literature now links the high chloride 
content and low SID of NS to acute kidney injury (AKI), acidemia, hyperkalemia, vascular 
permeability, inflammation, coagulopathy, fluid overload, and death.25  In particular, when 
infused in large volumes—as is common in septic shock—NS induces a hyperchloremic 
metabolic acidosis due to the dilution of plasma bicarbonate within a constant carbon 
dioxide environment in the absence of an alternative buffer.45  In blood with normal protein 
levels, the SID (abbreviated Na + K – Cl) is approximately +40 mEq/L.  Infusion of NS with 
a SID of 0 (154 Na + 0 K – 154 Cl) produces an acidemia.46  Such a hyperchloremic 
metabolic acidosis is pro-inflammatory in cell culture experiments27 and has been associated 
with mortality following non-cardiac surgery.30  Moreover, since acidemia is often attributed 
to tissue hypoperfusion in shock, a low blood pH following NS resuscitation may propagate 


 
  8
a feed-forward cycle of excessive fluid administration and volume overload, which itself has 
been associated with adverse clinical outcomes in multiple adult and pediatric studies. 
 
However, despite suggestive relative efficacy and safety for balanced fluids like LR over NS 
for resuscitation of pediatric septic shock, whether there is a benefit for either NS or a more 
balanced fluid strategy remains unproven, particularly for pediatric septic shock.  Because 
crystalloid fluids are so commonly used, even a small relative benefit of one fluid 
resuscitation strategy could provide a substantial public health impact.  Unfortunately, 
because of unique pathophysiology and epidemiology for pediatric versus adult septic 
shock, results from ongoing adult fluid trials are unlikely to be generalizable to pediatric 
patients.  Given both types of fluids are inexpensive, stable at room temperature, commonly 
used, have identical storage and dosing volumes, and are of proven clinical benefit, 
crystalloids fluids provide the ideal scenario for a large pragmatic comparative effectiveness 
trial.  The proposed pilot study will address the specific feasibility concerns necessary to 
next perform a larger trial that will definitively determine the comparative effectiveness of 
NS versus LR in pediatric septic shock. 
 
Enrollment of patients as close to the initiation of fluid resuscitation is critical, and the lack 
of early enrollment has been a major criticism of previous fluid resuscitation trials in adult 
studies.22,23  In the United States, the majority of children begin fluid resuscitation in the 
emergency department in which the therapeutic goal is generally to achieve hemodynamic 
stability prior to transfer to an inpatient setting, including the intensive care unit.  
Consequently, fluid resuscitation with volumes up to (and exceeding) 80 mL/kg commonly 
occur in the pediatric ED.  Delaying enrollment of patients until after admission to an 
intensive care unit, thus, risks substantial volume of pre-study fluid resuscitation that may 
dilute the main effect of a specified fluid intervention.  Such contamination with pre-study 
fluid resuscitation has been a primary criticism of previous sepsis studies focusing on adults 
admitted to an ICU, in which receipt of a mean fluid volume of 2000 mL prior to study 
enrollment has been reported in several studies.22,23  Therefore, enrollment of children with 
suspected septic shock in the ED setting as close to initiation of fluid resuscitation as 
possible is necessary to maximize the potential differential effect of NS versus LR fluid.   
 
1.6 Compliance Statement 
This study will be conducted in full accordance with all applicable Children’s Hospital of 
Philadelphia Research Policies and Procedures and all applicable Federal and state laws and 
regulations including 45 CFR 46, 21 CFR Parts 50, 54, 56, 312,  and 314. .  We will also 
follow the Good Clinical Practice: Consolidated Guideline approved by the International 
Conference on Harmonization (ICH) except for a limited scope and timeframe for 
monitoring clinical adverse events (AEs) given the comparative effectiveness nature of the 
proposed study involving two interventions with routine clinical use in pediatric sepsis and 
well-documented efficacy and safety profiles of both NS and LR. 
The investigators will perform the study in accordance with this protocol, will obtain 
consent when possible, and will report unanticipated problems involving risks to subjects or 
others in accordance with The Children’s Hospital of Philadelphia IRB Policies and 
Procedures and all federal requirements. Collection, recording, and reporting of data will be 


 
  9
accurate and will ensure the privacy, health, and welfare of research subjects during and 
after the study.  
 
 


 
  10
2 
STUDY OBJECTIVES 
The purpose of the proposed pilot study is to determine the feasibility of performing a large, 
pragmatic, randomized, open-label trial comparing the clinical effectiveness and safety of 
fluid resuscitation with NS versus LR for pediatric septic shock. 
2.1 Primary Objective (or Aim) 
The primary objective of this study is to determine compliance with study fluid 
administration, throughout the intervention phase, within each randomized arm using a 
pragmatic study design.   
Specifically, we will determine if the proposed study design is feasible to provide a 
clinically important difference in crystalloid fluid type between the two study arms by 
measuring the proportion of intravenous crystalloid fluid administered as 0.9% saline for 
pediatric patients with suspected septic shock randomized to fluid resuscitation with either 
saline or lactated Ringer’s. 
2.2 Secondary Objectives (or Aim) 
The secondary objectives are to: 
 Estimate the proportion of eligible pediatric patients with suspected septic shock who 
may be enrolled into a large randomized pragmatic trial of fluid resuscitation with 
saline versus lactated Ringer’s. 
 Demonstrate feasibility of patient enrollment into a pragmatic fluid resuscitation trial 
using Exception from Informed Consent (EFIC). 
 
 


 
  11
3 
INVESTIGATIONAL PLAN 
3.1 General Schema of Study Design 
The overall design for this pilot study is a randomized, open-label pragmatic clinical trial of 
two different crystalloid fluids to resuscitate pediatric septic shock.  The two arms include 
0.9% “normal” saline (NS; control arm) and lactated Ringer’s (LR, intervention arm).  See 
Figure 1 for an overview of the study design and outcome assessment.  
3.1.1 Screening Phase 
Potential subjects will be referred by the treating team in the ED, but a member of the study 
team will perform final screening for eligibility based upon the protocol inclusion and 
exclusion criteria prior to enrollment of the subject.  Triggers for potential enrollment to be 
considered by the treating team will include initial fluid resuscitation with at least 20 mL/kg 
intravenous (IV)/intraosseous (IO) crystalloid fluid for clinical concern for septic shock.  To 
ensure rapid and appropriate eligibility and enrollment, ED staff (including ED attendings 
and fellows) will be included as study co-investigators and be trained regarding study 
enrollment criteria and procedures. 
When time permits, parental/guardian permission (informed consent) will be obtained prior 
to any study related procedures being performed.  However, under most circumstances, the 
life-threatening nature of septic shock and the narrow therapeutic window for fluid 
resuscitation (on the order of minutes after presentation and shock recognition) will preclude 
sufficient time for an appropriate discussion of the study to properly seek informed consent 
and assent.  In these cases, enrollment will proceed under the conditions of “exception from 
informed consent” (EFIC) with notification of the subject’s legally authorized representative 
(LAR) as described in Section 9.6.3. 
3.1.2 Intervention Phase  
The intervention to be tested is fluid resuscitation with LR compared to the “usual practice” 
control fluid of NS.  Other than prescribing which crystalloid fluid to use, the intervention 
will be purposely implemented without intense efforts to standardize timing and volume of 
fluid resuscitation or other components of clinical care. 
 
The proposed interventional plan is that, prior to receipt of >40 mL/kg of crystalloid bolus 
fluid, eligible patients will be randomized to receive either NS or LR for all remaining fluid 
administration (bolus and maintenance) for up to 48 hours.  The study period will end at 
11:59pm on the calendar day following randomization such that all patients receive at least 
24 hours of study fluid, which is the time-window from presentation in which most fluid 
resuscitation is completed for septic shock.27 This time point for terminating the intervention 
phase was selected because it provided a pragmatic endpoint that can be used by clinicians 
to signal the point at which to cease study fluid administration.  Selective fluid 
administration has been previously shown to result in widely different amounts of saline 
use,47 though application of these findings in adults using a different allocation strategy to 
the one proposed for our study is not clear.  Study fluids will not be blinded due to costs and 
interventions that are not in keeping with a simple, pragmatic trial and based on results from 
the previously published SPLIT fluid trial in which two-thirds of clinicians correctly 


 
  12
identified the randomized crystalloid patients received (despite blinding) as electrolyte 
differences following NS or LR provide clear indication of fluid selection.35  The volume 
and need for additional fluid, as well as all other aspects of care, will be at the discretion of 
the treating team which will be educated to follow the CHOP ED and/or PICU Sepsis 
Clinical Pathways both as part of routine care and for specific use in the proposed study (see 
Appendix 5).  All other care will be at the discretion of the clinical team.  As study fluids 
will not be blinded, patient-level randomization will minimize selection bias due to 
awareness of group assignment.  Study fluids can be stopped for clinician concerns noted 
during routine care (e.g., hyponatremia, hyperkalemia, hypercalcemia, cerebral edema).  
Adherence to the study intervention will be monitored through random chart audits of both 
eligible subject enrollment and the volume of study arm crossover.  Study arm cross-over is 
defined as a subject randomized to NS who subsequently receives LR during the 
intervention period or a subject randomized to NS who subsequently receives NS during the 
intervention period. 
 
NOTE:  Because calcium-containing solutions, including LR, can precipitate when 
administered simultaneously with ceftriaxone through the same infusion line, teams will be 
educated to follow usual, routine clinical practice for administration of LR with ceftriaxone.  
This includes use of either different infusion lines or, if the same infusion in used for 
sequential administration, then the line must be thoroughly flushed between infusions with a 
compatible fluid as per usual, routine clinical practice.  These practices are consistent with 
usual, routine care that would otherwise be performed for patients prescribed LR outside of 
this study.  An example of existing safety mechanisms within usual, routine clinical practice 
is that the following warning is issued within the electronic order entry system to advise 
caution when ceftriaxone is prescribed and administered: 
 
“Ceftriaxone and calcium-containing solutions may be administered sequentially of one 
another for use in patients greater than28 days if infusion lines are thoroughly flushed 
(with a compatible fluid) between infusions.” 
In addition, clinical staff will also be targeted for education about safe administration of LR 
with other medications, such as ceftriaxone, prior to and throughout the study. 
 
NOTE:  Because LR should not be administered simultaneously with citrate anticoagulated 
blood through the same administration set, teams will be educated to follow usual, routine 
clinical practice for administration of LR with blood products.  Clinical staff will be targeted 
for education about safe administration of LR with blood products prior to and throughout 
the study. 
 
NOTE:  Both NS and LR pose risk of a hypersensitivity reaction during IV/IO infusion.  
Teams will be educated to following usual, routine clinical practice for discontinuation of 
administration of study fluid if signs and/or symptoms of hypersensitivity reaction develops. 
 
3.1.3 Follow-up Phase 
After 11:59 pm on the calendar day following randomization, no further study fluid will be 
administered solely for research purposes and all care, including any subsequent crystalloid 


 
  13
fluid administration, will be at the discretion of the clinical team.  The follow-up phase will 
continue for the duration of the hospitalization or up through 90 days following study 
enrollment, whichever comes first.  Final determination of subject study completion versus 
withdrawal, as well as assessment of vital status and clinical outcomes will occur at hospital 
discharge or 90 days following study enrollment, whichever comes first. 
3.2 Allocation to Treatment Groups and Blinding 
Randomization will be performed using 1:1 permuted blocks.  Randomization sequence will 
be generated prior to the start of the study and will be filed using a series of numbered, 
opaque envelopes.  Envelopes with study arm assignment will be stored in close proximity 
to crystalloid fluids in the CHOP ED.  Treatment allocation will be revealed to the clinical 
care team after eligibility for enrollment has been determined to be appropriate by asking a 
member of the care team to open the next sequentially numbered envelope.  The number of 
the envelope and study arm assignment will be recorded in a log after opening the envelope.  
The clinical team will then be directed to use the assigned study fluid for all subsequent 
crystalloid fluid administration within the remainder of the study window.  Compliance with 
study fluid administration will be the primary feasibility assessment in this study (Aim 1).   
Fluid administration will be open-label and neither the subject nor the care team will be 
blinded to the allocated treatment assignment.  Blinding study fluid is not pragmatic and 
unlikely to even be possible. In the SPLIT fluid trial, two-thirds of clinicians correctly 
identified the randomized crystalloid patients received as electrolyte differences following 
NS or LR provide clear indication of fluid selection.35  However, randomization following 
study enrollment will help to minimize selection bias that might occur due to pre-enrollment 
awareness of study group assignment. 
3.3 Study Duration, Enrollment and Number of Sites 
3.3.1 Duration of Study Participation 
The study duration per subject will be up to 90 days, with up to 1 day for screening, up to 2 
days for Phase 1 (Intervention Phase), and up to 89 subsequent days (or until hospital 
discharge, whichever comes first) for follow-up. 
3.3.2 Total Number of Study Sites/Total Number of Subjects Projected 
The study will be conducted at one investigative site in the United States (the Children’s 
Hospital of Philadelphia). The University of Utah will act as the Data Coordinating Center 
(DCC) for this study, but they will not be engaged in human subjects research.  Their role is 
limited to the receipt of a limited dataset from the CHOP investigators. 
Recruitment will stop when 70 subjects are enrolled and randomized.  It is expected that 
approximately 80 eligible subjects will be enrolled to produce 70 evaluable subjects.  
3.4 Study Population 
Eligibility criteria are designed to enroll a broad, heterogeneous cohort of pediatric patients 
with suspected septic shock who are easily recognizable within routine clinical practice and 


 
  14
are representative of the broader population of pediatric patients treated for suspected septic 
shock. 
3.4.1 Inclusion Criteria 
1) Males or females age >6 months to <18 years 
2) Clinician concern for septic shock, operationalized as: 
a) a “positive” ED sepsis alert confirmed at the physician led “sepsis huddle” OR 
b) a physician diagnosis of suspected septic shock requiring parenteral antibiotics and 
fluid resuscitation as per the ED sepsis management pathway 
NOTE:  Condition 2a above is met by: 
A. Tachycardia or hypotension for age AND 
B. Fever (home or ED >38 °F), hypothermia, or other signs/symptoms of infection 
AND  
 
At least one of C, D, or E 
 
C. Flash (< 1 second) or delayed (>3 seconds) capillary refill 
D. Altered mental status 
E. Existing high-risk condition, including: 
i. <56 days-old 
ii. Asplenia 
iii. Bone marrow or solid organ transplant 
iv. Central venous catheter 
v. Malignancy 
vi. Significant neurological dysfunction or technological dependence at 
baseline 
vii. Other immunodeficiency or immunocompromised 
 
As per the existing CHOP ED Sepsis Alert, the presence of A and B and either C, D, or 
E will be determined by the triage nurse (and then continuously by the ED treating nurse 
if criteria are not initially met).  If these criteria are met, then a “sepsis huddle” will be 
called with immediate physician bedside patient evaluation for possible septic shock.  
Patients who are considered to have suspected septic shock will be treated on the CHOP 
ED sepsis management protocol (Appendix 5) and will be considered for study 
eligibility 
NOTE:  Condition 2b above is met by any patient who does not meet criteria for a “sepsis 
huddle” but is diagnosed by the treating ED physician with suspected septic shock requiring 
parenteral antibiotics and fluid resuscitation. 
Combining both the nurse-driven electronic sepsis alert with physician judgement to identify 
suspected septic shock in the CHOP emergency department, we have documented a 99.4% 
sensitivity and 99.1% specificity to identify patients who met international consensus 
criteria for severe sepsis/septic shock while only 5.5% of ED patients who developed severe 


 
  15
sepsis/septic within 24 hours of ED presentation were missed.48  However, because the 
positive predictive value of this combined approach was 25.4%, we have required the 
additional inclusion criterion of administration of at least 20 mL/kg IV/IO fluid resuscitation 
with additional fluid deemed likely to be necessary to treat poor perfusion, defined as either 
hypotension or abnormal (either “flash” or >3 second) capillary refill (as determined by 
clinician’s judgment). 
 
3) Administration of at least 20 mL/kg IV/IO fluid resuscitation 
4) Receipt of ≤40 mL/kg IV/IO crystalloid fluid prior to randomization 
5) Additional fluid deemed likely to be necessary to treat poor perfusion, defined as either 
hypotension or abnormal (either “flash” or >2 second) capillary refill (as determined by 
clinician’s judgment)10 
NOTE:  Due to the pragmatic nature of this study that is designed to reflect usual clinical 
practice, we will not define specific thresholds for either hypotension or abnormal capillary 
refill but rather defer to the treating clinician’s discretion to determine hypotension and 
abnormal capillary refill. 
6) Parental/guardian permission (informed consent) if time permits; otherwise, EFIC 
criteria met 
NOTE:  For patients who may be transferred to the CHOP ED from an outside facility, 
many will have started fluid resuscitation prior to arrival in the CHOP ED.  If volume of 
crystalloid fluid administration cannot be easily determined such that receipt of ≤40 mL/kg 
IV/IO crystalloid volume cannot be easily verified, these patients will be operationalized as 
not meeting the ≤40 mL/kg inclusion criterion.  
NOTE:  Patients who are randomized to a study arm at ≤40 mL/kg crystalloid fluid 
resuscitation but for whom study fluid is not initiated until after >40 mL/kg will still be 
included and should commence with administration of study fluid for the duration of the 
remaining intervention phase. 
3.4.2 Exclusion Criteria 
Reflecting the pragmatic design of the proposed study, exclusion criteria are purposely 
limited to ensure maximal external validity.  FDA listed “contraindications” to LR are 
reflected as absolute exclusions (e.g., age < 6 months), while FDA listed “warnings” and 
“precautions” to LR administration are incorporated into the below listed exclusion criteria 
(see Table 2 in Section 1.4 for summary of FDA recommendations for use of LR in the 
pediatric and critically ill population).  In addition, exclusion criteria are operationalized to 
reflect the common clinical practice (and guideline recommendations) to begin 
administration of either NS or LR to resuscitate septic shock without delays imposed by 
waiting for laboratory diagnostic tests.   


 
  16
1) Clinician judgement that patient’s condition deems it unsafe to administer either NS or 
LR (since patients will be equally likely to receive NS or LR at time of study 
enrollment), including (but not limited to): 
a) Clinical suspicion for impending brain herniation based on data available at or before 
patient meets criteria for study enrollment 
b) Known hyperkalemia, defined as non-hemolyzed whole blood or plasma/serum 
potassium > 6 mEq/L, based on data available at or before patient meets criteria for 
study enrollment 
c) Known hypercalcemia, defined as plasma/serum total calcium >12 mg/dL or whole 
blood ionized calcium > 1.35 mmol/L, based on data available at or before patient 
meets criteria for study enrollment 
d) Known acute fulminant hepatic failure, defined as plasma/serum ALT >10,000 U/L 
or total bilirubin >12.0 mg/dL, based on data available at or before patient meets 
criteria for study enrollment 
e) Known history of severe hepatic impairment, defined as diagnosis of cirrhosis, “liver 
failure”, or active listing for liver transplant 
f)  Known history of severe renal impairment, defined as current dependency on 
peritoneal dialysis or hemodialysis 
g) Known metabolic disorder, inborn error of metabolism, or primary mineralcorticoid 
deficiency (e.g., mitochondrial disorder, urea cycle disorder, amino acidemia, fatty 
acid oxidation disorder, glycogen storage disorder, congenital adrenal hypoplasia, 
Addison’s disease) as reported by subject, LAR or accompanying caregiver, or as 
listed in the medical record 
NOTE:  Due to the short therapeutic time window available for fluid resuscitation—and 
therefore study enrollment (see Section 3.1.1.)—in pediatric septic shock, it is not feasible to 
wait for diagnostic tests to identify medical conditions.  Therefore, exclusion will be based 
on medical conditions that are known (or, in the case of impending brain herniation, 
suspected) at or before the time a patient otherwise meets criteria for study enrollment.  If 
such data are not available and the treating clinician does not otherwise, in his/her best 
judgement, deem it unsafe to administer either NS or LR, then the patient will be eligible for 
study enrollment if they meet all other inclusion and exclusion criteria.  Given the dynamic 
nature of sepsis, should an enrolled subject be noted to have a condition for which further 
administration of either NS or LR is deemed to be unsafe, the subject will be withdrawn 
from further study fluid administration. Because potassium, calcium, and liver function tests 
are already measured in all patients with suspected septic shock as part of routine care, there 
is no specific mandate to measure these values for the sole purposes of this study. 
2) Known pregnancy determined by routine clinical history disclosed by patient and/or 
LAR (or other accompanying acquaintance) 
NOTE:  The exclusion of pregnant women is indicated under the provisions for “exception 
from informed consent” rather than a specific need to exclude pregnancy women from the 
interventions to be test in this study.  Given the absence of data or plausible adverse 
biological effect for either NS or LR in pregnancy (see FDA inserts for NS and LR in 
Appendix 1 and Appendix 2, respectively), the recommended use of crystalloid fluid for 
resuscitation of pregnant women with septic shock,12 and the absence of data supporting a 


 
  17
relative difference in efficacy or safety for use of NS versus LR on the developing fetus 
during any trimester,49 there is no specific need to exclude pregnant women from the 
interventions to be tested in this study beyond the requirements for enrollment under 
“exception from informed consent”. In addition, since 2012, none of the 1,420 patients 
treated for sepsis in the CHOP ED has had a positive pregnancy test.  Therefore, because 
waiting for biochemical testing for pregnancy (e.g., urine β-HCG) would either cause most 
post-pubertal female patients become ineligible for enrollment (due to receipt of >40 mL/kg 
of fluid) or delay fluid resuscitation (putting potential subjects at risk of harm) and given the 
extremely low risk for diagnosing pregnancy in this patient population and given the safe 
use of both NS and LR in pregnancy, there will not be a requirement to delay study 
enrollment while awaiting results of a pregnancy test.  Any subject enrolled in the study who 
is subsequently determined to be pregnant as part of routine clinical care, which at CHOP 
includes testing for pregnancy in all female patients of child-bearing age, will be 
immediately withdrawn from this study.  
3) Known prisoner as determined by routine social history disclosed by patient and/or LAR 
(or other accompanying acquaintance) 
4) Known allergy to either normal saline or lactated Ringer’s as determined by routine 
allergy history disclosed by patient and/or LAR (or other accompanying acquaintance) 
or as indicated in the medical record 
5) Indication of prior declined consent to participate based on presence of a “PRoMPT 
BOLUS Opt-Out” bracelet with appropriate messaging embossed into the bracelet (see 
IRB study 17-013950) or the presence of the patient’s name on an opt-out list that will 
be kept up-to-date and checked prior to randomization. 
Concurrent participation in another interventional trial will not be considered an exclusion 
criteria because such co-enrollment is not expected to impact the feasibility aims and 
outcomes for this study. 
Subjects that do not meet all of the enrollment criteria may not be enrolled. Any violations 
of these criteria must be reported in accordance with IRB Policies and Procedures.  
 
 


 
  18
4 
STUDY PROCEDURES 
4.1 Screening Visit 
Patients will be screened at arrival to the ED (i.e., at ED triage) and continuously throughout 
the ED course for presence of eligibility criteria.  Referrals for potential subject enrollment 
will be made by the ED care team if there is clinician concern for septic shock and need for 
crystalloid fluid resuscitation assessed by the care team.  Although all members of the ED 
care team may participate in subject referral, a member of the study team will review and 
concur with the treatment team’s eligibility assessment prior to enrollment of the subject.    
To ensure rapid and appropriate eligibility and enrollment, ED staff (including ED 
attendings and fellows) will be included as study co-investigators and be trained regarding 
study enrollment criteria and procedures   Once patients are determined to be eligible, the 
following study procedures will occur: 
 Informed Consent (if time permits) or determination of EFIC 
 Randomization 
In addition, review of the daily ED triage logs and use of the ED sepsis pathway order set 
will be performed by study staff to determine potentially eligible patients who were not 
enrolled.  The reason for non-enrollment for all eligible patients will be determined by 
querying the attending physician of record and/or relevant members of the clinical care 
team.  
4.2 Intervention Phase 
The intervention phase will start immediately following the patient’s first 20 mL/kg and 
randomization has been determined, and will end at 11:59 pm on the calendar day following 
randomization.  During this period, the follow study procedures will occur: 
 Dispense study fluid 
 Monitor study fluid adherence 
 If enrollment after EFIC, review inclusion/exclusion criteria 
 If enrollment after EFIC, inform subject and LAR of study enrollment (as soon as 
feasibly possible) 
 Medical record review 
 Adverse event reporting 
4.3 Follow-up Phase 
The follow-up phase will start after 11:59 pm on the calendar day following randomization 
and will end at hospital discharge or 90 days following randomization, whichever comes 
first.  During this period, the following study procedures will occur: 


 
  19
 Open-label fluid treatment 
 If enrollment after EFIC and not accomplished during intervention phase, inform 
subject and LAR of study enrollment (as soon as possible) 
 Medical record review 
 Adverse event reporting 
 Outcome assessment 
4.4 Concomitant Medication 
All prior and concomitant use of antibiotics, acyclovir, corticosteroids, bicarbonate, parental 
calcium, blood products, crystalloid and colloid fluids (including hypertonic saline), 
mannitol, intravenous immunoglobulin, diuretics, non-steroidal anti-inflammatory 
medications (NSAIDS), unfractionated or low-molecular weight heparin, vasoactive 
infusions (i.e., dopamine, dobutamine, epinephrine, norepinephrine, phenylephrine, 
milrinone, vasopressin) within one day prior to the screening visit and through the end of the 
study will be recorded. The dates of administration, dosage, and reason for use will be 
included.  
4.5 Rescue Medication Administration 
Open-label use of hypertonic saline, mannitol, unfractionated or low-molecular weight 
heparin, systemic or local tissue plasminogen activator (tPA), or other “blood thinner”, 
parenteral calcium, and parenteral bicarbonate will be recorded, including dates of 
administration, dosage, and reason for use. 
4.6 Subject Completion/Withdrawal 
Subjects may withdraw from the study at any time without prejudice to their care, including 
following notification of study enrollment under EFIC.  Subjects may also be discontinued 
from the study at the discretion of the Investigator (at any point) for lack of adherence to 
study treatment or at the discretion of the attending physician of record (during the 
intervention phase only) if his/her clinical judgment deems it no longer safe to continue to 
administer either NS or LR.  The Investigator may also withdraw subjects to protect the 
subject for reasons of safety or for administrative reasons.  It will be documented whether or 
not each subject completes the clinical study. If the Investigator becomes aware of any 
serious, related adverse events after the subject completes or withdraws from the study, they 
will be recorded in the source documents and on the CRF. 
4.6.1 Early Termination Point 
Subjects who withdraw from the study will have all procedures enumerated for the follow-
up phase in Section 4.3 performed at the early termination point (rather than at hospital 
discharge or study day 90).  
In addition, subjects randomized to LR in this unblinded study for whom routine, clinician-
directed physical and/or laboratory assessment reveals the following criteria within the up-


 
  20
to-48 hour time window of the intervention phase will not be required to receive additional 
study fluid as part of this protocol and will be transitioned to an appropriate fluid as 
determined by the discretion of the treating clinical team.  Recognizing that hepatic and 
renal injury are a) common in septic shock, b) often improved by fluid resuscitation, and c) 
vary along a spectrum of mild dysfunction (common) to severe failure (uncommon), 
stopping criteria are defined when either an immediate unsafe condition is noted or when 
persistent or worsening organ injury indicates that continued LR administration may be 
cumulatively unsafe (e.g., potassium administration despite worsening oliguria or lactate 
administration despite worsening hepatic function). 
 Hyperkalemia defined as blood potassium >6 mEq/L confirmed on immediate repeat 
testing  
 Hypercalcemia defined as blood total calcium >12 mg/dL or ionized calcium >0.35 
mmol/L confirmed on immediate repeat testing  
 Severe hepatic impairment defined as rise in blood ALT to >10,000 U/L or total 
bilirubin >12.0 mg/dL 
 Severe renal impairment defined as initiation of renal replacement therapy 
(continuous or intermittent hemodialysis or peritoneal dialysis) or urine output <0.5 
ml/kg/hr for 16 hours 
 
NOTE:  Hepatic impairment was defined as a fulminant rise in ALT or total bilirubin 
because other markers of liver function are not commonly recommended for use in pediatric 
septic shock.  For example, an acute elevation in INR is more commonly indicative of 
hematologic dysfunction than hepatic impairment in pediatric septic shock.50 
 
NOTE:  Urine output <0.5 ml/kg/hr for 16 hours indicates renal injury (“I”) in the pRIFLE 
scoring system and stage II kidney injury in the KDIGO scoring system.51  Creatinine and 
creatinine clearance will not be used as stopping criteria in the absence of oliguria or 
initiation of renal replacement therapy because intermittent lab testing may limit the utility 
of these measurements compared to continuous urine output monitoring and blood creatinine 
is a poor proxy for a patient’s handling of potassium in that most acute kidney injury in 
sepsis is caused by acute tubular necrosis, which promotes electrolyte wasting despite a rise 
in blood creatinine.  As an example, in a prior randomized trial of NS versus LR following 
kidney transplant (as a model of severe acute kidney injury), 19% of patients in the NS 
developed hyperkalemia >6 mEq/L compared to 0% in the LR group.52  Consequently, urine 
output is the most useful clinical indicator of potential electrolyte retention. 
 
The laboratory values noted above, including potassium, total calcium, ionized calcium, 
ALT, and bilirubin, will be ordered as determined to be clinically indicated by the treating 
clinical team rather than prescribed by this study protocol.  Because patients with septic 
shock have wide variability in illness severity and clinical course, including large 
differences in the amount and timing of fluid administration, pre-specifying which 
laboratory values to obtain and when to obtain them could result in additional unnecessary 
phlebotomy and/or access of indwelling lines both of which would impose additional harm 
(e.g., pain) and risk (e.g., central-line associated bloodstream infection risk increases with 
additional line accesses) that may not have been experienced outside of the study.  
Therefore, rather than pre-specifying in the study protocol the laboratory values to obtain 


 
  21
and the time points or timeframe at which to obtain them, the study protocol will utilize the 
institution’s existing laboratory recommendations within the clinical sepsis pathway, which 
includes potassium and total calcium at least every 12 hours, ionized calcium every 2 hours 
(as part of blood gas analysis), and ALT and bilirubin every 24 hours for patients with active 
septic shock admitted to the pediatric intensive care unit (with more frequent laboratory 
assessments in the subset of patients with more severe illness undergoing ongoing fluid [and 
other] resuscitation).  At CHOP, there are no hospital guidelines for ongoing management of 
patients treated for septic shock in the ED who are subsequently admitted to the floor 
following resolution of shock.  It is anticipated that ongoing fluid resuscitation outside of the 
ED setting will be almost exclusively limited to patients who require admission to the PICU, 
such that the existing clinical sepsis pathway will prompt clinicians to ascertain laboratory 
values appropriately in those patients at risk for fluid-related abnormalities for whom study 
fluids will no longer be recommended. The timeframes included within the clinical sepsis 
pathway provide adequate windows to re-assess safety of ongoing study fluid administration 
because these potential adverse laboratory effects are related to cumulative fluid 
administration rather than any one particular fluid bolus. 
 
For subjects randomized to either NS or LR in whom routine, clinician-directed physical 
and/or laboratory assessment reveals clinical concern for hypersensitivity to the study fluid 
to which they were randomized, will not be required to receive additional study fluid as part 
of this protocol within the up-to-48 hour time window of the intervention phase. 
 
Any subjects who meet the above “stopping criteria” will remain in the study for data 
collection and outcome assessment.  Clinician-prescribed fluid administered within the 
intervention phase will continue to be recorded, including any potential continued use of LR 
and/or alternative fluid. 
 
 


 
  22
5 
STUDY EVALUATIONS AND MEASUREMENTS 
5.1 Screening and Monitoring Evaluations and Measurements 
5.1.1 Medical Record Review 
The following variables will be abstracted from the medical chart (paper or electronic). 
 Name 
 Medical record number 
 CSN number 
 Date/time ED arrival and triage 
 Date/time of transfer/discharge from the ED 
 Date/time of hospital admission 
 Date/time of PICU admission 
 Date of birth 
 Race 
 Ethnicity 
 Comorbid medical/surgical conditions 
 Pre-hospital medications 
 Date, time, and volume of all study fluid administration 
 Date, time, and volume of all non-study parenteral fluid administration, including all 
crystalloids, colloids, blood productions, medications, continuous infusions, and 
flushes 
 Total daily recorded volume administered (all “in’s”) and excreted/removed (all 
“out’s”) 
 Date/time of medications/pharmaceuticals administrated during ED and 
hospitalization 
 Laboratory tests (including date/time and results) 
 Microbiology tests 
 Radiological tests 


 
  23
 Date/time of PICU transfer/discharge 
 Date/time of hospital discharge 
 Vital status at hospital discharge, study withdrawal, or 90 days following 
randomization, whichever comes first 
5.1.2 Laboratory Evaluations 
No routine laboratory evaluations will be required to be performed as part of this study.  
However, blood levels of lactate, potassium, calcium, sodium, and chloride are routinely 
measured at presentation and serially over time in pediatric patients with suspected or 
confirmed septic shock.  Any such laboratory evaluations that are performed during the 
course of routine clinical care in the ED or during the hospitalization may be abstracted from 
the medical chart. 
No laboratory testing will be required in this study beyond that which is performed as part of 
routine clinical practice.  Because both NS and LR are already FDA-approved with 
demonstrable efficacy and safety for reversing shock and there exists a long history of 
clinical experience in using both NS and LR in pediatric patients with septic shock, there 
does not exist sufficient equipoise to justify a clinical trial to investigate either the individual 
efficacy or safety profile of NS or LR.  Rather, this feasibility study is the first step towards 
a larger, multicenter comparative effectiveness study which will determine the relative 
efficacy and safety of NS versus LR.  The relative benefit one fluid over the other was not 
been proven or even sufficiently tested in large prospective studies and there is, therefore, 
equipoise for the question of comparative effectiveness.  The goal of the comparative 
effectiveness study will be to determine if there are clinically overt and significant benefits 
of either NS or LR, relative to each other.  We therefore will seek to measure clinically overt 
and significant efficacy and safety outcomes which would be identified as part of routine 
clinical practice rather than specifying biochemical laboratory tests that may identify values 
outside the range of normal but would not otherwise be considered “clinically overt and 
significant”.  For example, there is no compelling reason to shift clinical practice from 
predominant NS resuscitation to predominant LR resuscitation solely because of 
hyperchloremia if this biochemical abnormality does not translate into a “clinically overt and 
significant” patient outcome.  For these reasons, no laboratory testing will be required 
beyond that which is performed as part of routine clinical practice.  However, as described 
in Section 6.3.4, for the purposes of this feasibility study, we will track laboratory testing 
performed as part of routine clinical practice in order to determine the frequency that 
laboratory results are available for the specified safety outcome measures listed in Section 
5.4.  In addition, if the designated “stopping criteria” listed in Section 4.6.1 are identified 
during the course of routine, clinician-directed physical and/or laboratory assessment, no 
further study fluid will be recommended. 
5.1.3 Radiographic Evaluations 
No routine radiographic evaluations will be required as part of this study.  However, 
radiographic studies that are performed during the course of routine clinical care will be 


 
  24
abstracted from the medical chart as needed to determine site of infection, diagnosis of 
venothromboembolism, and diagnosis of cerebral edema/intracranial hypertension.  
5.2 Feasibility Evaluations 
5.2.1 Aim 1 
The primary outcome for Aim 1 will be the proportion of total crystalloids administered as 
saline in each arm, and the secondary outcome will be the proportion of total crystalloids 
administered as non-study fluid (i.e., cross-over) in each arm. 
The primary outcome will be measured in each subject by dividing the total volume (in mL) 
of NS administered as fluid boluses or continuous IV/IO fluids (numerator) by the total 
volume (in mL) of all crystalloids (NS, LR, and Plasma-lyte [with or without dextrose 
and/or other electrolyte additives]) administered as fluid boluses or continuous IV/IO fluids 
during the intervention phase (denominator).  NS or LR (or other crystalloid) administered 
to “flush” a medication or check line patency, as a “carrier” fluid designed to maintain 
IV/IO patency or assist delivery of another medication, or used solely as a diluent for 
another medication will be excluded from both the numerator and denominator. 
The secondary outcome will be measured in each subject by dividing the total volume (in 
mL) of non-study fluid given as either NS (for patients randomized to the LR arm) or LR 
(for patients randomized to the NS arm), including pre-study enrollment crystalloid fluids 
(numerator), by the total volume (in mL) of NS plus LR [with or without dextrose and/or 
other electrolyte additives]) administered as fluid boluses or continuous IV/IO fluids during 
the intervention phase (denominator).  NS or LR (or other crystalloid) administered to 
“flush” a medication or check line patency, as a “carrier” fluid designed to maintain IV/IO 
patency or assist delivery of another medication, or used solely as a diluent for another 
medication will be excluded from both the numerator and denominator. 
5.2.2 Aim 2 
The outcome for Aim 2 will be the proportion of eligible patients treated in the CHOP ED 
who are enrolled, randomized, and treated with study fluid.  This outcome will be measured 
by dividing the number of eligible patients treated in the CHOP ED who are enrolled, 
randomized, and treated with study fluid (numerator) by the total number of eligible patients 
treated in the CHOP ED (denominator) over the entire enrollment period of the study. 
5.2.3 Aim 3 
The outcomes for Aim 3 will be the proportion of eligible patients who meet criteria for 
EFIC who are not enrolled, randomized, and treated with study fluid or, if enrolled, 
withdraw prior to completion of the follow-up phase.  This outcome will be measured by 
dividing the number of patients eligible but not enrolled through EFIC and/or withdraw prior 
to completion of the follow-up phase (numerator) by the number of eligible patients who 
meet criteria for EFIC (denominator) over the entire enrollment period of the study. 


 
  25
5.3 Efficacy Evaluation 
This pilot study will not be powered to determine efficacy.  However, the following efficacy 
outcomes planned for use in a subsequent large pragmatic trial will be measured: 
 All-cause hospital mortality (censored at 90 days following randomization), 
measured as vital status at hospital discharge 
 Hospital-free days, measured as the number of calendar days alive and out of the 
hospital between randomization (day 0) and day 27.  Patients who die prior to 
hospital discharge will be recorded as “zero” hospital-free days.  Because follow-up 
will not proceed after hospital discharge, patients who may have died after hospital 
discharge but before day 27 will be recorded as having as many hospital-free days up 
to day 27 as if they had survived to day 27. 
 New inpatient dialysis, measured as treatment (or intention to treat if subject does 
not tolerate treatment) with any renal replacement therapy (including slow 
continuous ultrafiltration, continuous or intermittent hemodialysis, hemofiltration, or 
hemodiafiltration, or peritoneal dialysis) that was not a continuation of pre-hospital 
chronic therapy. 
 Hospital length of stay, measured as the number of calendar days between ED arrival 
and ED or hospital discharge (whichever occurs later). 
5.4 Safety Evaluation 
This pilot study will not be powered to determine safety.  However, the following safety 
outcomes planned for use in a subsequent large pragmatic trial will be measured if 
ascertained as part of routine clinical practice: 
 Hyperlactatemia, measured as at least one venous or arterial blood lactate 
measurement >4 mmol/L within four calendar days of randomization 
 Hyperkalemia, measured as at least one venous or arterial blood potassium 
measurement >6 mEq/L (without hemolysis) within four calendar days of 
randomization 
 Hypercalcemia, measured as at least one venous or arterial blood ionized calcium 
measurement of >1.35 mEq/L or total calcium >12 mEq/L within four calendar days 
of randomization 


 
  26
 Hypernatremia, measured as at least one venous, arterial, or capillary blood sodium 
measurement of >155 mEq/L within four calendar days of randomization 
 Hyponatremia, measured as at least one venous, arterial, or capillary blood sodium 
measurement of <128 mEq/L within four calendar days of randomization 
 Hyperchloremia, measured as at least one venous, arterial, or capillary blood 
chloride measurement of >110 mEq/L within four calendar days of randomization 
 Clotting of intravenous line in patients who received both ceftriaxone and LR, within 
four calendar days of randomization 
 Therapy for brain herniation, measured as treatment with hyperosmolar therapy 
(hypertonic saline and/or mannitol) for radiographic and clinical determination of 
new impending or present brain herniation (but not including a presumptive clinical 
diagnosis of brain herniation that is disproven by subsequent radiographic studies) 
within four calendar days of randomization 
 Therapy for thromboembolism, measured as radiographic or clinical determination 
of new venous or arterial thromboembolism requiring initiation of therapeutic 
anticoagulation for the purposes of treating thromboembolism, within seven calendar 
days of randomization 


 
  27
6 
STATISTICAL CONSIDERATIONS 
6.1 Primary Endpoint 
The primary endpoint will be the proportion of total crystalloids administered as saline in 
each arm during the intervention phase (Aim 1). 
6.2 Secondary Endpoints 
Secondary endpoints will include the following: 
 The proportion of total crystalloids administered as non-study fluid (i.e., cross-over) in 
each arm (Aim 1). 
 The proportion of eligible patients treated in the pediatric ED who are enrolled, 
randomized, and treated with study fluid (Aim 2). 
 The proportion of eligible patients who meet criteria for EFIC who are enrolled, 
randomized, and treated with study fluid and do not withdraw prior to completion of the 
follow-up phase. 
 
6.3 Statistical Methods 
6.3.1 Baseline Data  
Baseline and demographic characteristics will be summarized by standard descriptive 
summaries (e.g. means and standard deviations for continuous variables such as age and 
percentages for categorical variables such as gender). 
6.3.2 Feasibility Analysis 
The primary analysis will be based on an intention-to-treat approach and will include all 
subjects randomized whether or not study fluid was administered.   
The primary endpoint will be defined as meeting feasibility criteria if either of the following 
criteria are met: 
3) There is an absolute difference in the mean use of NS between arms of at least 65% 
with a lower 95% CI border of >60%.  For example, feasibility criteria would be met 
if 90% of crystalloid fluid in the NS arm was NS compared to only 25% in the LR 
arm.  The proportion of NS use in each arm will be compared using the chi-squared 
test with a 95% bootstrap confidence interval with bias correction (assuming skewed 
distribution of data) around the difference in the proportion of NS use in each arm. 
4) At least 85% of subjects in the NS arm receive ≥90% of study fluid as NS during the 
study window and at least 80% of subjects in the LR arm receive ≥75% of study 
fluid as LR. 
The secondary endpoints will be defined as meeting feasibility criteria if: 


 
  28
 The mean proportion of total crystalloids administered as non-study fluid (i.e., cross-
over) is ≤ 25% in each arm (for example, ≤25% of total crystalloid is administered as 
NS for patients randomized to the LR arm). 
 The proportion of eligible patients treated in the pediatric ED who are enrolled, 
randomized, and treated with study fluid is >65%. 
 EFIC is approved by the IRB at CHOP 
 The proportion of eligible patients who meet criteria for EFIC who are not enrolled 
or who are enrolled but withdraw prior to completion of the follow-up phase is 
≤10%.  
6.3.3 Efficacy Analysis 
Efficacy endpoints will be tracked between groups as part of this pilot study, but no formal 
statistical comparisons will be undertaken due to insufficient statistical power.  As part of 
our secondary feasibility analysis, however, we will determine the proportion of patients 
with complete data available for each efficacy endpoint listed in Section 5.3 to ensure that it 
is indeed feasible to capture the efficacy outcome measures planned for a subsequent large 
multicenter trial. 
For subjects who may withdraw prior to death and prior to hospital discharge and for whom 
permission is not granted for continued follow-up of associated clinical efficacy outcomes, 
the National Death Index will be queried for survival status.  According to FDA regulations, 
when a subject withdraws from a study, the data collected on the subject to the point of 
withdrawal remains part of the study database and may not be removed.  If a subject 
withdraws from the interventional portion of a study and does not consent to continued 
follow-up of associated clinical outcome information, the investigator must not access for 
purposes related to the study the subject’s medical record or other confidential records 
requiring the subject’s consent. However, an investigator may review study data related to 
the subject collected prior to the subject’s withdrawal from the study, and may consult 
public records, such as those establishing survival status 
6.3.4 Safety Analysis 
Safety endpoints will be tracked between groups as part of this pilot study, but no formal 
statistical comparisons will be undertaken due to insufficient statistical power.  As part of 
our secondary feasibility analysis, however, we will determine the proportion of patients 
with complete data available for each safety endpoint listed in Section 5.5 to ensure that it is 
indeed feasible to capture the safety outcome measures planned for a subsequent large 
multicenter trial.  Specifically, we will track laboratory testing performed as part of routine 
clinical practice in order to determine the frequency that laboratory results are available for 
the specified safety outcome measures listed in Section 5.4.  It is notable that routine clinical 
practice for sepsis includes frequent (i.e., daily or more) measurement of blood lactate, 
sodium, potassium, chloride, and calcium. 
6.4 Sample Size and Power 
In a previous PECARN study called the FLUID trial (data not yet published), nearly 1400 
pediatric patients presenting to the ED with diabetic ketoacidosis (DKA) were randomized 
to different fluid volumes and different fluid types (normal saline vs. half-normal saline).  


 
  29
We used FLUID data on adherence to fluid type assignment to simulate adherence in the 
proposed study, assuming that the LR arm will behave like the half-NS arm (i.e., the study 
intervention arm) and the NS arm will behave like the NS arm (i.e., the control arm) in the 
FLUID trial.  In the FLUID trial, the mean percentage of correct fluid given was 96% in the 
NS arm and 91% in the half-NS arm.  About 90% of subjects in the NS arm received at least 
85% NS, while about 89% of those in the half-NS arm received at least 75% half-NS.  
Through simulation, by sampling from FLUID data, with 35 patients in each arm, the 
probability that at least 85% of subjects in the NS arm and 80% in the LR arm will receive 
the “adequate” amount of correct study fluids (i.e., ≥90% of study fluid as NS in NS arm 
and ≥75% of study fluid as LR in the LR arm) is approximately 80% (study power for 
criterion #2 of the Aim 1 feasibility analysis described in Section 6.3.2). 
6.5 Interim Analysis 
Although a specific interim analysis will not be performed as part of this pilot feasibility 
study, we will include a potential early stop role for an imbalance in mortality between the 
two groups if there is a difference of more than six deaths in one group compared to the 
other after enrollment of at least 36 subjects (approximately 18 per group).  An imbalance of 
at least six deaths will provide statistical significance at the level of 0.05 between the two 
groups.  Hospital deaths will be monitored continuously as they occur throughout the course 
of the study.  If the potential early stop rule is reached, the DCC will provide these data to 
the DSMB for an interim review and consideration to proceed versus terminate the study 
based on their review of the study data, cause of death, and/or other possible data deemed 
necessary by the DSMB. 


 
  30
7 
STUDY MEDICATION 
7.1 Description 
Existing hospital supplies of NS and LR will be utilized for this study without any change to 
packaging or labeling. 
7.1.1 Packaging 
Both NS and LR will be supplied in their usual bags and/or syringes that are in current use 
as part of routine clinical practice. 
7.1.2 Labeling 
Only FDA-approved hospital-issued fluids will be used for this study.  The current supply of 
fluids used at CHOP to be included in this study is NS manufactured by Baxter Healthcare 
Corporation and LR manufactured by Baxter Healthcare Corporation.  Both NS and LR will 
be labeled as per their existing labels that are in current use as part of routine clinical 
practice.  NS is labeled as “0.9% Sodium Chloride Injection USP” and LR is labeled as 
“Lactated Ringer’s Injection USP” as part of routine clinical practice.  Although an IND will 
be sought for this study for the purposes of EFIC, since only FDA-approved study fluids that 
are used as part of routine clinical care for pediatric septic shock (as well as other 
indications) will be used for this study, no additional labeling will be applied to bags of 
either NS or LR for the purposes of this study.  At CHOP, while NS remains the most 
common fluid to treat pediatric septic shock in the ED, 50% of the resuscitation fluids used 
to treat children with septic shock in the pediatric intensive care unit are NS and 50% are 
LR.  Given both NS and LR are commonly used in routine clinical practice and both are 
FDA-approved, application of study-specific labeling can only contribute to medication 
errors by altering routine clinical practice.  Given the pragmatic nature of the proposed study 
design that is required to expand this work to the larger PECARN network, enroll several 
thousand patients, and optimize external validity, it is not practical to employ a dedicated 
study team to guard against medication errors that may ensue by introducing a non-
standardized label on FDA-approved, hospital-issued fluids to be used in this study. 
7.1.3 Dosing 
Both NS and LR have identical dosing recommendations for use as crystalloid fluid 
resuscitation in pediatric septic shock, which is 20 mL/kg of body weight administered as 
rapid IV/IO bolus. Actual doses administered can vary based on clinician preference and/or 
patient clinical condition.  This study will not prescribe a specific dose of either NS or LR to 
be administered; rather, all dosing decisions will remain at the discretion of the clinical care 
team with guidance as per existing ED and PICU sepsis pathways (see Appendix 5). 
7.1.4 Treatment Compliance and Adherence 
Because study fluids can only be given by the clinical care team (rather than self-
administered by the patient and/or LAR), there will be no concerns for patient or 
parent/guardian-related issues with treatment compliance and adherence. 


 
  31
Compliance/adherence with use of study fluid consistent with the randomized arm will be 
tracked for every patient as part of Aim 1 of this pilot trial.  Details of this assessment are 
described further in Sections 5.2.1 and 5.7.2. 
7.1.5 Drug Accountability 
The basis of this feasibility study is to establish and test the feasibility of a pragmatic study 
design that will ultimately be extended to at least 18 sites through the PECARN network and 
will enroll several thousand patients. Therefore, it is not practical to account for details of 
fluid administered (including, for example, lot number and residual volume not 
administered) beyond that which is collected for clinical purposes.  Because both NS and LR 
are already used in common clinical practice at CHOP, are both FDA-approved, and all 
decisions regarding timing and volume of fluid to be administered will be governed by the 
treating clinical team (rather than study protocol), no specific study procedures will be 
established to monitor study fluid accountability.  Rather, administration and disposal of 
residual volumes of both NS and LR will occur as part of routine practice carried out at 
CHOP.  No fluid will be specifically supplied for the purposes of this study since all 
decisions regarding timing and volume of fluid will be determined by the clinical care team 
and because there is no meaningful cost differential for the administration of either NS or 
LR.  Thus, because all study patients will receive an efficacious fluid (either NS or LR) to 
reverse shock without additional fluid-related costs generated by participating in this study, 
hospital-stocked fluid supplies will be utilized for this study without need for additional 
accountability beyond routine practice. 


 
  32
8 
SAFETY MANAGEMENT 
8.1 Clinical Adverse Events 
Septic shock is a complex and life-threatening condition for which we expect a wide range 
of potential adverse events, including organ dysfunction, hospital-acquired infections, and 
death, to occur as part of the routine clinical course.  In addition, because all 
intravenous/intraosseous medications, including crystalloid fluids such as NS and LR, can 
result in intravenous and/or intraosseous extravasation with soft tissue infiltrates, we expect 
that intravenous and/or intraosseous extravasation with soft tissue infiltrates will occur as 
part of the routine clinical care for some subjects enrolled in this study.  Since all decisions 
to administer fluids for a specified indication, timing, and/or volume remain at the discretion 
of the clinical care team, we do not consider intravenous and/or intraosseous extravasation 
with soft tissue infiltrates to be an unexpected event.  Finally, because of the strong existing 
safety profile of both NS and LR, common clinical use of both fluids to treat septic shock, 
pragmatic study design with limited, targeted data collection, and because there is no 
biologic plausible reason to anticipate that adverse events related to study fluid 
administration should occur remote from fluid administration itself, we will not plan to 
continuously monitor for clinical adverse events (AEs).  Instead, we will monitor for AEs by 
a chart review that will occur at two time points—1) after the end of the intervention phase 
and 2) at 5-7 days after the intervention phase (or at hospital discharge, whichever comes 
first) as shown in Appendix 3.  We will limit the time period for determination of AEs to 5-7 
days following the end of the administration of study fluid because there is no biologically 
plausible reason to anticipate that either LR or NS should lead to adverse events remote 
from the immediate intervention period.  We selected a time period of 5-7 days following 
the end of the intervention period in order to ensure that no clinically significant AEs are 
missed in this pilot feasibility study in order to better inform a subsequent large randomized 
multicenter trial. 
If AEs are identified, the AE will be reported as they arise as described in Section 8.5 and 
then will be followed through to resolution or hospital discharge, whichever comes first.  In 
addition, we will also monitor for the specific safety endpoints noted in Section 5.4 that we 
have a priori identified as potential events that may be differentially impacted by use of NS 
or LR.  These safety endpoints will be ascertained through intermittent data collection 
throughout the intervention and follow-up phases and at hospital discharge or 90 days 
following randomization, whichever comes first. 
8.2 Adverse Event Reporting 
Unanticipated problems related to the research involving risks to subjects or others that 
occur during the course of this study (including SAEs) will be reported to the IRB in 
accordance with CHOP IRB SOP 408: Unanticipated Problems Involving Risks to Subjects. 
AEs that are not serious but that are notable, unanticipated, and could involve risks to 
subjects will be summarized in narrative or other format and submitted to the IRB at the 
time of continuing review.  


 
  33
8.3 Definition of an Adverse Event 
An adverse event is any untoward medical occurrence in a subject who has received an 
intervention (drug, biologic, or other intervention) and is not anticipated to occur as a part of 
the routine clinical course of septic shock.  Because septic shock is a complex and life-
threatening condition for which we anticipate a wide range of potential medical events, 
including organ dysfunction, hospital-acquired infections, and death, to occur as part of the 
routine clinical course, there are few events that will be unanticipated.  However, the 
occurrence of an AE does not necessarily have to have a causal relationship with the 
treatment.  An AE can therefore be any unfavorable or unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with 
the use of a medicinal product, whether or not considered related to the medicinal product, 
that was not anticipated to occur as part of the routine clinical course of septic shock. 
All unanticipated AEs (including serious AEs) will be noted in the study records and on the 
case report form with a full description including the nature, date and time of onset, 
determination of non-serious versus serious, intensity (mild, moderate, severe), duration, 
causality, and outcome of the event.  AEs that occur within the timeframe noted in Section 
8.1 will be followed until either resolution or hospital discharge, whichever occurs first. 
Intensity of AEs will be defined as follows: 
 Mild:  mild event of its type that does not interfere with routine activities 
 Moderate:  moderate event of its type that interferes with routine activities 
 Severe:  severe event of its type that makes it impossible to perform routine activities 
8.4 Definition of a Serious Adverse Event (SAE) 
As noted above, septic shock is a complex and life-threatening condition that commonly 
causes organ dysfunction, need for invasive medical and surgical therapies (including, but 
not limited to, mechanical ventilation, renal replacement therapy, plasma exchange, 
extracorporeal membrane oxygenation, and cardiopulmonary resuscitation), subsequent 
hospital-acquired infections, and even death.  Consequently, the development of new or 
progressive organ dysfunction, need for invasive medical and surgical therapies (including, 
but not limited to, mechanical ventilation, renal replacement therapy, plasma exchange, 
extracorporeal membrane oxygenation, and cardiopulmonary resuscitation), identification of 
a hospital-acquired infection, and death are all anticipated to occur as part of routine clinical 
practice for subjects enrolled in this study (see Table 3 below for list of expected and 
possible unexpected adverse events). 
An SAE will be defined as any unanticipated adverse drug experience that results in any of 
the following outcomes:  
 an unanticipated life-threatening event (at risk of death at the time of the event), or  
 requires prolongation of existing hospitalization, or 
 a persistent or significant disability/incapacity. 


 
  34
Other important unanticipated medical events that may not be life-threatening or require 
hospitalization may be considered a serious adverse drug event when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
A distinction should be drawn between serious and severe AEs.  A severe AE is a major 
event of its type.  A severe AE does not necessarily need to be considered serious.  For 
example, nausea which persists for several hours may be considered severe nausea, but 
would not be an SAE.  On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke, but would be an SAE.  
8.4.1 Relationship of SAE to study drug or other intervention 
The relationship of each SAE to the study intervention will be characterized using one of the 
following terms in accordance with CHOP IRB Guidelines: definitely, probably, possibly, 
unlikely or unrelated.  
8.5 IRB/IEC Notification of SAEs and Other Unanticipated Problems 
The Investigator will promptly notify the IRB of all on-site unanticipated, serious Adverse 
Events that are related to the research activity. Other unanticipated problems related to the 
research involving risk to subjects or others will also be reported promptly. Written reports 
will be filed using the eIRB system and in accordance with the timeline below. External 
SAEs that are both unexpected and related to the study intervention will be reported 
promptly after the investigator receives the report.  
Type of Unanticipated 
Problem 
Initial Notification  
(Phone, Email, Fax) 
Written Report 
Internal (on-site) SAEs 
that are Life Threatening  
24 hours 
Within 2 calendar days 
Internal (on-site) SAEs 
All other SAEs 
7 days 
Within 7 business days 
Unanticipated Problems 
Related to Research 
7 days  
Within 7 business days 
All other AEs 
N/A 
Brief Summary of important 
AEs may be reported at time 
of continuing review 
 
8.5.1 Reporting procedures 
AEs will only be reported if judged by the investigators to be related to administration of 
study fluid.  SAEs will be reported regardless of whether these are judged to be related to 
administration of study fluid.  See “Adverse Event Reporting” in Appendix 3 for a flow 
diagram outlining the need for and timing of reporting of AEs and SAEs. 


 
  35
AEs and SAEs to be collected for subjects enrolled in this study are listed in Table 3, along 
with classification as either expected within the study population of pediatric patients with 
septic shock or unexpected.  All of the events lists in Table 3 could potentially be related to 
the study fluid intervention, though this determination will be made on a case-by-case basis.  
Other unexpected events not listed in Table 3 will not be collected unless the clinical care 
team and/or the study investigators determine that the event may be related to the study fluid 
intervention.   
Table 3:  Adverse Events To Be Collected 
Event 
AE or SAE 
Expected in Pediatric Sepsis 
Death1 
SAE 
Expected 
Cardiac arrest requiring CPR 
SAE 
Expected 
Arrhythmia requiring intervention 
AE 
Not Expected 
Vasoactive infusion 
SAE 
Expected 
Extracorporeal membrane oxygenation 
(ECMO) 
SAE 
Expected 
Invasive mechanical ventilation 
SAE 
Expected 
Non-invasive mechanical ventilation 
AE 
Expected 
Dialysis (not pre-existing) 1 
SAE 
Expected 
Liver dysfunction 
SAE 
Expected 
Limb necrosis 
SAE 
Expected 
Brain herniation2 
SAE 
Not Expected 
Seizure 
AE 
Not Expected 
Pulmonary embolus 
SAE 
Not Expected 
Deep venous thrombosis 
AE 
Expected 
Central venous line clot requiring 
pharmacologic therapy2 
AE 
Expected 
Bleeding (not requiring massive 
transfusion protocol) 
AE 
Expected 
Bleeding (requiring massive 
transfusion protocol) 
SAE 
Not Expected 


 
  36
Hospital-acquired infection3 
AE 
Expected 
Pressure ulcer 
AE 
Expected 
IV infiltrate (grade 3 or 4) 
AE 
Expected 
Rash 
AE 
Expected 
Hyperlacatatemia > 4 mmol/L2 
AE 
Expected 
Hyperkalemia >6 mEq/L2 
AE 
Not Expected 
Hypercalcemia (ionized calcium > 
1.35 mEq/L or total calcium > 12 
mEq/L) 2 
AE 
Not Expected 
Hypernatremia >155 mEq/L2 
AE 
Not Expected 
Hyponatremia <128 mEq/L2 
AE 
Not Expected 
Hyperchloremia >110 mEQ/L2 
AE 
Expected 
1Event also included as pre-specified efficacy outcome 
2Event also included as pre-specified adverse outcome 
3Includes central line-associated bloodstream infection, urinary tract infection (both 
catheter-associated and non-catheter-associated), ventilator-associated pneumonia, 
ventilator-associated tracheitis, hospital-acquired viral infection, surgical site infection, and 
C. difficile colitis) 
 
8.5.2 Follow-up report 
If an SAE has not resolved at the time of the initial report and new information arises that 
changes the investigator’s assessment of the event, a follow-up report including all relevant 
new or reassessed information (e.g., concomitant medication, medical history) will be 
submitted to the IRB. The investigator is responsible for ensuring that all SAE are followed 
until either resolved or stable.  
8.6 Investigator Reporting of a Serious Adverse Event to Sponsor 
Reporting will be consistent with all regulatory and sponsor requirements, including the IND 
submitted to the FDA.  Dr. Scott Weiss, a CHOP co-investigator, will be the sponsor for the 
IND. 
8.7 Medical Emergencies 
Medical emergencies that might develop during the course of the study will be diagnosed 
and treated at the discretion of the clinical team.  


 
  37
9 
STUDY ADMINISTRATION 
9.1 Treatment Assignment Methods 
9.1.1 Randomization 
Prior to enrollment of any subjects, a complete randomization scheme will be completed 
using a 1:1 permuted blocks.  The randomization sequence will be filed within a series of 
sequentially numbered, opaque envelopes.  A supply cart with both NS and LR will be 
available where the randomization envelopes are located and will be immediately available 
for enrollments, so as not to delay treatment of subjects.  While not specifically a goal of this 
study, we do anticipate that the presence of the supply cart may actually enhance the speed 
of treatment since the fluid will be immediately available at the bedside. 
9.1.2 Blinding 
Study fluids will not be blinded due to costs and interventions that are not in keeping with a 
simple, pragmatic trial.  Moreover, it may not even be possible to effectively blind clinicians 
to study fluid assignment due to common electrolyte differences following NS or LR that 
will suggest a specific fluid selection.  This scenario was borne out in the previously 
published SPLIT fluid trial in which two-thirds of clinicians correctly identified the 
randomized crystalloid patients received (despite blinding) based on diverging electrolyte 
profiles.32 
9.2 Data Collection and Management 
Data will be managed and stored by the University of Utah Data Coordinating Center 
(DCC), which has an established working relationship with PECARN (the planned research 
network for the subsequent multicenter pragmatic trial).  We will work with the DCC to 
create the electronic case report form (CRF) for this study.  The CRF will be password-
protected with the safeguards noted below to maintain confidentiality for all data entered 
into the CRF.  The CRF will be password-protected and entered via CHOP-issued 
computers. There will be a separate master list linking subject PHI and study data and will 
be stored separately from the study data and will only be accessible to the CHOP study 
team. Locally secured, identifiable information and partially identifiable information will be 
stored locally at CHOP for this pilot study.  
The Data Coordinating Center has a state-of-the-art computer infrastructure with a dedicated 
server room with a fire suppression system, air conditioning, cooling system and separate air 
filtering. The server facility is locked separately from the remainder of the Data 
Coordinating Center and access to the building is monitored by security personnel year 
round. The Data Coordinating Center coordinates its network infrastructure and security 
with the Health Sciences Campus (HSC) information systems at the University of Utah. This 
provides the Data Coordinating Center with effective firewall hardware, automatic network 
intrusion detection, and the expertise of dedicated security experts working at the 
University. 
 
Network equipment includes four high-speed switches. User authentication is centralized 
with two Windows 2008 domain servers. Communication over public networks is encrypted 


 
  38
with virtual point-to-point sessions using SSL or VPN technologies, both of which provide 
at least 128 bit encryption. REDCap, OpenClinica (Web-based clinical studies data 
management system), eRoomTM (Web-based collaborative workspace) and other web 
applications use the SSL protocol to transmit data securely over the Internet. Direct access to 
Data Coordinating Center machines is only available while physically located inside the 
Data Coordinating Center offices, or via a VPN client. All network traffic is monitored for 
intrusion attempts, security scans are regularly run against our servers, and IT staff are 
notified of intrusion alerts. 
 
Production servers running mission critical applications are clustered and configured for 
failover events. Servers are backed up with encryption through a dedicated backup server 
that connects across an internal 10 gigabit network to a tape drive. Storage area networking 
(SAN) applications, clusters, and switch-to-switch links are also on a 10 gigabit network. 
Incremental backups occur hourly during the week. Incremental backups also are performed 
nightly with full system backups occurring every week. Tapes are stored in a fireproof safe 
inside the data center facility, and full backups are taken to an off-site commercial storage 
facility. Security is maintained with Windows 2008 user/group domain-level security. 
 
Users at both CHOP and University of Utah will be required to change their passwords 
every 90 days, and workstations at University of Utah will time out after 5 minutes of 
inactivity. All files are protected at group and user levels; database security is handled in a 
similar manner with group level access to databases, tables, and views in Microsoft SQL 
Server. All portable computers at University of Utah are whole-disk encrypted. 
  
9.3 Confidentiality 
All data and records generated during this study will be kept confidential in accordance with 
Institutional policies and HIPAA on subject privacy and the Investigator and other site 
personnel will not use such data and records for any purpose other than conducting the 
study. 
The PI and other research personnel have all completed training and received certification in 
Human Subjects Research Protection and HIPAA. All project staff hired will also 
successfully complete this training prior to engaging in any research or treatment with study 
participants and renew this training as required by their institution. 
The investigators and staff of the Data Coordinating Center are fully committed to the 
security and confidentiality of all data collected for the PRoMPT Bolus-Feasibility study. 
All Data Coordinating Center personnel at the University of Utah have signed 
confidentiality agreements concerning all data encountered in the center. Violation of these 
agreements may result in termination from employment at the University of Utah. In 
addition, all personnel involved with data coordinating center data systems have received 
Human Subjects Protection and HIPAA education. 
The staff, reviewers and investigators involved with this study will be required to sign 
agreements from the Data Coordinating Center that relate to maintenance of passwords, 
information system security, and data confidentiality. 


 
  39
No identifiable data will be used for future study without first obtaining IRB approval. The 
investigator will obtain a data use agreement between the provider (the PI) of the data and 
any recipient researchers (including others at CHOP) before sharing a limited dataset (PHI 
limited to dates and zip codes).  
9.4 Regulatory and Ethical Considerations 
9.4.1 Data and Safety Monitoring Plan 
The principal investigator will be responsible for overseeing data collection and the safety of 
all study procedures.  In addition, a Data Safety Monitoring Board (DSMB) will be 
convened made up of representatives who are independent of the study investigators. 
Before initiation of the clinical study, the sponsor-investigator will arrange a pretrial 
monitoring visit with the IND & IDE Support Program and the Office of Research 
Compliance (ORC) to confirm clinical trial readiness.  After enrolling and starting 
administration of the investigational agent to the first subject, the sponsor-investigators will 
contact ORC to arrange a monitoring visit.  Thereafter, ORC will monitor the study at least 
once during the course of the pilot.  Monitoring activities will be guided by ICH E6 section 
5.18.  Monitoring of subject data will be initiated at 100% verification of the data recorded. 
This may be amended, and a tapered approach to monitoring may be employed, if conduct 
and documentation of the study reaches a level of reliability that would permit valid 
conclusions based upon a sampling of data 
9.4.2 Data Safety Monitoring Board (DSMB) 
The PRoMPT Bolus – Feasibility study will have a Data Safety Monitoring Board (DSMB) 
composed of five members from the CHOP/University of Pennsylvania community who 
have no other involvement in any aspect of the proposed study.  Members of the DSMB will 
be invited by the study investigators in consultation with the DCC.  At least one member 
will be knowledgeable in medical ethics and at least one member will be a patient advocate.   
The DSMB will have a charter, will approve the protocol prior to implementation, and will 
meet prior to initiation of subject enrollment, after hospital discharge of the first 36 subjects, 
and again at the conclusion of the study along with meetings scheduled ad hoc as necessary. 
The purpose of the DSMB will be to advise the study investigators regarding the continuing 
safety of study subjects and the continuing validity and scientific merit of the study.  The 
DSMB is responsible for monitoring accrual of study subjects, adherence to the study 
protocol, assessments of data quality, review of serious adverse events and other subject 
safety issues, and review of formal statistical analyses.  The DCC will send reports relating 
to these topics to DSMB members ten days prior to each DSMB meeting and will notify the 
DSMB if the mortality difference exceeds the predetermined stopping rule noted in Section 
6.5. 
The DCC will remotely staff DSMB meetings and produce minutes of open sessions.  
Minutes of closed or executive sessions of the DSMB will be produced and retained by the 
DSMB Chairperson.  These closed minutes will not be available outside the DSMB prior to 
the end of the study.   


 
  40
The DSMB Chairperson will prepare a summary of each DSMB meeting that conveys the 
public conclusions of the DSMB, with respect to protocol alterations and recommendations 
concerning continuation of the study.  The summary will be provided to the DCC and the 
DCC will send this summary to all participating investigators for submission to their 
respective Institutional Review Boards. 
The DSMB will meet prior to the start of subject enrollment and then after enrollment of all 
subjects for this feasibility study.  The DSMB, however, will have the discretion to alter 
meeting timing and frequency, as well as meet ad hoc as necessary throughout the course of 
the study.   
9.4.3 Risk Assessment 
Because both NS and LR have both been previously proven as efficacious for fluid 
resuscitation of pediatric septic shock, both NS and LR are currently used in common 
clinical practice for this indication, and because patients will only be considered eligible if 
the clinical care team (usually the attending physician) deems it safe for the patient to 
receive both NS and LR, the risks presented by this study will be limited.  However, because 
there is a prospect of a relative benefit in efficacy and/or safety for one fluid over the other, 
subjects may be randomized to an arm with relatively inferior efficacy or relatively worse 
safety. 
Several safeguards have been put in place to minimize risk of randomized (rather than 
clinician-prescribed) fluid administration, including: 
a) Because of the FDA noted caution in using lactate-containing fluids, such as LR, in 
patients <6 months of age, only patients >6 months-old will be eligible for this study. 
b) Any patients for whom clinician judgement deems it unsafe to administer NS or LR 
will be excluded from enrollment, with specified exclusions noted (but not limited 
to) clinical suspicion for impending brain herniation, known hyperkalemia, known 
hypercalcemia, and known fulminant hepatic failure. 
c) Exclusion of patients with known pregnancy, known prisoner status, or known 
allergy to NS or LR. 
In addition, post-marketing risks reported with infusion of either NS, LR, or both fluids are 
listed in Table 4.  All of these risks that have been reported with (but not necessarily 
causally linked to) use of either NS, LR, or both and are all consistent with the risks subjects 
would experience if they received these fluids as part of clinical care.  Therefore, 
participation in this study is unlikely to expose patients to risks beyond that incurred as part 
of routine clinical care.  However, since it is likely that more patients will receive LR than 
otherwise would as part of routine clinical care, there may be a slight increase in risk for the 
study population as a whole than would otherwise be the case as part of routine clinical care. 
Table 4:  Reported risks associated with infusion of NS and/or LR 
Risk 
Reported with NS 
Reported with LR 
Anaphylaxis/anaphylactoid reaction 
X 
X 


 
  41
Angioedema/Laryngeal edema 
X 
X 
Chest pain/chest discomfort 
X 
X 
Bronchospasm 
 
X 
Dyspnea/Respiratory distress 
X 
X 
Cough 
X 
X 
Urticaria or other rash 
X 
X 
Pruritis 
X 
X 
Nausea 
X 
X 
Pyrexia 
X 
X 
Infusion site reaction (erythema, pruritis, 
numbness, pain, edema, extravasation) 
X 
X 
Bradycardia 
 
X 
Tachycardia 
 
X 
Hypotension 
 
X 
Anxiety 
X 
X 
Headache 
X 
X 
Dysgeusia (metallic taste in mouth) 
 
X 
Paresthesias 
 
X 
Sneezing 
 
X 
Hyperkalemia 
Xa 
X 
Hypervolemia 
X 
X 
Pulmonary edema 
X 
X 
Acid-base disturbance 
Xa 
X 
Hyponatremia 
 
X 
Hyperlactatemia 
 
X 
Hypernatremia 
X 
 


 
  42
Hyperchloremia 
X 
 
Hypercalcemia 
 
X 
Acute kidney injury 
Xa 
X 
Infection 
Xa 
X 
Coagulopathy 
X 
X 
Venothromboembolism 
X 
Xb 
Cerebral edema 
X 
Xb 
 aRisk reported in patients receiving both NS and LR but may be more common with NS 
bRisk reported in patients receiving both NS and LR but may be more common with LR 
The other major risk to subjects enrolled in this study is breach of patient confidentiality, 
which is itself limited by the safeguards noted in Section 8.3. 
9.4.4 Potential Benefits of Trial Participation 
Because fluid resuscitation with either NS or LR may offer relative superior efficacy and/or 
safety, there is a prospect of direct benefit to subjects from trial participation. 
Additionally, indirect benefits to society are clear because this pilot study will help to inform 
a larger pragmatic comparative effectiveness study to meet the needs of clinicians making 
treatment decisions about fluid resuscitation for pediatric patients with suspected septic 
shock.  By informing the most beneficial and safe crystalloid fluid for clinicians to select, 
society (and future patients) may benefit from a reduction in sepsis-associated morbidity and 
mortality. 
9.4.5 Risk-Benefit Assessment 
Because NS and LR are both known to be efficacious for resuscitation of pediatric septic 
shock and both fluids are currently used in clinical practice, there is a minimal expected 
impact on the overall risk-benefit balance to patient to participation in this trial beyond that 
which would be incurred as part of ordinary routine clinical practice.  Nonetheless, because 
subjects enrolled in this study will receive type of fluid determined by randomization rather 
than clinician-prescribed (as in usual practice) and there is a potential for a relative benefit in 
efficacy and/or safety for one fluid over the other, the risks incurred by enrollment in this 
study may be slightly higher than in clinical practice.  However, this small potential for risk 
for subjects randomized to a relatively inferior fluid is balanced by the prospect of direct 
benefit for subjects randomized to a relatively superior fluid with all subjects having an 
equal chance of randomization to either arm.  The primary benefit of this trial for patients is 
that each patient has a random chance to be exposed to a potentially more effective fluid 
resuscitation strategy. Given the lack of definitive data indicating which fluid is more 
effective and, thus equipoise, it cannot be known before the study which fluid arm may or 


 
  43
may not provide the most benefit.  Risks due to breach of confidentiality are another risk, 
but this will be mitigated by the steps outlined in Section 8.3. 
Given the potential of direct patient benefit with only minimal risk greater than routine 
clinical care, the study is justified to proceed based on the balance between risks and 
benefits. 
9.5 Recruitment Strategy 
Subjects will be recruited as part of routine clinical practice within the CHOP pediatric ED.  
Prospective subjects will be identified by the clinical care team when they meet eligibility 
criteria.  We anticipate that activation of the CHOP ED Sepsis Pathway order set will be a 
primary trigger to consider eligibility for inclusion of a patient in this study.  However, 
patients do not necessarily have to be treated on the CHOP ED sepsis pathway to be 
considered for eligibility of enrollment into this study.  A member of the study team—
including ED attendings and fellows included and trained as study co-investigators—will 
ensure subjects meet all eligibility criteria prior to study enrollment.  After eligibility is 
confirmed and, in the rare cases were sufficient time is available for prospective informed 
consent, a member of the study team—including ED attendings and fellows included and 
trained as study co-investigators—will seek informed consent.  For most cases, however, we 
anticipate that conditions will not permit sufficient time for prospective informed consent 
and we will proceed with enrollment under Exception From Informed Consent (EFIC, see 
Section 9.6.3) for which a member of the clinical care team, under the supervision of the 
attending physician of record or his/her designee, will be responsible for obtaining an “opt-
out” from the LAR when possible (see Section 9.6.3 for further details of “opt-out” plan).   
Study fliers (approved under CHOP IRB study 17-013950) will be posted in the CHOP ED 
to further inform potential subjects and LARs of this study. 
Based on internal data from CHOP and published estimates,53 we anticipate 189-290 eligible 
patients per 100,000 ED visits.  With approximately 20,000 visits over 4 months to the 
CHOP ED, we anticipate sufficient subjects to achieve the study goals with enrollment over 
4 months. 
9.6 Informed Consent/Assent and HIPAA Authorization 
Subjects will be enrolled using a combination of written informed consent and HIPAA 
Authorization, if feasible, or Exception From Informed Consent (EFIC) under specified 
conditions (see below). 
We seek a waiver of assent for all subjects (see below). 
9.6.1 Informed Consent and HIPAA Authorization 
For patients who meet inclusion criteria and in the rare scenario where sufficient time is 
available to properly and ethically seek prospective informed consent without endangering 
the patient, the parents or legal guardians (i.e., LARs) will be approached for study 
enrollment.  A trained member of the study team—including ED attendings and fellows 
included and trained as study co-investigators—will engage them in a discussion regarding 
reasons for the study, the study procedures, and the risks and benefits and answer all 


 
  44
questions.  A study team physician will also be available to explain the medical aspect of the 
study and answer questions during the consent process.  Due to anticipated critical nature of 
the patients’ condition in septic shock, this discussion may take place at the patient’s bedside 
or in an alternative location (e.g., family conference room) at the parent/guardian’s option 
and the consenter’s discretion.  Regardless of the where this discussion takes place, all 
reasonable safeguards to ensure patient privacy will be taken.  If it is necessary for a study 
team member to discuss the study with the LAR via phone (e.g., LAR cannot be physically 
present but time permits for prospective informed consent), then written informed consent 
will still be obtained by either faxing or emailing the informed consent form to the LAR for 
a written signature. 
 
For patients who meet inclusion criteria and in the rare scenario where sufficient time is 
available to properly and ethically seek prospective informed consent without endangering 
the patient, we will also obtain written permission for HIPAA Authorization on the 
combined consent-HIPAA authorization form.   
 
We will provide a copy of the combined consent-HIPAA authorization document to the 
parent/guardian and will write a note in the patient’s medical record documenting the 
informed consent discussion. 
 
If the LAR consents to participate in the study, the LAR will be notified that PHI will be 
retained indefinitely in a coded fashion with all safeguards in place to maintain 
confidentiality as described in Section 8.3. 
 
9.6.2 Waiver of Assent 
We are seeking a waiver assent for all patients due to the critical nature of the patients' 
illness in septic shock, often with altered mental status and neurologic dysfunction from a 
combination of sepsis encephalopathy, shock, hypoxemia, hypercarbia, and/or hyperthermia, 
which will make them unable to participate in a meaningful way.  However, any patients 
who are capable and willing to participate in the prospective informed consent discussion (in 
rare scenarios where it is appropriate) will be involved and engaged in this process. 
 
9.6.3 Exception From Informed Consent (EFIC) 
Enrollment of subjects under Exception from Informed Consent (EFIC) requires the 
following conditions to be present: 
1) Subjects are in a life-threatening situation, available treatments are unproven or 
unsatisfactory, and the collection of valid scientific evidence is necessary to 
determine the safety and effectiveness of a therapy 
2) Obtaining prospective informed consent is not feasible 
3) Subjects may benefit from the research 
4) Research could not be carried out without an EFIC  


 
  45
The specific elements of our study that meet each of these conditions are: 
1) Septic shock is a life-threatening medical emergency requiring immediate therapy, 
analogous to myocardial infarction, stroke, or trauma 12.  There are currently no data 
proving the most effective crystalloid fluid to use for initial, immediate resuscitation 
of children (or adults) with septic shock and existing guidelines are silent as to which 
crystalloid fluid to use as first-line therapy (with both NS and LR currently 
considered to be equivalent options).  Prior observational studies in adults and 
pediatric patients have not been able to determine the comparative safety and 
effectiveness of different available crystalloid fluids to use for resuscitation in septic 
shock, leading to multiple calls for prospective randomized trials to provide the 
necessary evidence to determine comparative effectiveness. 
 
2) The current ACCM guidelines to treat hemodynamic shock in pediatric sepsis 
recommend crystalloid fluid resuscitation within 15 minutes of recognition of septic 
shock.  Thus, in most instances, this exceedingly short time window is too short for a 
proper discussion of prospective informed consent, including sufficient opportunity 
to explain study procedures, discuss risks/benefits, and answer all questions, to be 
feasible.  Expanding the therapeutic window beyond 15 minutes would result in 
either 1) delay of fluid resuscitation which would place patients at risk of life-
threatening complications of untreated septic shock, including cardiac arrest and 
death and/or 2) administration of a large volume of pre-study, non-randomized fluids 
that will prevent the necessary clinically important separation between study arms to 
determine comparative effectiveness of NS versus LR resuscitation.  Our data from 
CHOP and two additional published studies demonstrate that 25-55% of deaths due 
to pediatric septic shock occur within 24 hours of presentation, necessitating rapid 
screening, enrollment, and randomization if we are to maximize the chances of 
identifying a benefit for one resuscitation strategy versus another.  In addition, 
because of the pragmatic study design, front-line clinicians will be required to screen 
and enroll eligible patients.  Given the life-threatening nature of septic shock and 
need for prompt resuscitation, removing a member of the clinical care team to seek 
prospective informed consent may compromise clinical care and place patients at 
risk of life-threatening complications of untreated septic shock, including cardiac 
arrest and death.  Finally, our data from a survey conducted in the CHOP ED, 
supports that parents/guardians would prefer not to be approached for informed 
consent in the initial critical period of their child’s emergency care.  Therefore, in 
most instances, obtaining informed consent will not be feasible. 
In rare circumstances, fluid resuscitation may be necessarily delayed such as with 
parental or clinician initial preference to avoid or limit fluid resuscitation (e.g., 
concern for concurrent heart failure for which large-volume, rapid fluid resuscitation 
may not be in the best interest of the patient) or with delayed IV/IO access.  In these 
rare circumstances when the therapeutic window is extended beyond 15 minutes 
from recognition of septic shock, there may be an opportunity to seek prospective 
informed consent. 


 
  46
3) Because fluid resuscitation with either NS or LR may offer relative superior efficacy 
and/or safety, there is a prospect of direct benefit to subjects from trial participation. 
 
4) Because informed consent is not feasible (as noted above), this study could not be 
carried out without EFIC.  Moreover, alternative study designs, such as observational 
studies have already proven insufficient to determine comparative effectiveness of 
NS versus LR.  Finally, the study proposed does not meet the human subjects 
research obligations needed to obtain a waiver of informed consent. 
As required by EFIC, if the LAR is immediately and physically present during the 15 minute 
therapeutic window, a member of the care team will notify the LAR that this study is being 
conducted in conjunction with routine sepsis care and that details regarding the study will be 
provided as soon as feasibly possible.  The study team will first seek to inform of study 
enrollment and the option to withdraw from continued participation: (a) the subject, (b) then 
the subject's legally authorized representative if the subject remains incapacitated, and (c) 
then the subject's family if the LAR is unavailable, to comply with the EFIC requirements. 
Given the short therapeutic time window of 15 minutes following recognition of septic 
shock, anything more than a brief notification of the intent to randomize to one of two 
efficacious fluids would constitute a contrived and hollow attempt to adequately inform the 
LAR of the study details. Still, if the LAR objects to study participation after this 
notification, then the patient will not be enrolled.  As part of this discussion to offer 
opportunity to opt-out of study enrollment, a member of the ED care team will first seek 
“opt-out” from the a) potential subject, b) then the subject’s LAR if the subject remains 
incapacitated or age <8 years, and c) then the subject’s family if the LAR is not available.  
The ED staff will be provided with recommended “opt-out” language to ensure a reasonably 
consistent approach for pre-enrollment study opt-out.  Recommended language will include 
that a) participation is voluntary, b) subjects do not have to agree to participation to continue 
to receive care at CHOP, and c) that subjects can withdraw without penalty or loss of 
benefits to which the subject is otherwise entitled.  However, if the subject is incapacitated 
or <8 years and neither the LAR or family member are immediately and physically present, 
then we will forego pre-enrollment opt-out in order to not delay treatment or study 
enrollment.  As part of this pilot study, we will offer a quantitate debriefing to ED providers 
following enrollment through EFIC to ascertain concerns about the enrollment and opt-out 
procedures. 
In addition, the LAR for each subject enrolled via EFIC will be approached as soon as 
feasibly possible to inform of subject study enrollment and provided the opportunity to 
continue or withdraw from further study participation.  To facilitate this discussion, we will 
provide the LAR with a “Post-Enrollment Opt-Out Information Sheet” which will 
summarize the details of the study, including that the subject was enrolled and treated 
without their consent (as there was no time to obtain it), that the IRB has approved an 
excpetion from informed consent for the study, and what the procedures for continued 
participation will be required (i.e., possibly additional study fluid and medical record 
review).  In addition, the “Post-Enrollment Opt-Out Information Sheet” will disclose that 
continued participation is voluntary, not necessary to continue to receive care at CHOP, and 
that subjects can withdraw without penalty or loss of benefits to which the subject is 


 
  47
otherwise entitled.  The LAR will also be provided with the prospective Informed Consent 
Form as a means of providing complete information about what this study involves, though 
the LAR will not be asked to sign the Informed Consent document. In order to document 
this encounter, we will ask the LAR to either sign the Post-Enrollment Opt-Out Information 
Sheet if physically present or have a study team member sign the form if the discussion 
occurs over the phone.  We acknowledge that the LAR’s signature will neither constitute nor 
substitute for informed consent, as these patients would have been enrolled under EFIC.  
However, because of concerns raised by potential PECARN sites for a possible future 
multicenter trial and our own ethical interests, we feel it is important to document that the 
study indeed discussed the details of the study with the subject/LAR and provided an 
opportunity to opt-out/withdraw by asking the LAR to sign that this discussion took place.  
Whether the subject/LAR chooses to continue in the study post-enrollment or not, we will 
document their decision on the “Post-Enrollment Opt-Out Information Sheet” to 
acknowledge this discussion. 
For subjects enrolled via EFIC, if the subject's LAR or family member could not be informed of the 
subject's participation prior to the subject's death, they will be informed after the subject's death. 
Our full proposal for executing the elements of EFIC, including community consultation, 
public disclosure, and submission of an investigational new drug application to the Federal 
Drug Authority (FDA), have been separately described in detail under a separate applicate to 
the CHOP IRB (IRB # 17-013950).  Because of the challenges of EFIC, particularly in a 
pediatric population, we have ensured that the study team includes individuals with prior 
experience in this area.  Dr. Jill Baren is a recognized expert in human subjects regulations 
related to clinical trials and has experience with EFIC through a prior pediatric trial in 
PECARN.54  In addition, Dr. Nathan Kuppermann, Professor of Pediatrics at the University 
of California at Davis, is an experienced clinical trialist in pediatric emergency care and will 
provide support, mentorship, and oversight to Dr. Weiss for his IND application to the FDA 
for use of EFIC and to Dr. Balamuth as the principal investigator of this EFIC-based study. 
All efforts to contact legally authorized representative and/or family members when 
prospective informed consent cannot be obtained will be documented and this information 
will be made available to the IRB at the time of continuing review.  In addition, all IRB- 
approved materials used for public disclosure will be submitted to the IND and Public 
Docket 95S-0158, as required.  In addition, we will also submit the materials used to 
disclose the study results following completion of the clinical investigation. 
9.6.4 Non-English Speakers 
Non-English speaking families should be afforded the same opportunity to participate in 
human subjects research as English-speaking families, especially when there is a prospect 
for direct benefit.  For non-English speaking parents/guardians (LARs), an interpreter will 
assist in the prospective informed consent discussion (if time permits as described above in 
Section 8.6.1) using the standardized short-form consent form process.  Informed consent 
will be documented using the CHOP standard short-form consent document in the 
appropriate native language and on a Study Summary Document written in English.  When 
an in-person interpreter is available, the interpreter will be in the same room with the 


 
  48
investigators and may act as witness to sign the witness/interpreter section of the Study 
Summary Document if the LAR agrees to prospective informed consent. 
If a non-English speaking subject meets criteria for enrollment via EFIC an interpreter fluent 
in both English and the native language of the subject (parent/guardian) will assist in the 
pre- and post-enrollment opt-out discussion.  The pre-enrollment opt-out discussion will 
take place as soon as it is possible for a member of ED care team to identify an appropriate 
translator (e.g., in-person or via phone) and proceed with the opt-out discussion, just as it 
would occur for English speakers.  However, just as if an English-speaking subject is 
incapacitated or <8 years and neither the LAR or family member are immediately and 
physically present, we will forego pre-enrollment opt-out in order to not delay treatment or 
study enrollment.  Because availability of an interpreter may be a limiting factor, we do 
acknowledge the potential for non-English speakers to be less likely than English speakers 
to have the opportunity to opt-out prior to subject enrollment and initiation of study 
intervention procedures.  Nonetheless, this consideration needs to be balanced against equal 
access to the opportunity to participate—and potentially benefit from enrollment—in this 
study (as mandated by the requirement for “justice” under the Belmont Report).  Given the 
short therapeutic time window of 15 minutes following recognition of septic shock to 
administer fluids and enroll subjects into this study, we anticipate that there will rarely be 
sufficient time to proceed with pre-enrollment opt-procedures regardless of English or non-
English language and, thus, we feel that differential potential for pre-enrollment opt-out by 
language is largely theoretical.   
For post-enrollment opt-out discussions, an interpreter fluent in both English and the native 
language of the subject (parent/guardian) will assist in the post-enrollment opt-out 
discussion and help to interpret the “Post-Enrollment Opt-Out Form”.  When an in-person 
interpreter is available, the interpreter will be in the same room with the investigators and 
may act as witness to sign the witness/interpreter section of the “Post-Enrollment Opt-Out 
Form”.  In the case that an in-person interpreter is not available, a phone interpreter who is 
fluent in both English and the native language of the patient (parent/guardian) will be 
utilized and a separate third-party witness to the phone conversation will sign the “Post-
Enrollment Opt-Out Form” as the witness.  
The interpreter/witness will not be part of the study team or otherwise involved with the 
study.  If a phone interpreter is utilized for prospective informed consent, we will ask that 
the interpreter email the investigators a statement attesting to the LAR's understanding of the 
study and consent to participate.  if a phone interpreter is used in the post-enrollment opt-out 
discussion, then a separate third-party witness may sign the "Post-Enrollment Opt-Out 
Form" to attest that the discussion took place with an appropriate interpreter. 
9.7 Payment to Subjects/Families 
No payment, reimbursement, gifts, or compensation of any kind will be provided to 
subjects/families for participation in this study. 
 
 
 


 
  49
10 PUBLICATION 
This pilot study is not specifically designed for publication, but rather to assess feasibility 
for implementation of a subsequent large multicenter pragmatic randomized trial.  However, 
should the decision be made to disseminate the results of our pilot study, we will only 
present and/or publish de-identified aggregate data following appropriate peer review. 


 
  50
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APPENDIX 
Appendix 1:  FDA package insert for NS 
Appendix 2:  FDA package insert for LR 
Appendix 3:  Timing of adverse event collection 
Appendix 4:  Decision-tree for adverse event reporting 
Appendix 5:  Fluid Management Algorithm