Direct Peritoneal Resuscitation in Gastroschisis
Phase: PHASE1
Conditions: Gastroschisis
Sponsor: University of Arkansas

 
 
 
Direct Peritoneal Resuscitation in Gastroschisis 
 
12/20/2018 
 
NCT03205553 
 
 

Title: Direct Peritoneal Resuscitation in Gastroschisis 
PI: Bavana Ketha 
Sponsor: UAMS 
Version: 12 
IRB: #206573 
Date: 12/20/2018 
Page 1 
Study Title: 
Direct Peritoneal Resuscitation in Gastroschisis 
 
Principal Investigator:  
Bavana Ketha, MD 
Arkansas Children’s Hospital 
 
 
 
 
Co-Investigator: 
Samuel D. Smith, MD 
Arkansas Children’s Hospital 
 
 
 
Study Neonatologist 
Sherry Courtney, MD 
and Sub-Investigator: 
Arkansas Children’s Hospital 
 
 
Sub-investigator: 
Patrick Bonasso, MD, MBA 
 
 
 
Medical Monitor:  
M. Sid Dassinger, MD 
 
 
 
Study location: 
Arkansas Children’s Hospital (ACH) 
1 Children’s Way 
Little Rock, AR 72202 
 
Arkansas Children’s Research Institute (ACRI) 
13 Children’s Way 
Little Rock, AR 72202 
 
Sponsor: 
University of Arkansas for Medical Sciences 
 
Version: 
12 
 
Date: 
12/20/2018 
 

Title: Direct Peritoneal Resuscitation in Gastroschisis 
PI: Bavana Ketha 
Sponsor: UAMS 
Version: 12 
IRB: #206573 
Date: 12/20/2018 
Page 2 
Table of Contents 
Abbreviations 
4 
Background and Rationale 
5 
Study Summary 
6 
Hypothesis 
6 
Study Objectives 
6 
Investigational Product 
7 
Study Population 
7 
Eligibility Criteria 
7 
Randomization 
8 
Study Design and Procedures 
8 
Calendar of Procedures and Assessments 
15 
Schedule of Procedures and Assessments 
16 
Risks and Benefits 
18 
Subject Withdrawal from Study 
19 
Safety Monitoring 
19 
Adverse Events 
21 
Monitoring 
24 
Data Handling and Record Keeping 
24 
Data Analysis 
24 
Ethical Considerations 
24 
Dissemination of Data 
25 
References 
26 
Appendices 
28 
 
 

Title: Direct Peritoneal Resuscitation in Gastroschisis 
PI: Bavana Ketha 
Sponsor: UAMS 
Version: 12 
IRB: #206573 
Date: 12/20/2018 
Page 3 
Abbreviations 
ACH – Arkansas Children’s Hospital 
ACRI – Arkansas Children’s Research Institute 
AE – Adverse Event 
AKI – Acute Kidney Injury 
ALT – Alanine Aminotransferase 
APGAR Score – Appearance, Pulse, Grimace, Activity, and Respiration 
AST – Aspartate Aminotransferase 
BP – Blood Pressure 
CBC – Complete Blood Count 
CFR – Code of Federal Regulation 
CHND – Children’s Hospital National Database 
CRF – Case Report Form 
d – Day 
Diff - Differential 
DPR – Direct Peritoneal Resuscitation 
GGT – Gamma-Glutamyl Transferase 
GI – Gastrointestinal 
G-Tube – Gastrostomy Tube 
HR – Heart Rate 
INR – International Normalized Ratio 
IV – Intravenous 
JP drain – Jackson-Pratt drain 
KDIGO – Kidney Disease: Improving Global Outcomes 
kcal – kilocalorie 
kg – kilogram 
LAR – Legally Authorized Representative(s) 
MAP – Mean Arterial Blood Pressure 
mL – milliliter 
mm – millimeter 
MRN – Medical Record Number 
NEC – Necrotizing Enterocolitis 
NICU – Neonatal Intensive Care Unit 
OB/GYN – Obstetrics & Gynecology 
OG Tube – Orogastric Tube 
PI – Principal Investigator 
PTN – Pediatric Trials Network 
RR – Respiratory rate 
SAE – Serious Adverse Event 
SoC – Standard of Care 
SpO2 – Pulse Oximetry 
TPN – Total Parenteral Nutrition 
UAMS – University of Arkansas for Medical Sciences 
 

Title: Direct Peritoneal Resuscitation in Gastroschisis 
PI: Bavana Ketha 
Sponsor: UAMS 
Version: 12 
IRB: #206573 
Date: 12/20/2018 
Page 4 
Background and Rationale 
Gastroschisis is a clinical condition characterized by a defect in the normal development of the abdominal 
wall. The defect is present to the right of the umbilicus leading to in utero bowel evisceration and exposure 
to amniotic fluid. After birth and prior to operation, the usual treatment consists of covering the bowel 
with an impermeable plastic bag to prevent additional fluid losses and bowel desiccation. Subsequent 
operative intervention occurs either in the operating room or in the neonatal intensive care unit. Two 
surgical options include primary closure of the abdomen or placement of a silastic silo followed by 
subsequent closure several days later as a staged procedure. The main reason the abdominal wall is not 
closed initially is due to fear of abdominal compartment syndrome, a condition caused by high intra-
abdominal pressures leading to respiratory and circulatory compromise. The key points of the initial 
surgery involve examining the intestine for any signs of atresia, bowel compromise, and either placement 
of the bowels back into the abdomen or a spring-loaded silo. 
 
Arkansas Children’s Hospital (ACH) has one of the highest rates of gastroschisis patients in the country 
and therefore has extensive experience managing these patients. We currently do not know why ACH has 
one of the highest rates of gastroschisis, but it has been postulated it may be due to some factor more 
common in low socioeconomic status population. ACH is the only pediatric hospital in the state of 
Arkansas. Quarterly, reviews of the Children’s Hospital National Database (CHND) are performed to track 
the institutions progress in comparison to national trends. ACH’s current surgical practice is to place nearly 
all patients in a silastic silo for staged reduction. Rarely are patients with gastroschisis treated with primary 
surgical closure at our institution. Serial reductions are performed and once the abdominal contents are 
at the level of the fascia the abdomen is closed in the operating room. Previous data indicates an average 
of five days from birth for final reduction and closure. After closure, there can be significant intestinal 
dysmotility with a prolonged ileus and a delayed return of bowel function. Generally, those with 
uncomplicated gastroschisis spend approximately 26 days in the neonatal intensive care unit before 
discharge home. 
 
From historical CHND data, we know our patients with simple gastroschisis have an average length of stay 
of 29 days, average of 5 days until abdominal wall closure, average of 7 days until start of enteral feeding 
after abdominal wall closure and average of 10 days until meeting 100 kcal per kg per day enteral feeds. 
 
Direct Peritoneal Resuscitation 
The University of Louisville has been at the forefront of research for Direct Peritoneal Resuscitation (DPR). 
This technique uses clinically available peritoneal dialysis solution instilled into the abdomen with an initial 
bolus of 500 mL followed by a rate of 1.5 mL/kg/h in adults undergoing closure of the abdominal wall after 
traumatic injuries [1]. 
 
The aforementioned lab has also studied DPR in a rat model of hemorrhagic shock. The model has shown 
decreased mortality and increased intestinal and liver blood flow [2-5]. The group further investigated the 
use of DPR in a rat model of Necrotizing Enterocolitis (NEC) and discovered that 1.5% and 2.5% peritoneal 
dialysis solutions used as DPR improved intestinal blood flow, and with the 1.5% solution, there was less 
hyperglycemia than in the group treated with the 2.5% solution [6-10]. 
 
DPR has also been studied in the treatment of severely injured trauma patients and has shown a decrease 
in days until closure with improved outcomes [10, 11]. A randomized controlled study of 103 subjects 
requiring damage control surgery, i.e. open abdominal cavities, found that peritoneal resuscitation 
reduced the time to definitive abdominal closure, reduced intra-abdominal infections and reduced 
mortality [11]. 

Title: Direct Peritoneal Resuscitation in Gastroschisis 
PI: Bavana Ketha 
Sponsor: UAMS 
Version: 12 
IRB: #206573 
Date: 12/20/2018 
Page 5 
Exposure of the abdominal viscera and its placement in a silo puts the neonate in a metabolically stressed 
state. Using DPR has been shown to counteract the systemic inflammatory response, leading to dilation 
of arterioles in the intestine resulting in reduced organ ischemia and cellular hypoxia [12]. 
 
Several case series have demonstrated safety of peritoneal dialysis in infants with recent abdominal 
surgery and intestinal perforation [13-15]. In pediatric patients, peritoneal resuscitation has been used in 
two infants with perforated NEC who were too unstable to undergo laparotomy. Both survived and went 
on to undergo laparotomy [16]. 
 
We consider the patient with gastroschisis as an equivalent to the general surgery patient with the open 
abdomen and that adjunctive DPR treatment may be able to accelerate abdominal closure and improve 
outcomes. 
 
Ultrasounds 
Optimal timing to begin feeds in neonates with gastroschisis remains unclear. A previous study performed 
by our research group concluded that bedside ultrasound is a feasible tool to detect return of bowel 
function in neonates with gastroschisis [17]. 
 
Study Summary 
This is a prospective double-arm study designed to evaluate the tolerability of direct peritoneal 
resuscitation (DPR) in neonates with gastroschisis. The experimental arm (DPR group) will receive 
adjuvant DPR with standard treatment for gastroschisis (staged silo closure). The control arm (SoC group) 
will receive standard treatment for gastroschisis without DPR. The objectives are (1) to determine if 
subjects treated with DPR will have a more benign hospital stay as measured by time to full enteral feeds 
of 100 kcal/kg/day and (2) to monitor the effect of Dianeal 1.5% dialysis solution on the hemodynamics, 
serum electrolytes, lactic acid, respiratory function, and other parameters. 
 
Hypothesis 
Hypotheses: We hypothesize that the DPR group will have a more benign hospital course as measured by 
time to full enteral feeds of 100 kcal/kg/day. We will also assess time to abdominal wall closure, time on 
TPN, length of hospital stay and intestinal motility post-closure using bedside ultrasounds. Secondly, we 
hypothesize that there will be no deleterious effects related to introducing the peritoneal dialysis solution 
into the silo. 
 
Study Objectives 
Primary Objectives: 
1. To demonstrate that subjects treated with DPR will have a more benign hospital course as measured 
by time to full enteral feeds. The primary outcome measure will be time to full feeds of 100 
kcal/kg/day. Secondary outcomes will include length of time until abdominal wall closure, time on 
TPN, time to intestinal motility, and total days in the hospital. 
 
2. To demonstrate that the use of DPR in neonates with gastroschisis treated with staged silo closure 
will result in no significant changes in commonly measured clinical and laboratory safety parameters. 
This will be measured with more frequent clinical and laboratory assessments for the DPR group. Vital 
signs and strict intake and output will be monitored every 6 hours for 48 hours after the maximum 
dialysate infusion volume has been reached, then every 12 hours. Sodium, potassium, blood glucose 
and lactate levels will be monitored every 6 hours via heelstick, central/arterial line or venipuncture 

Title: Direct Peritoneal Resuscitation in Gastroschisis 
PI: Bavana Ketha 
Sponsor: UAMS 
Version: 12 
IRB: #206573 
Date: 12/20/2018 
Page 6 
per NICU standard practice for 24 hours after the maximum dialysate infusion volume has been 
reached, then every 12 hours through Post-Closure Day 1. 
 
Investigational Product 
Dianeal PD-2 1.5% is a sterile, nonpyrogenic, hypertonic peritoneal dialysis solution containing dextrose, 
a monosaccharide, as the primary osmotic agent. Routine peritoneal dialysis in neonates and infants 
utilizes up to 40 mL/kg of dialysate per dwell. It will be administered via a 10 mm flat JP drain as a bolus 
infusion every 6 hours until the abdominal wall is closed (generally 3-5 days), but not to exceed 7 days 
maximum. The initial bolus infusion will be 10 mL/kg of Dianeal 1.5%. If tolerated, each subsequent 
infusion will be increased by 10 mL/kg of Dianeal 1.5% up to a goal infusion of 40 mL/kg (to a maximum 
volume of 100 mL) as tolerated. 
 
The investigational product will be kept in a secure, limited-access storage in the ACRI research pharmacy 
under the direction of the research pharmacists who will be responsible for maintaining the supply 
according to the manufacturer’s specifications, dispensing the drug for administration, and maintaining 
all drug accountability logs. 
 
Study Population 
We will prospectively enroll all neonates with the diagnosis of gastroschisis presenting to ACH within 12 
hours after birth for whom consent is signed by the parent(s)/LAR. We anticipate enrolling 40 subjects at 
Arkansas Children’s Hospital. All subjects that have their abdominal wall defect closed will be defined as 
having completed active participation in the study. 
 
Eligibility Criteria 
Inclusion criteria: 
• 
Diagnosis of Gastroschisis 
• 
Male or Female, any ethnicity 
• 
Neonates [18] 
 
Exclusion criteria: 
• 
Primary gastroschisis repair 
• 
Vanishing gastroschisis 
• 
Encapsulating peritoneal sclerosis 
• 
Infants < 2 kg and < 34 weeks gestation 
• 
Infants > 12 hours at enrollment 
• 
Severe hypotension, defined as either: 
o Mean arterial blood pressure (MAP) < gestational age in weeks, or 
o Systolic blood pressure (BP) < 45 or diastolic BP < 20 
• 
Severe Hypertension defined as Systolic BP > 90 or diastolic > 60 
• 
Culture-positive sepsis 
• 
Known or strongly suspected inborn errors of metabolism 
• 
Significant cardiac disorders, including cyanotic congenital heart disease, ductal-dependent 
congenital heart disease, and critical congenital heart disease (lesions requiring surgery or catheter-
based intervention in the first year of life) 
• 
Respiratory failure, defined as any requirement of positive pressure ventilation at the time of 
enrollment, or FiO2 > 50% 

Title: Direct Peritoneal Resuscitation in Gastroschisis 
PI: Bavana Ketha 
Sponsor: UAMS 
Version: 12 
IRB: #206573 
Date: 12/20/2018 
Page 7 
• 
Any other condition, that, in the opinion of the investigator, might interfere with the safe conduct of 
the study or place the subject at increased risk 
• 
Lactic acidosis with at least one or more of the following: 
o Characterized by increased blood lactate levels (> 5 mmol/L) on two occasions at least 6 hours 
apart 
o Severe metabolic acidosis with an arterial pH ≤ 7.0 
o Bicarbonate < 14 or CO2 < 12 
o Base excess of > -10 mEq/L 
• 
Neonatal Acute Renal Failure, defined as serum creatinine > 2.0 mg/dL with anuria in the first 12 hours 
of life 
• 
Neonatal Acute Hepatic Failure, defined as INR > 3 [19] 
• 
Liver function test abnormalities defined as AST > 200, ALT > 200, GGT > 100 [19] 
• 
Electrolyte abnormalities, defined as: 
o Sodium < 130 or > 150 mEq/L 
o Potassium < 3.0 or > 6.5 mEq/L 
• 
Hyperglycemia (> 150 mg/dL) or hypoglycemia (< 40 mg/dL) 
Note: Potentially eligible subjects may be randomized and the silo placed according to the assigned study 
arm before all laboratory results are available. Laboratory values will be verified for eligibility prior to 
administration of DPR. Any ineligible subjects will be withdrawn from the study and may be replaced. 
 
Randomization 
The randomization schedule will be generated by the biostatistics department and the Principal 
Investigator (PI) will maintain a randomization log listing the subjects’ ID and study arm assignment. 
Subjects will be randomized to either the DPR group or SoC group. If the subject is assigned to receive 
DPR, the ACRI Research Pharmacist will dispense the 1.5% Dianeal solution. The PI will calculate the dose 
to be distributed based on the subject’s weight at the time of enrollment and administer the appropriate 
volume of 1.5% Dianeal solution as per instructions in the Investigational Product section. 
 
Study Design and Procedures 
This is a prospective double-arm study designed to evaluate the tolerability of direct peritoneal 
resuscitation (DPR) in neonates with gastroschisis. The experimental arm (DPR group) will receive 
adjuvant DPR with standard treatment for gastroschisis (staged silo closure). The control arm (SoC group) 
will receive standard treatment for gastroschisis only. All subjects will be placed in a silo shortly after birth 
and within 2 hours of admission to the NICU and subsequently serially reduced in silo with umbilical tape 
until the bowel contents are at the level of fascia and deemed suitable for closure. 
 
A. SoC Group 
The SoC group will be placed in silo within 2 hours of admission to the NICU per standard practice. These 
subjects will have no change in current clinical management by the neonatologists or pediatric surgeons 
and will not receive peritoneal dialysis fluid. 
 
B. DPR Group 
The DPR group will be placed in a silo within 2 hours of admission to the NICU with a drain placed at the 
top of the silo as described below. At the time of silo placement for staged procedure, the JP drain will be 
placed intra-abdominally beneath the fascia at the base of the small bowel mesentery. Subjects will be 
treated with adjuvant direct peritoneal resuscitation (DPR) until the abdomen is closed, which is usually 
four to five days. No additional incisions will be made. 

Title: Direct Peritoneal Resuscitation in Gastroschisis 
PI: Bavana Ketha 
Sponsor: UAMS 
Version: 12 
IRB: #206573 
Date: 12/20/2018 
Page 8 
Set-up of Silo 
The silo will be placed within 2 hours of admission to the NICU as per 
standard of care. Through the top of the silo a flat 10 mm JP drain will be 
placed and secured with suture and sterile, adhesive tape at the top of the 
silo to create a seal. This drain will allow for aspiration of peritoneal fluid 
for specimen collection and instillation of Dianeal 1.5% (DPR group only). 
 
Drain manipulation 
The JP drain will be sterilely placed through top of the silo at time of the silo 
placement into abdominal cavity. A closed system will be created using 
Medline One-link Needle-free IV connector to the drain to allow for sterile 
placement of the dialysate. There will not be any planned drain 
replacements. If the drain or silo replacement is necessary due to 
unforeseen circumstances, the abdomen will be prepped in standard sterile 
fashion and the silo with drain will be replaced in same manner as when it 
was initially placed. There will be no increased risk of underlying infection 
with placement of the silo or drain. 
 
Set-up for DPR 
The dialysate fluid will be placed in syringe under sterile conditions in the Research Pharmacy. The syringe 
will then be connected to the JP drain via a needle free IV connector. The connector will be cleaned with 
an alcohol wipe at the time of fluid instillation into the JP drain. 
1. Instillation of fluid - Process will be repeated every 6 hours (± 30 minutes) until abdomen is closed. 
a. Fluid will be warmed at bedside using dry heat not to exceed 37°C/98°F. 
b. An initial bolus of 10 mL/kg of Dianeal 1.5% via the JP drain will be given. If tolerated, each 
subsequent bolus will be increased by 10 mL/kg of Dianeal 1.5% up to a goal infusion of 40 mL/kg 
of Dianeal 1.5% (to a maximum volume of 100 mL) as tolerated via the JP drain. 
c. The maximum dose that will be administered, based on a historical data (CHND), is 100 mL. 
d. Dialysate will dwell for 1 hour after instillation of fluid. Any excess fluid will then be removed via 
JP drain. 
2. Data for DPR 
a. Blood samples will be obtained at the same time that routine laboratory values are performed. 
Supplementary research safety labs will require additional blood samples. 
i. Complete CBC, sodium, potassium, bicarbonate/CO2, chloride, BUN, creatinine, calcium, 
phosphate, albumin, glucose and magnesium 
ii. Labs per standard of care are drawn each morning. 
iii. Monitoring of additional labs will be per the discretion of the NICU team if necessary for 
pertinent patient care and monitoring. 
iv. Heart rate, respiratory rate, blood pressure and pulse oximetry recordings will be recorded as 
part of the routine patient care. We will collect these measurements every 6 hours (± 30 
minutes) at the time peritoneal fluid is infused. 
b. Volume of fluid instillation and removal (date/time) will be documented in the medical record. 
c. IV Fluids given 
 
 

Title: Direct Peritoneal Resuscitation in Gastroschisis 
PI: Bavana Ketha 
Sponsor: UAMS 
Version: 12 
IRB: #206573 
Date: 12/20/2018 
Page 9 
Antibiotic regimen for both treatment groups 
• 
5 days of ampicillin and gentamicin will be given. 
• 
No additional doses beyond 5 days unless clinically indicated. 
• 
Ampicillin Sodium: Q8H, IV (100 mg/kg q8) 
• 
Gentamicin Sulfate: Q24H, IV (4 mg/kg q24) 
 
No additional antibiotics will be given as part of standard care. Post-surgical antibiotics will be 
administered at the discretion of the surgeon as required. 
 
Standardized treatment algorithms 
To minimize inter-subject management variation and bias in the interpretation of the results the following 
standardized criteria or algorithms are provided: 
 
i. Timing of abdominal closure/determination of readiness for closure 
• 
Serial reductions are performed with silastic silo placement for staged reduction using umbilical tape 
ties. The silo is assessed daily on morning rounds by the surgical team. Once the abdominal contents 
are at the level of the fascia, the abdomen is closed in the operating room. The average day to closure 
historically from CHND data is 5 days (Appendix C). 
ii. Initiation and advancement of enteral feeds 
• 
Enteral feeding is begun after orogastric (OG) tube output has stopped and a bowel movement 
has occurred. OG tube output is checked at least every 4 hours (± 30 minutes) and/or before each 
feeding per NICU standard practice. Initiation of feeds is a clinical decision based on decreased 
gastric tube output, abdominal x-rays, and passing of stool. The initiation of enteral feeds is 
assessed daily on morning rounds by the neonatology team. Feedings start at an average of 7 days 
following abdominal wall closure. The advancement of enteral feeds will be based on standard 
practice at Arkansas Children’s Hospital (Appendix D). Most feedings are started every six hours 
and advanced to every three hours as tolerated. 
iii. Tapering of parenteral nutrition 
• 
Tapering of the parenteral nutrition is congruent with the increase in enteral feeding, which is 
calculated based on the amount of nutrition and calories needed. The combination of parenteral 
nutrition and enteral feeding will be 100 kcal/kg/day. As the enteral feeding is increased, the TPN 
will be reduced proportionately. This is assessed once daily on morning rounds by the neonatology 
team. 
iv. Management of IVF/nutrition during DPR (i.e., changes in maintenance fluid or TPN rate during 
infusion) 
• 
The amount of IVFs is dependent on the subject’s weight and calculated based on the volume of 
enteral feeds required to meet the subject’s caloric needs. This is assessed daily on morning 
rounds by the neonatology team. IVF management changes will be made when clinically indicated 
by the neonatologists and guided by the subject’s laboratory values. The current practice is not 
to replace the fluid lost during silo placement due to bowel edema often seen in these patients; 
thus, no additional changes are planned for the management of IVFs or nutrition during the 
intervention. The amount of dialysate fluid given will be documented in the medical record; it will 
dwell for 1 hour and then any remaining fluid will be removed. 
 
Routine Laboratory Tests for both treatment groups 
To reduce the risk of iatrogenic anemia and assure that excessive amounts of blood are not collected from 
any patient, the maximum allowable blood draw volumes are established per single phlebotomy 
collection. During routine daily lab draws, up to 1 mL of blood will be obtained for standard medical care. 

Title: Direct Peritoneal Resuscitation in Gastroschisis 
PI: Bavana Ketha 
Sponsor: UAMS 
Version: 12 
IRB: #206573 
Date: 12/20/2018 
Page 10 
All other standard care laboratory tests will be performed at the discretion of treating neonatologists. 
Routine daily labs for gastroschisis patients include: 
- 
Complete Blood Count (CBC) with differential 
- 
Magnesium 
- 
Renal function panel (sodium, potassium, chloride, bicarbonate/CO2, BUN, creatinine, calcium, 
phosphate, albumin, glucose) 
 
Research Laboratory Tests 
Additional research labs for safety monitoring will be drawn via heelstick, central/arterial line or 
venipuncture per NICU standard practice. The first capture of research labs should coincide with routine 
labs to avoid repeat blood draws. Up to 2 mL of blood for research may be drawn each day in addition to 
the routine daily labs. 
 
SoC Group 
A research lab for lactate only will be drawn every 24 hrs (± 30 minutes) through Post-Closure Day 1. 
 
DPR Group 
Additional research labs will be drawn every 6 hrs (± 30 minutes) for 24 hours after the maximum 
dialysate infusion volume is reached, then every 12 hrs (± 30 minutes) through Post-Closure Day 1. 
Research labs include: 
- 
Lactate 
- 
Sodium 
- 
Potassium 
- 
Glucose 
 
Glucose via heelstick, central/arterial line or venipuncture per NICU standard practice will also be 
obtained within 1 hour prior to infusion and 1 hour (± 15 minutes) post-infusion for the first day of 
treatment. 
 
The total amount of blood to be withdrawn per day, accounting for the additional research labs above for 
safety monitoring, will be up to 3 mL. 
 
Ultrasound 
We will perform trans-abdominal ultrasound imaging on all enrolled subjects from the time of abdominal 
wall closure until feedings have commenced. Additional imaging will be performed if the neonatology 
team has warranted a stop to feeding the neonate. This noninvasive modality will be used to determine 
categorization of intestinal motility. Abdominal ultrasound will be performed each morning at the bedside 
by the PI or other trained study personnel. 
 
We will document the presence of intestinal motility with continuous recording of ultrasound in all four 
quadrants for 30 seconds. Clips will be stored from each abdominal quadrant with the linear probe. If 
bowel motility is not recognized by 3 weeks post-operative, then the imaging will be terminated. A 
separate computer workstation connected to the image server will be used for image viewing and data 
analysis. Images and videos will be reviewed for quality and assessment of motility. To assess motility, the 
investigators will identify all distinct bowel loops visualized in the video clips and count movements in 
each of the bowel loops identified in the clip to determine a motility count for each quadrant. Videos will 
be classified as poor, fair or good. Motility will be quantified as the total number of distinct peristaltic 
movements visualized in each abdominal quadrant over 30 seconds. Cumulative motility (CM) will be 

Title: Direct Peritoneal Resuscitation in Gastroschisis 
PI: Bavana Ketha 
Sponsor: UAMS 
Version: 12 
IRB: #206573 
Date: 12/20/2018 
Page 11 
calculated as the sum of motility from all four abdominal quadrants. Mean motility (MM) will be calculated 
as the mean number of distinct peristaltic movements per patient on each day of life imaged. A global 
descriptive score of bowel activity will also be assigned for each quadrant with the following categories: 
no, low, normal, or hyperactive peristalsis [20]. 
 
Data to be obtained (No. 1-13 are already obtained and available as part of the neonates’ medical 
records): 
All data collected as recorded by the NICU for the Children’s Hospital Network Database (CHND) will be 
reviewed for the research. Data with an asterisks (*) are not included in the standard CHND database. 
1. Demographics 
a. MRN, admit date, birth date, re-admission, gender, mother’s zip code, birth weight, admit weight, 
gestation, birth head circumference 
2. Transport and admission 
a. Referral source 
b. Morbidities and diagnoses present at admission 
c. Lines, tubes, and drains present at admission 
3. Maternal, prenatal, perinatal (This is part of the neonates’ medical record  and will be abstracted from 
the neonates chart.) 
a. Maternal race/ethnicity, age, prenatal care, prenatal vaccination history* (as available) [21], any 
congenital anomalies that were diagnosed prenatally, maternal substance use history, infant or 
maternal toxicology screen results, maternal infection history* (including risk factors for 
infections (as available)) [21], maternal antenatal conditions, antenatal steroids, antenatal 
magnesium, prenatal ultrasound findings, obstetric antenatal conditions, multiplicity of births, 
delivery type, APGAR score, indications for C-section 
4. Infection 
a. Blood stream infection, total ventilation days, surgical site infection, and ventilator-associated 
pneumonia, drain or catheter-related infections 
5. Surgery 
a. Respiratory mode support with surgical time frame, lab values with surgical time frame, 
complications associated with surgical time frame, surgical procedures, complications 
6. Interventions during this admission as recorded by the NICU for the Children’s Hospital Network 
Database 
7. Date of discharge from NICU 
a. Discharge disposition 
8. Patients discharge to home/foster care 
9. Mortality 
10. GI 
a. Did this infant have functional or structural short gut syndrome at the time of discharge? 
b. Classification of gastroschisis at time of silo placement - Imaging to be taken at time of initial 
evaluation. 
i. Simple 
ii. Complex: atresia, stenosis, perforation, volvulus 
iii. Appearance 

Title: Direct Peritoneal Resuscitation in Gastroschisis 
PI: Bavana Ketha 
Sponsor: UAMS 
Version: 12 
IRB: #206573 
Date: 12/20/2018 
Page 12 
1. Pristine 
2. Matted bowel with peel 
3. Staining of amniotic fluid 
4. Staining of bowel serosa 
c. # of days of empiric antibiotics 
d. Type/Staging of closure of gastroschisis 
e. Complications associated with closure 
f. Additional closure techniques(s) 
g. Closure timing 
11. Other complications 
a. Bacterial overgrowth, late ischemia, NEC, stricture, volvulus, malabsorption, transfer for bowel or 
liver transplant 
12. Feeding and medications 
a. Medications and immunizations [21] 
b. Hyperalimentation 
c. Enteral feedings 
i. Route of feeding at initiation 
ii. Reached 100 kcal/kg/d 
iii. Route of feeding when reached 100 kcal/kg/d 
1. Type of gavage/gastrostomy tube feeding 
iv. Type of enteral nutrition when reached 100 kcal/kg/d 
v. Change in feeding regimen 
1. Date change was made 
2. Why change was made 
13. Ultrasound 
a. Cumulative motility 
b. Mean motility 
14. Additional data 
a. Gastrostomy tube residuals: date, time, and cc 
b. X-ray reads daily by radiology 
c. Reason and time of change in feeding regimen 
d. Stool output 
15. Adverse events* 
a. The durability of treatment effectiveness as well as potential longer-term adverse events will be 
assessed via chart reviews of pediatric follow-up visits or follow-up phone calls up to 90 days after 
discharge. 
 
Timeline 
We estimate that after approval, it will take approximately 2-3 years to accrue and follow subjects as a 
single-site study and 6 months to analyze data and prepare manuscripts. 
 
 

Title: Direct Peritoneal Resuscitation in Gastroschisis 
PI: Bavana Ketha 
Sponsor: UAMS 
Version: 12 
IRB: #206573 
Date: 12/20/2018 
Page 13 
Calendar of Procedures and Assessments 
 
                                                          
1 Silo placement only or silo and JP drain placement per randomized group assignment 
2 Q6 hrs (± 30 min) for 48 hrs after maximum volume, then Q12 hrs (± 30 min) 
3 Q12 hrs (± 30 min) 
4 Per NICU Standard Practice 
5 All: CBC w/ Diff, Magnesium, Sodium, Potassium, Chloride, Bicarbonate/CO2, BUN, Creatinine, Calcium, Phosphate, Albumin, Glucose, Q24 hrs (± 30 min) 
6 SoC Group: Lactate only, Q24 hrs (± 30 min) same time as Routine Lab 
7 DPR Group: Lactate, Sodium, Potassium, Glucose, Q6 hrs (± 30 min) for 24 hrs after maximum volume, then Q12 hrs (± 30 min) 
8 DPR Group: Q6 hrs (± 30 min), dwell for 1 hr, then remove excess fluid - 10 mL/kg initial bolus, then increase by 10 mL/kg up to 40 mL/kg (100 mL maximum volume) 
9 DPR Group only: Glucose within 1 hr prior to every infusion and 1 hr (± 15 min) every post-infusion for the first day (24hrs) of treatment 
10 Daily bedside ultrasound will be performed from post-closure Day 1 to time of full feeds and if feeds are stopped for any reason 
11 The clinical course of each AE should be followed until resolution, stabilization, or until it has been determined that the study treatment is not the cause. 
Assessment 
Screening 
(Day of Birth 
0-12 hrs) 
Staged Reduction 
(Day of Birth 
0-24 hrs) 
Day of Life 
1-7 
Day of 
Closure 
Post-Closure 
Day 1 
Post-Closure 
Day 2 until 
Discharge 
Day of 
Discharge 
Post-Discharge 
Follow-Up 
(up to 90 days) 
Informed Consent 
X 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
Silo/JP Drain placement1 
X 
 
 
 
 
 
 
 
Verify lab values for eligibility 
 
X 
 
 
 
 
 
 
Vitals (HR, RR, BP/MAP, SpO2) 
X2 
X2 
X2 
X2 
X3 
X3 
X4 
 
Weight 
X 
X 
X 
X 
X 
 
 
 
Routine Labs5 
X 
 
X 
X 
X 
X 
 
 
Research Labs67 
X 
X 
X 
X 
X 
 
 
 
G-tube placement4 
X3 
 
 
 
 
 
 
 
Instill DPR8 
 
X 
X 
 
 
 
 
 
Intake/Output 
 
X2 
X2 
X2 
X3 
X4 
 
 
Glucose pre- & post-infusion9 
 
X 
X 
 
 
 
 
 
Bedside ultrasound 
 
 
 
 
X 
X10 
 
 
AE assessment11 
 
X 
X 
X 
X 
X 
X 
X 
Remove OG-tube & Initiate EBM/Formula4 
 
 
 
 
 
X 
 
 
Chart Review or Phone Call 
 
 
 
 
 
 
 
X 

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Sponsor: UAMS 
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Schedule of Procedures and Assessments 
Screening (Day of Birth from 0-12 hours) 
• 
Informed Consent 
• 
Randomization 
• 
Silo placement (within 2 hours of admission to the NICU) 
o JP drain placed and secured per randomization 
• 
Vital signs: heart rate (HR), respiratory rate (RR), MAP/BP, pulse oximetry (SpO2) 
• 
Weight 
• 
Routine Daily labs per NICU standard practice: 
o Complete CBC 
o Magnesium 
o Renal Function Panel (sodium, potassium, chloride, CO2, BUN, creatinine, calcium, phosphate, 
albumin, glucose) 
• 
Research lab (both groups): 
o Lactate 
• 
G-tube placement per NICU standard practice 
 
Staged Reduction Day 1 (Day of Birth from 0-24 hours) 
• 
Verify laboratory values for eligibility 
• 
Instill DPR for DPR group every 6 hrs (± 30 minutes) 
• 
Blood glucose within 1 hour prior to infusion and 1 hour (± 15 minutes) post-infusion for the first 24 
hrs of DPR 
• 
Vital signs every 6 hrs (± 30 minutes): HR, RR, MAP/BP, SpO2 
• 
Weight 
• 
Strict intake/output every 6 hrs (± 30 minutes) 
• 
DPR Group research labs every 6 hrs (± 30 minutes): 
o Sodium 
o Potassium 
o Glucose 
o Lactate 
• 
Adverse events 
 
Day of Life 1 - Day of Life 7 
• 
Instill DPR for DPR group every 6 hrs (± 30 minutes) until abdomen is closed 
• 
Blood glucose within 1 hour prior to infusion and 1 hour (± 15 minutes) post-infusion for the first 24 
hrs of DPR 
• 
Vital signs every 6 hrs (± 30 minutes) for 48 hours after maximum dialysate infusion volume (100 mL) 
is reached, then every 12 hrs (± 30 minutes): HR, RR, MAP/BP, SpO2 
• 
Weight 
• 
Strict intake/output every 6 hrs (± 30 minutes) for 48 hours after maximum dialysate infusion volume 
(100 mL) is reached, then every 12 hrs (± 30 minutes) 
• 
Routine daily labs per NICU standard practice: 
o Complete CBC 
o Magnesium 
o Renal Function Panel (sodium, potassium, chloride, CO2, BUN, creatinine, calcium, phosphate, 
albumin, glucose) 

Title: Direct Peritoneal Resuscitation in Gastroschisis 
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• 
SoC Group research lab (every 24 hrs (± 30 minutes) at the same time as routine daily labs: 
o Lactate 
• 
DPR Group research labs every 6 hrs (± 30 minutes) for 24 hours after maximum dialysate infusion 
volume (100 mL) is reached, then every 12 hrs (± 30 minutes): 
o Sodium 
o Potassium 
o Glucose 
o Lactate 
• 
Adverse events 
 
Day of Abdominal Closure (generally 3-5 days, up to Day 7) 
• 
Vital signs every 6 hrs (± 30 minutes) for 48 hours after maximum dialysate infusion volume (100 mL) 
is reached, then every 12 hrs (± 30 minutes): HR, RR, MAP/BP, SpO2 
• 
Weight 
• 
Strict intake/output every 6 hrs (± 30 minutes) for 48 hours after maximum dialysate infusion volume 
(100 mL) is reached, then every 12 hrs (± 30 minutes) 
• 
Routine daily labs per NICU standard practice: 
o Complete CBC 
o Magnesium 
o Renal Function Panel (sodium, potassium, chloride, CO2, BUN, creatinine, calcium, phosphate, 
albumin, glucose) 
• 
SoC Group research lab (every 24 hrs (± 30 minutes) at the same time as routine daily labs: 
o Lactate 
• 
DPR Group research labs every 6 hrs (± 30 minutes) for 24 hours after maximum dialysate infusion 
volume (100 mL) is reached, then every 12 hrs (± 30 minutes): 
o Sodium 
o Potassium 
o Glucose 
o Lactate 
• 
Abdominal closure per surgical standard practice 
• 
Adverse events 
 
Post-Closure Day 1 
• 
Vital signs every 6 hrs (± 30 minutes) for 48 hours after maximum dialysate infusion volume (100 mL) 
is reached, then every 12 hrs (± 30 minutes): HR, RR, MAP/BP, SpO2 
• 
Weight 
• 
Strict intake/output 6 hrs (± 30 minutes) for 48 hours after maximum dialysate infusion volume (100 
mL) is reached, then every 12 hrs (± 30 minutes) 
• 
Routine daily labs per NICU standard practice: 
o Complete CBC 
o Magnesium 
o Renal Function Panel (sodium, potassium, chloride, CO2, BUN, creatinine, calcium, phosphate, 
albumin, glucose) 
• 
Bedside ultrasound 
• 
SoC Group research lab (every 24 hrs (± 30 minutes) at the same time as routine daily labs: 
o Lactate 

Title: Direct Peritoneal Resuscitation in Gastroschisis 
PI: Bavana Ketha 
Sponsor: UAMS 
Version: 12 
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• 
DPR Group research labs every 6 hrs (± 30 minutes) for 24 hours after maximum dialysate infusion 
volume (100 mL) is reached, then every 12 hrs (± 30 minutes): 
o Sodium 
o Potassium 
o Glucose 
o Lactate 
• 
Adverse events 
 
Post-Closure Day 2 until Day of Discharge 
• 
Vital signs every 12 hrs (± 30 minutes): HR, RR, MAP/BP, SpO2 
• 
Strict intake/output per NICU standard practice 
• 
Routine labs per NICU standard practice 
• 
Removal of OG-tube and initiation of EBM/Formula per clinical decision and NICU standard practice 
• 
Bedside ultrasound until full feeds are achieved and if feeds are stopped for any reason 
• 
Adverse events 
 
Day of Discharge 
• 
Vital signs: HR, RR, MAP/BP, SpO2 
• 
Hospital Discharge 
• 
Adverse events 
 
Post-Discharge Follow-up (up to 90 days following hospital discharge) 
• 
Chart review or phone call 
• 
Adverse events 
 
Risks and Benefits 
Both groups will have the same underlying risks secondary to gastroschisis repair, anesthesia and surgery 
independent of the silo placement. These risks include allergic reaction to medicines, breathing problems 
(including problems requiring intubation and ventilation), bleeding, infection, inflammation of 
peritoneum, organ injury, problems with digestion and malabsorption, dysmotility, and abdominal wall 
hernia. 
 
As this is a novel procedure, the risk for infection secondary to placement and retention of the JP drain, 
for the DPR group, is unknown. However, given that the JP drain will be sterilely placed and secured to 
the silo bag under sterile conditions, we estimate that the risk of JP drain placement and retention in the 
silo would not be appreciably higher than the risk of infection secondary to standard gastroschisis repair 
(12.5%). Additionally we estimate that the risk for infection secondary to placement and retention of JP 
drain within the peritoneum beneath the fascia at the base of the small bowel mesentery would not be 
substantially higher than the risk of infection secondary to standard gastroschisis repair (12.5%). 
 
Subjects may also have the risk of potential for loss of confidentiality. Measures to protect the 
confidentiality of study participants will be implemented as described in the Data Handling and 
Recordkeeping section below. 
 
Additional risks for babies who undergo DPR treatment may include electrolyte imbalances, which will be 
monitored via laboratory values. 

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Babies in the DPR group are at risk for Encapsulating Peritoneal Sclerosis, allergic reaction to corn 
(including anaphylaxis), and possible reactions with insulin or other concomitant medications and 
treatments. 
 
Other possible adverse reactions may include lactic-acidosis, fungal peritonitis, peritonitis bacterial, 
catheter-related infections, hypovolemia, hypervolemia, fluid retention, hypokalemia, hyponatremia, 
dehydration, hypochloremia, hypotension, hypertension, dyspnea, peritonitis, peritoneal cloudy effluent, 
vomiting, diarrhea, nausea, constipation, abdominal pain, abdominal distension, abdominal discomfort, 
Stevens-Johnson syndrome, urticaria, rash (including pruritic, erythematous and generalized), pruritus, 
myalgia, muscle spasms, musculoskeletal pain, generalized edema, pyrexia, malaise, infusion site pain, 
and catheter related complication. 
 
Potential benefits for these subjects include earlier closure, fewer ventilator days, earlier feeding and 
decreased length of stay. 
 
There will be no direct benefits to the study participants in the SoC group; however, knowledge gained 
from the study could potentially benefit subjects in the future as it guides us in best practices for pediatric 
patients with gastroschisis. 
 
Subject Withdrawal from Study 
Subjects’ parent(s)/LAR may choose to withdraw from the study for any reason. Additionally, the 
investigator may choose to remove subjects from the study. This may occur for the following reasons: 
• 
Serious adverse event believed to be related to investigational product 
• 
Intolerable side effects 
• 
Clinically significant laboratory abnormalities 
• 
The investigator believes it is in the best interest of the subject to discontinue the study 
 
Any subject withdrawing their consent to participate in the study or their authorization to use their 
protected health information will be withdrawn from the study. Neonates who are withdrawn from the 
study will no longer undergo any study-related procedures or data collection. Standard of care treatment 
will be continued. 
 
Reasons why subjects are discontinued from the clinical trial will be documented on the Study Termination 
Form. 
 
Safety Monitoring 
Given the risk for fluid and electrolyte imbalances, close monitoring will be provided for the DPR group by 
using more frequent clinical and laboratory assessments in addition to standard NICU monitoring. Vital 
signs and strict intake and output will be monitored every 6 hrs for 48 hours after maximum dialysate 
infusion volume (100 mL) is reached, then every 12 hrs (± 30 minutes). Sodium, potassium, blood glucose 
and lactate levels will be monitored every 6 hours (± 30 minutes) via heelstick, central/arterial line or 
venipuncture per NICU standard practice for 24 hours after the maximum dialysate infusion volume is 
reached, then every 12 hrs (± 30 minutes) through Post-Closure Day 1. 
 
 

Title: Direct Peritoneal Resuscitation in Gastroschisis 
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Subject will also be monitored for the following potential adverse events: 
 
1. Hypokalemia: If the potassium falls to <3.0, additional potassium will added to the IV fluid at the 
discretion of the treating and study physicians. 
2. Lactic acidosis: Lactate levels will be monitored with laboratory checks at least every 12 hours during 
the treatment phase. Continued monitoring of lactic acidosis will include laboratory checks, fluid 
replacement, and stopping infusion of the dialysate fluid. 
3. Hyperglycemia: During the first day (24 hrs) of treatment, blood glucose will be obtained within 1 hour 
prior to infusion and 1 hour (± 15 minutes) post-infusion in addition to routine daily assessments. The 
neonatologists will change IVFs to contain less dextrose as needed. 
4. Hypovolemia: This will be treated with fluid replacement. Blood pressure monitoring and urine output 
assessment will guide management for amount of fluid replacement needed. 
5. Peritonitis: This will be evaluated daily by examination of the effluent dialysate for any cloudiness. 
Cloudy fluid will be sent to the laboratory for cell count, gram stain, and culture. If the cell count is 
elevated, the subject will receive antibiotics as indicated. Subjects with confirmed peritonitis will be 
withdrawn from the study. 
6. Definite (culture positive) sepsis: Neonates with active clinical sepsis will be excluded from the study 
by the hemodynamic parameter exclusion criteria (hypotension, hyper/hypoglycemia, lactic acidosis, 
etc.). During the dialysate infusion period, subjects who develop definite (culture positive) sepsis will 
be withdrawn from the study. 
7. Acute Kidney Injury (AKI): AKI will be staged using the “Neonatal AKI KDIGO Classification” Table below 
(Selewski et al [22]). Subjects who develop AKI > Stage 2 will be withdrawn from the study. 
 
 
Individual Subject Discontinuation 
If a subject develops any of the individual subject discontinuation criteria below, the study drug will be 
immediately discontinued: 
• 
Positive blood culture 
• 
Documented peritonitis 
• 
Lactic acid > 5 mmol/L 
• 
pH < 7.1 
• 
Sodium < 125 mEq/L or > 150 mEq/L 
• 
Potassium < 2.5 mEq/L 
• 
Continued hyperglycemia > 250 for more than 12 hours 
• 
Definite (culture positive) sepsis 
• 
Stage 3 AKI [22] 

Title: Direct Peritoneal Resuscitation in Gastroschisis 
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Sponsor: UAMS 
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Subjects who develop any of the individual subject discontinuation criteria will be evaluated and 
monitored until resolution of the adverse events and laboratory values have returned to baseline. These 
subjects will no longer receive DPR, but will continue with assessments per the schedule of procedures 
and assessments. 
 
Study Discontinuation 
The study will be stopped if more than 3 subjects in the DPR group develop any one of the individual 
subject discontinuation criterion above. 
 
Adverse Events 
For purposes of this study, the following will be considered adverse events of special interest if they occur 
before study completion: 
1. Bradycardia: defined as a heart rate < 100 bpm for ≥ 20 seconds 
2. Desaturation: defined as SpO2 < 80% for ≥ 20 seconds 
3. A sustained apnea event defined as lasting ≥ 20 seconds and coinciding with at least one of the 
following: 
• 
HR < 100 bpm 
• 
Desaturation (oxygen saturation < 80%) 
4. Other AES of special interest have been adopted from England et al.’s adverse event tables for the 
Pediatric Trials Network (PTN) [23] (Appendix E). 
5. Infections [21] 
 
Definitions 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study. Intercurrent illnesses or injuries should be regarded as AEs. Abnormal 
results of diagnostic procedures are considered to be AEs if the abnormality: 
• 
results in study withdrawal 
• 
is associated with a serious AE 
• 
is associated with clinical signs or symptoms 
• 
leads to additional treatment or to further diagnostic tests 
• 
is considered by the investigator to be of clinical significance 
 
Serious Adverse Event 
Serious AE (SAE) means any untoward medical occurrence at any dose: An event is “serious” if it involves 
considerable detriment or harm to one or more persons (who may or may not be participants), or required 
intervention to prevent one or more persons from experiencing considerable detriment or harm. SAEs 
include: 
• 
Death 
• 
Life-threatening experience – Disease or condition where the likelihood of death is high unless 
the course of the disease/condition is interrupted or diseases/conditions with potentially fatal 
outcomes where the endpoint of the clinical trial analysis is survival 
• 
Inpatient hospitalization or prolongation of hospitalization 
• 
Persistent or significant disability/incapacity 
• 
Congenital anomaly/birth defect in participant’s offspring 

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Sponsor: UAMS 
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• 
Any other important medical event that, based upon appropriate medical judgment, may 
jeopardize the participant and may require medical or surgical intervention to prevent one of the 
outcomes listed above. Examples include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, the development of drug dependency or drug abuse, suicidal ideation or 
attempts, or the unintentional revealing of some genetic information to insurers. 
 
Related 
An event is “related” if more likely than not it was caused by the research activity. 
 
Unexpected 
An event is “unexpected” when its specificity, nature, severity or incidence is not accurately reflected in 
the consent form, protocol, or investigator’s brochure previously reviewed and approved by the IRB. 
Examples include a lower rate of response to treatment or a side effect that is more severe than initially 
expected. 
 
Study Period 
All AEs will be recorded by the Investigator from the time of the start of study drug through the end of 
the designated follow-up period. All AEs will be recorded on the AE CRF. All relevant historical medical 
conditions that are known/diagnosed prior to the administration of study drug(s) are to be recorded. 
 
Abnormal Laboratory Values Defined as AEs 
An abnormal laboratory value is considered to be an AE if the laboratory abnormality is characterized by 
any of the following: 
• 
Results in discontinuation from the study 
• 
Requires treatment, modification of study drug dose, or any other therapeutic intervention 
• 
Is judged by the Investigator to be of significant clinical impact/importance 
• 
Grade 3 or Grade 4 lab abnormalities regardless of significance 
 
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis or 
syndrome should be recorded as an AE. If the laboratory abnormality was not a part of a diagnosis or 
syndrome, then the abnormality should be recorded as the AE. 
 
Monitoring, Recording and Reporting of AEs 
All AEs occurring during the study period must be recorded. The clinical course of each event should be 
followed until resolution, stabilization, or until it has been determined that the study treatment or 
participation is not the cause. SAEs that are still ongoing at the end of the study period must be followed 
for up to 30 days to determine the final outcome. Any SAE that occurs after the study period and is 
considered to be possibly related to the study treatment or study participation should be recorded and 
reported immediately to the Sponsor. 
 
All subjects will be monitored for AEs during the study. Assessments may include monitoring the subject's 
clinical symptoms; laboratory, pathological, radiological, or surgical findings; physical examination; or 
other appropriate tests and procedures. 
 

Title: Direct Peritoneal Resuscitation in Gastroschisis 
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AE data collection and reporting, which are required as part of every study, are done to ensure the safety 
of subjects enrolled in the studies and those who will enroll in future protocols. AEs are to be reported in 
a routine fashion at scheduled times during the trial, such as with the annual continuing review to the IRB. 
Certain AEs must be reported in an expedited fashion to allow for timely monitoring of subject safety and 
care. 
 
The reporting of these events depends on the characteristics of the event: 
1. Seriousness (grading of event) 
2. Relatedness to study treatment 
3. Expectedness 
 
Steps to Determine if the Event Requires Expedited Reporting: 
1. Determine whether the adverse event is related to the investigational drug. Attribution categories 
are as follows: 
• 
Unrelated 
• 
Unlikely 
• 
Possible 
• 
Probable 
• 
Definite 
2. Determine expectedness of event. Expected events are those previously identified resulting from 
administration of the agent. An adverse event is considered unexpected when the type or severity 
of the event is not listed in the package insert, protocol, or consent form. 
 
Note: This includes all events that occur within 30 days of the last dose/use of protocol treatment. Any 
event occurring more than 30 days after the last dose that is possible, probably, or definitely attributable 
to the investigational drug must be reported according to the instructions above. 
 
Expedited Reporting of AEs 
Institutional Review Board Reporting 
Only adverse events meeting the UPIRTSO (Unanticipated Problem Involving Risks to Subjects or Others) 
will need to be reported to the UAMS IRB within the required 10-day allotment of being notified of the 
event. UPIRTSO requires that an unanticipated problem meet the following qualifications: a) 
unanticipated or unexpected; b) related to the research; and c) involves new or increased risk to the 
subject(s). All other adverse events should be recorded and reported to the UAMS IRB at continuing 
review. 
 
Sponsor Reporting 
The Sponsor will be promptly notified of all SAEs that are related to the study intervention and 
unanticipated/unexpected. These SAEs will be reported to the Sponsor using the FDA MedWatch 3500A. 
All other SAEs will be reported to the Sponsor and FDA in the Annual Progress Report. The Sponsor will 
report events to FDA in accordance with 21 CFR 312. 
 
Deaths that are related to research will be reported to the Sponsor immediately upon Investigator 
notification. A death due to a terminal condition of the research participant would be considered 
anticipated and not related to the research. THE SPONSOR WILL REPORT DEATHS TO FDA IN ACCORDANCE 
WITH 21 CFR 312. 

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Sponsor: UAMS 
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Monitoring 
Clinical site monitoring will be conducted by the UAMS Office of Research Regulatory Affairs (ORRA) to 
ensure that the rights and well-being of trial participants are protected; that the reported trial data are 
accurate, complete, and verifiable; and that the conduct of the trial is in compliance with the currently 
approved protocol/amendment(s), ICH GCP, and applicable regulatory requirements. 
 
Monitoring specialists from ORRA will conduct periodic on-site, comprehensive monitoring as determined 
by a protocol-specific monitoring plan, which will be provided by the ORRA Monitoring Unit. 
 
Data Handling and Recordkeeping 
The Principal Investigator will carefully monitor study procedures to protect the safety of research 
subjects, the quality of the data and the integrity of the study. All study subject material will be assigned 
a unique identifying code or number. The key to the code will be kept in a file on a password-protected 
computer in the principal investigator’s locked office. The data files will be kept in a separate file on the 
password-protected computer in the principal investigator’s locked office. The only individuals who will 
have access to the code and information that identifies the subject in this study will be limited to 
investigators on this study. All data will be de-identified after analysis is complete by destroying the code 
key. De-identified data will be maintained as per UAMS and ACRI policy (currently all data will be kept 
until the last subject is 21 years of age plus 2 years) and destroyed per institutional guidelines. 
 
All ultrasound studies will be transferred and stored on a secure image server located in the PI’s office. 
The studies will be labeled prior to performing the study with a coded identification number based on the 
patients MRN. A separate computer workstation connected to the image server will be used for image 
viewing and data analysis. The ultrasounds will be reviewed on this separate password-protected 
computer only viewed by study personnel. All data will be de-identified after analysis is complete by 
destroying the code key. De-identified data will be maintained as per UAMS policy (currently seven years 
after publication) and destroyed per institutional guidelines. 
 
Data Analysis 
Demographic variables will be assessed for differences between groups. Categorical variables will be 
examined using Fisher’s Exact Test or Chi Square Test. Continuous data will be examined using Students’ 
T-test. All tests will be two-sided assuming a significance level of 5%. The dependent variable will be tested 
to ensure the assumption of normality is met. 
 
The primary outcome measure is time to full enteral feeds of 100 kcal/kg/day. Using a two-sample t-test, 
we estimated that a sample size of 20 in each of the two groups will yield at least 80% power to detect a 
6-day difference in mean time to goal enteral feeds (100 kcal/kg/day) assuming a common standard 
deviation of 7 and a two-sided significance level of 5%. 
 
The proposed data analyses and sample size calculations were conducted with the support of statisticians 
at ACRI using SAS® Software, Version 9.4[24]. 
 
Ethical Considerations 
This study is to be conducted according to applicable government regulations and Institutional research 
policies and procedures. 

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The parent(s)/LAR of each potential subject identified as meeting inclusion criteria for this study will be 
approached to discuss participation in this study by trained study personnel. The person obtaining consent 
will go over the informed consent comprehensively with the parent(s)/LAR. The risks and rationale of this 
study will be outlined and all questions will be answered. The volunteer natures of this project will be 
emphasized, including uninhibited withdrawal from the study at any time. No coercion or undue influence 
will be used in the consent process. A copy of the signed consent will be given to the subject’s 
parent(s)/LAR, and the informed consent process will be documented in each subject’s research record in 
a separate process note. 
 
Ways of consenting parent(s)/LAR: 
1. Mother or father (if mother and father are married)/LAR consented prenatally in OB/GYN clinic. 
2. Mother or father (if mother and father are married)/LAR consented after birth via faxed consent to 
the OB unit and returned to PI. The faxed consent will then be witnessed by bedside nurse. 
a. The person obtaining consent will fax a consent form to the OB unit and conduct the consent 
process conversation by phone once the mother or father/LAR has the form in hand. 
b. After the person obtaining consent has verified that all questions have been answered, the 
mother or father/LAR will sign the consent and it will be faxed back. 
c. The person conducting the consent process will then sign the form, and a signed copy of this form 
will be given/sent to the mother or father/LAR. 
d. No research-related activities will be performed until the signed and witnessed consent form is 
received by ACH study personnel. 
3. Consent obtained at bedside from mother or father (if mother and father are married)/LAR. 
 
Dissemination of Data 
This clinical trial will be registered at ClinicalTrials.gov, and information will be updated in a timely 
manner. 
 
Results of this study may be used for presentations, posters, or publications. The publications will not 
contain any identifiable information that could be linked to a participant. 
 
 

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References 
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abdominal wall closure after damage control surgery. J Am Coll Surg. 2010 May; 210(5): 658-667. 
2. Hurt RT, Matheson PJ, Smith JW, et al. Preservation of hepatic blood flow by direct peritoneal 
resuscitation improves survival and prevents hepatic inflammation following hemorrhagic shock. 
American journal of physiology Gastrointestinal and liver physiology 2012; 303:G1144-1152. 
3. Hurt RT, Zakaria el R, Matheson PJ, et al. Hemorrhage-induced hepatic injury and hypoperfusion can 
be prevented by direct peritoneal resuscitation. Journal of gastrointestinal surgery: official journal of 
the Society for Surgery of the Alimentary Tract 2009; 13:587-594. 
4. Matheson PJ, Mays CJ, Hurt RT, et al. Modulation of mesenteric lymph flow and composition by direct 
peritoneal resuscitation from hemorrhagic shock. Arch Surg 2009; 144:625-634. 
5. Zakaria el R, Li N, Garrison RN. Mechanisms of direct peritoneal resuscitation-mediated splanchnic 
hyperperfusion following hemorrhagic shock. Shock 2007; 27:436-442. 
6. Downard CD, Grant SN, Matheson PJ, et al. Altered intestinal microcirculation is the critical event in 
the development of necrotizing enterocolitis. Journal of pediatric surgery 2011; 46:1023-1028. 
7. Downard CD, Matheson PJ, Shepherd JA, et al. Direct peritoneal resuscitation augments ileal blood 
flow in necrotizing enterocolitis via a novel mechanism. Journal of pediatric surgery 2012; 47:1128-
1134. 
8. Maki AC, Matheson PJ, Shepherd JA, et al. Intestinal microcirculatory flow alterations in necrotizing 
enterocolitis are improved by direct peritoneal resuscitation. The American surgeon 2012; 78:803-
807. 
9. Walker SK, Matheson PJ, Schreiner MT, et al. Intraperitoneal 1.5% Delflex improves intestinal blood 
flow in necrotizing enterocolitis. The Journal of surgical research 2013. 
10. Matheson PJ, Franklin GA, Hurt RT, et al. Direct peritoneal resuscitation improves obesity-induced 
hepatic dysfunction after trauma. Journal of the American College of Surgeons 2012; 214:517-528; 
discussion 528-530. 
11. Smith JW, Franklin GA, Matheson PJ, et al. Randomized control trial evaluating the efficacy of 
peritoneal resuscitation in the management of trauma patients undergoing damage control surgery. 
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12. Weaver JL and Smith JW. Direct Peritoneal Resuscitation: A review. Int J Surg. 2016 Sep; 33(Pt B): 237-
241. 
13. Mattoo TK, Ahmad GS. Peritoneal dialysis in neonates after major abdominal surgery. American 
journal of nephrology 1994; 14:6-8. 
14. Alon U, Bar-Maor JA, Bar-Joseph G. Effective peritoneal dialysis in an infant with extensive resection 
of the small intestine. American journal of nephrology 1988; 8:65-67. 
15. Canpolat FE, Yurdakok M, Yigit S, et al. Can peritoneal dialysis be used in preterm infants with 
gastrointestinal perforation? Pediatrics international: official journal of the Japan Pediatric Society 
2010; 52:834-835. 
16. Hopkins JW, Chandramouli B, Wall P. Preliminary resuscitation for perforated necrotizing 
enterocolitis: 2 cases treated with initial direct peritoneal resuscitation. Journal of pediatric surgery 
2011; 46:237-240. 
17. Gurien LA, Wyrick DL, Dassinger MS, et al. Use of bedside abdominal ultrasound to confirm intestinal 
motility in neonates with gastroschisis: A feasability study. Journal of Pediatric Surgery 2017; 56(5): 
715-717. 
18. Guidance for Industry-ICH E11: Clinical Investigation of Medicinal Products in the Pediatric Population, 
US Department of Health and Human Services, Food and Drug Adminitration, Center for Drug 

Title: Direct Peritoneal Resuscitation in Gastroschisis 
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Sponsor: UAMS 
Version: 12 
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Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), ICH 
(International Council for Harmonisation), December 2000. 
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collection, analysis, and presentation of immunization safety data. Vaccine. 2016; 34(49):6038-6046. 
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24. SAS® software, Version 9.4 of the SAS System for Arkansas Childrens Research Institute. Copyright© 
2016 SAS Institute Inc. SAS and all other SAS Institute Inc. product or service names are registered 
trademarks or trademarks of SAS Institute Inc., Cary, NC, USA. 
 
 

Title: Direct Peritoneal Resuscitation in Gastroschisis 
PI: Bavana Ketha 
Sponsor: UAMS 
Version: 12 
IRB: #206573 
Date: 12/20/2018 
Page 26 
Appendix A 
Dianeal Solution 
Dianeal PD-2 Peritoneal Dialysis Solutions are sterile, nonpyrogenic and contain no bacteriostatic or 
antimicrobial agents or added buffers. 
 
 
Each 1000 mL of Dianeal Peritoneal Dialysis Solution contains: 
Components 
Contents 
Glucose, BP 
1.5 % - 15.0 g 
Sodium Chloride, BP 
5.38 g 
Sodium Lactate 
4.48 g 
Magnesium Chloride Hexahydrate, BP 50.8 g 
Calcium Chloride Dihydrate, BP 
PD-2 257 mg 
Water For Injections, BP 
QS 
 
 
Dianeal PD-2 Peritoneal Dialysis Solution with 1.5% Glucose: 
Components 
Contents 
Glucose .H2O 
Sodium 
Calcium 
Magnesium 
Chloride 
Lactate 
Approximate Osm 
76 mmol/L 
132 mmol/L 
1.75 mmol/L 
0.25 mmol/L 
96 mmol/L 
40 mmol/L 
346 mOs 
 
 

Title: Direct Peritoneal Resuscitation in Gastroschisis 
PI: Bavana Ketha 
Sponsor: UAMS 
Version: 12 
IRB: #206573 
Date: 12/20/2018 
Page 27 
Appendix B 
Gastroschisis 
 
Initial Treatment 
Place infant right side down 
- Replogle to LIS 
- Cover lower body with bowel bag 
- Antibiotics: Ampicillin & Gentamicin 
Admission labs 
 
Silo Placement at Bedside 
Preparation 
- Ensure there are no perforations, ischemic bowel, atresias 
- Make sure Replogle is in place and functional 
- Lay patient on right side if bowel appears ischemic 
Equipment 
- Gather from the OR: Concept battery powered pencil cautery. 
- Gather from NICU: Betadine, umbilical artery catheterization tray, and silos size 3-6 (box in NICU). 
Technique Tips 
- Splay mesentery to avoid kinking 
- If opening fascia, inject lidocaine first 
- Cauterize fascia on top of the back end of a forcep 
- Open fascia upward first about 0.5 cm 
- Try not to cut skin unless needed 
- Measure defect & pick silo size resulting in 1 cm overlap 
- Lubricate silo with sterile saline 
- Caution during placement → Liver & Spleen 
- Ensure contents move easily within silo and are viable 
- Consider milking meconium distally out of colon, succus proximally into Replogle and emptying 
bladder with palpation. 
 
Silo Reduction 
- Carefully apply umbilical or trach tape to silo sequentially daily. 
- Do not clamp bowel 
- Once at level of fascia, patient is taken to operating room for closure. 
 
Post-Closure 
a. When Replogle output clears and decreases, start formula or EBM and follow NICU protocols. 
b. Continue Zantac or Prevacid 
c. Glycerin enemas BID until stooling spontaneously 
 
Failure to tolerate initiated diet 3-4 wks after closure → Contrast Enema to rule out atresia or 
meconium plugs. 
 
 

Title: Direct Peritoneal Resuscitation in Gastroschisis 
PI: Bavana Ketha 
Sponsor: UAMS 
Version: 12 
IRB: #206573 
Date: 12/20/2018 
Page 28 
Appendix C 
NICU Feeding Protocols
 

Title: Direct Peritoneal Resuscitation in Gastroschisis 
PI: Bavana Ketha 
Sponsor: UAMS 
Version: 12 
IRB: #206573 
Date: 12/20/2018 
Page 29 
Appendix D 
Adverse Event Table – Laboratory Values [23] 
 
Adverse Event 
Serious Adverse Event 
 
Conventional Units 
International System (SI) 
Conventional Units 
International System (SI) 
Electrolytes 
 
 
 
 
Hyponatremia 
120–124 mEq/L 
120–124 mmol/L 
<120 mEq/L 
<120 mmol/L 
Hypernatremia 
150–159 mEq/L 
150–159 mmol/L 
>159 mEq/L 
>159 mmol/L 
Hypokalemia 
2.0–2.5 mEq/L 
2.0–2.5 mmol/L 
<2.0 mEq/L 
<2.0 mmol/L 
Hyperkalemia 
7–7.9 mEq/L 
7.0–7.9 mmol/L 
>7.9 mEq/L 
>7.9 mmol/L 
Bicarbonate: Low 
12–14 mEq/L 
12–14 mmol/L 
<12 mEq/L 
<12 mmol/L 
Bicarbonate: High 
35–45 mEq/L 
30–45 mmol/L 
>45 mEq/L 
>45 mmol/L 
Hypocalcemia (ionized) 
4.1–4.2 mg/dL 
0.7–1.05 mmol/L 
<4.1 mg/dL 
<0.7 mmol/L 
Hypercalcemia (ionized) 
5.4–5.7 mg/dL 
1.3–1.6 mmol/L 
>5.7 mg/dL 
>1.6 mmol/L 
Renal 
 
 
 
 
BUN 
60–100 mg/dL 
21.42–35.7 mmol/L 
>100 mg/dL 
>35.7 mmol/L 
Creatinine 
1.5–2.5 mg/dL 
132.6–221 μmol/L 
>2.5 mg/dL 
>221 μmol/L 
Endocrine 
 
 
 
 
Hypoglycemia 
25–36 mg/dL 
1.4–2 mmol/L 
<25 mg/dL 
<1.4 mmol/L 
Hyperglycemia 
250–500 mg/dL 
13.9–27.8 mmol/L 
>500 mg/dL 
>27.8 mmol/L 
Gastrointestinal 
 
 
 
 
Aspartate aminotransferase 
200–1000 U/L 
3.34–16.7 μkat/L 
>1000 U/L 
>16.7 μkat/L 
Alanine aminotransferase 
200–1000 U/L 
3.34–16.7 μkat/L 
>1000 U/L 
>16.7 μkat/L 
Alkaline phosphatase 
1000–1400 U/L 
16.4–23.4 μkat/L 
>1400 U/L 
>23.4 μkat/L 
Conjugated bilirubin 
3-10 mg/dL 
51.3–171 μmol/L 
>10 mg/dL 
>171 μmol/L 
Gamma-glutamyl transferase 
100–125 U/L 
1.7–2.1 μkat/L 
>125 U/L 
>2.1 μkat/L 
Hypertriglyceridemia 
500–1200 mg/dL 
5.7–13.6 mmol/L 
>1200 mg/dL 
>13.6 mmol/L 
Hematologic 
 
 
 
 
Leukopenia 
0.5–2 × 103/μL 
0.5–2 × 109/L 
<0.5 × 103/μL 
<0.5 × 109/L 
Leukocytosis 
30-50 × 103/μL 
30-50 × 109/L 
>50 × 103/μL 
>50 × 109/L 
Anemia: hemoglobin 
7–9 g/dL 
70–90 g/L 
<7 g/dL 
<70 g/L 
Anemia: hematocrit 
20–26% 
0.24–0.26 
<20% 
<0.24 
Polycythemia: hemoglobin 
23–24 g/dL 
230–240 g/L 
>24 g/dL 
>240 g/L 
Polycythemia: hematocrit 
66–70% 
0.66–0.7 
>70% 
>0.7 
Thrombocytopenia 
50–100 × 103/μL 
50–100 × 109/L 
<50 × 103/μL 
<50 × 109/L 
Thrombocytosis 
450–1000 × 103/μL 
450–1000 × 109/L 
>1000 × 103/μL 
>1000 × 109/L 
Prothrombin time 
18–22 seconds 
18–22 seconds 
>22 seconds 
>22 seconds 
Activated partial thromboplastin time 
79–101 seconds 
79–101 seconds 
>101 seconds 
>101 seconds 
Lactate 
45.1–90.1 mg/dL 
5–10 mmol/L 
>90.1 mg/dL 
>10 mmol/L 
Musculoskeletal 
 
 
 
 
Creatine kinase 
470–600 U/L 
7.9–10 μkat/L 
>600 U/L 
>10 μkat/L 
Respiratory 
 
 
 
 
Acidosis: pH 
7.10–7.19 
7.15–7.19 
<7.10 
<7.15 
Alkalosis: pH 
7.50–7.60 
7.50–7.60 
>7.60 
>7.60 
pCO2: low* 
25–30 mEq/L 
25–30 mEq/L 
<25 mEq/L 
<25 mEq/L 
pCO2: high* 
55–65 mEq/L 
55–65 mEq/L 
>65 mEq/L 
>65 mEq/L 
Base Excess: low* 
-10 – -15 mEq/L 
-10 – -15 mEq/L 
>-15 mEq/L 
>-15 mEq/L 
Base Excess: high* 
+5 – +10 mEq/L 
+5 – +10 mEq/L 
>+10 mEq/L 
>+10 mEq/L 
*Laboratory values added to the original table 
 

Title: Direct Peritoneal Resuscitation in Gastroschisis 
PI: Bavana Ketha 
Sponsor: UAMS 
Version: 12 
IRB: #206573 
Date: 12/20/2018 
Page 30 
Adverse Event Table – Clinical Entities [23] 
Adverse Event 
Serious Adverse Event 
Gastrointestinal 
 
 
Necrotizing enterocolitis 
 
Bell Stage II or III 
Intestinal perforation 
 
Intra-abdominal free air without preceding pneumatosis 
Musculoskeletal 
 
 
Fracture 
Fracture treated with immobilization 
Fracture with any surgical intervention needed or known 
lasting sequelae 
Respiratory 
 
 
Respiratory failure 
 
Initiation of mechanical ventilation or some defined 
change 
Pneumothorax 
Present but no intervention required 
Intervention required (e.g., chest tubes, sclerosis therapy 
and/or operative) 
Apnea 
 
Requiring initiation of mechanical ventilation 
Pulmonary hypertension 
 
Present and initiation of medical therapy to treat 
pulmonary hypertension (e.g., nitric oxide, milrinone, 
sildenafil) 
Neurological 
 
 
Seizure 
 
Present and treated with anticonvulsant 
Intraventricular hemorrhage 
 
Grade 3-4 
Periventricular leukomalacia 
 
Present on imaging 
Cardiology 
 
 
Hypotension 
 
Requiring pressors 
ECG QTc prolongation 
460 – 485 ms 
> 485 ms 
Supraventricular tachycardia 
Episode resolves spontaneously or with vagal maneuvers 
Requiring medical drug therapy or electroconversion to 
revert to sinus rhythm 
Infectious Disease 
 
 
Wound infection 
Requiring only local intervention (e.g., topical 
antimicrobial) 
Requiring systemic antimicrobial therapy or surgery 
Urinary tract infection 
 
Positive urine culture treated with systemic antibiotics or 
antifungals 
Cellulitis 
Requiring only local intervention (e.g., antimicrobial) 
Requiring systemic antimicrobial therapy or surgery 
Bloodstream infection 
 
Positive blood culture requiring systemic antimicrobial 
Meningitis 
 
Positive cerebral spinal fluid culture requiring systemic 
antimicrobial 
Ophthalmologic 
 
 
Conjunctivitis 
Requiring only local intervention (e.g., topical 
antimicrobial) 
Requiring systemic antimicrobial therapy or surgery 
Retinopathy of prematurity 
Any stage 
Any stage requiring surgical or medical intervention 
Otolaryngology 
 
 
Hearing impairment 
 
Confirmed hearing loss, either unilateral or bilateral 
Drug mediated 
 
 
Infusion related reaction 
Mild transient reaction or reaction that responds promptly 
to symptomatic treatment (e.g., antihistamines, NSAIDS, 
narcotics, IV fluids) 
Prolonged reaction that does not respond promptly to 
symptomatic treatment (e.g., antihistamines, NSAIDS, 
narcotics, IV fluids) or life-threatening reaction that 
requires urgent intervention 
Infusion site extravasation 
Erythema with or without associated symptoms (e.g., 
edema, pain, induration, phlebitis) 
Significant tissue injury leading to ulceration, necrosis, 
operative intervention indicated, or urgent intervention 
indicated 
Injection site reaction 
Tenderness with or without associated symptoms (e.g., 
warmth, erythema, itching, lipodystrophia, edema) 
Significant tissue injury leading to ulceration, necrosis, 
operative intervention indicated, or urgent intervention 
indicated 
Allergic reaction 
Transient flushing, rash, drug fever that responds promptly 
to symptomatic treatment (e.g., antihistamines, NSAIDS, 
narcotics) 
Prolonged reaction that does not respond promptly to 
symptomatic treatment (e.g., antihistamines, NSAIDS, 
narcotics, IV fluids) or life-threatening reaction that 
requires urgent intervention 
Anaphylaxis 
Acute onset of illness with skin and/or mucosal tissue 
manifestations and either respiratory compromise or 
hypotension that requires parental medication 
intervention 
Acute onset of illness with skin and/or mucosal tissue 
manifestations and either respiratory compromise or 
hypotension that is life-threatening and requires urgent 
intervention