Clinical trial NCT03894904
Conditions: Pediatrics Anesthesia Vasospasm
Keywords: Heparin Papaverine
Sponsor: The University of Texas Health Science Center, Houston
Start date: 2019-04-01; Completion date: 2020-10-10
Enrollment: 100 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare intraoperative papaverine plus heparin to heparin alone for prevention of arterial spasm and maintenance of patency of peripheral arterial catheters during surgery in pediatric patients. The hypothesis is that periodic, intraoperative small-volume boluses of diluted papaverine plus heparin in peripheral arterial catheters of pediatric patients will prevent arterial spasm and help maintain patency of arterial catheters during general anesthesia.

Detailed description:
Peripheral arterial catheters measure blood pressure with every heartbeat and provide valuable information regarding the status of the heart and the overall well being. It is of utmost importance to maintain the utility and patency of these catheters throughout the procedure. As standard procedure, heparin, a blood thinner, is used routinely during the surgical procedure to keep these catheters from clotting, and papaverine, an arterial relaxation agent, is used after surgery to maintain patency of these catheters.

In this study, participants will be randomized to receive two boluses of papaverine with heparin during the procedure (experimental arm) or heparin alone during the procedure (control arm) \[in both arms, the first bolus will be administered as soon as the arterial catheter is placed and secured and again one hour after initial bolus\]. If the arterial catheter spasm/patency or waveform does not improve 10 minutes after the second bolus, then the anesthesiology care team will consider treating clinically with 0.3 mg of papaverine.

Arms: arm 1: 1 mL bolus of papaverine (0.12 mg/mL) plus heparin (2 units/mL) in saline (NaCl 0.9%) will be administered as soon as the arterial catheter is placed and secured, and a 1 mL bolus of papaverine (0.12 mg/mL) plus heparin (2 units/mL) in saline (NaCl 0.9%) will be administered one hour after initial bolus. If the arterial catheter spasm/patency or waveform does not improve 10 minutes after the second bolus, then the anesthesiology care team will consider treating clinically with 0.3 mg of papaverine. arm 2: 1 mL bolus of heparin (2 units/mL) in saline (NaCl 0.9%) will be administered as soon as the arterial catheter is placed and secured, and a 1 mL bolus of heparin (2 units/mL) in saline (NaCl 0.9%) will be administered one hour after initial bolus. If the arterial catheter spasm/patency or waveform does not improve 10 minutes after the second bolus, then the anesthesiology care team will consider treating clinically with 0.3 mg of papaverine.
Interventions: intervention 1: Papaverine intervention 2: Heparin intervention 3: Rescue papaverine, as needed
Intervention descriptions: intervention 1: 0.12 mg/mL papaverine administered as soon as the arterial catheter is placed and secured, and 0.12 mg/mL papaverine administered one hour after initial dose intervention 2: 2 units/mL heparin administered as soon as the arterial catheter is placed and secured, and 2 units/mL heparin administered one hour after initial dose intervention 3: If the arterial catheter spasm/patency or waveform does not improve 10 minutes after the second papaverine plus heparin or heparin only dose, then the anesthesiology care team will consider treating clinically with 0.3 mg of papaverine.

Protocol documents:
Prot_001.pdf: 
IRB NUMBER: HSC-MS-19-0059 
IRB APPROVAL DATE: 08/05/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Small Volume Bolus Of Papaverine versus Heparin To Maintain Patency Of 
Peripheral Arterial Catheters In Pediatric Patients Undergoing Surgical Procedures: 
Randomized, Controlled Trial, Double-Blind,Pilot Study 
 
NCT03894904 
 
Version Date: 08/05/2019 
 
 


IRB NUMBER: HSC-MS-19-0059 
IRB APPROVAL DATE: 08/05/2019 
 
Title: Small Volume Bolus Of Papaverine versus Heparin To Maintain Patency Of 
Peripheral Arterial Catheters In Pediatric Patients Undergoing Surgical Procedures: 
Randomized, Controlled Trial, Double-Blind,Pilot Study. 
 
Principal Investigator: 
Nischal K. Gautam, MD-Consent Patient, Study Design, Data Collection and Data Analysis 
 
Co Investigators 
Olga Pawalek, MD-Consent Patient, Data Collection 
Evelyn Griffin, MD-Consent Patient, Data Collection 
Richard Hubbard, MD-Consent Patient, Data Collection 
Anil M DeSilva, MD-Consent Patient, Data Collection 
Ranu Jain, MD-Study Design, Consent Patient, Data Collection 
Maria Matuszczak, MD-Study Design, Consent Patient, Data Collection 
Jessica Rochkind, MD-Consent Patient, Data Collection 
Kayla Edmonds, CAA-Consent Patient, Data Collection 
 
 
Hypothesis: 
Periodic small volume boluses of diluted papaverine in peripheral arterial catheters of pediatric 
patients will prevent arterial spasm and help maintain patency of arterial catheters during 
general anesthesia. 
 
Background: 
What is the problem? -- Overdamping of arterial waveform and inability to aspirate from 
peripheral arterial catheters minimizing their utility in pediatric population undergoing general 
anesthesia for surgical procedures. 
a) Pediatric patients undergoing complex surgical repairs or those with complex 
comorbidities often require continuous arterial pressure monitoring to help maintain 
hemodynamics and obtain blood samples to ensure optimal therapy. However, the 
accuracy of this system is subject to wide variability due to patient characteristics 
(caliber of the vessels), site of cannulation (radial versus posterior tibial), the type of 
catheter (size and material), and the catheter-tubing-transducer-flush system. We notice 
that maintaining the patency of peripheral arterial catheters in this age group is a difficult 
issue many pediatric anesthesiologists face, especially during lengthy surgical 
procedures or when temperature instability is present (cardiopulmonary bypass). 
Unfractionated Heparin, normal saline and papaverine have been shown to prolong 
patency of peripheral arterial catheters in neonates and children{Heulitt:1993un, 
Griffin:2005bo} when used in a continuous pump-based infusion in the intensive care 
setting. While the continuous infusion ensures patency of peripheral arterial catheters in 
an intensive care setting, this method is not convenient for use during surgery. 
Intraoperatively, the peripheral arterial catheter-tubing-transducer is usually connected to 
a pressurized bag of normal saline or heparinized saline (2 units/mL) allowing for 
continuous leaching up to 3 mL/hour. 


IRB NUMBER: HSC-MS-19-0059 
IRB APPROVAL DATE: 08/05/2019 
 
 
What do we do at our institution currently? 
Intraoperatively, peripheral arterial catheters are placed and secured by the pediatric 
anesthesia care team, and a pressurized heparin (2 units/mL) bag (500mL) is connected 
to the transducer to maintain patency. Towards the end of surgery, the pediatric 
anesthesia care team transitions the fast flush system to a continuous pump-based 
papaverine/heparin infusion system before transporting the patients to the intensive care 
unit. However, as rescue, the anesthesia care team frequently uses papaverine bolus 
(0.3 mg) in patients undergoing cardiac surgery to treat arterial spasm whenever arterial 
catheter spasm is suspected. 
 
What is the advantage of adding papaverine bolus to arterial line catheter care during general 
anesthesia? 
Papaverine is an alkaloid obtained from opium with a characteristic effect of relaxation of 
all smooth muscle, especially when spasmodically contracted. Papaverine acts directly 
on the muscle itself, unrelated to innervation, and the relaxation is prominent if spasm 
exists. The current standard of care is to administer papaverine after surgery to help 
relax the blood vessel and keep the catheter open for reliable blood pressure monitoring 
and sampling. There is evidence that papaverine infusion helps to relax arterial blood 
vessels in pediatric patients. 
We do use this drug intraoperatively as a rescue with anecdotal evidence of relief of 
spasm. However, we do not know if administering papaverine bolus during surgery will 
help prevent or treat vasospasm. This study may help the study doctors learn things that 
may help other patients in the future. 
With current practice and care of catheters in ICU, arterial catheters remain patent 
during standard infusions of papaverine. Adopting this strategy, we hypothesize that 
small volume boluses of papaverine/heparin (1mL of 0.12 mg/mL papaverine, heparin 
2units/mL premixed syringe made by the pharmacy) during general anesthesia can 
maintain and prolong patency of these arterial catheters. This volume was chosen to 
mimic a one hour’s dose of papaverine that the patient would have received as a 
continuous infusion in the ICU setting. See methods for more dosing details. 
 
Study Method: 
Prospective study- Parental consent will be obtained. The surgical list will be evaluated to 
review all patients age 0-17 years who would require elective placements of arterial catheters 
based on patients clinical complexity (ex. congenital heart disease) or based on the type of 
surgery (ex. open heart surgery) 
 
Exclusion criteria: 
1. Patients with a history of significant liver dysfunction. 
2. Patients undergoing liver transplants. 
3. Patients with Grade 2 or more of intraventricular hemorrhage. 
4. All preterm patients with a gestational age less than 37 weeks at the time of surgery. 


IRB NUMBER: HSC-MS-19-0059 
IRB APPROVAL DATE: 08/05/2019 
 
Randomization- A predetermined randomization list will be followed to allocate the patient to the 
treatment group or control group. 
 
Double Blinding- The patients, patient’s family, principal investigator, and the anesthesiology 
care team will be blinded to the allocation list. 
 
Syringe Blinding- A member of the anesthesiology care team not involved in direct patient care 
will be given the randomizer list. 
This team member will be given 2 syringes. 
1. 
a) 
The 50mL premixed syringe of papaverine as dispensed from pharmacy ( NaCl 
0.9% inj 48.8 mL + papaverine 6mg+ heparin 100 units) 
2. 
b) 
10 mL of 2 units/mL of heparin from the pressurized fast flush bag from the 
operating room. 
 
Based on the list, one of the below will be aspirated in a Research syringe 
3. 
1) 
2 mL from the premixed-papaverine syringe will be aspirated in a sterile aseptic 
fashion in a 3 mL BD syringe and labelled as RESEARCH SYRINGE, with patient 
identifiers, date and time of constitution, expiry time and signature. 
4. 
2) 
2 mL of heparinized solution from the 2 units/mL heparin syringe will be aspirated 
in a 3 mL BD syringe and labelled as RESEARCH SYRINGE, with patient identifiers, 
date and time of constitution, expiry time and signature. 
 
 
Time of administration: (see Figure 1: Flowchart) 
The arterial catheters of all patients will be connected to the pressurized heparin flush system. 
All patients will receive 1 mL volume bolus from the “research syringe” as soon as the arterial 
catheter is placed and secured. Subsequent bolus from the “research syringe” will occur one 
hour after initial bolus. 
 
1) An intention to treat with 0.3 mg of papaverine (0.1mL from the papaverine vial) will be 
considered by the anesthesiology care team, if the arterial catheter spasm/patency or 
waveform does not improve 10 minutes after the second “research syringe” bolus (1 
hour after initial placement). 


IRB NUMBER: HSC-MS-19-0059 
IRB APPROVAL DATE: 08/05/2019 
 
@ t=0 mins: Administer 1 mL from “research syringe” 
@t=55 mins: Data Collection 
Peripheral arterial line is secured and transduced 
Data Collection @t=5 mins 
@t60mins: Administer 1 mL 
from “research syringe” 
Do not administer anything; continue 
to monitor 
@t=65 mins: Data Collection 
@t=75 mins:Data Collection 
@t70 mins: Administer “intention to treat” with 0.3 
mg (0.1mL) of papaverine 
Do not administer anything; continue 
to monitor 
Figure 1. Flowchart 
 
 
 
 
 
 
If Yes 
If No 
 
If Yes 
If No 
 
If Yes 
If No 
 
 
Data Collected: 
(Routine standard operating procedure data) 
1. Patient Demographics 
a. gestational age 
b. age at operation 
c. weight at birth 
d. weight at operation 
e. primary diagnosis 
f. 
other diagnosis (syndrome, ductal dependency) 
2. Operative Variable 
a. type of surgery 
b. duration of surgery 
3. Arterial Catheters 
a. time of placement 


IRB NUMBER: HSC-MS-19-0059 
IRB APPROVAL DATE: 08/05/2019 
 
b. site of catheterization 
c. number of attempts 
d. localization technique 
e. catheter placement technique 
f. 
Size and material type of the arterial catheter 
g. tubing length from the catheter to transducer 
h. Filtering set on arterial monitoring at a frequency higher than the natural 
frequency. For example, if patients heart rate is 70bpm, then a Filter frequency of 
(70*10)/60=11 Hz and above will be set. For a heart rate of 140bpm, a Filter of 
20Hz will be set. 
4.  Indicators of arterial waveform patency performed from baseline and then every 1 hour 
intraoperatively 
a. color changes at catheter site (presence or absence of local axon reflex with fluid 
flushes after placement) when the arterial line is accessible 
b. presence/ absence of a dicrotic notch ( a distinct dicrotic notch implies system 
has good resolution at higher frequencies and is not overdamped) 
c. ability to draw lab sample 
i. 
Negative aspiration is easy and draws back freely without cavitation using 
a 3 mL BD syringe 
ii. 
Negative aspiration is difficult (cavitation during negative aspiration, takes 
more than 30 seconds to draw 1 mL) using a 3 mL BD syringe 
d. Square wave test-A fast flush system will be used. Pressure bag will be set to 
300 mmHg and the resultant waveform will be recorded on paper 
e. Presence of Oscillations- Yes/no, how many above baseline (there should be at 
least one bounce. If the system does not oscillate, then there is too much 
damping). There should be no more than two oscillations. 
i. 
Amplitude of D1 
ii. 
Amplitude of D12 (The amplitude of each oscillation is no greater than ⅓ 
of previous oscillation) 
iii. 
Arterial Blood pressure reading compared with NIBP measurement at 
times of measurement. 
iv. 
Postoperatively, we will measure the duration of catheter patency (# 
hours/days) and the reason for discontinuation up to two days after the 
procedure. 
5. Measurement of hemodynamics (HR, BP, ETCO2) before Papaverine/Heparin or 
Heparin bolus and at 1 min, 5min and 10 mins after bolus. 
 
Primary Outcome: 
1. Indicators of intraoperative arterial waveform patency as mentioned above in Data 
Collection section 4a to 4d 
 
Data Handling and Record Keeping 
All information will be kept strictly confidential and all data collection sheets will be kept in a 
binder which will be locked in the office of the principal investigator. A linking log will be 


IRB NUMBER: HSC-MS-19-0059 
IRB APPROVAL DATE: 08/05/2019 
 
maintained to keep patient information separate from the data collection sheet. All data will be 
manually entered into a secure electronic database that will encrypted and password protected. 
(https://www.uth.edu/uthshare/) 
 
Quality Control and Assurance 
There are no plans to have ongoing third party monitoring. Data will be reviewed and audited 
internally to ensure that data is consistent, accurate and complete. 
 
Sample Size: 
Since this is a pilot study, we will collect data on 50 patients in each group. Based on the 
Cohen’s d for an anticipated effect size of 0.5 (we will use anyone of the indicators of patency 
as mentioned above), desired power level of 0.8 and a probability level of 0.05, we will re-submit 
for a full trial. 
The list of potential patients will be obtained daily from the operating room log. Care4 records 
and OR Tracking will be used to screen for patients. The research team will make contact with 
the family member while obtaining the surgical and or the anesthesia consent. 
 
Study Risks: 
Papaverine acts on all smooth muscle cells and relieves vascular spasm. It is metabolized by 
the liver. There are no perceivable risks from exposure to papaverine bolus as it is standard of 
care to subject all patients in ICU to continuous infusion of papaverine after OR to maintain 
patency of arterial catheter and has been well studied in neonates and pediatric patients 
{Griffin:2005bo, Boris:1998wp, Heulitt:1993un}. Side effects of papaverine can include nausea, 
headache, flushing, bleeding, or allergic reaction. These side effects are rare. 
 
Data and Safety Monitoring: 
This study will not have a formal data and safety monitoring board. All subjects will be monitored 
by the Investigators for any adverse events, though none are anticipated. All unanticipated 
problems (adverse events, protocol deviations) will be reported to the IRB as required in a 
timely fashion. 
 
Ethics: 
We are seeking IRB approval for this study from CPHS. 
 
Discussion of risks and possible benefits of participating in this study will be provided to the 
subjects and their families. Consent forms describing in detail the study procedures, and risks 
are given to the subject and written documentation of informed consent is required prior to 
starting the study. 
Consent forms will be IRB-approved and the subject will be asked to read and review the 
document. Upon reviewing the document, the investigator will explain the research study to the 
subject and answer any questions that may arise. The subject will sign the informed consent 
document prior to any procedures being done specifically for the study. The subjects should 
have the opportunity to discuss the study or think about it prior to agreeing to participate. The 
subjects may withdraw consent at any time throughout the course of the study. A copy of the 
informed consent document will be given to the subjects for their records. The rights and 
welfare of the subjects will be protected by emphasizing that the quality of their medical care will 


IRB NUMBER: HSC-MS-19-0059 
IRB APPROVAL DATE: 08/05/2019 
 
not be adversely affected if they decline to participate in this study. 
 
Publication Plan: 
We plan to publish the results of the study in a peer reviewed scientific journal. Study results will 
not be returned to the research subjects. However, information regarding the study will be 
available on www.clinicaltrials.gov. 
 
 
References: 
 
 
1 
 Heulitt MJ, Farrington EA, O'Shea TM, Stoltzman SM, Srubar NB, Levin DL. Double- 
blind, randomized, controlled trial of papaverine-containing infusions to prevent failure of 
arterial catheters in pediatric patients. Crit Care Med. 1993 Jun;21(6):825–9. 
 
2 
 Griffin MP, Siadaty MS. Papaverine prolongs patency of peripheral arterial catheters in 
neonates. J Pediatr. 2005 Jan;146(1):62–5. 
 
3 
 Boris JR, Harned RK, Logan LA, Wiggins JW. The use of papaverine in arterial sheaths 
to prevent loss of femoral artery pulse in pediatric cardiac catheterization. Pediatr Cardiol. 
1998 Sep;19(5):390–7.