Clinical trial NCT05575219
Conditions: Withdrawal; Therapeutic Substance
Sponsor: The University of Texas Health Science Center, Houston
Start date: 2022-10-08; Completion date: 2024-02-15
Enrollment: 128 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine if the protocolized use of clonidine will reduce dexmedetomidine withdrawal symptoms, reduce PICU length of stay, and reduce costs related to sedation during hospital admission.

Detailed description:

Arms: arm 1: Participants will be observed for dexmedetomidine withdrawal and clonidine will be started at clinician discretion. arm 2: A protocol for clonidine initiation will be implemented based on the time on dexmedetomidine and the average hourly dose of dexmedetomidine.
Interventions: intervention 1: Clonidine (without protocolized initiation) intervention 2: Clonidine (protocolized initiation)
Intervention descriptions: intervention 1: Participants will be observed for dexmedetomidine withdrawal and clonidine will be started at clinician discretion. intervention 2: * Observe participants without initiating clonidine with dexmedetomidine infusion time of 72-119 hours. To wean off dexmedetomidine, decrease the infusion by 25% of the starting dose every 6 hours.
* Begin clonidine at 1 mcg/kg enterally every 6 hours for participants with dexmedetomidine infusion time of 120-144 hours.
* Begin clonidine at 1.5 mcg/kg enterally every 6 hours for participants with dexmedetomidine infusion times of 145-167 hours.
* Begin clonidine at 2 mcg/kg enterally every 6 hours for participants with dexmedetomidine infusion time of \>/= 168 hours or with infusion time of 120-167 hours at doses \>/= 1.1 mcg/kg/min.
* If clonidine is started decrease the dexmedetomidine infusion by 25% of the starting dose 1 hour after each dose of clonidine until off (wean every 6 hours).

Protocol documents:
Prot_SAP_000.pdf: 
IRB NUMBER: HSC-MS-22-0410 
IRB APPROVAL DATE: 11/15/2024 
Page 1 of 12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocolized initiation of clonidine to prevent dexmedetomidine withdrawal: A 
prospective cohort study 
 
NCT05575219 
 
Version Date: 11/15/2024 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


IRB NUMBER: HSC-MS-22-0410 
IRB APPROVAL DATE: 11/15/2024 
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Protocol Template Version Jan 2018 
Adapted from NIH protocol template and ICH Guidelines 
 
 
Protocol Title: 
Protocolized initiation of clonidine to prevent dexmedetomidine withdrawal: 
A prospective cohort study 
Principal Investigator: 
Andrea Heifner, MD 
 
Co-Investigators: 
Thao Nguyen, DO; David McMann, MD; Monica Lee, PharmD; Weng Man 
Lam, PharmD; Alvaro Coronado Munoz, MD 
Study Coordinator: 
n/a 
 
Population: 
Patients aged 4 weeks-18 years admitted to the Children’s Memorial 
Hermann Hospital- Texas Medical Center Pediatric Intensive Care Unit and 
Heart Center Intensive Care Units requiring dexmedetomidine infusion for 
greater than 72 hours. 
Number of Sites: 
Single site 
 
Study Duration: 
12 months 
 
Subject Duration: 
PICU or HCICU admission to hospital discharge 
 
 
General Information 
- 
Our study will evaluate the implementation of a clonidine initiation protocol to mitigate 
dexmedetomidine withdrawal. 
 
Background Information 
− The use of dexmedetomidine for PICU sedation has become common place since its introduction to 
clinical practice in the mid-2000s. Dexmedetomidine is a centrally acting alpha agonist that is about 
8 times more potent than clonidine (8). Its use is favored in PICUs due to achievement of adequate 
sedation without depressing the respiratory drive, this fact allows dexmedetomidine to be used in 
both intubated and non-intubated patients. As use of dexmedetomidine became more widespread, 
it has been noted to cause withdrawal symptoms including agitation, tachycardia, hypertension, and 
insomnia (11, 15). A survey to PICU providers in the United States completed in 2019 found that 88% 
of responders had concerns about dexmedetomidine withdrawal and 81% managed this concern 
with a regimented wean and initiation of clonidine (14). The majority of published studies on 
dexmedetomidine withdrawal note symptoms after 72 hours or more of continuous infusion. The 
results of these studies are mixed; however, clonidine initiation is consistently not statistically 
different from a slow dexmedetomidine wean over days and is associated with lower drug costs (2, 
3, 7, 8, 9, 10, 12). At our institution it is usual to start clonidine to transition off dexmedetomidine 
but, at this time we do not have a protocolized way to do this it is rather done at the discretion of 
the attending physician with assistance from the clinical pharmacy specialists. When the decision to 
start clonidine is made, generally after about five days on dexmedetomidine therapy, it is most 
often started at 1 mcg/kg/dose every 6 to 8 hours regardless of the time on or cumulative dose of 


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IRB APPROVAL DATE: 11/15/2024 
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dexmedetomidine given. Dexmedetomidine weaning practices are highly variable at this time and 
are most often not done at regular intervals related to clonidine dosing and it is not unusual for 
dexmedetomidine weaning to last for two to three days. We currently use dexmedetomidine in all 
ages admitted to our PICU. Our hypothesis is that with use of a standardized protocol for 
dexmedetomidine weaning and clonidine initiation we can reduce the burden of dexmedetomidine 
withdrawal in our PICU. 
 
Objectives 
− Our primary objective is to reduce dexmedetomidine withdrawal symptoms with the protocolized 
use of clonidine. Our secondary objectives include reduction in total number of hours on 
dexmedetomidine infusion, reduction in PICU length of stay, reduction in costs related to dexmede 
during hospital admission. 
− Our study aims to prospectively assess the use of clonidine to mitigate dexmedetomidine 
withdrawal using a clonidine initiation protocol. For the purposes of the study, withdrawal is defined 
as at least one of the following: increase in heart rate, systolic blood pressure or diastolic blood 
pressure by at least 10% from the 24 hours prior to dexmedetomidine weaning to the 24 hours after 
dexmedetomidine is discontinued AND at least one of the following: two documented Withdrawal 
Assessment Tool (WAT-1) scores of ≥ 3 or two study questionnaire scores of ≥ 3 from the time of 
first dexmedetomidine wean to the time dexmedetomidine is off for 72 hours. 
 
Study Design 
− Our study will be a prospective pre and post interventional cohort design with data collection 
beginning prior to implementation of the study protocol to assess our current practices and rates of 
dexmedetomidine withdrawal. We plan to collect pre intervention data for 6 months. We will then 
implement the study protocol in our PICU only and continue to collect data for an additional 6 
months to compare outcomes. We plan to introduce/ implement and troubleshoot the protocol 
over a 2 week period after completion of the preintervention phase. Throughout the entire 12 
month study period we will collect the same data in our Heart Center Intensive Care Unit without 
implementing the study protocol as a control. 
− Patients will be recruited from both the Children’s Memorial Hermann Pediatric ICU and the 
Children’s Memorial Hermann Heart Center ICU for the entire 12 month duration of the study 
period. 
− We expect to collect data preintervention for 6 months followed by an additional 6 months of data 
collection with implementing the intervention with goal to enroll 150 patients in both the pre and 
post intervention data sets. 
− Continuation of the implemented protocol beyond the 6 month data collection period will be at the 
discretion of the PICU medical director. 
− Data will be collected from chart review and from discussion with both the bedside nursing team 
and physician team during dexmedetomidine weaning/ clonidine initiation. 
− Primary outcome: Dexmedetomidine withdrawal. Withdrawal is defined as at least one of the 
following: increase in heart rate, systolic blood pressure or diastolic blood pressure by at least 10% 
from the 24 hours prior to dexmedetomidine weaning to the 24 hours after dexmedetomidine is 
discontinued AND at least one of the following: two documented WAT-1 scores of ≥ 3 or two study 


IRB NUMBER: HSC-MS-22-0410 
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questionnaire scores of ≥ 3. WAT and questionnaire scores will be collected every 12 hours starting 
with the first dexmedetomidine wean until 72 hours after dexmedetomidine is discontinued. 
− Secondary outcomes: We also aim to reduce the total number of dexmedetomidine infusion hours, 
PICU length of stay and dexmedetomidine/clonidine costs during hospitalization. We will compare 
the average of these data points from the pre and post intervention data sets to assess for 
reduction. 
− 
Efficacy and safety of both dexmedetomidine and clonidine are well established. 
 
Study Population 
− Patients aged 4 weeks to 18 years admitted to our PICU or HCICU and placed on dexmedetomidine 
for sedation. 
− 
Inclusion criteria: 
o Age 4 weeks to 18 years 
o Dexmedetomidine infusion for >/= 72 hours 
− 
Exclusion criteria: 
o Admission for head trauma 
o Psychiatric history 
o Use of alpha-2 agonist medications at home 
o Death while on dexmedetomidine 
− We will use a cut off of 72 hours or more of continuous dexmedetomidine infusion as the majority 
of published studies on dexmedetomidine withdrawal noted symptoms after this amount of time or 
started weaning with or without clonidine administration at this time. We exclude patients with 
head trauma or psychiatric history as one of the main symptoms of dexmedetomidine is agitation it 
may be difficult to differentiate this being due to withdrawal versus related to disease process. We 
also exclude patients who are prescribed alpha-2 agonists as home medications as they will be 
placed back onto these mediations regardless of time of dexmedetomidine therapy. 
− We will assess all patients during the study period admitted to our PICU/HCICU for 
dexmedetomidine use and duration of use prior to enrollment into our cohort. 
 
Study Procedures 
− We will obtain information from chart review during and after patient discharges. Specifically, MRN, 
age, gender, primary admission diagnosis, number of hours on dexmedetomidine infusion, total 
cumulative dose of dexmedetomidine, average hourly dose of dexmedetomidine, SBS scores 
minimum every 12 hours starting 24 hours prior to dexmedetomidine wean and ending when 
dexmedetomidine is off for 24 hours, WAT-1 and CAPD scores at least every 12 hours starting with 
first dexmedetomidine wean until dexmedetomidine is off for 72 hours, descriptions of agitation or 
insomnia in daily physician progress notes, agitation/insomnia questionnaires, need for rescue doses 
of clonidine or resumption of dexmedetomidine, highest documented heart rate and blood pressure 
24 hours prior to dexmedetomidine wean and 24 hours after dexmedetomidine discontinuation, 
dexmedetomidine weaning schedule, length of ICU and hospital stay, other sedation medications 
used with timing and enteral sedation wean, cost associated with dexmedetomidine and clonidine. 
In the pre-intervention phase, we will also collect data related to clonidine initiation, ie after how 
many hours on dexmedetomidine, at what dose and frequency, and clonidine tapering schedule. 


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− The agitation/insomnia questionnaires will be given to the bedside nurse by a member of the study 
group once every 24 hours starting the day dexmedetomidine is first weaned until 
dexmedetomidine has been off for 72 hours. It will be collected for research purposes only and will 
not become part of the medical record. The purpose of this questionnaire is to assess insomnia and 
agitation in a standardized manner as it is common for these symptoms to not be documented in 
the nursing or physician notes. 
− 
During the intervention phase we will use a tiered approach to treat dexmedetomidine withdrawal. 
o We will observe patients without initiating clonidine with dexmedetomidine infusion time of 
72-119 hours. To wean off dexmedetomidine we will decrease the infusion by 25% of the 
starting dose every 6 hours. 
o We will begin clonidine at 1 mcg/kg enterally every 6 hours for patients with 
dexmedetomidine infusion time of 120-144 hours. We will decrease the dexmedetomidine 
infusion by 25% of the starting dose 1 hour after each dose of clonidine until off (wean every 
6 hours). 
o We will begin clonidine at 1.5 mcg/kg enterally every 6 hours for patients with 
dexmedetomidine infusion time of 145-167 hours. We will decrease the dexmedetomidine 
infusion by 25% of the starting dose 1 hour after each dose of clonidine until off (wean every 
6 hours). 
o We will begin clonidine at 2 mcg/kg enterally every 6 hours for patients with 
dexmedetomidine infusion time of >/= 168 hours or with infusion time of 120-167 hours at 
doses >/= 1.1 mcg/kg/min. We will decrease the dexmedetomidine infusion by 25% of the 
starting dose 1 hour after each dose of clonidine until off (wean every 6 hours). 
− To implement this clonidine dosing and dexmedetomidine weaning schedule we will create a Care4 
MPP versus using a paper order set given to the primary resident and fellow taking care of the 
enrolled patients. Administration of clonidine and weaning of dexmedetomidine will be carried out 
by bedside nursing staff per physician orders. 
− As patients are being weaned from dexmedetomidine we will monitor WAT-1 scores at least every 
12 hours to assess for withdrawal. A WAT-1 score of >/= 3 will indicate presence of withdrawal 
symptoms. With scores between 3 and 5 we will continue to monitor without change in clonidine 
dosing. If scores are >/= 6 we will step up the dose by 0.5 mcg/kg/dose up to a maximum dose of 3 
mcg/kg/dose. 
− Once dexmedetomidine is off and patient is stable (ie no withdrawal symptoms) for 48 hours we will 
begin weaning clonidine by 20% every day until the medication is off. If patients are on other 
enteral sedation (ie methadone and/or lorazepam) their weaning schedule will include 20% 
reductions in those medications on alternating days. For example, a patient on clonidine, 
methadone, and lorazepam will have clonidine weaned on day 1, then methadone on day 2, then 
lorazepam on day 3, and so on. This is our standard weaning practice at this time and will not 
change with protocol initiation. 
− Clonidine tablets are compounded to an oral suspension in the Children’s Memorial Hermann 
Inpatient Pediatric Pharmacy for patients who are unable to swallow tablets due to age, 
development or condition. The pharmacy compounds a 20 microgram/milliliter oral suspension for 
inpatient use. Only one concentration of clonidine oral suspension is utilized at this institution to 
prevent possible errors from having multiple concentrations available. The recipe is as follows: 


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o Ten 0.1 mg clonidine tablets are crushed in a glass mortar and pestle with 1-2 milliliters 
of simple syrup to serve as a levigating agent. Once all tablet particles are crushed 
homogenously, the contents are transferred into a calibrated amber bottle and more 
simple syrup is added to achieve a total quantity of 50 milliliters. The final compounded 
clonidine concentration is 0.02 milligrams/milliliter or 20 micrograms/milliliter. Once the 
oral suspension is compounded, it is kept in the pharmacy, refrigerated at 4° C and given 
a stability of 28 days from date of compounding. The Children’s Memorial Hermann 
Inpatient Pediatric Pharmacy, located on the 10th floor of Hermann Pavilion, is 
responsible for compounding, storing, maintaining, and dispensing the clonidine oral 
suspension. Prior to being dispensed, the oral solution is shaken to disperse the 
clonidine oral suspension and each patient-specific dose is drawn into an oral syringe to 
be checked by a pharmacist. One checked for accuracy, the clonidine syringe is delivered 
to the floor and kept in the unit refrigerator in a patient-specific medication bin until 
ready to for administration. 
 
Data and Safety Monitoring 
− Potential adverse effects of our treatment protocol include withdrawal from dexmedetomidine 
despite initiation of clonidine and hypotension, bradycardia, or over sedation associated with the 
clonidine taper. We will identify withdrawal as defined above and side effects of clonidine by 
continuous cardiac monitoring and nursing assessments. 
o If a patient experiences decrease in blood pressure or heart rate with clonidine dosing, we 
will give a fluid bolus or atropine based on age standard norms. In general, the minimum 
tolerated blood pressure before treatment will be the 5th percentile for age and minimum 
tolerated heart rate before treatment will be < 50 with or without associated hypotension. 
 
In addition to acute treatment of vital sign instability we will decrease the clonidine 
dose by 0.5 mcg/kg/dose to start with the next dose. 
o If a patient experiences oversedation, defined as excessive sleepiness and monitored with 
neurologic checks by bedside nursing, we will decrease the clonidine dose by 0.5 
mcg/kg/dose starting with the next dose. 
o All patients admitted to the PICU or HCICU are placed on continuous cardiac monitoring 
with telemetry to measure heart rate, blood pressure, respiratory rate and pulse oximetry. 
Vitals are recorded into the EMR based on cardiac monitoring approximately every 1 hour 
during ICU admission. 
− We will report any hemodynamic instability requiring intervention or over sedation requiring 
increased respiratory support to the IRB. 
− We will assess for adverse events daily while patients are on clonidine therapy. Adverse events will 
be documented with our results. 
− We will intermittently monitor for protocol deviations and follow up with the primary physician 
team for reasoning. 
− 
We as a research team will monitor data continuously for completion and correctness. 
 
Statistics 
− We will use a variety of statistical methods due to the number of discrete and non-discrete variables 
we plan to obtain in our data collection including student t-test for parametric continuous variables, 


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IRB APPROVAL DATE: 11/15/2024 
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Mann Whitney U-test for non-parametric continuous variables, fisher exact test; chi-squared test, 
and multi-variable logistic regression. 
− We plan to enroll 300 patients (150 in both the pre and post intervention cohorts) based on 35% 
incidence of dexmedetomidine withdrawal noted in a retrospective cohort study completed by 
Nguyen et al at our center completed in 2019. (12) From this incidence, we used a conservative 
estimate of a 50% reduction in rate of withdrawal in our calculations to obtain a power of 80%. 
− 
Level of significance will be set to a p value of <0.05. 
− 
All eligible subjects will be included in our analysis. 
 
Ethics 
− We will not obtain written consent from individual patient’s families as we are not deviating from 
standard of care and there is minimal harm associated with empiric use of clonidine for 
dexmedetomidine withdrawal. A member of the study team will provide families (and patients >/= 
7) with information regarding the study and obtain their verbal consent/assent for data collection 
and study participation. 
− 
To protect patient privacy all data will be deidentified prior to data analysis. 
 
Data handling and record keeping 
− Any protected health information (PHI) identifiers, medical record number, extracted or obtained 
from medical chart records or received from medical providers will be kept strictly confidential and 
will not be shared with anyone not directly associated with the study. Any data collected in log 
format will be kept under lock and key, and access will only be permitted by the primary 
investigators and the research staff. Data transferred to an electronic database will be maintained 
on a computer that is encrypted and password protected with access only by the research staff. 
 
− 
Records will be kept until the end of the study and then any PHI that has not been de-identified will 
be destroyed. Any codes or links relating back to individually identifiable PHI will also be destroyed. 
Electronic records will be deleted, and paper records or logs will be shredded. 
 
Publication Plan 
− 
We plan for publication in a peer reviewed journal at the conclusion of our study. 
− 
Results will not be returned to research subjects. 


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WAT-1 scoring 
 


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SBS Scoring 
 


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CAPD Scoring 
 


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Clonidine Compounding Recipe 
 
 
 
 
 
Clonidine will be compounded into a liquid formulation, maintained, stored, and dispensed by the 
Children’s Memorial Hermann inpatient pharmacy located on the 10th floor of the Hermann pavilion. 


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