Trial of Vasopressin and Epinephrine to Epinephrine Only for In-Hospital Pediatric Cardiopulmonary Resuscitation
| Status: | Completed |
|---|---|
| Conditions: | Cardiology |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | Any - 18 |
| Updated: | 4/2/2016 |
| Start Date: | April 2008 |
| End Date: | December 2011 |
| Contact: | Tia Tortoriello Raymond, M.D. |
| Email: | Tiaraymond@me.com |
| Phone: | 9725337175 |
A Prospective, Randomized, Controlled Trial of Combination Vasopressin and Epinephrine to Epinephrine Only for In-Intensive Care Unit Pediatric Cardiopulmonary Resuscitation
Cardiac arrest has a very poor prognosis, especially with prolonged efforts at
resuscitation, and unfortunately, survivors are often severely neurologically impaired. CPA
in children is often the result of a prolonged illness rather than a sudden, primary cardiac
event as is frequent in adults. This necessitates that resuscitation research must be
conducted separately for pediatric and adult patients. Authorities currently endorse the use
of epinephrine for restoring spontaneous circulation based on its ability to maintain
diastolic blood pressure and subsequent blood flow to the heart during resuscitation.
However, human studies have shown no clear survival benefit of epinephrine and have
elucidated concerning adverse effects. Recently, both the European Resuscitation Council and
the American Heart Association have recognized the use of vasopressin as a promising
vasoconstrictor and an alternative or adjunct to epinephrine in the resuscitation of adults.
Vasopressin causes profound vasoconstriction without the adverse effects of epinephrine and
is associated with improved blood flow to the heart and brain. This increased cerebral blood
flow has been associated with better neurologic outcome in animal studies. In light of
compelling animal and human studies of combined vasopressin and epinephrine, pediatric
trials are indicated for vasopressin usage in pediatric CPR. This study will evaluate the
addition of the administration of vasopressin to standard advanced CPR therapy (epinephrine
alone) for pediatric patients that experience in-intensive care unit CPA to assess for
improved time to return of spontaneous circulation (ROSC), survival to 24 hours, survival to
hospital discharge, and neurologic outcome. When a patient experiences a CPA, standard
Pediatric Advanced Life Saving (PALS) protocols as endorsed by the American Heart
Association will be initiated. This will include receiving epinephrine as the first
vasopressor medication. Patients will then be randomized to receive vasopressin (treatment
group) or epinephrine (control group) as the second vasopressor medication, if needed. If
more then two doses of vasopressor medication is required in either group, epinephrine will
be administered according to the PALS algorithm until the end of the event. All CPA events
meeting inclusion criteria will be entered into the National Registry of Cardiopulmonary
Resuscitation (NRCPR) Database, which tracts all CPA events at Children's Medical Center
Dallas. Prior to commencement of the RCT, a pilot trial of 10 patients will be completed to
assess preliminary safety, feasibility, and effectiveness of combination
epinephrine-vasopressin for pediatric in-intensive care unit CPA refractory to initial
epinephrine dosing. All pilot patients will receive vasopressin as the second vasopressor
medication.
resuscitation, and unfortunately, survivors are often severely neurologically impaired. CPA
in children is often the result of a prolonged illness rather than a sudden, primary cardiac
event as is frequent in adults. This necessitates that resuscitation research must be
conducted separately for pediatric and adult patients. Authorities currently endorse the use
of epinephrine for restoring spontaneous circulation based on its ability to maintain
diastolic blood pressure and subsequent blood flow to the heart during resuscitation.
However, human studies have shown no clear survival benefit of epinephrine and have
elucidated concerning adverse effects. Recently, both the European Resuscitation Council and
the American Heart Association have recognized the use of vasopressin as a promising
vasoconstrictor and an alternative or adjunct to epinephrine in the resuscitation of adults.
Vasopressin causes profound vasoconstriction without the adverse effects of epinephrine and
is associated with improved blood flow to the heart and brain. This increased cerebral blood
flow has been associated with better neurologic outcome in animal studies. In light of
compelling animal and human studies of combined vasopressin and epinephrine, pediatric
trials are indicated for vasopressin usage in pediatric CPR. This study will evaluate the
addition of the administration of vasopressin to standard advanced CPR therapy (epinephrine
alone) for pediatric patients that experience in-intensive care unit CPA to assess for
improved time to return of spontaneous circulation (ROSC), survival to 24 hours, survival to
hospital discharge, and neurologic outcome. When a patient experiences a CPA, standard
Pediatric Advanced Life Saving (PALS) protocols as endorsed by the American Heart
Association will be initiated. This will include receiving epinephrine as the first
vasopressor medication. Patients will then be randomized to receive vasopressin (treatment
group) or epinephrine (control group) as the second vasopressor medication, if needed. If
more then two doses of vasopressor medication is required in either group, epinephrine will
be administered according to the PALS algorithm until the end of the event. All CPA events
meeting inclusion criteria will be entered into the National Registry of Cardiopulmonary
Resuscitation (NRCPR) Database, which tracts all CPA events at Children's Medical Center
Dallas. Prior to commencement of the RCT, a pilot trial of 10 patients will be completed to
assess preliminary safety, feasibility, and effectiveness of combination
epinephrine-vasopressin for pediatric in-intensive care unit CPA refractory to initial
epinephrine dosing. All pilot patients will receive vasopressin as the second vasopressor
medication.
CONCISE SUMMARY OF PROJECT:
The study design will be a prospective, randomized, controlled clinical trial to be
conducted in the PICU of CMC Dallas (UT Southwestern Medical Center) following a pilot trial
enrolling 10 patients. This study will be undertaken after consultation with and acceptance
by the resuscitation committee and PICU at CMC. Pediatric patients that experience
in-hospital CPA who remain in cardiac arrest despite CPR and an initial, standard dose of
epinephrine (0.01 mg/kg), will be randomly assigned to receive either standard dose
epinephrine (0.01 mg/kg) or vasopressin (0.8 units/kg) rescue as the second vasopressor
medication.
SUMMARY OF STUDY PROCEDURES:
When a patient experiences a CPA, standard Pediatric Advanced Life Saving (PALS) protocols
will be followed. This will include: establishment of an airway, support of breathing
including supplemental oxygen, evaluation of cardiac rhythm, chest compressions, electrical
defibrillation if appropriate, and administration of epinephrine as the first vasopressor
medication. The quality of CPR will be monitored and reported by the documenting nurse for
the event, to include rate of ventilation, rate and depth of chest compressions, and no-flow
time (time without chest compressions). In addition, monitoring of end-tidal CO2, diastolic
blood pressure via arterial line if present, and human observation and coaching will be
employed to track CPR quality. The patient will then be randomized to receive either
epinephrine (control group) or vasopressin (treatment group) as the second vasopressor
medication if needed. If further doses of medication are required in either group,
epinephrine will be administered according to the PALS algorithm until the end of the CPA
event as defined below. Thus, the only difference between the groups will be the replacement
of epinephrine with vasopressin as the second vasopressor medication in the algorithm. A
total of 120 patients will be enrolled in the randomized, controlled trial portion of the
study.
After completion of PICU staff training and prior to the randomized, controlled trial, a
pilot trial of vasopressin resuscitation involving 10 patients will be conducted to test the
feasibility and safety of study methodology. Pilot participants who meet inclusion criteria
will be enrolled serially from the PICU at CMC. Study protocol for the treatment group of
the randomized, control trial (vasopressin + epinephrine) will be followed. Collected
information will be reviewed by members of a Data Safety and Monitoring Board (DSMB) before
proceeding to the next phase of the trial. These patients will not be included in the final
analysis.
The requirement of two doses of resuscitation medications will provide adequate time for
randomization and use of vasopressin. It will also exclude those children with rapidly
reversible conditions who would not have time to benefit from vasopressin versus epinephrine
intervention. Stratified randomization technique will be used to control for the effect of
vasopressor infusions the patient is receiving at the time of cardiac arrest. Stratification
will be based on 4 groups i.e., epinephrine, vasopressin, both, or neither. In order to
avoid extreme imbalance in the size of the treatment arms, a permuted block design will be
used and the size of each block will be set at 6. SPSS pseudo-random number generator will
be used to design the randomization charts. Randomization will be accomplished by the PICU
pharmacist via sealed envelopes designating study arm assignment that will be available on
every code cart in the PICU. Thus, the study medication will be blinded to all but the
pharmacist.
On admission to the PICU, families of all patients will be informed and educated of this
ongoing study with exception from informed consent (EFIC) via posters in the waiting rooms
and a brochure regarding the study clearly explaining how to "opt out" of inclusion. The
number of patients who "opt out" of inclusion will be documented and available to the IRB at
their request. Representatives of the study will be available by phone 24 hours a day and in
person in the waiting room daily to discuss the study and answer questions. Parents will be
informed of inclusion within 24 hours in person or by phone or letter if unavailable. This
notification will be documented and consent will be elicited for follow up data collection.
CPA events will be limited to those occurring in the PICU only. Providers that respond to
CPA events will be in-serviced regarding the study protocol prior to implementation via
didactic sessions. Input from pharmacists and providers in the PICU will be sought to assure
the easiest implementation possible. Vasopressin is currently available for administration
on all resuscitation (code) carts at CMC. Inclusion and exclusion criteria will be posted on
all code carts to assist providers. Current protocol at CMC to enter all CPA events into the
National Registry of Cardiopulmonary Resuscitation (NRCPR) will be followed. This data is a
complete account of the events of the CPA and will be sufficient to meet all of the study's
stated goals and objectives. Only data pertinent to the outcomes of this study will be
reviewed from the database. This data will also be reviewed to assure standardization of
execution of the study protocol.
Time to Completion Given that 89 CPA events met inclusion criteria from January 2005 to June
2006 in the PICU at CMC, approximately 30 months will be required to enroll 130 total
patients into this study (10 patients in pilot trial, 120 patients in main study). Subjects
will be enrolled in the study until discharge or in-hospital death.
Definition CPA End of Event
1. . ROSC that is sustained for > 20mins with no further need for chest compressions,
including with a pacemaker or extracorporeal membrane oxygenation OR
2. . Resuscitation event is terminated and patient is declared dead (unresponsive to
advanced life support, medical futility, advance directive, restriction by family
member)
SPECIAL PRECAUTIONS:
A full resuscitation team will be present whenever vasopressin is administered including a
physician, nurse, respiratory technician, clinical technician, and pharmacist. A sign will
be clearly posted on the bed of any patient whose proxy has "opted" the patient out of the
study or who meets any other exclusion criteria. The DSMB will evaluate the study for clear
benefit or harm, lack of efficacy, or unacceptable toxicity of vasopressin.
SOURCES OF RESEARCH MATERIALS/ COLLECTION OF FOLLOW UP DATA:
Data from CPA events will be collected from the NRCPR database which is completed at the
conclusion of every CPA event currently at CMC. Data is collected in six major categories of
variables: (1) Facility data, (2) Patient demographic data, (3) Pre-event data, (4) Event
data, (5) Outcome data, and (6) Quality improvement data. All patient identifiers will be
destroyed at the earliest possible opportunity. Data will be de-identified for analysis.
This data will include laboratory and treatment data from the hospitalization in the PICU at
CMC before, during, and after resuscitation. Specifically, this data will include: age,
gender, vital signs, treatments, laboratory results, neurologic exam (PCPC and POPC scores)
and physical exam. The data collection is based on in-hospital Utstein-style guidelines.
The study design will be a prospective, randomized, controlled clinical trial to be
conducted in the PICU of CMC Dallas (UT Southwestern Medical Center) following a pilot trial
enrolling 10 patients. This study will be undertaken after consultation with and acceptance
by the resuscitation committee and PICU at CMC. Pediatric patients that experience
in-hospital CPA who remain in cardiac arrest despite CPR and an initial, standard dose of
epinephrine (0.01 mg/kg), will be randomly assigned to receive either standard dose
epinephrine (0.01 mg/kg) or vasopressin (0.8 units/kg) rescue as the second vasopressor
medication.
SUMMARY OF STUDY PROCEDURES:
When a patient experiences a CPA, standard Pediatric Advanced Life Saving (PALS) protocols
will be followed. This will include: establishment of an airway, support of breathing
including supplemental oxygen, evaluation of cardiac rhythm, chest compressions, electrical
defibrillation if appropriate, and administration of epinephrine as the first vasopressor
medication. The quality of CPR will be monitored and reported by the documenting nurse for
the event, to include rate of ventilation, rate and depth of chest compressions, and no-flow
time (time without chest compressions). In addition, monitoring of end-tidal CO2, diastolic
blood pressure via arterial line if present, and human observation and coaching will be
employed to track CPR quality. The patient will then be randomized to receive either
epinephrine (control group) or vasopressin (treatment group) as the second vasopressor
medication if needed. If further doses of medication are required in either group,
epinephrine will be administered according to the PALS algorithm until the end of the CPA
event as defined below. Thus, the only difference between the groups will be the replacement
of epinephrine with vasopressin as the second vasopressor medication in the algorithm. A
total of 120 patients will be enrolled in the randomized, controlled trial portion of the
study.
After completion of PICU staff training and prior to the randomized, controlled trial, a
pilot trial of vasopressin resuscitation involving 10 patients will be conducted to test the
feasibility and safety of study methodology. Pilot participants who meet inclusion criteria
will be enrolled serially from the PICU at CMC. Study protocol for the treatment group of
the randomized, control trial (vasopressin + epinephrine) will be followed. Collected
information will be reviewed by members of a Data Safety and Monitoring Board (DSMB) before
proceeding to the next phase of the trial. These patients will not be included in the final
analysis.
The requirement of two doses of resuscitation medications will provide adequate time for
randomization and use of vasopressin. It will also exclude those children with rapidly
reversible conditions who would not have time to benefit from vasopressin versus epinephrine
intervention. Stratified randomization technique will be used to control for the effect of
vasopressor infusions the patient is receiving at the time of cardiac arrest. Stratification
will be based on 4 groups i.e., epinephrine, vasopressin, both, or neither. In order to
avoid extreme imbalance in the size of the treatment arms, a permuted block design will be
used and the size of each block will be set at 6. SPSS pseudo-random number generator will
be used to design the randomization charts. Randomization will be accomplished by the PICU
pharmacist via sealed envelopes designating study arm assignment that will be available on
every code cart in the PICU. Thus, the study medication will be blinded to all but the
pharmacist.
On admission to the PICU, families of all patients will be informed and educated of this
ongoing study with exception from informed consent (EFIC) via posters in the waiting rooms
and a brochure regarding the study clearly explaining how to "opt out" of inclusion. The
number of patients who "opt out" of inclusion will be documented and available to the IRB at
their request. Representatives of the study will be available by phone 24 hours a day and in
person in the waiting room daily to discuss the study and answer questions. Parents will be
informed of inclusion within 24 hours in person or by phone or letter if unavailable. This
notification will be documented and consent will be elicited for follow up data collection.
CPA events will be limited to those occurring in the PICU only. Providers that respond to
CPA events will be in-serviced regarding the study protocol prior to implementation via
didactic sessions. Input from pharmacists and providers in the PICU will be sought to assure
the easiest implementation possible. Vasopressin is currently available for administration
on all resuscitation (code) carts at CMC. Inclusion and exclusion criteria will be posted on
all code carts to assist providers. Current protocol at CMC to enter all CPA events into the
National Registry of Cardiopulmonary Resuscitation (NRCPR) will be followed. This data is a
complete account of the events of the CPA and will be sufficient to meet all of the study's
stated goals and objectives. Only data pertinent to the outcomes of this study will be
reviewed from the database. This data will also be reviewed to assure standardization of
execution of the study protocol.
Time to Completion Given that 89 CPA events met inclusion criteria from January 2005 to June
2006 in the PICU at CMC, approximately 30 months will be required to enroll 130 total
patients into this study (10 patients in pilot trial, 120 patients in main study). Subjects
will be enrolled in the study until discharge or in-hospital death.
Definition CPA End of Event
1. . ROSC that is sustained for > 20mins with no further need for chest compressions,
including with a pacemaker or extracorporeal membrane oxygenation OR
2. . Resuscitation event is terminated and patient is declared dead (unresponsive to
advanced life support, medical futility, advance directive, restriction by family
member)
SPECIAL PRECAUTIONS:
A full resuscitation team will be present whenever vasopressin is administered including a
physician, nurse, respiratory technician, clinical technician, and pharmacist. A sign will
be clearly posted on the bed of any patient whose proxy has "opted" the patient out of the
study or who meets any other exclusion criteria. The DSMB will evaluate the study for clear
benefit or harm, lack of efficacy, or unacceptable toxicity of vasopressin.
SOURCES OF RESEARCH MATERIALS/ COLLECTION OF FOLLOW UP DATA:
Data from CPA events will be collected from the NRCPR database which is completed at the
conclusion of every CPA event currently at CMC. Data is collected in six major categories of
variables: (1) Facility data, (2) Patient demographic data, (3) Pre-event data, (4) Event
data, (5) Outcome data, and (6) Quality improvement data. All patient identifiers will be
destroyed at the earliest possible opportunity. Data will be de-identified for analysis.
This data will include laboratory and treatment data from the hospitalization in the PICU at
CMC before, during, and after resuscitation. Specifically, this data will include: age,
gender, vital signs, treatments, laboratory results, neurologic exam (PCPC and POPC scores)
and physical exam. The data collection is based on in-hospital Utstein-style guidelines.
Inclusion Criteria:
- All children, ages 0 to 18 years, admitted to the PICU who experience CPA requiring
either chest compressions and/or defibrillation. This will include males, females and
Spanish speaking individuals.
- Patients must require at least 2 doses of vasopressor medication during the CPA event
(all patients would receive epinephrine as first dose, followed by either epinephrine
or vasopressin as second dose depending on randomization, all subsequent doses
required would be epinephrine) given via any route (intravenous, intraosseous, or
endotracheal).
Exclusion Criteria:
- Do Not Attempt Resuscitate (DNAR) patients
- Chemical code only (i.e., no CPR/defibrillation)
- Events not requiring chest compressions and/or defibrillation
- Events with a pulse requiring synchronized or unsynchronized cardioversion
- Successful internal cardiac device defibrillation of Vfib/pVT that initiates the
resuscitation event
- Defibrillation for Vfib/pVT without administration of a vasopressor
- All patients in the custody of the State of Texas
- Any patient whose parent or guardian "opts out" of the study
- Any patient who is pregnant
- Any patient whose attending physician "opts out" of the study
- Any patient who does not consent to follow up data collection
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