Measures to Lower the Stress Response in Pediatric Cardiac Surgery

Stress Response in Children Undergoing Cardiac Surgery: a Prospective Randomized Comparison Between Low Dose Fentanyl (LDF), Low Dose Fentanyl Plus Dexmedetomidine (LDF + Dex) and High Dose Fentanyl (HDF).

Cardiac surgery induces a measurable stress response in patients which leads to increased morbidity and mortality post-operatively. Through clinical observation, anesthesiologists have determined that varying the combinations of anesthesia drugs used during surgery and just after reduces the stress response, and by extension, morbidity and mortality. However, only a few studies have explored this phenomenon scientifically.

Study Overview

• Status: Completed
• Conditions: Tetralogy of Fallot (TOF); Ventricular Septal Defects (VSD); Atrioventricular Septal Defects (AVSD)
• Intervention / Treatment: Drug: Fentanyl (High Dose); Drug: Fentanyl (Low Dose); Drug: Fentanyl (Low Dose) + Dexmedetomidine

Detailed Description

In this study, we aim to demonstrate comparatively that use of dexmedetomidine in addition to low dose narcotics reduces the stress response in cardiac surgical patients and results in less morbidity and mortality. Additionally, dexmedetomidine (Dex) should facilitate safe early extubation in pediatric cardiac patients, which results in decreased ventilator associated co-morbidities. Patients will be randomly assigned to three groups; one group will receive low dose fentanyl (LDF), one will receive low dose fentanyl with dexmedetomidine (LDF + Dex), and one will receive high dose fentanyl (HDF). Blood samples will be collected post-induction, post-sternotomy, after going on cardiopulmonary bypass, at the completion of surgery, and post-operatively to determine the patients' stress hormone levels. The patients will receive standard post-operative care, and clinical data collected as part of this care will be used to determine the incidence of morbidity and mortality. The results of the blood tests will be correlated with the incidence of morbidity and mortality to demonstrate the relative effectiveness of the different anesthesia methods.

Blood samples will be analyzed for the presence of the stress hormones cortisol, epinephrine, norepinephrine, adrenocorticotropic hormone (ACTH), Interleukin 8 (IL-8), TNF-alpha (Tumor Necrosis Factor), and nitrated albumin. Arterial blood gas, glucose and lactate levels, heart rate, blood pressure, use of vasoactive support, length of ventilator use, post-operative mortality, post-operative morbidity, length of Intensive Care Unit (ICU) stay, and length of hospital stay will be recorded.

Children previously enrolled in the surgery study will complete assessments of their cognitive ability, developmental status, and emotional and behavioral adjustment. For the neuro-developmental outcome follow up, Children's cognitive ability will be assessed using the Stanford-Binet Intelligence Scales, 5th Edition (SB5). The SB5 is a widely-used measure of intellectual functioning that is normed for ages 2 and up. The test takes 30-50 minutes to administer to young children, and provides an overall Intelligence Quotient (IQ) score, as well as scores for five primary factors of cognitive ability: Fluid Reasoning, Knowledge, Quantitative Reasoning, Visual-Spatial Processing; and Working Memory. The SB5 has demonstrated excellent reliability and validity.

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 3 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Childrens with the diagnosis of tetralogy of fallot, ventricular septal defect and atrioventricular septal defect who are under one year of age.

Exclusion Criteria:

• Patients who are having reoperation.
• Patients with comorbidities, such as heart failure.
• Patients receiving digoxin preoperatively.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Fentanyl (High Dose); This arm will receive a total of 25 mcg/kg of Fentanyl (High Dose) in two divided doses. First half-dose given at induction and second half-dose given before incision.	Drug: Fentanyl (High Dose); Fentanyl (High Dose) 25 mcg/kg in two divided doses. Half-dose will be given at induction and the second half-dose given prior to incision.; Other Names: Fentanyl citrate
Active Comparator: Fentanyl (Low Dose); This arm will receive a total of 10 mcg/kg of Fentanyl (Low Dose). First half-dose will be given at induction and second half -dose given before incision.	Drug: Fentanyl (Low Dose); Fentanyl (Low Dose) 10 mcg/kg in two divided doses. Half-dose will be given at induction and the second half-dose given prior to incision.; Other Names: Fentanyl citrate
Active Comparator: Fentanyl (Low Dose) + Dexmedetomidine; This arm will receive10 mcg/kg of Fentanyl (Low Dose) -2 divided doses. Dexmedetomidine (Dex) loading dose-1 mcg/kg over 10 min, then Dex infusion at 0.5mcg/kg/hr.	Drug: Fentanyl (Low Dose) + Dexmedetomidine; Fentanyl (Low Dose) + Dexmedetomidine. Dexmedetomidine at 1mcg/kg loading dose over 10 minutes, followed by an infusion at a rate of 0.5mcg/kg/hr. In addition, this group will receive a total of 10 mcg/kg Fentanyl (Low Dose). Half the dose will be given at induction and the second half before incision.; Other Names: Fentanyl citrate + Precedex for dexmedetomidine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ACTH and Cytokine Levels	N = 48 n = 16 (LDF); n = 17 (HDF); n = 15 (LDF + Dex) ACTH assayed by enzyme-linked immunosorbent assay (ELISA); Cytokine levels in plasma were measured using the Immulite automated chemiluminometer. Measured cytokines include interleukin (IL)-6, IL-8, IL-10, and tumor necrosis factor-α.	Blood draws to measure cytokines levels within one hour of draw: after induction; after sternotomy; after starting cardiopulmonary bypass; at the end of the procedure; and 24 hours after the procedure.
Comparisons Between Groups for Narcotic and/or Dexmedetomidine Intervention Influence on Length of CTICU Stay.		Hospital admission to discharge from CTICU (average of 2-4 days)
Comparisons Between Groups for Narcotic and/or Dexmedetomidine Intervention Influence on Time on Ventilator.		Time of intubation to extubation (variable)
Stanford-Binet Intelligence Scales	The Stanford-Binet test evaluates the overall IQ score from the assessment of cognitive ability. The test consists of 15 subtests, grouped into the four area scores. Six subtests are administered to all age levels. The subtests are: Vocabulary, Comprehension, Pattern Analysis, Quantitative, Bead Memory, and Memory for Sentences. Number of tests administered and test difficulty are based on the test taker's age and performance on subtest measuring word knowledge. The word knowledge subtest is given to all test takers and is the first subtest administered. A score of 100 is in the normal or average range. Higher scores suggest a higher level of functioning related to each category. (University of Cincinnati, 2003) Raw scores for each subtest within the overall test are converted to scaled scores using a table within each test manual to look up equivalents. Scaled scores are then converted to standard scores (range=50-150).	1-4 yrs. post-surgery
Stress Hormone Levels	Cortisol, epinephrine, and norepinephrine assayed by enzyme-linked immunosorbent assay (ELISA).	Blood draws to measure stress hormone levels within one hour of draw: after induction; after sternotomy; after starting cardiopulmonary bypass; at the end of the procedure; and 24 hours after the procedure.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stanford-Binet Cognitive Ability	The Stanford-Binet Intelligence Scale is now in its fifth edition (SB5) and was released in 2003. It is a cognitive ability and intelligence test that is used to diagnose developmental or intellectual deficiencies in young children. The test measures five weighted factors and consists of both verbal and nonverbal subtests. The five factors being tested are knowledge, quantitative reasoning, visual-spatial processing, working memory, and fluid reasoning. Raw scores for each subtest within the overall test are converted to scaled scores using a table within each test manual to look up equivalents. Scaled scores are then converted to standard scores (range=50-150). Higher scores suggest a higher level of functioning related to each category.	1-4 yrs post-surgery
ABAS-II	The ABAS-II is designed to evaluate whether an individual displays various functional skills necessary for daily living without the assistance of others. Thus, this instrument focuses on independent behaviors and measures what an individual actually does, in addition to measuring what he or she may be able to do. In addition, the ABAS-II focuses on behaviors an individual displays on his or her own, without assistance from others. The Parent/Primary Caregiver Form is a comprehensive, diagnostic measure of the adaptive skills that have primary relevance for the functioning of infants, toddlers, and preschoolers in the home and other settings, and can be completed by parents or other primary care providers. Each composite or domain score is determined by summing the appropriate scaled scores and then determining its equivalent composite or domain score by looking it up in a table located in the manual.The range for all scores is 50-150, with a higher score equaling a better outcome.	1-4 yrs post-surgery

Collaborators and Investigators

• Sponsor: Nationwide Children's Hospital
• Investigators: Principal Investigator: Aymen N Naguib, MD, Nationwide Children's Hospital

Publications and helpful links

General Publications

• Mukhtar AM, Obayah EM, Hassona AM. The use of dexmedetomidine in pediatric cardiac surgery. Anesth Analg. 2006 Jul;103(1):52-6, table of contents. doi: 10.1213/01.ane.0000217204.92904.76.
• Mellon RD, Simone AF, Rappaport BA. Use of anesthetic agents in neonates and young children. Anesth Analg. 2007 Mar;104(3):509-20. doi: 10.1213/01.ane.0000255729.96438.b0.
• Anand KJ, Hickey PR. Halothane-morphine compared with high-dose sufentanil for anesthesia and postoperative analgesia in neonatal cardiac surgery. N Engl J Med. 1992 Jan 2;326(1):1-9. doi: 10.1056/NEJM199201023260101.
• Anand KJ, Hansen DD, Hickey PR. Hormonal-metabolic stress responses in neonates undergoing cardiac surgery. Anesthesiology. 1990 Oct;73(4):661-70. doi: 10.1097/00000542-199010000-00012.
• Kapoor MC, Ramachandran TR. Inflammatory response to cardiac surgery and strategies to overcome it. Ann Card Anaesth. 2004 Jul;7(2):113-28.
• Gruber EM, Laussen PC, Casta A, Zimmerman AA, Zurakowski D, Reid R, Odegard KC, Chakravorti S, Davis PJ, McGowan FX Jr, Hickey PR, Hansen DD. Stress response in infants undergoing cardiac surgery: a randomized study of fentanyl bolus, fentanyl infusion, and fentanyl-midazolam infusion. Anesth Analg. 2001 Apr;92(4):882-90. doi: 10.1097/00000539-200104000-00016.

Study record dates

Study Major Dates

• Study Start: November 1, 2008
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: February 19, 2009
• First Submitted That Met QC Criteria: February 19, 2009
• First Posted (Estimate): February 20, 2009

Study Record Updates

• Last Update Posted (Actual): July 27, 2018
• Last Update Submitted That Met QC Criteria: July 2, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: Dexmedetomidine; stress response; VSD; pediatric cardiac surgery; early extubation; TOF; AVSD
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Congenital Abnormalities; Heart Defects, Congenital; Cardiovascular Abnormalities; Heart Septal Defects; Tetralogy of Fallot; Heart Septal Defects, Ventricular; Endocardial Cushion Defects; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Analgesics, Non-Narcotic; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Analgesics, Opioid; Narcotics; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anticoagulants; Chelating Agents; Sequestering Agents; Calcium Chelating Agents; Fentanyl; Dexmedetomidine; Citric Acid; Sodium Citrate
• Other Study ID Numbers: IRB08-00029; 101911 (Other Identifier: FDA)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No