NICardipine Neuroprotection in AortiC Surgery (NICNACS)

Aortic Aneurysm, Thoracic Clinical Trial

— NICNACS  

Official title:

NICardipine Neuroprotection in AortiC Surgery (NICNACS)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00508118
• Other study ID #: Pro00001612
• Status: Terminated
• Phase: Phase 2
• First received: July 25, 2007
• Last updated: July 29, 2014
• Start date: January 2008
• Est. completion date: April 2008

Study information

• Verified date: January 2013
• Source: Duke University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

Objective

The objective of this study is to discover whether an infusion of nicardipine is able to reduce the time taken to achieve electrocerebral silence (ECS) during cardiopulmonary bypass (CPB) for aortic surgery.

Hypothesis

By inhibiting cold-induced cerebral vasoconstriction, nicardipine will maintain cerebral blood flow and allow more rapid cooling of the brain during CPB. This will manifest as a reduction in the time taken to achieve ECS and also as a reduction in overall CPB time.

Description:

Patients undergoing thoracic aortic surgery at Duke University Medical Center (DUMC) requiring hypothermic circulatory arrest (HCA) and neurophysiologic monitoring (NIOM) will give written informed consent and be enrolled into the study. Exclusion criteria will include previously documented allergy to nicardipine and age less than 18 years. Patients will then be randomized to one of two study groups: general anesthesia with or without nicardipine. Pre-operatively they will undergo clinical evaluation determined by the attending surgeon and anesthesiologist. During the pre-induction time period, all usual monitors and intravenous devices will be placed at the discretion of the attending anesthesiologist. In addition to the standard anesthetic monitors (Bispectral Index [BIS] and cerebral oximetry), transcranial Doppler (TCD) will be placed. Furthermore, the neurophysiology technician will place both standard EEG and somatosensory evoked potential (SSEP) electrode configurations. During the pre-induction time period, midazolam use will be at the discretion of the anesthesiologist but will be limited to a maximum dose of 0.1 mg/kg; other benzodiazepines will not be allowed. Opioid (fentanyl) administration will be at the discretion of the anesthesiologist. Total benzodiazepine and opioid doses will be recorded and converted to midazolam and fentanyl equivalents for subsequent analysis.

When ready, patients will be transported into the operating room and anesthesia will be induced. Induction will consist of propofol (1 - 5 mg/kg single intravenous bolus), fentanyl and vecuronium for neuromuscular blockade. Other drugs and dosages of opioids and neuromuscular blockers are at the discretion of the anesthesiologist. After induction and tracheal intubation, patients will receive maintenance anesthesia of 0.5 minimal alveolar concentration (MAC) isoflurane in a 50% air/oxygen balanced mixture supplemented with fentanyl at the discretion of the anesthesiologist. At the onset of cardiopulmonary bypass (CPB), study drug (nicardipine or equivalent volume of placebo - 0.9% saline) infusion at 5 mg/hr will be initiated, and patients will receive 0.5 MAC isoflurane in the CPB circuit sweep gas. Bolus doses of 100mcg phenylephrine will be administered to both groups in order to maintain a constant mean arterial pressure of at least 50 mmHg. Cooling will occur primarily through the CPB machine. When the patient's brain temperature reaches 28o C, isoflurane (via the pump) will be reduced to 0.25 MAC. When ECS on EEG and ablation of cortical responses on SSEP have both occurred, CPB and study drug infusion will be halted, and thoracic aortic surgery will be commenced. After aortic repair has occurred, CPB and study drug infusion at 5 mg/hr will be reinstated, anesthesia administration resumed, and the patient actively rewarmed. When the patient's brain temperature reaches 28o C (as recorded by nasopharyngeal temperature), patients will receive 0.5 MAC isoflurane. After the patient has been fully re-warmed and is ready for separation from CPB, study drug infusion will be halted. At this point, but not before, commercially available nicardipine may be infused if so desired. 10 ml blood samples will be drawn from the pump at baseline and 15 minute intervals thereafter until HCA is achieved. When the pump is restarted, further samples will be drawn at 15 minute intervals until the patient separates from CPB after which no further samples will be taken. One sample of 10 ml will be drawn from the retrograde cardioplegia line immediately after placement (baseline) and one sample will be drawn immediately prior to separation from CPB. In total, approximately 100 ml of blood will be drawn from the patient for research purposes. This volume represents a tiny percentage of the excess volume associated with the pump prime, and is insignificant in terms of its effect on hemodynamics.

Baseline patient characteristics will be collected in the pre-operative period and will include age, sex, weight, height, blood pressure, heart rate, temperature, comorbidities, type of aortic disease, and American Society of Anesthesiologists (ASA) grade. Prior to initiation of CPB, several factors will be recorded including arterial blood pressure, heart rate, cerebral oximetry, bispectral index score (BIS), latency & amplitude of SSEP, frequency of EEG background, cerebral blood flow assessed by middle cerebral artery (MCA) velocity on TCD, and nasopharyngeal temperature. During cooling, BIS scores, cerebral oximetry, and MCA velocity by TCD will be noted for each 0.5o C decrement in nasopharyngeal temperature; the duration from CPB initiation to 3 characteristic EEG changes (1. rhythmic delta, 2. Generalized periodic epileptiform discharge (GPED), 3. burst suppression) as defined by the neurophysiologist, the duration from CPB initiation to 2 characteristic SSEP changes (1. latency increase of >10%, 2. amplitude decrease of 50% from baseline), and hemodynamics at each 1o C nasopharyngeal temperature drop will also be recorded. At the time of HCA, several factors will be documented including nasopharyngeal temperature, duration from CPB initiation (the primary endpoint measure), total opioid doses, cerebral oximetry, BIS score, MCA velocity by TCD, hemodynamics. During rewarming, factors will be documented in the same fashion and at the same intervals as during cooling. At the first attempt at separation from CPB, documented factors will include BIS score, cerebral oximetry, MCA velocity by TCD, duration from CPB reinstitution to first attempt at separation, total dose of study drug, nasopharyngeal temperature, and hemodynamics. Finally, in addition to any Adverse Events (AEs) that may have occurred, data relating to length of ICU stay, length of hospital stay, in-hospital mortality, in-hospital acute kidney injury (defined as a 50% rise from baseline in serum creatinine, and of at least 0.3 mg/dl or need for dialysis), in-hospital stroke, in-hospital myocardial infarction, and discharge disposition from hospital (home, skilled nursing facility, other institution) will be recorded postoperatively.

With the exception of the on-pump blood draws, in this protocol there are no additional procedures or safety measures indicated or necessary for the purpose of research only. All anesthetic regimens and monitoring techniques are currently standard of care. Nicardipine infusion is currently widely used during cardiac anesthesia and post-operative cardiac recovery.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 7
• Est. completion date: April 2008
• Est. primary completion date: April 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• All adult (>18 years) patients at Duke University Medical Center (DUMC) presenting for elective aortic surgery scheduled to include a period of deep hypothermic circulatory arrest.

Exclusion Criteria:

• Failure to provide written informed consent

• Emergency operation

• Documented allergy to nicardipine

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Aortic Aneurysm
• Aortic Aneurysm, Thoracic

Intervention

Drug:
• Nicardipine
on bypass
• 0.9% saline
on bypass

Locations

Country	Name	City	State
United States	Duke University Medical Center	Durham	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Duke University

Country where clinical trial is conducted

United States, 

References & Publications (14)

Dahlbacka S, Mäkelä J, Kaakinen T, Alaoja H, Heikkinen J, Laurila P, Kiviluoma K, Salomäki T, Tuominen H, Ohtonen P, Lepola P, Biancari F, Juvonen T. Propofol is associated with impaired brain metabolism during hypothermic circulatory arrest: an experimental microdialysis study. Heart Surg Forum. 2006;9(4):E710-8; discussion E718. — View Citation

Fleck TM, Czerny M, Hutschala D, Koinig H, Wolner E, Grabenwoger M. The incidence of transient neurologic dysfunction after ascending aortic replacement with circulatory arrest. Ann Thorac Surg. 2003 Oct;76(4):1198-202. — View Citation

Ghariani S, Liard L, Spaey J, Noirhomme PH, El Khoury GA, de Tourtchaninoff M, Dion RA, Guerit JM. Retrospective study of somatosensory evoked potential monitoring in deep hypothermic circulatory arrest. Ann Thorac Surg. 1999 Jun;67(6):1915-8; discussion 1919-21. — View Citation

Guérit JM, Verhelst R, Rubay J, el Khoury G, Noirhomme P, Baele P, Dion R. The use of somatosensory evoked potentials to determine the optimal degree of hypothermia during circulatory arrest. J Card Surg. 1994 Sep;9(5):596-603. — View Citation

Hirotani T, Kameda T, Kumamoto T, Shirota S. Aortic arch repair using hypothermic circulatory arrest technique associated with pharmacological brain protection. Eur J Cardiothorac Surg. 2000 Nov;18(5):545-9. — View Citation

Khaladj N, Peterss S, Oetjen P, von Wasielewski R, Hauschild G, Karck M, Haverich A, Hagl C. Hypothermic circulatory arrest with moderate, deep or profound hypothermic selective antegrade cerebral perfusion: which temperature provides best brain protection? Eur J Cardiothorac Surg. 2006 Sep;30(3):492-8. Epub 2006 Jul 20. — View Citation

Levy WJ, Pantin E, Mehta S, McGarvey M. Hypothermia and the approximate entropy of the electroencephalogram. Anesthesiology. 2003 Jan;98(1):53-7. — View Citation

Pokela M, Jäntti V, Lepola P, Romsi P, Rimpiläinen J, Kiviluoma K, Salomäki T, Vainionpää V, Biancari F, Hirvonen J, Kaakinen T, Juvonen T. EEG burst recovery is predictive of brain injury after experimental hypothermic circulatory arrest. Scand Cardiovasc J. 2003 Jun;37(3):154-7. — View Citation

Puri GD, Bagchi A, Anandamurthy B, Dhaliwal RS. The Bispectral Index and induced hypothermia--electrocerebral silence at an unusually high temperature. Anaesth Intensive Care. 2003 Oct;31(5):578-80. — View Citation

Sakamoto T, Hatsuoka S, Stock UA, Duebener LF, Lidov HG, Holmes GL, Sperling JS, Munakata M, Laussen PC, Jonas RA. Prediction of safe duration of hypothermic circulatory arrest by near-infrared spectroscopy. J Thorac Cardiovasc Surg. 2001 Aug;122(2):339-50. — View Citation

Speziali G, Russo P, Davis DA, Wagerle LC. Hypothermia enhances contractility in cerebral arteries of newborn lambs. J Surg Res. 1994 Jul;57(1):80-4. — View Citation

Stecker MM, Cheung AT, Pochettino A, Kent GP, Patterson T, Weiss SJ, Bavaria JE. Deep hypothermic circulatory arrest: I. Effects of cooling on electroencephalogram and evoked potentials. Ann Thorac Surg. 2001 Jan;71(1):14-21. — View Citation

Stecker MM, Cheung AT, Pochettino A, Kent GP, Patterson T, Weiss SJ, Bavaria JE. Deep hypothermic circulatory arrest: II. Changes in electroencephalogram and evoked potentials during rewarming. Ann Thorac Surg. 2001 Jan;71(1):22-8. — View Citation

Stecker MM, Escherich A, Patterson T, Bavaria JE, Cheung AT. Effects of acute hypoxemia/ischemia on EEG and evoked responses at normothermia and hypothermia in humans. Med Sci Monit. 2002 Apr;8(4):CR223-8. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Duration From Initiation of Cardiopulmonary Bypass (CPB) to Electrocerebral Silence (ECS), Defined as no Discernable Electroencephalographic Activity at an Amplification of 2 Micro Volts (µV)/mm, Confirmed for 3 Minutes		Day of surgery	No
Secondary	Temperature at Which ECS Occurs		Day of surgery through discharge	No
Secondary	Temperature at Which Ablation of(SSEP)Occurs		Day of surgery through discharge	No
Secondary	Time Points of EEG Patterns		Day of surgery through discharge	No
Secondary	Time Points for SSEP Latency and Amplitude Changes		Day of surgery through discharge	No
Secondary	Bispectral Index Scores (BIS)		Day of surgery through discharge	No
Secondary	Cerebral Oximetry Measurements		Day of surgery through discharge	No
Secondary	Transcranial Doppler Measurements		Day of surgery through discharge	No