Effects of Lipid Emulsion on the Pharmacokinetic and Pharmacodynamic Properties of Metoprolol.

NCT02924454 | Completed Phase 4

• 1 other identifier: Intralipid-Metoprolol
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

The aim of this study is to investigate whether intravenous lipid emulsion is effective in attenuating the clinical effects of a cardioactive drug, exemplified by the beta-blocking agent metoprolol. In addition, the investigators will clarify how intravenous lipid emulsion affects the pharmacokinetic parameters of metoprolol.

Conditions

Drug Overdose; Overdose of Beta-adrenergic Blocking Drug; Blood Pressure

Keywords

metoprolol; lipid emulsion; pharmacodynamics; pharmacokinetics

Outcome Measures

Primary Outcomes (1)

• Change in heart rate from baseline compared between study days

  Arterial catheter connected to a pressure transducer records heart rate (beats per minute).

  From baseline to + 120 minutes.

Secondary Outcomes (13)

• Area under the plasma concentration versus time curve (AUC) of metoprolol on days with co-administration of intravenous lipid emulsion compared to days with lipid emulsion placebo.

  0, +10, +20, +30, +40, +50, +60, +90, +120 minutes post metoprolol dose.

• Peak plasma concentration (Cmax) of paracetamol on days with co-administration of intravenous lipid emulsion compared to days with lipid emulsion placebo.

  0, +10, +20, +30, +40, +50, +60, +90, +120 minutes post metoprolol dose.

• Area under the plasma concentration versus time curve (AUC) of paracetamol on days with co-administration of intravenous lipid emulsion compared to days with lipid emulsion placebo.

  0, +10, +20, +30, +40, +50, +60, +90, +120 minutes post metoprolol dose.

• Time to peak plasma concentration (Tmax) of paracetamol on days with co-administration of intravenous lipid emulsion compared to days with lipid emulsion placebo.

  0, +10, +20, +30, +40, +50, +60, +90, +120 minutes post metoprolol dose.

• Percent change in plasma levels of standard biochemical measurements from baseline compared between study days.

  Changes at +30 and +60 minutes from baseline.

Study Arms (4)

Metoprolol-Lipid emulsion

EXPERIMENTAL

intervention 1: metoprolol Intervention 2: intravenous lipid emulsion

Drug: metoprolol; Drug: intravenous lipid emulsion

Metoprolol - normal saline

EXPERIMENTAL

intervention 1: metoprolol intervention 2: Sodium chloride 0.9% solution - lipid emulsion dummy

Drug: metoprolol; Drug: Sodium chloride 0.9% solution - lipid emulsion dummy

Normal saline-Lipid emulsion

EXPERIMENTAL

intervention 1: Sodium chloride 0.9% solution - metoprolol dummy intervention 2: intravenous lipid emulsion

Drug: intravenous lipid emulsion; Drug: Sodium chloride 0.9% solution - metoprolol dummy

Normal saline-normal saline

EXPERIMENTAL

intervention 1: Sodium chloride 0.9% solution - metoprolol dummy intervention 2: Sodium chloride 0.9% solution - lipid emulsion dummy

Drug: Sodium chloride 0.9% solution - lipid emulsion dummy; Drug: Sodium chloride 0.9% solution - metoprolol dummy

Interventions

metoprolol DRUG

One hundred and twenty ml, 0.5 mg metoprolol/ml (as metoprolol tartrate) is administered as an intravenous bolus injection followed by a continuous infusion. Infusion is halted if heart rate drops below 35 bpm or systolic blood pressure drops below 80 mm Hg, or the participant experiences subjective side effects. Infusion stops at T=30 minutes.

Also known as: metoprolol tartrate, Seloken, ATC: C07AB02

Metoprolol - normal saline; Metoprolol-Lipid emulsion

intravenous lipid emulsion DRUG

Intravenous lipid emulsion 20 % is administered as an intravenous bolus infusion (1.5 ml/kg) followed by continuous infusion (infusion rate: 0.25 ml/kg/min). Lipid emulsion infusion is stopped at T = 30 minutes.

Also known as: Intralipid, ATC: B05BA02

Metoprolol-Lipid emulsion; Normal saline-Lipid emulsion

Sodium chloride 0.9% solution - lipid emulsion dummy DRUG

Isotonic 0.9 % sodium chloride solution is administered as an intravenous bolus infusion (1.5 ml/kg), followed by continuous infusion (infusion rate: 0.25 ml/kg/min). Infusion is stopped at T = 30 minutes.

Also known as: Normal saline

Metoprolol - normal saline; Normal saline-normal saline

Sodium chloride 0.9% solution - metoprolol dummy DRUG

Saline solution is administered as an intravenous bolus injection followed by a continuous infusion to T=30 minutes.

Also known as: Normal saline

Normal saline-Lipid emulsion; Normal saline-normal saline

Eligibility Criteria

• Age: 20 Years - 30 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• \- healthy male.

You may not qualify if:

• Abnormal blood levels of sodium, potassium, creatinine, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, albumin, bilirubin, hemoglobin, HbA1c, cholesterol fractions.
• Abnormal urine albumin to creatinine ratio.
• Abnormal function of CYP2D6 metabolism (ultrarapid or slow metabolizer)
• Any heart disease or hypertension
• Sinoatrial block
• Second or third degree atrioventricular block
• Heart failure
• profound bradycardia or hypotension
• sinoatrial node disease
• metabolic acidosis
• untreated pheochromocytoma
• asthma
• chronic obstructive pulmonary disease
• intermittent claudicatio
• diabetes

Sponsors & Collaborators

• Mikkel Bring Christensen: lead

Study Sites (1)

Bispebjerg University Hospital Copenhagen

Copenhagen Northwest, Capital Region of Denmark, 2400, Denmark

Location

Related Publications (21)

• Hoffman RS, Howland MA, Lewin NA, Nelson L, Goldfrank LR, Flomenbaum N, editors. Goldfrank's toxicologic emergencies. Tenth edition. New York: McGraw-Hill Education; 2015. 1882 p.

  BACKGROUND

• Picard J, Ward SC, Zumpe R, Meek T, Barlow J, Harrop-Griffiths W. Guidelines and the adoption of 'lipid rescue' therapy for local anaesthetic toxicity. Anaesthesia. 2009 Feb;64(2):122-5. doi: 10.1111/j.1365-2044.2008.05816.x.

  PMID: 19143686 BACKGROUND

• Tebbutt S, Harvey M, Nicholson T, Cave G. Intralipid prolongs survival in a rat model of verapamil toxicity. Acad Emerg Med. 2006 Feb;13(2):134-9. doi: 10.1197/j.aem.2005.08.016. Epub 2006 Jan 25.

  PMID: 16436797 BACKGROUND

• Di Gregorio G, Schwartz D, Ripper R, Kelly K, Feinstein DL, Minshall RD, Massad M, Ori C, Weinberg GL. Lipid emulsion is superior to vasopressin in a rodent model of resuscitation from toxin-induced cardiac arrest. Crit Care Med. 2009 Mar;37(3):993-9. doi: 10.1097/CCM.0b013e3181961a12.

  PMID: 19237909 BACKGROUND

• Weinberg G, Ripper R, Feinstein DL, Hoffman W. Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity. Reg Anesth Pain Med. 2003 May-Jun;28(3):198-202. doi: 10.1053/rapm.2003.50041.

  PMID: 12772136 BACKGROUND

• Weinberg GL, Di Gregorio G, Ripper R, Kelly K, Massad M, Edelman L, Schwartz D, Shah N, Zheng S, Feinstein DL. Resuscitation with lipid versus epinephrine in a rat model of bupivacaine overdose. Anesthesiology. 2008 May;108(5):907-13. doi: 10.1097/ALN.0b013e31816d91d2.

  PMID: 18431127 BACKGROUND

• Weinberg GL, VadeBoncouer T, Ramaraju GA, Garcia-Amaro MF, Cwik MJ. Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats. Anesthesiology. 1998 Apr;88(4):1071-5. doi: 10.1097/00000542-199804000-00028.

  PMID: 9579517 BACKGROUND

• Rosenblatt MA, Abel M, Fischer GW, Itzkovich CJ, Eisenkraft JB. Successful use of a 20% lipid emulsion to resuscitate a patient after a presumed bupivacaine-related cardiac arrest. Anesthesiology. 2006 Jul;105(1):217-8. doi: 10.1097/00000542-200607000-00033. No abstract available.

  PMID: 16810015 BACKGROUND

• Litz RJ, Popp M, Stehr SN, Koch T. Successful resuscitation of a patient with ropivacaine-induced asystole after axillary plexus block using lipid infusion. Anaesthesia. 2006 Aug;61(8):800-1. doi: 10.1111/j.1365-2044.2006.04740.x.

  PMID: 16867094 BACKGROUND

• Bet 2: intralipid/lipid emulsion in beta-blocker overdose. Emerg Med J. 2011 Nov;28(11):991-3. doi: 10.1136/emermed-2011-200722.

  PMID: 22002529 BACKGROUND

• Blaber MS, Khan JN, Brebner JA, McColm R. "Lipid rescue" for tricyclic antidepressant cardiotoxicity. J Emerg Med. 2012 Sep;43(3):465-7. doi: 10.1016/j.jemermed.2011.09.010. Epub 2012 Jan 12.

  PMID: 22244291 BACKGROUND

• Espinet AJ, Emmerton MT. The successful use of intralipid for treatment of local anesthetic-induced central nervous system toxicity: Some considerations for administration of intralipid in an emergency. Clin J Pain. 2009 Nov-Dec;25(9):808-9. doi: 10.1097/AJP.0b013e3181af739e.

  PMID: 19851162 BACKGROUND

• Finn SD, Uncles DR, Willers J, Sable N. Early treatment of a quetiapine and sertraline overdose with Intralipid. Anaesthesia. 2009 Feb;64(2):191-4. doi: 10.1111/j.1365-2044.2008.05744.x.

  PMID: 19143698 BACKGROUND

• Foxall G, McCahon R, Lamb J, Hardman JG, Bedforth NM. Levobupivacaine-induced seizures and cardiovascular collapse treated with Intralipid. Anaesthesia. 2007 May;62(5):516-8. doi: 10.1111/j.1365-2044.2007.05065.x.

  PMID: 17448066 BACKGROUND

• Ludot H, Tharin JY, Belouadah M, Mazoit JX, Malinovsky JM. Successful resuscitation after ropivacaine and lidocaine-induced ventricular arrhythmia following posterior lumbar plexus block in a child. Anesth Analg. 2008 May;106(5):1572-4, table of contents. doi: 10.1213/01.ane.0000286176.55971.f0.

  PMID: 18420879 BACKGROUND

• Marwick PC, Levin AI, Coetzee AR. Recurrence of cardiotoxicity after lipid rescue from bupivacaine-induced cardiac arrest. Anesth Analg. 2009 Apr;108(4):1344-6. doi: 10.1213/ane.0b013e3181979e17.

  PMID: 19299810 BACKGROUND

• Shah S, Gopalakrishnan S, Apuya J, Shah S, Martin T. Use of Intralipid in an infant with impending cardiovascular collapse due to local anesthetic toxicity. J Anesth. 2009;23(3):439-41. doi: 10.1007/s00540-009-0754-3. Epub 2009 Aug 14.

  PMID: 19685131 BACKGROUND

• Warren JA, Thoma RB, Georgescu A, Shah SJ. Intravenous lipid infusion in the successful resuscitation of local anesthetic-induced cardiovascular collapse after supraclavicular brachial plexus block. Anesth Analg. 2008 May;106(5):1578-80, table of contents. doi: 10.1213/01.ane.0000281434.80883.88.

  PMID: 18420881 BACKGROUND

• Weinberg GL. Lipid infusion therapy: translation to clinical practice. Anesth Analg. 2008 May;106(5):1340-2. doi: 10.1213/ane.0b013e31816a6c09. No abstract available.

  PMID: 18420841 BACKGROUND

• Fettiplace MR, Akpa BS, Ripper R, Zider B, Lang J, Rubinstein I, Weinberg G. Resuscitation with lipid emulsion: dose-dependent recovery from cardiac pharmacotoxicity requires a cardiotonic effect. Anesthesiology. 2014 Apr;120(4):915-25. doi: 10.1097/ALN.0000000000000142.

  PMID: 24496123 BACKGROUND

• Litonius E, Tarkkila P, Neuvonen PJ, Rosenberg PH. Effect of intravenous lipid emulsion on bupivacaine plasma concentration in humans. Anaesthesia. 2012 Jun;67(6):600-5. doi: 10.1111/j.1365-2044.2012.07056.x. Epub 2012 Feb 21.

  PMID: 22352703 BACKGROUND

MeSH Terms

Conditions

Drug Overdose

Interventions

Metoprolol; Fat Emulsions, Intravenous; soybean oil, phospholipid emulsion; Sodium Chloride; Saline Solution

Condition Hierarchy (Ancestors)

Prescription Drug Misuse; Drug Misuse; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Emulsions; Colloids; Dosage Forms; Pharmaceutical Preparations; Parenteral Nutrition Solutions; Pharmaceutical Solutions; Solutions; Therapeutic Uses; Pharmacologic Actions; Chemical Actions and Uses; Specialty Uses of Chemicals; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds; Crystalloid Solutions; Isotonic Solutions

Study Officials

• Mikkel B Christensen, MD, PhD

  Bispebjerg University Hospital, Copenhagen

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MD, PhD

Study Record Dates

• First Submitted: September 6, 2016
• First Posted: October 5, 2016
• Study Start: September 1, 2016
• Primary Completion: March 10, 2017
• Study Completion: March 10, 2017
• Last Updated: April 12, 2017

Record last verified: 2017-04

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)