Effects of Lipid Emulsion on the Pharmacokinetic and Pharmacodynamic Properties of Metoprolol.
Condition: Drug Overdose; Overdose of Beta-adrenergic Blocking Drug; Blood Pressure
MeSH terms: Drug Overdose
Study type: Interventional
Phase: Phase 4

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.
    

Detailed description: 
      Overdose or poisonings with cardioactive drugs can have serious consequences. In recent
      years, intravenous lipid emulsion has emerged as a possible treatment option in otherwise
      treatment-resistant cardiovascular collapse caused by poisonings with cardio-active drugs.

      Experimental evidence obtained from animal studies has been indicating a beneficial effect of
      intravenous lipid emulsion in the treatment of poisoning with various cardio-toxic
      medications. Based on these findings, the first reported cases on the use of intravenous
      lipid emulsion in the treatment of human cardiotoxicity caused by poisonings with local
      anesthetics were published in 2006. Subsequently, a steadily increasing number of case
      reports concerning the use of intravenous lipid emulsion in resuscitation and treatment of
      various medications poisonings have been published. Often patients had either cardiac arrest
      or severe circulatory failure treated according to guidelines for advanced life support prior
      to lipid emulsion therapy. It is noteworthy that a common observation following bolus
      infusion of lipid emulsion has been a rapid hemodynamic stabilization of the patient.

      Despite an increasing use of intravenous lipid emulsion in the treatment of the poisoned
      patient, the mechanism behind lipid rescue has not been elucidated. The most widely accepted
      hypothesis, the "lipid sink/sponge" model, suggests that intravenous lipid emulsion entraps
      xenobiotics intravascularly, thereby preventing them from reaching sites of toxicity.
      Additionally, intravenous lipid emulsion may redistribute xenobiotics to areas of higher
      lipid content. However, other mechanisms of actions of lipid emulsion, supported by
      observations from animal experiments, are vasoconstrictive and cardio-tonic effects. These
      effects could be secondary to direct activation of sodium, potassium or calcium channels in
      the myocardium, or alternatively fatty acid-induced modulation of the metabolic properties of
      mitochondria. Both mechanisms could result in hemodynamic stabilization. The potential
      beneficial effects of lipid emulsion on hemodynamic instability beyond the lipid sink have
      led to the notion that intravenous lipid emulsion could be valuable in the treatment of
      poisonings with non-lipophilic xenobiotics.

      At present, it remains however unclear to what extent the evidence concerning resuscitation
      of the poisoned patient with lipid emulsion may reflect publication bias. To our knowledge,
      only one controlled human trial has been conducted at present. In a randomized crossover
      study, Litonius et al. investigated the effects of lipid emulsion on plasma concentrations of
      bupivacaine in eight healthy subjects. It was found that lipid emulsion lowered the total
      plasma concentrations of bupivacaine. This was attributed to an altered distribution and
      contradicted so the above hypothesis of a lipid sink-mechanism as the fraction of non-lipid
      bound bupivacaine was unchanged. The mechanism by which lipid emulsion may attenuate the
      effects of cardio toxic xenobiotics must therefore still be regarded as undecided. This lack
      of evidence calls for further human studies in order to elucidate the pharmacokinetic and
      pharmacodynamic consequences of intravenous lipid emulsion. The purpose of this double blind,
      randomized placebo-controlled crossover clinical trial is to investigate the effects of
      intravenous lipid emulsion on the pharmacokinetic and pharmacodynamic properties of the
      adrenoceptor antagonist metoprolol in a human model of beta blocker overdose.

      The study includes a total of five visits; a screening visit and four trial days. At the
      screening visit, anthropometric data (weight, height, blood pressure and pulse) is measured.
      Additionally, blood samples are collected in accordance with exclusion criteria. A spot urine
      sample measuring the albumin/creatinine ratio is collected and an electrocardiogram (ECG) is
      recorded to verify normality of heart rhythm and electrical impulses. In addition, an
      investigator carries out a clinical examination. Based on the clinical examination, urine and
      blood tests and ECG measurement, the investigator assesses whether the trial participant meet
      all inclusion criteria and no exclusion criteria.

      After screening and inclusion, participants will be invited to four trial days at the trial
      site. On each day participants are required to be fasting for 10 hours (including water,
      coffee and tobacco). A peripheral venous line is inserted into each antecubital vein. An
      arterial catheter connected to a pressure transducer is inserted into the radial artery in
      the wrist. In randomized order, one of the four interventions are performed (see below). A
      standard 12 lead ECG is placed on the participant as well as a 5 lead ECG connected to a
      computer.

      At T=0, metoprolol intravenous solution (0.5 mg metoprolol/ml as metoprolol tartrate) or
      placebo is administered as an intravenous bolus injection. Continuous infusion of
      metoprolol/placebo is then administered until T=30 minutes. 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. Intravenous lipid
      emulsion (Intralipid 20 %) or saline solution is shortly thereafter administered as an
      intravenous bolus infusion (1.5 ml/kg) followed by a continuous infusion (infusion rate: 0.25
      ml/kg/min). Lipid emulsion/dummy infusion is stopped at T = 30 minutes. One gram of
      paracetamol administered as a disintegrating tablet dissolved in 50 ml of water is given per
      os shortly before study start on each day.

      Repeated ECG's are recorded and blood is drawn for measurements of routine biochemistry
      parameters and serum concentrations of metoprolol and paracetamol. A drop of blood is used to
      test glucose levels using a blood glucose meter. Cardiovascular parameters (heart rate, blood
      pressure, pulse contour curve/arterial pressure wave) are recorded via the arterial catheter
      and pressure transducer connected to a computer. The participant is closely monitored on site
      until T=120 minutes.
    

Intervention name(s): metoprolol; intravenous lipid emulsion; Sodium chloride 0.9% solution - lipid emulsion dummy; Sodium chloride 0.9% solution - metoprolol dummy
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): 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.; 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.; 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.; Saline solution is administered as an intravenous bolus injection followed by a continuous infusion to T=30 minutes.
Other intervention name(s): metoprolol tartrate; Seloken; ATC: C07AB02; Intralipid; ATC: B05BA02; Normal saline; Normal saline
Intervention MeSH terms: Metoprolol; Pharmaceutical Solutions; Soybean oil, phospholipid emulsion; Fat Emulsions, Intravenous
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science
Keywords: metoprolol; lipid emulsion; pharmacodynamics; pharmacokinetics