Plasma concentrations of laudanosine, but not of atracurium, are increased during the anhepatic phase of orthotopic liver transplantation in pigs

J. F. Pittet, E. Tassonyi, C. Schopfer, D. R. Morel, G. Mentha, M. Fathi, C. Le Coultre, D. A. Steinig, A. Benakis

Research output: Contribution to journalArticle

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Abstract

To quantify the changes in plasma concentrations of atracurium and laudanosine induced by the lack of hepatic function and circulation, the authors studied nine domestic pigs (22-25 kg) undergoing an orthotopic liver transplantation, and three control animals without surgery, using atracurium as the muscle relaxant. After intubation facilitated by isoflurane 2-3%, anesthesia was maintained with isoflurane (0.5% in oxygen) and fentanyl (4 μg · kg-1 · hr-1). Ventilation was controlled to keep end-tidal CO2 at 35-40 mmHg, body temperature maintained at 35.5-37.5°C, and arterial pH at 7.35-7.50. The right sciatic nerve was stimulated with a nerve stimulator delivering a single twitch at 0.1 Hz with 0.2-ms duration, at supramaximal stimulation. The force of the corresponding evoked isometric muscle contraction was continuously measured by a force-displacement transducer. A single iv bolus of atracurium (2 mg/kg) was given to obtain a 90-95% twitch depression, followed 5 min later by a constant-rate iv infusion of atracurium at 120 μg · kg-1 · min-1 maintained during the entire investigation. Blood samples for plasma atracurium and laudanosine concentrations were drawn every 15 min. In the control group, plasma concentrations of atracurium remained stable between 6.5-8.0 μg/ml following initial bolus injection; plasma concentrations of laudanosine increased during the first 60 min, then remained stable between 0.69-0.74 μg/ml up to the end of the study. In animals undergoing transplantation, plasma concentrations of atracurium remained stable between 10-12 μg/ml, despite a 90-min duration of liver exclusion. In contrast, plasma concentrations of laudanosine were significantly increased 45 min after the hepatic vessels were clamped (from 0.57 ± 0.03 μg/ml to 0.91 ± 0.02 μg/ml, mean ± SE, P <0.05), increased further to peak values of 1.25 ± 0.05 μg/ml after 90 min, and remained at these elevated concentrations after restoration of circulation to the transplanted liver. The results of the present study demonstrate that in pigs plasma clearance of atracurium does not depend on hepatic function. In contrast, plasma clearance of its major metabolite laudanosine is strongly dependent on liver function.

Original languageEnglish
Pages (from-to)145-152
Number of pages8
JournalAnesthesiology
Volume72
Issue number1
Publication statusPublished - 1990

Fingerprint

Atracurium
Liver Transplantation
Swine
Liver
Isoflurane
Liver Circulation
Sus scrofa
Isometric Contraction
laudanosine
Fentanyl
Sciatic Nerve
Muscle Contraction
Body Temperature
Transducers
Intubation
Ventilation
Anesthesia
Transplantation
Oxygen
Muscles

Keywords

  • Liver: transplantation
  • Measurement techniques: high performance liquid chromatography
  • Neuromuscular relaxants: atracurium
  • Pharmacokinetics: atracurium; laudanosine
  • Sympathetic nervous system, catecholamines: norepinephrine

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Cite this

Plasma concentrations of laudanosine, but not of atracurium, are increased during the anhepatic phase of orthotopic liver transplantation in pigs. / Pittet, J. F.; Tassonyi, E.; Schopfer, C.; Morel, D. R.; Mentha, G.; Fathi, M.; Le Coultre, C.; Steinig, D. A.; Benakis, A.

In: Anesthesiology, Vol. 72, No. 1, 1990, p. 145-152.

Research output: Contribution to journalArticle

Pittet, JF, Tassonyi, E, Schopfer, C, Morel, DR, Mentha, G, Fathi, M, Le Coultre, C, Steinig, DA & Benakis, A 1990, 'Plasma concentrations of laudanosine, but not of atracurium, are increased during the anhepatic phase of orthotopic liver transplantation in pigs', Anesthesiology, vol. 72, no. 1, pp. 145-152.
Pittet, J. F. ; Tassonyi, E. ; Schopfer, C. ; Morel, D. R. ; Mentha, G. ; Fathi, M. ; Le Coultre, C. ; Steinig, D. A. ; Benakis, A. / Plasma concentrations of laudanosine, but not of atracurium, are increased during the anhepatic phase of orthotopic liver transplantation in pigs. In: Anesthesiology. 1990 ; Vol. 72, No. 1. pp. 145-152.
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abstract = "To quantify the changes in plasma concentrations of atracurium and laudanosine induced by the lack of hepatic function and circulation, the authors studied nine domestic pigs (22-25 kg) undergoing an orthotopic liver transplantation, and three control animals without surgery, using atracurium as the muscle relaxant. After intubation facilitated by isoflurane 2-3{\%}, anesthesia was maintained with isoflurane (0.5{\%} in oxygen) and fentanyl (4 μg · kg-1 · hr-1). Ventilation was controlled to keep end-tidal CO2 at 35-40 mmHg, body temperature maintained at 35.5-37.5°C, and arterial pH at 7.35-7.50. The right sciatic nerve was stimulated with a nerve stimulator delivering a single twitch at 0.1 Hz with 0.2-ms duration, at supramaximal stimulation. The force of the corresponding evoked isometric muscle contraction was continuously measured by a force-displacement transducer. A single iv bolus of atracurium (2 mg/kg) was given to obtain a 90-95{\%} twitch depression, followed 5 min later by a constant-rate iv infusion of atracurium at 120 μg · kg-1 · min-1 maintained during the entire investigation. Blood samples for plasma atracurium and laudanosine concentrations were drawn every 15 min. In the control group, plasma concentrations of atracurium remained stable between 6.5-8.0 μg/ml following initial bolus injection; plasma concentrations of laudanosine increased during the first 60 min, then remained stable between 0.69-0.74 μg/ml up to the end of the study. In animals undergoing transplantation, plasma concentrations of atracurium remained stable between 10-12 μg/ml, despite a 90-min duration of liver exclusion. In contrast, plasma concentrations of laudanosine were significantly increased 45 min after the hepatic vessels were clamped (from 0.57 ± 0.03 μg/ml to 0.91 ± 0.02 μg/ml, mean ± SE, P <0.05), increased further to peak values of 1.25 ± 0.05 μg/ml after 90 min, and remained at these elevated concentrations after restoration of circulation to the transplanted liver. The results of the present study demonstrate that in pigs plasma clearance of atracurium does not depend on hepatic function. In contrast, plasma clearance of its major metabolite laudanosine is strongly dependent on liver function.",
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T1 - Plasma concentrations of laudanosine, but not of atracurium, are increased during the anhepatic phase of orthotopic liver transplantation in pigs

AU - Pittet, J. F.

AU - Tassonyi, E.

AU - Schopfer, C.

AU - Morel, D. R.

AU - Mentha, G.

AU - Fathi, M.

AU - Le Coultre, C.

AU - Steinig, D. A.

AU - Benakis, A.

PY - 1990

Y1 - 1990

N2 - To quantify the changes in plasma concentrations of atracurium and laudanosine induced by the lack of hepatic function and circulation, the authors studied nine domestic pigs (22-25 kg) undergoing an orthotopic liver transplantation, and three control animals without surgery, using atracurium as the muscle relaxant. After intubation facilitated by isoflurane 2-3%, anesthesia was maintained with isoflurane (0.5% in oxygen) and fentanyl (4 μg · kg-1 · hr-1). Ventilation was controlled to keep end-tidal CO2 at 35-40 mmHg, body temperature maintained at 35.5-37.5°C, and arterial pH at 7.35-7.50. The right sciatic nerve was stimulated with a nerve stimulator delivering a single twitch at 0.1 Hz with 0.2-ms duration, at supramaximal stimulation. The force of the corresponding evoked isometric muscle contraction was continuously measured by a force-displacement transducer. A single iv bolus of atracurium (2 mg/kg) was given to obtain a 90-95% twitch depression, followed 5 min later by a constant-rate iv infusion of atracurium at 120 μg · kg-1 · min-1 maintained during the entire investigation. Blood samples for plasma atracurium and laudanosine concentrations were drawn every 15 min. In the control group, plasma concentrations of atracurium remained stable between 6.5-8.0 μg/ml following initial bolus injection; plasma concentrations of laudanosine increased during the first 60 min, then remained stable between 0.69-0.74 μg/ml up to the end of the study. In animals undergoing transplantation, plasma concentrations of atracurium remained stable between 10-12 μg/ml, despite a 90-min duration of liver exclusion. In contrast, plasma concentrations of laudanosine were significantly increased 45 min after the hepatic vessels were clamped (from 0.57 ± 0.03 μg/ml to 0.91 ± 0.02 μg/ml, mean ± SE, P <0.05), increased further to peak values of 1.25 ± 0.05 μg/ml after 90 min, and remained at these elevated concentrations after restoration of circulation to the transplanted liver. The results of the present study demonstrate that in pigs plasma clearance of atracurium does not depend on hepatic function. In contrast, plasma clearance of its major metabolite laudanosine is strongly dependent on liver function.

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KW - Measurement techniques: high performance liquid chromatography

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KW - Sympathetic nervous system, catecholamines: norepinephrine

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