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Anesth Analg 2001;93:400-404
© 2001 International Anesthesia Research Society

CRITICAL CARE AND TRAUMA

The Pharmacokinetics of Cisatracurium in Patients with Acute Respiratory Distress Syndrome

Gilles Dhonneur, MD, PhD*, Charles Cerf, MD*, Franck Lagneau, MD{dagger}, Jean Mantz, MD, PhD{ddagger}, Catherine Gillotin, PharmD§, and Philippe Duvaldestin, MD, PhD*

*Department of Anaesthesia and Intensive Care Unit, Henri-Mondor Hospital, Creteil, France; {dagger}Department of Anaesthesia and Intensive Care Unit, Beaujon Hospital, Clichy, France; {ddagger}Department of Anaesthesia and Intensive Care Unit, Bichat Hospital, Paris, France; and §Glaxo Wellcome Laboratories, Marly-le-Roi, France

Address correspondence and reprint requests to Philippe Duvaldestin, MD, Department of Anaesthesia and Intensive Care Unit, Henri-Mondor Hospital, 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Creteil, France. Address e-mail to philippe .duvaldestin{at}hmn.ap-hop-paris.fr


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Continuous neuromuscular blockade is often necessary in patients being treated for acute respiratory distress syndrome (ARDS) to optimize oxygenation. In this study, neuromuscular blockade (no response to two responses at the train-of-four stimulation at the orbicularis oculi muscle) was achieved in six patients with ARDS by a continuous infusion of cisatracurium. The plasma concentration of cisatracurium during the infusion averaged 1.00 (0.25–1.45) µg/mL, expressed as median (range). The clearance and half-life were 6.5 (3.3–7.6) mL · min-1 · kg-1 and 25 (16–48) min, respectively. The laudanosine plasma concentrations were 0.70 (0.12–1.20) µg/mL. The pharmacokinetic variables of cisatracurium are similar to those of patients without organ failure undergoing elective surgery. Plasma laudanosine levels always remained well less that those associated with seizure activity in animal models. Long-term infusion of cisatracurium was not associated with any side effects. Cisatracurium is a suitable muscle relaxant when deep and continuous levels of muscle relaxation are required in patients treated for ARDS.

IMPLICATIONS: We studied the pharmacokinetics of cisatracurium in six patients treated for respiratory distress syndrome by continuous muscle relaxation. A deep degree of neuromuscular blockade corresponding to abolition of two responses at the orbicularis oculi to train-of-four stimulation was obtained in all patients. The pharmacokinetic variables observed in these severely ill patients were similar to those of anesthetized patients. No accumulation of laudanosine was seen. Cisatracurium appears to be suitable when continuous muscle relaxation is required in critically ill patients.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
In patients with acute respiratory distress syndrome (ARDS), continuous infusion of muscle relaxants in association with sedative-hypnotics and analgesics are often necessary to improve oxygenation. Although the mechanism by which muscle paralysis improves oxygenation in these patients remains unelucidated, respiratory muscles are paralyzed. Complete paralysis of respiratory muscles may reduce oxygen consumption (1,2), facilitate mechanical ventilation by preventing respiratory movements (3), and increase chest wall compliance (4). Achieving this target deep level of neuromuscular blockade is required because respiratory muscles and especially the diaphragm are resistant to muscle relaxants (5,6).

The continuous administration of cisatracurium appears particularly adapted to such objectives. Because cisatracurium is devoid of histamine-releasing properties (7) and is four- to fivefold more potent than atracurium, the risk of laudanosine accumulation is probably less in comparison to atracurium (8). In addition, after prolonged neuromuscular blockade, recovery from paralysis appears much more rapid after an infusion of cisatracurium than of vecuronium (9). In this study, the pharmacokinetics of cisatracurium were studied in patients with ARDS with intense levels of neuromuscular blockade induced by cisatracurium.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After approval by the National Ethics Committee and after informed consent was obtained from family members, we studied six patients treated for ARDS. Exclusion criteria consisted of preexistent treatment with muscle relaxants. At the time of inclusion, all patients had a PaO2 to inspired oxygen concentration (%) ratio of <200 (Table 1). All patients were sedated with a continuous infusion of fentanyl or sufentanil plus midazolam. The degree of neuromuscular blockade was assessed by measuring the number of evoked responses of the orbicularis oculi to facial nerve train-of-four stimulation (TOF) by use of skin surface electrodes.


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  		Table 1. Characteristics of the Patients
 
Cisatracurium was administered as a bolus of 0.1 mg/kg followed by a continuous infusion at an initial rate of 3 µg · kg-1 · min-1 adjusted to obtain zero or two responses to TOF stimulation. During the first 2 h of the study, the setup of the neuromuscular blocking effect of cisatracurium was adapted by measuring the evoked response at the orbicularis oculi every 15 min. The infusion rate of cisatracurium was adjusted by increasing or decreasing the infusion rate by 1 µg · kg-1 · min-1 every 15 min. Thereafter, the response of the orbicularis oculi was checked every 12 h. The same level of paralysis was maintained during the continuous infusion of cisatracurium. When this treatment was judged unnecessary in light of improvement of the respiratory status, cisatracurium infusion was stopped. The recovery from paralysis was assessed by monitoring the number of evoked responses to TOF at the adductor pollicis muscle every 15 min. When four responses were detected, double burst stimulation was applied every 15 min until no more fade was detected by tactile evaluation.

Arterial blood samples (5 mL) were withdrawn every 6 h during the continuous infusion of cisatracurium and at 5, 10, and 20 min and 1, 3, 6, 12, 24, 36, and 48 h after the infusion was discontinued. Immediately after sampling, the blood was centrifuged for 30 s, and 2 mL of plasma was transferred into tubes containing 8 mL of sulfonic acid 0.015 M and stored at -80°C until subsequent analysis. The concentrations of cisatracurium and laudanosine were further assayed by high-pressure liquid chromatography (8). Noncompartmental methods were used to calculate the following cisatracurium steady-state pharmacokinetic variables with WinNonlin software, version 1.5(Pharsight, Mountain View, CA): the average plasma concentration of cisatracurium during the infusion, the area under the curve of plasma concentration versus time, the plasma clearance (CL) as the ratio of the area under the curve to the total dose infused, the elimination half-life (t1/2), and the total apparent volume of distribution (VD), as follows: VD = 1.44 CL x t1/2. Data are expressed as median (range).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Of the six patients studied, three had renal failure and were treated by hemodialysis. The duration of cisatracurium infusion varied from 15 to 168 h. The degree of neuromuscular blockade assessed at the orbicularis oculi varied slightly between patients and during the time course of the study (Fig. 1). The infusion rate of cisatracurium averaged 5.6 (1.8–8.8) µg · kg-1 · min-1. After the infusion of cisatracurium was stopped, the four responses to TOF were observed at the adductor pollicis muscle between 0 and 300 min (median, 52 min) (Table 2). The absence of fade to double burst stimulation was observed between 60 and 360 min (median, 97 min) after discontinuation of the infusion.



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  		Figure 1. Individual values of the train-of-four response ratio during the continuous infusion of cisatracurium.

 

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  		Table 2. Characteristics of Recovery from Paralysis Assessed at the Adductor Pollicis Muscle After Discontinuation of the Infusion of Cisatracurium
 
The median (range) concentration of cisatracurium during the time period of infusion was 1.00 (0.25–1.45) µg/mL (Fig. 2). After the infusion of cisatracurium was discontinued, a rapid decline in the plasma concentration was observed, t1/2 being 25 (16–48) min (Table 3). The steady-state volume of distribution and CL were 260 (92–425) mL/kg and 6.5 (3.3–7.6) mL · min-1 · kg-1, respectively. Individual laudanosine plasma concentrations are shown in Figure 3. The observed plasma concentration of laudanosine averaged 0.70 µg/mL. The largest laudanosine concentration was 2.0 µg/mL and was observed in a patient with normal renal function after 45 h of cisatracurium infusion. No side effect attributed to the continuous infusion of cisatracurium was observed in this study.



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  		Figure 2. Individual values of plasma concentration of cisatracurium during its continuous infusion in six patients treated for acute respiratory distress syndrome.

 

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  		Table 3. Cisatracurium Infusion and Pharmacokinetic Variables
 


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  		Figure 3. Individual values of plasma concentration of laudanosine during the continuous infusion of cisatracurium in six patients treated for acute respiratory distress syndrome.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
This study shows that during intense and prolonged neuromuscular blockade induced by a continuous infusion of cisatracurium, the plateau of plasma concentration of cisatracurium averaged 1.0 µg/mL, although large interindividual variations were observed in plasma concentrations and in the duration of cisatracurium infusion. When the infusion was discontinued, the decline in plasma concentration of cisatracurium was rapid in all patients, because the mean plasma half-life was 25 minutes and the cisatracurium concentration was below the limit of detection of our method in all patients less than six hours after the infusion was discontinued.

The pharmacokinetics of cisatracurium have been characterized both in anesthetized patients (10–13) and in patients treated in intensive care units (ICUs) for different pathologies (14). In previous studies, the level of neuromuscular blockade, based on the monitoring of the adductor pollicis muscle and the infusion rate, was adjusted to maintain at least one evoked response to TOF stimulation (14,15). In our study, the magnitude of depression of neuromuscular response was assessed at the orbicularis oculi muscle. Because this muscle is more resistant than the adductor pollicis to muscle relaxants, this may explain why the dose of cisatracurium infused was larger, averaging 5.6 µg · kg-1 · min-1 instead of 3.2 and 3.8 µg · kg-1 · min-1 in previous studies (14,15).

The pharmacokinetic characteristics of cisatracurium found in our patients do not differ greatly from those observed in the previous study of Boyd et al. (14) in terms of elimination kinetics, because t1/2 was 28 minutes instead 25 minutes in our study. The CL averaged 550 mL/min in the study of Boyd et al. (14) and is 518 mL/min in our study. Half of our patients had renal failure, which influenced neither t1/2 nor the CL.

In comparison, the pharmacokinetics of vecuronium are different between anesthetized patients and patients treated in the ICU (16). The main explanation for this difference is the influence of liver and kidney dysfunction on the elimination kinetics of vecuronium (17–19) in contrast to cisatracurium, whose elimination is predominantly through Hofmann hydrolysis (20). The prolonged recovery from long-term administration of vecuronium in critically ill patients is related to altered elimination kinetics or increasing concentrations of the 3-OH active metabolite (21).

The plasma concentrations of laudanosine observed in this study were less than the values of plasma concentrations associated with seizure activity in animal models. In anesthetized dogs, laudanosine plasma concentrations >10 µg/mL induced epileptic electroencephalographic spiking (22). Despite the relatively large doses of cisatracurium administered in this study, the concentrations of laudanosine averaged 0.70 µg/mL, the highest value being 2.0 µg/mL. In comparison, Boyd et al. (14) observed peak plasma laudanosine of 1.3 µg/mL in one individual during the continuous infusion of cisatracurium at a slower rate of 0.18 mg/h than in our study.

It can be argued that the large dose of cisatracurium infused, and consequently the deep level of neuromuscular blockade achieved, in our patients is not necessary and may cause prolonged paralysis (23). There is no certainty concerning the level of neuromuscular blockade that improves ventilation and oxygenation status in patients requiring ventilatory support for ARDS. Muscle relaxants are indicated in the most severe cases of acute lung injury to optimize gas exchange through a decrease in the work of breathing, an increase in chest compliance, an elimination of breathing efforts, or a combination of these (24). We assume that this goal requires the paralysis of respiratory muscles. Because the response of the orbicularis oculi to neuromuscular blocking drugs resembles that of respiratory muscles (6), this muscle seems well adapted to this objective and has been used previously in critically ill patients (3,25).

Several reports suggest that the long-term administration of neuromuscular blocking drugs may favor the development of acquired neuromyopathy in critically ill patients (23,26–28). Repeated monitoring of neuromuscular function and periodic drug discontinuation have been recommended in critically ill patients treated with muscle relaxants (23). However, there are no data demonstrating that the incidence of myopathy is related to the degree of pharmacologic neuromuscular blockade.

In conclusion, the continuous infusion of cisatracurium appears to be well adapted to the treatment of sedated patients in ICUs when a deep level of permanent neuromuscular blockade is required. Even at high infusion rates, there seems to be no evidence of laudanosine accumulation in critically ill patients, including those with renal impairment. The pharmacokinetics of cisatracurium in these patients are not different from those observed in healthy anesthetized patients and are characterized by a rapid clearance rate. These findings explain why a rapid recovery from neuromuscular blockade can be achieved after discontinuing the infusion.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Coggeshall JW, Marini JJ, Newman JH. Improved oxygenation after muscle relaxation in adult respiratory distress syndrome. Arch Intern Med 1985; 145: 1718–20.[Abstract]
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Accepted for publication April 10, 2001.





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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press