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Original Article

Effect of different doses of cisatracurium on intraocular pressure in sedated patients

Sator-Katzenschlager, S. M.*†; Oehmke, M. J.*; Kontaratos, M.; Wedrich, A.; Heinze, G.; Weinstabl, C.

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European Journal of Anaesthesiology (EJA): November 2002 - Volume 19 - Issue 11 - p 823-828
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Abstract

Introduction

Intraocular pressure (IOP) is influenced by multiple factors including respiration, cardiovascular reactions and a variety of drugs [1]. Avoiding a rise in IOP is of particular importance in patients with glaucoma or those undergoing penetrating keratoplasty. In this context, the use of succinylcholine to provide transient paralysis is controversial [2]. Available alternatives include non-depolarizing neuromuscular blocking drugs such as atracurium and vecuronium, which have a prolonged onset and duration of action. For some years, cisatracurium has also been routinely used in the clinical setting. Cisatracurium, a benzylisoquinoline neuromuscular blocking drug with intermediate action, is one of 10 stereoisomers of atracurium and is characterized by a 3-4-fold neuromuscle blocking potency in comparison with atracurium [3]. Further, cisatracurium has a lesser impact on the autonomous nervous system than atracurium [4] and is not a trigger of histamine release [5]. It is eliminated largely by Hofmann elimination destruction without organ involvement. The resulting laudanosine concentration in equipotent doses is, however, only 10-20% of the concentration measured after the administration of atracurium [6,7].

The aim was to determine the effects of various doses of cisatracurium on IOP, excluding, as far as possible, any concomitant factors (hypnotics, atropine, induction, cough, etc.). This was the reason for the study being conducted in patients who were in good ophthalmological health, in a stable cardiopulmonary condition and under sedation. A first test series examined the effect of the intubation dose (2 × ED95) as compared with the primary substance, atracurium. A second test series compared the effect of ED95 (0.05 mg kg−1) with the repeat dose (0.02 mg kg−1).

Methods

After the study had been approved by the Ethics Committee of the Vienna University Hospital and patients had given informed consent, we examined the changes in IOP after the administration of atracurium and different doses of cisatracurium in a prospective, randomized double-blind study of crossover design. The investigation was conducted in 30 postoperative adult patients who met the following criteria: stable haemodynamic and respiratory condition, controlled artificial ventilation of the lungs and continuous sedation, without known ophthalmological pathology, and preoperative classification of ASA I or II. Patients remained in the intensive care unit for rewarming and to ensure a controlled, benign wake-up phase following extended surgery (Table 1). At the time of examination, the patients' cardiopulmonary situation was stable, they had no laboratory abnormalities or neuromuscular diseases, and they were free from any known allergies to non-depolarizing neuromuscular blocking drugs. Patients whose underlying or concomitant diseases were indicative of a potential association with an IOP change (brain oedema, thoracic trauma, etc.) were excluded from the study. Patients were not liable to receive catecholamines during the study. Lung ventilation was volume-controlled (Evita ventilator®; Dräger, Lübeck, Germany) with FiO2 = 0.3−0.4. End-tidal carbon dioxide (CO2) partial pressure was 4.7-6.0 kPa; body temperature was 36-37°C. The haemodynamic status was monitored by continuous recordings of the electrocardiogram (ECG), heart rate (HR), mean arterial pressure (MAP, invasive) and central venous pressure (CVP). The respiratory variables arterial CO2 (PaCO2) and arterial oxygen saturation (SPO2, measured by pulse oximetry) were monitored. The patients were continuously sedated with midazolam 0.05-0.1 mg kg−1 h−1 (Dormicum®; Hofmann-La Roche AG, Basel, Switzerland) and sufentanil 1-3 μg kg−1 h−1 (Sufenta®; Janssen Pharmaceutica, Beerse, Belgium). Likewise, no neuromuscular blocking drugs were administered for a minimum of 6 h prior to the onset of examination.

Table 1
Table 1:
Operation and diagnosis of patients.

In a first test series, 20 patients selected from a randomization list in a crossover mode received a bolus dose of atracurium (0.5 mg kg−1 Tracrium®) and cisatracurium (0.1 mg kg−1, Nimbex®; both Glaxo Wellcome Operations, Greenford, UK) via the intravenous route, with the second dose not being administered until 6 h after the first. In a second test series, 10 patients received 0.02 and 0.05 mg kg−1 cisatracurium in an identical crossover procedure (Fig. 1). IOP were always obtained from the left eye by the same ophthalmologist, who was blinded to the study medication and who used a Perkins' hand-held applanation tonometer (Perkins MK2®; Clement Clarke International Ltd, Harlow, UK) [8]. The measurements were taken before (T0) and 1 (T1), 5 (T5), 10 (T10), 15 (T15), 20 (T20) and 45 (T45) min after the application of the bolus dose. Concomitantly, HR, MAP, CVP, PaCO2 and SPO2 were also recorded.

Figure 1
Figure 1:
Design of the study.

IOP and all other haemodynamic and respiratory variables were described as mean ± SD. Differences to baseline values within groups were statistically tested using the Bonferroni-Holm adjusted paired t-test. To compare repeated measures between groups, the average height of the IOP curve from T0 to T20 was computed as a summary measure and compared using ANOVA for crossover designs [9], and adjusted for a potential periodic effect. P < 0.05 was considered as significant. The statistical analysis system SAS 6.12® (SAS Institute, Inc., Cary, NC, USA) was used for statistical analysis.

Results

There were no significant differences between the 30 patients examined for characteristics data (age, body weight, gender) (Table 2). No changes between or within groups were observed with regard to the haemodynamic (HR, MAP, CVP) and respiratory (PaCO2, SPO2) variables measured concomitantly (Table 3). The application of neuromuscular blocking drugs resulted in a decrease of IOP from roughly identical baseline values. One minute after administration, a twofold ED95 of atracurium and cisatracurium showed a significant decrease of IOP from 13.6 ± 2.1 to 12.6 ± 2.0 mmHg for atracurium and from 13.0 ± 1.6 to 11.9 ± 2.0 mmHg for cisatracurium. After 5 min, the IOP was 8.7 ± 2.4 and 8.4 ± 2.4 mmHg, respectively. The maximum mean reduction after 10 min was 7.9 ± 2.1 mmHg for atracurium and 6.7 ± 2.2 mmHg for cisatracurium. After that, the IOP rose again and after 45 min nearly reached baseline values of 12.0 ± 2.1 mmHg for atracurium and 11.8 ± 2.1 mmHg for cisatracurium (Fig. 2). When comparing the two substances at equipotent dosages, no significant difference was found (P = 0.27). The effect of the IOP decrease was stronger for cisatracurium by an average of 0.54 mmHg within the first 20 min. The 95% confidence interval was between −0.46 and 1.56 mmHg. There was no periodic effect (P = 0.82).

Table 2
Table 2:
Patient characteristics.
Table 3
Table 3:
Heart rate, mean arterial pressure, central venous pressure, arterial carbon dioxide partial pressure and arterial oxygen saturation measured by pulse oximetry before (T0) as well as 1 (T1), 5 (T5), 10 (T10), 15 (T15), 20 (T20) and 45 (T45) min after the administration of atracurium and cisatracurium (each 2 × ED95), and cisatracurium 0.02 mg kg−1 and cisatracurium 0.05 mg kg−1.
Figure 2
Figure 2:
Intraocular pressure (IOP; mmHg) before and 1, 5, 10, 15, 20 and 45 min after application of atracurium (•) and cisatracurium (▵), each 2 × ED95 (n = 20). Data are group means with SD. The level of significance in comparison with baseline values is *P < 0.05.

The administration of ED95 (=0.05 mg kg−1) of cisatracurium produced a maximum effect after 10 min (T10) with a decrease of IOP to 8.4 ± 1.9 mmHg. The application of the repeat dose of cisatracurium (0.02 mg kg−1) led to the most pronounced and significant IOP decrease to 9.9 ± 3.4 mmHg after 15 min. Again, baseline values were approximately reached after 45 min (Fig. 3). When comparing the two groups, which were treated in a crossover mode, no significant difference was observed either (P = 0.44). The effect of IOP reduction was greater by 0.43 mmHg in patients treated with 0.05 mg kg−1 cisatracurium than in patients receiving 0.02 mg kg−1 within the first 20 min. The 95% confidence interval was between −0.78 and 1.64 mmHg. No periodic effect was observed (P = 0.37).

Figure 3
Figure 3:
Intraocular pressure (IOP; mmHg) before and 1, 5, 10, 15, 20 and 45 min after application of cisatracurium 0.02 mg kg−1 (♦) and cisatracurium 0.05 mg kg−1 (□) (n = 10). Data are group means with SD. The level of significance in comparison with baseline values is *P < 0.05.

Discussion

In patients with glaucoma and in ophthalmic surgery, ensuring a stable or reduced IOP (normal 10-20 mmHg) and, above all, avoiding unexpected increases of IOP is of crucial importance. It is known that the depolarizing neuromuscular blocking drug succinylcholine leads to an increase in IOP [10,11], and that the non-depolarizing neuromuscular blocking drugs have either no effect on, or result in, a decrease in IOP [1,12,13]. Jantzen and colleagues [14] observed a decrease in IOP 5 and 10 min after the administration of vecuronium. As this reduction of IOP was associated with a decrease in CVP, they assumed that the reduced IOP was the result of improved orbicular drainage. To determine the effect of the more recent, non-depolarizing neuromuscular blocking drug cisatracurium on IOP, we performed the present study using atracurium as a reference substance. The non-depolarizing neuromuscular blocking drugs, e.g. vecuronium, rocuronium and pancuronium, have not been shown to have any differences in their effects on IOP [13,15,16]. To minimize the concomitant factors, we performed the investigation in patients who were continuously sedated and intubated and who were in a stable cardiopulmonary status. The effects of sedation, in terms of a minor decrease in IOP [17], were thus in a steady-state and did not have any influence on the investigation. Given the constant performance of haemodynamic and respiratory variables (Table 3), changes in IOP due to circulatory reactions or variable respiration or ventilation patterns such as may occur during induction and, above all, intubation [18] may be excluded. To examine the first group, we used equipotent dosages of atracurium and cisatracurium, administering the twofold ED95, which corresponds to the intubation dose. The second group received an effective dose (ED95) and a repeat dose of cisatracurium. Both groups were treated in a crossover mode with a 6 h delay between the two different doses. We were thus able to examine realistic concentrations of activity. The IOP was measured with a Perkins' hand-held applanation tonometer [8], which is easy to use when measuring IOP precisely in the supine position according to Goldmann's applanation method. All measurements were performed as a standard routine with patients in the supine position. The 45 min examination corresponded to the clinical duration of action of cisatracurium after the administration of a twofold ED95[19]. Considering the onset time and duration of activity, the course of IOP roughly correlated with the pharmacodynamic profile of atracurium and cisatracurium. Only a minor delay of IOP decrease compared with the onset time of relaxation was observed. When comparing both substances, there was no difference between the intubation doses with regard to the course of IOP. The onset, extent and duration of the decrease in IOP were almost identical. IOP was reduced to approximately half of its baseline value (Fig. 2). Application of lower doses of cisatracurium also led to a decrease in IOP, with the onset time prolonged and the extent reduced, which was suggestive of dose dependency. The maximum decrease in IOP was about 40% of the effective dose ED95 and nearly 30% after the repeat dose. However, a significant and clinically relevant difference between the two dosages could not be observed (Fig. 3).

A decrease in IOP, which is necessary for ophthalmological purposes and which can be achieved by sedation or anaesthesia (administration of hypnotics, etc.) [20] or by using a carbonic anhydrase inhibitor or osmotically active substances [21], in intubated patients, as our findings suggest, is also attainable by relaxation with cisatracurium. A reduction of IOP with hypnotics or osmotically active infusions in patients undergoing ophthalmological surgery, who tend to be elderly and affected by a variety of conditions, may lead to dangerous circulatory situations. In view of its excellent circulatory stability and rare side-effects in patients with endotracheal intubation, the non-depolarizing neuromuscular blocking drug cisatracurium therefore represents a favourable alternative.

The exact mechanism of action for this effect of non-depolarizing neuromuscular blocking drugs is unknown. One important effect is certainly the action of neuromuscular blocking drugs on the extraocular muscles [22]. Considering the finding of Kelly and colleagues [11] that the IOP increased after the administration of succinylcholine - both with intact extraocular muscles and after the surgical separation of the ocular muscles from the bulb - a limit to the effect of neuromuscular blocking drugs on IOP changes exclusively to the orbital muscles appears to be insufficient. In view of the stable haemodynamic and respiratory situation during the study, IOP changes as a result of altered chorioidal perfusion are also unlikely. Likewise, an effect of the osmotic pressure gradient cannot be assumed considering the short duration of the study. The remaining potential mechanisms for IOP changes due to the action of neuromuscular blocking drugs, apart from effects on the extraocular muscles, are central actions or actions on the trabecular level that lead to a changing aqueous humour balance. It can be concluded that the neuromuscular blocking drug cisatracurium is suitable in clinical situations where both relaxation and a decrease in IOP are required. In view of the lack of action on the heart and circulatory system, as described in the literature, cisatracurium may also be recommended for use at lower dosages to achieve or maintain relaxation in patients with several ailments who require a reduction of IOP in addition to muscle relaxation.

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Keywords:

NEUROMUSCULAR NON-DEPOLARIZING AGENTS, atracurium, cisatracurium; OCULAR PHYSIOLOGY, intraocular pressure

© 2002 European Academy of Anaesthesiology