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On-line version ISSN 1806-907X
Rev. Bras. Anestesiol. vol.52 no.3 Campinas May/June 2002
Cisatracurium pharmacodynamics in renal transplantation *
Farmacodinámica del cisatracúrio en el transplante renal
Ismar Lima Cavalcanti, TSA, M.D.I; Maria Angela Tardelli, TSA, M.D.II; Rita de Cássia Rodrigues, TSA, M.D.II
IResponsável pelo CET/SBA do
Hospital Geral de Nova Iguaçu, RJ
IIProfessora Adjunta da Disciplina de Anestesiologia, Dor e Terapia Intensiva Cirúrgica da Escola Paulista de Medicina da Universidade Federal de São Paulo, UNIFESP
BACKGROUND AND OBJECTIVES: Cisatracurium
seems to be beneficial, especially for patients with organ dysfunction, due
to organ-independent Hofmann elimination and a lower trend to histamine release.
This study aimed at determining cisatracurium pharmacodynamic profile in renal
METHODS: Participated in this study 30 patients who were distributed in two groups: 15 healthy patients submitted to maxillofacial surgery, and 15 patients with chronic renal failure submitted to renal transplantation. All patients were anesthetized with etomidate, sufentanil and 0.5% to 1% sevoflurane . Intravenous cisatracurium was administrated after anesthetic induction and additional 0.05 mg.kg-1 was injected whenever T1 recovered 25%. Neuromuscular function was continuously monitored by acceleromyography using TOF stimulation, through supramaximal ulnar nerve stimulation.
RESULTS: Onset time (4.1 and 4.9 min), clinical duration (68.9 and 75.4 min) and recovery time (20.2 and 28 min) were similar between normal and renal failure groups, respectively. Time spent until T4/T1 > 0.7 (34.3 and 51.4 min), and > 0.9 (49.7 and 68.6 min) since the last 25% recovery of T1 were statistically different between groups, with the higher values observed in the renal failure group. Accumulation ratio was 1.08.
CONCLUSIONS: Onset, clinical duration and recovery time were comparable between groups. Time to T4/T1 > 0.7 and > 0.9 was longer in the renal failure group as compared to the normal group and cisatracurium did not show cumulative effects in the renal failure group.
Key words: NEUROMUSCULAR BLOCK, Nondepolarizing: cisatracurium; SURGERY, Urologic: renal transplantation
JUSTIFICATIVA Y OBJETIVOS: La escoja del
cisatracúrio, especialmente en los enfermos con insuficiencia orgánica,
parece ser benéfica, debido a su eliminación órgano independiente
de Hofmann y menor tendencia a liberar histamina. Este trabajo tiene como objetivo
determinar, en enfermos portadores de insuficiencia renal crónica, la farmacodinámica
del cisatracúrio durante el transplante renal.
MÉTODO: Fueron estudiados 30enfermos divididos en dos grupos, 15 con función renal normal sometidos a cirugía bucomaxilo-facial y 15 portadores de insuficiencia renal crónica sometidos a transplante renal bajo anestesia general con etomidato, sufentanil y sevoflurano en concentraciones entre 0,5 y 1% de fracción expirada. Recibieron dosis venosa de 0,15 mg.kg-1 de cisatracúrio en la inducción y 0,05 mg.kg-1 todas las veces que T1 recuperaba 25%. La función neuromuscular fue monitorizada de forma continua por aceleromiografia utilizando el patrón de estimulación secuencia de cuatro estímulos, a través de la estimulación supramáxima del nervio ulnar.
RESULTADOS: Los resultados referentes a la farmacodinámica del cisatracúrio muestran que el inicio de acción (4,1 y 4,9 min), la duración clínica (68,9 y 75,4 min) y el índice de recuperación (20,2 y 28 min) fueron semejantes entre los grupos normal e insuficiencia renal, respectivamente. Los tiempos para la relación T4/T1 llegar a 0,7 (34,3 y 51,4 min) y 0,9 (49,7 y 68,6 min) a partir del último 25% de T1 presentaron diferencia estadísticamente significante entre los grupos, con los mayores valores en el grupo de insuficiencia renal. La razón de acumulación fue igual a 1,08.
CONCLUSIONES: El inicio de acción, la duración clínica y el índice de recuperación son semejantes entre los dos grupos, el tiempo para la relación T4/T1 llegar a 0,7 ó 0,9 fue mayor en el grupo de insuficiencia renal de que en el grupo normal y el cisatracúrio no presentó efecto acumulativo en el grupo de insuficiencia renal.
Chronic renal failure is a consequence of irreversible renal function degeneration. The poor kidney excretion, metabolic and endocrine function leads to uremic syndrome characterized by several systemic changes, especially metabolic, neurological and muscular. Chronic renal failure approach involves different techniques. In patients with progressive renal tissue destruction, dialysis and renal transplantation are indicated to reestablish renal function. Transplantations offer the possibility of reestablishing renal function in addition to correcting uremia metabolic abnormalities 1. In the USA, renal transplantation corresponds to one third of solid organ transplantations 2.
General anesthesia is the most widely used anesthesia technique for renal transplantation. Neuromuscular blockers are part of general anesthesia and are necessary to assure muscle relaxation needed for tracheal intubation, assisted ventilation and surgical field facilitation 3.
Cisatracurium pharmacological properties, especially the uniqueness of having virtually kidney-independent excretion, make it a potential agent for renal failure patients 4.
Studies published to date on cisatracurium in chronic renal failure patients have not been performed in renal transplanted patients and this has motivated our study.
This study aimed at establishing cisatracurium pharmacodynamics in chronic renal failure patients, during renal transplantation.
After the Ethical Research Committee approval and the patients informed consent, participated in this study 30 patients aged 16 to 65 years. Patients were distributed in two groups according to their renal function. Patients with normal renal function, physical status ASA I and submitted to elective maxillofacial surgeries were included in the control group (LN). Patients with chronic renal failure, physical status ASA III, to be submitted to renal transplantation were included in the renal failure group (RF). All patients had creatinine clearance < 10 ml.min-1 and were submitted to dialysis up to 24 hours before surgery. To be included in this group, all patients received azathioprine, cyclosporine and prednisolone.
All patients were clinically evaluated before surgery. The following parameters were evaluated: hemoglobin, hematocrit, creatinine, electrolytes (sodium, potassium and calcium), albumin, fasting glycemia, chest X-ray and ECG. All patients were informed about the anesthetic technique. Patients were premedicated with oral midazolam (7.5 mg), one hour before surgery.
Standardized monitoring consisted of pulse oximetry, inspired and expired gases multianalysis, invasive blood pressure and peripheral and esophageal temperature.
Neuromuscular function (NMF) was continuously monitored by acceleromyography in the upper contralateral limb to the venous access using TOF stimulation with supramaximal ulnar nerve stimulation through two 1 cm surface electrodes placed on the wrist. Surface electrode installation was preceded by cleaning, degreasing, trichotomy and skin drying. Abductor pollicis muscle contraction strength amplitude obtained as response to stimulation was recorded by accelerometry. The monitored limb was permanently immobilized. Peripheral temperature was maintained by convection heating with a thermal blanket.
Neuromuscular blockade level (NMB) was quantified as a percentage of initial standard response amplitude - T1/T0 - where T1 represents first TOF response amplitude and T0 the standard response with no NMB level.
Venous access was obtained in a large vein punctured with a 16G catheter which was used for hydration and drug administration.
Anesthesia was induced in both groups with intravenous alfentanil (0.5 mg), followed by preoxygenation with 100% O2 under mask in a ventilatory system with CO2 absorber. The admission gas flow was 6 L.min-1. Intravenous etomidate (0.2 mg.kg-1 ) was administered 3 minutes later. Patients were ventilated under mask with 100% O2 and 0.5% to 1% end tidal sevoflurane for some minutes, while an observer (number 1) checked supramaximal stimulation response which was considered as the first standard response. Five minutes after stabilinzing muscle response to TOF stimulation, 0.15 mg.kg-1 cisatracurium was injected in 10 seconds and intravenous sufentanil (1 µg.kg-1 ) was administered at the same speed, followed by its continuous infusion in a maximum dose of 0.5 µg.kg-1.h-1. Tracheal intubation was performed 3 minutes after cisatracurium injection.
Controlled ventilation was installed and end tidal CO2 (PET CO2 ) was maintained between 34 and 38 mmHg.
Patients warming was controlled to maintain esophageal temperature between 36 and 37ºC.
Anesthesia was maintained with 100% oxygen, 0.5% to 1% sevoflurane end tidal concentration and sufentanil in the same infusion speed. When blood pressure or heart rate were > 20% of preanesthetic baseline values, 0.2 µg.kg-1 sufentanil were injected. To maintain neuromuscular block in Group RF, 0.05 mg.kg-1 intravenous cisatracurium was administered when T1 recovered 25% of initial contraction. Group LN has not received maintenance doses.
Systolic and diastolic blood pressure and heart rate were recorded in the following moments:
0 = preanesthetic;
1 = 1 minute after cisatracurium injection;
2 = 3 minutes after cisatracurium injection;
3 = immediately after tracheal intubation;
4 = 5 minutes after cisatracurium injection;
5 = when T1 = 0%;
6 = at first T1 25% recovery;
7 = at last T1 75% recovery;
8 = when T1/T0 = 0.7;
9 = when T1/T0 = 0.9.
Time elapsed for total absence of muscle response (100% blockade, T1 = zero) was observed after cisatracurium injection.
Time for 25% and 75% neuromuscular function recovery and time elapsed considering the last T1 25% recovery were recorded at surgery completion, so that the ratio between contraction height of last and first TOF response was = 0.7 and 0.9.
Anesthesia was maintained until recovery of 100% neuromuscular function. All patients were extubated in the operating room.
In all moments in which neuromuscular function data were recorded, blood pressure, heart rate, peripheral and central temperature data were also recorded.
The following parameters were adopted:
1) Onset: time - Time elapsed until 100% block
of muscle response (T1 = 0), after end of neuromuscular blocker injection;
2) Clinical duration - Time elapsed from the end of neuromuscular blocker administration to the first TOF response of 25% of baseline value;
3) Recovery time - Time elapsed between 25% and 75% spontaneous muscle response recovery;
4) T4/T1 ratio = 0.7 and 0.9 - Time elapsed until the T4/T1 ratio reaches 0.7 and 0.9 after the last T1 25% recovery.
5) Accumulation ratio - Duration of last maintenance dose divided by duration of first maintenance dose.
Data were submitted to Students t test for age, height and body mass index, to Chi-square test for gender, to Mann-Whitneys U test for pharmacokinetic parameters and to Kruskal-Wallis test for heart rate and mean blood pressure. Significance level was 5% (p < 0.05).
Groups were similar in age, weight, height, gender and body mass index (Table I).
Cisatracurium clinical duration and recovery time were similar between groups. Times for T4/T1 to reach 0.7 and 0.9 counted from the last 25% recovery of T1 were statistically different between groups with higher values for the renal failure group (Table II).
Cisatracurium has not shown cumulative effects in patients submitted to renal transplantation (Table III).
Heart rate remained stable in both groups (Table IV).
The normal group had a 24% and 19% mean blood pressure decrease in moments 4 and 5, as compared to moment 0. Mean blood pressure variations in the chronic renal failure group were not statistically significant during anesthesia (Table V).
Clinical experience has shown that the isomer 1R-cis, 1R-cis atracurium (cisatracurium), present in approximately 15% of the racemic mixture making up atracurium, had a lower trend to release histamine and higher muscle relaxation potency as compared to atracurium, confirming what had been previously found in animal experiments 6.
Hoffmanns elimination accounts for 77% of total body clearance and organ-dependent elimination accounts for 23%. Renal clearance, a component of organ-dependent clearance, accounts for 16% of total body clearance 7.
Acceleromyography is similar to mechanomyography which is considered the standard monitoring method in neuromuscular blocker studies. Acceleromyography in clinical phase IV studies, is considered an adequate monitoring method 8.
NMB onset is defined as time elapsed between NMB injection and T1 depression below 95% 8, and is affected by neuromuscular junction perfusion, neuromuscular blocker potency, dose and administration route, type of anesthesia and stimulation pattern 9-11.
In our observations, cisatracurium onset, although longer in the RF group was not statistically different from control and similar to that of Boyd et al. 12 and Soukup et al. 13, who applied as parameter T1 depression >95%. However, in studies by Boyd et al. 12 and Hunter et al. 14, there has been a statistically significant difference in time for 90% depression of T1, with longer times in chronic renal failure patients. Similar result was obtained by Dahaba et al. 15 who adopted as onset standard 100% of motor response depression.
Authors who have found significant neuromuscular blocker onset differences between patients with and without renal failure explain their results by the difference in hemodynamic behavior between groups. Cardiac output decrease in response to anesthetic agents in renal failure patients would account for the decrease in neuromuscular blocker supply to the neuromuscular junction 12,16. Considering that both studied groups showed no cardiovascular changes throughout anesthetic induction, this would justify onset time similarity. In all comparative studies where cisatracurium pharmacodynamics has been evaluated, including our study, onset was always longer in the chronic renal failure group, regardless of statistical significance. Hunter 16 suggests that such behavior could be a consequence of the mild increase in distribution volume in chronic renal failure patients.
Neuromuscular blocker onset is inversely related to the dose. Time for maximum blockade is markedly decreased with doses one to three times DE95. Above three times DE95 there is no apparent decrease of the for 100% blockade when doses are increased 17,18.
When comparing our study to Dahaba et al.s 15 who also considered onset as time to 100% motor block, it can be observed that values differed in 2 minutes. Dahaba et al. 15 used two times DE95, while our study used three times DE95, however. Soukoup et al. 13, using three times DE95, have found values approximately 1 minute below our study. This difference could be a consequence of the fact that Soukoup et al. 13 have defined onset as the time to 95% depression of the initial muscular response, while we have adopted 100% depression as the standard.
Inhalational anesthetics interfere with NMB pharmacody- namics by directly acting on the neuromuscular junction or indirectly by modifying their pharmacokinetics as result of hemodynamic changes. Inhalational anesthetics induce muscle relaxation in a dose-dependent manner 19.
Soukoup et al. 13 have used during induction 1 MAC sevoflurane associated to 60% nitrous oxide. Halogenate participation in onset must have been secondary since there was not enough time for the equilibrium between isoflurane end tidal concentration and the muscular compartment 11.
Our results were not influenced by the inhalational agent since sevoflurane in concentrations below 0.5 MAC is similar to total intravenous anesthesia in terms of neuromuscular function effects 20.
Concerning the hemodynamics effects of induction, etomidate did not induce significant changes of the hemodynamic parameters, so excluding the possibility of cardiac output changes interfering on onset 21-23.
Onset is also changed as a function of the frequency of neuromuscular function monitoring stimulation. Muscle response suppression is faster when higher stimulation frequencies are used (1 Hz) and slower with lower frequencies (0.1 Hz) 24. Stimulation pattern interference on onset was not a factor to be taken in consideration since all studies on cisatracurium pharmacodynamics have used TOF as the stimulation standard.
Clinical duration, or duration 25, is defined as the time, in minutes, from neuromuscular blocker administration to the first TOF stimulation response to recover 25% of baseline values 8.
Studies evaluating cisatracurium duration in renal failure patients, including ours, have recorded longer recovery times, however without statistical significance as compared to normal patients 12,13,15.
Cisatracurium pharmacokinetics study in end-stage renal failure patients has shown a 13% decrease in clearance as compared to normal renal function patients. This difference was highly significant (p < 0.005) 5. This result contrasts with atracuriums where clearance is similar for both groups 25. Cisatracurium t1/2b is approximately 4 minutes longer in chronic renal failure patients 4. These pharmacokinetic differences confirm pharmacodynamic studies findings on cisatracurium recovery characteristics in normal patients as compared to renal failure patients and could suggest some renal participation in cisatracurium clearance and less dependence on Hoffmanns elimination.
Cisatracurium duration, similar to other neuromuscular blockers, is prolonged with increased doses, however this effect is not as dose-dependent as it is the case with aminosteroid agents 26. So, 0.1 mg.kg-1, 0.2 mg.kg-1, 0.25 mg.kg-1 and 0.4 mg.kg-1 of cisatracurium in healthy adults result in clinical duration of 45, 68,79 and 91 minutes, respectively 26,27.
Results were not uniform when clinical duration was evaluated as a function of cisatracurium dose. Boyd et al. 12 and Soukoup et al. 13 results have shown similar times, between 45 and 50 minutes, although evaluating different doses (0.1 and 0.5 mg.kg-1, respectively). Our results with 0.15 mg.kg-1 of cisatracurium showed a clinical duration approximately 20 minutes longer for both groups. This difference could be attributed to the fact that isoflurane further increases muscle blood flow as compared to sevoflurane, what would promote faster neuromuscular blocker removal from the endplate 28.
Recovery time is defined as time elapsed for single stimulation response recovery between 25% and 75% of baseline values. This represents the initial neuromuscular blocker recovery phase 8. Generally in this phase there is a linear correlation between the logarithm of plasma concentration and drug effect 29. Recovery time is an objective measurement of neuromuscular blocker accumulation 30. Bozo 30 considers high accumulating neuromuscular blockers those with recovery time between 40 and 45 minutes, low accumulating those with values between 12 and 14 minutes and no accumulating those with values between 7 and 10 minutes. With the exception of some authors 13,27, who recorded 9 and 12 minutes for healthy patients recovery, in other studies where cisatracurium was evaluated in normal or renal failure patients, including ours, values were closer to 20 minutes 12,15,26,31. This value would classify atracurium as a blocker with some cumulative effect according to Bozos classification 30.
While in pharmacodynamic terms it is said that a neuromuscular blocker does not accumulate when 25% to 75% recovery does not depend on dose or blockade duration, in practice the term non-cumulative refers to those whose duration is not changed by repeated doses 30.
As to clinical duration, cumulative effect may be objectively measured by the accumulation ratio. Accumulation ratio is the last maintenance dose duration divided by the first maintenance dose duration. The closer to 1 and the higher the number of repeated doses, the lower will be a neuromuscular blocker accumulation 30.
The cumulative effect may be explained by pharmacokinetic factors. Neuromuscular blockers recovery is a function of their plasma concentration decrease. After a single neuromuscular blocker dose with minor plasma metabolism, plasma concentration is rapidly decreased due to redistribution from central to peripheral compartments. With maintenance doses, neuromuscular blocker amounts in peripheral compartments limit this distribution phase. So, decreased plasma concentrations are the result of drug metabolism and excretion. This is seen with pancuronium, pipecuronium, doxacuronium and, in a lesser degree, with vecuronium and rocuronium. Pharmacokinetic analysis of nondepolarizing neuromuscular blockers with high plasma metabolism, such as mivacurium, atracurium and cisatracurium, shows that there is no clear distribution phase with rapid plasma concentration decrease. The result is that blockade recovery depends more on metabolism than on redistribution, so the recovery is similar between first dose and repetition doses 30. There are no data in the literature on cisatracurium accumulation ratio. The use of this concept in our study has shown, in the renal failure group, an accumulation ratio of 1.08 when two or more repetition doses were administered. So, from this result, one could conclude that, in the conditions of our study, there is no cisatracurium cumulative effect in renal failure patients.
Total neuromuscular blocker recovery may be defined as the state in which any clinical test (for example, ability to raise the head for 5 seconds) or nervous stimulation model (with T4/T1 ratio > 0.7) will produce a response similar to that observed in patients awakening from a comparable general anesthesia where no NMB was used 30.
The incidence of residual blockade defined as T4/T1 < 0.7 in the recovery room, varies between 0% and 10% for intermediate action neuromuscular blockers and between 20% and 50% for long acting NMBs 32-41.
Until recently, a T4/T1 > 0.7 ratio was accepted as adequate neuromuscular blocker standard recovery for reflecting normal vital capacity and inspiratory effort 42,43. When T4/T1 = 0.7, there may be signs and symptoms of residual neuromuscular block, such as diplopia, weakened grip, inability to seat without help and intense facial weakness 44. Eriksson et al. 45,46, have shown that only T4/T1 > 0.9 is related to normal ventilatory response to hypoxemia. Upper esophageal sphincter tone is significantly decreased with potential gastric content regurgitation when T4/T1 = 0.8. However, swallowing difficulty disappears when T4/T1 > 0.9 47. In addition, it is necessary a T4/T1 = 0.9 to assure normal ventilation control during immediate postoperative period 48.
In our study, T4/T1 > 0.7 was below values reported in the literature, even as compared to those using 0.1 mg.kg-1 12,13,27,49,50. Lower values could be explained by the difference in T4/T1 > 0.7 recovery evaluation method. While we considered this time as from 25% of T1 to T4/T1 > 0.78, the above mentioned authors measured this time since cisatracurium injection.
Differently from other authors 12,13, we have found higher T4/T1 > 0.7 values in the chronic renal failure group with statistically significant differences. The same result was seen for T4/T1 > 0.9, although we did not find data in the literature on T4/T1 > 0.9.
Some considerations are needed to help explain the longer time found in the renal group for total neuromuscular block recovery evaluated by T4/T1 >0.7 and/or T4/T1 > 0.9.
TOF stimulation is the standard procedure to determine neuromuscular block level in a more sensitive way than single stimulation and is comparable to 50 Hz tetanus 43.
Muscle response depression to single stimulation and TOF stimulation fatigue result from blockers binding to different sites. Bowman 51 has suggested that fatigue could be the expression of neuromuscular blocker binding to presynaptic receptors while single stimulation response would be more a function of postsynaptic binding. Myographical and electrophysiological studies indicate that fatigue could result both from presynaptic and postsynaptic effects, depending on the neuromuscular blocker 52. Based on pre and postsynaptic sites, neuromuscular blockers could be divided in two groups. It seems that drugs with poor discrimination of pre and postsynaptic sites poorly differentiate between isolated and tetanic contractions, such as pancuronium and vecuronium. However, agents with more discriminating power between presynaptic (atracurium) and postsynaptic (hexamethonium) sites, better discriminate isolated from tetanic contractions 53.
Fatigue, expressed in the T4/T1 = 0.7 and 0.9 ratio and found in our study, can be explained by the theory of neuromuscular blockers ability of discriminating isolated and tetanic contractions.
Agents able to well differentiate pre and postsynaptic sites are those which better discriminate isolated and tetanic contractions. On the other hand, drugs with similar action in pre and postsynaptic sites poorly differentiate isolated and tetanic contractions 53.
The difference between both neuromuscular blockers electrophysiological behaviors is determined by the observation that for agents that discriminate pre and postsynaptic sites (isoquinolines) it is necessary to substantially increase the concentration in which the compound acts on tetanic contractions for them to also affect isolated contractions, what is not true for agents that poorly discriminate the sites (steroids). This way, it can be said that the first group affects neuromuscular transmission safety margin in just one component, while the second group would affect both components 53.
Cisatracurium, due to its isoquinoline structure, could well discriminate pre and postsynaptic sites; and being one of the atracurium components, it would have a similar behavior expressed by a higher presynaptic receptors affinity.
In addition, the renal group has differed from the control group by the use of immunosupressants and steroids. The interaction of immunosupressants and neuromuscular blockers is controversial. Cyclosporine potentiates atracurium and vecuronium and is associated to increased postoperative respiratory failure 54,55. Azathioprine does not interfere with neuromuscular blocker level. Chronic treatment with high steroid doses delays vecuronium-induced blockade 56.
The conclusion was that onset, clinical duration and recovery time were similar for normal and renal failure groups; time for T4/T1 ratio = 0.7 or 0.9 was longer in renal failure patients and cisatracurium does not seem to accumulate in chronic renal failure patients.
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Dr. Ismar Lima Cavalcanti
Address: Rua Alberto de Campos, 77 Cob. 1106 Ipanema
ZIP: 22471-020 City: Rio de Janeiro, Brazil
Submitted for publication August 15, 2001
Accepted for publication October 29, 2001
* Received from Hospital Universitário Pedro Ernesto da Universidade do Estado do Rio de Janeiro e da Disciplina de Anestesiologia, Dor e Terapia Intensiva Cirúrgica da Escola Paulista de Medicina da Universidade Federal de São Paulo (UNIFESP)