Effect of atracurium on pancuronium-induced neuromuscular block recovery

Abstracts

JUSTIFICATIVA E OBJETIVOS: Freqüentemente em cirurgias abdominais, na fase de fechamento da parede, há necessidade de doses adicionais de bloqueador neuromuscular. O objetivo deste estudo foi analisar, na vigência de recuperação parcial do bloqueio neuromuscular induzido pelo pancurônio, o efeito da administração de dose complementar de atracúrio sobre a recuperação espontânea do bloqueio neuromuscular. MÉTODO: Foram estudados 30 pacientes, divididos em dois grupos, 14 pacientes formaram o grupo pancurônio e 16 pacientes, o grupo atracúrio. A função neuromuscular foi monitorizada de forma contínua por acelerometria do músculo adutor do polegar, utilizando a seqüência de quatro estímulos (SQE), através da estimulação supramáxima do nervo ulnar. A indução da anestesia foi feita com propofol, fentanil, pancurônio 0,08 mg.kg-1 e a manutenção com N2O 60% em oxigênio e isoflurano na concentração expirada de 0,5%. Quando a primeira contração da seqüência de quatro estímulos (T1) recuperou 25%, o grupo pancurônio recebeu pancurônio 0,025 mg.kg-1 e o grupo atracúrio, 0,20 mg.kg-1 de atracúrio. Após a dose complementar foram anotados os tempos para recuperação espontânea de T1 igual a 10%, 25%, 75%, do índice de recuperação (IR25-75%) e da relação T4/T1 igual a 0,8. RESULTADOS: Os tempos de recuperação espontânea após dose complementar de pancurônio ou atracúrio não diferiram quando avaliados pela recuperação de T1 em 10% (45,00 ± 15,50 vs 49,69 ± 9,41), 25% (61,64 ± 18,58 vs 64,25 ± 12,51) e 75% (94,00 ± 28,52 vs 84,69 ± 16,50). O IR25-75% (32,36 ± 13,76 vs 20,44 ± 9,24) e o tempo de recuperação da relação T4/T1 = 0,8 (176,86 ± 29,57 vs 141,50 ± 29,57) foram menores no grupo do atracúrio. CONCLUSÕES: Nas condições deste estudo, a complementação com atracúrio não promoveu alteração na recuperação espontânea inicial do bloqueio neuromuscular induzido pelo pancurônio e promoveu diminuição de 20% no tempo de recuperação total.

BLOQUEADORES NEUROMUSCULARES; BLOQUEADORES NEUROMUSCULARES; BLOQUEADORES NEUROMUSCULARES; MONITORIZAÇÃO

SCIENTIFIC ARTICLE

Effect of atracurium on pancuronium-induced neuromuscular block recovery^*

Efecto de la administración del atracúrio sobre la recuperación del bloqueo neuromuscular inducido por el pancuronio

Luís Fernando Rodrigues Maria, M.D.^I; Maria Angela Tardelli, TSA, M.D.^II; Rita de Cássia Rodrigues, TSA, M.D.^II

^IMestre em Anestesiologia pela UNIFESP EPM

^IIProfessora Adjunta da Disciplina de Anestesiologia, Dor e Terapia Intensiva, UNIFESP EPM

^{Correspondence}

SUMMARY

BACKGROUND AND OBJECTIVES: Additional neuromuscular blocker doses are in general needed during wall closing after abdominal surgeries. This study aimed at determining during partial pancuronium-induced neuromuscular block recovery, the effect of additional atracurium dose on spontaneous neuromuscular block recovery.

METHODS: Participated in this study 30 patients divided in two groups: pancuronium group (n = 14) and atracurium group (n = 16). Neuromuscular function was continuously monitored by accelerometry of abductor pollicis muscle using TOF to supramaximally stimulate ulnar nerve. Anesthesia was induced with propofol, fentanyl and 0.08 mg.kg^-1 pancuronium, and was maintained with 60% N₂O in oxygen and 0.5% isoflurane expired concentration. When T₁ returned to 25% of control, 0.025 mg.kg^-1 pancuronium or 0.20 mg.kg^-1 atracurium were administered to pancuronium or atracurium group, respectively. Time for spontaneous T₁ recovery = 10%, 25%, 75% of recovery index (RI 25-75%) and time to T₄/T₁ equal 0.8 after complementary dose, were recorded.

RESULTS: There were no differences between groups on T₁ spontaneous recovery to 10% (45.00 ± 15.50 vs. 49.69 ± 9.41), 25% (61.64 ± 18.58 vs. 64.25 ± 12.51) and 75% (94.00 ± 28.52 vs. 84.69 ± 16.50). Recovery index (RI 25-75%) and time to T₄/T₁= 0.8 were shorter in the atracurium group.

CONCLUSIONS: In this study, atracurium complementation has made no difference in initial spontaneous recovery of pancuronium-induced neuromuscular block, but has decreased total recovery time in 20%.

Key Words: MONITORING: neuromuscular function; NEUROMUSCULAR BLOCKERS, Non-depolarizing: atracurium, pancuronium

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: Frecuentemente en cirugías abdominales, en la fase de cerramiento de la pared, hay necesidad de dosis adicionales de bloqueador neuromuscular. El objetivo de este estudio fue analizar, en la vigencia de recuperación parcial del bloqueo neuromuscular inducido por el pancuronio, el efecto de la administración de dosis complementares de atracúrio sobre la recuperación espontanea del bloqueo neuromuscular.

MÉTODO: Fueron estudiados 30 pacientes, divididos en dos grupos, 14 pacientes formaron el grupo pancuronio y 16 pacientes, el grupo atracúrio. La función neuromuscular fue monitorizada de forma continua por acelerometria del músculo aductor del pulgar, utilizando la secuencia de cuatro estímulos (SQE), a través de la estimulación supramáxima del nervio ulnar. La inducción de la anestesia fue hecha con propofol, fentanil, pancuronio 0,08 mg.kg^-1 y la manutención con N₂O 60% en oxígeno e isoflurano en la concentración expirada de 0,5%. Cuando la primera contracción de la secuencia de cuatro estímulos (T₁) recuperó 25%, el grupo pancuronio recibió pancuronio 0,025 mg.kg^-1 y el grupo atracúrio, 0,20 mg.kg^-1 de atracúrio. Después de la dosis complementar fueron anotados los tiempos para recuperación espontanea de T₁ igual a 10%, 25%, 75%, del índice de recuperación (IR25-75%) y de la relación T₄/T₁ igual a 0,8.

RESULTADOS: Los tiempos de recuperación espontanea después de la dosis complementar de pancuronio o atracúrio no divergieron cuando evaluados por la recuperación de T₁ en 10% (45,00 ± 15,50 vs 49,69 ± 9,41), 25% (61,64 ± 18,58 vs 64,25 ± 12,51) y 75% (94,00 ± 28,52 vs 84,69 ± 16,50). El IR25-75% (32,36 ± 13,76 vs 20,44 ± 9,24) y el tiempo de recuperación de la relación T₄/T₁ = 0,8 (176,86 ± 29,57 vs 141,50 ± 29,57) fueron mayores en el grupo en que la complementación fue realizada con pancuronio.

CONCLUSIONES: En las condiciones de este estudio, la complementación con atracúrio no promovió alteración en la recuperación espontanea inicial del bloqueo neuromuscular inducido por el pancuronio y promovió diminución de 20% en el tiempo de recuperación total.

INTRODUCTION

Neuromuscular blockers are beneficial in general anesthesia to promote relaxation needed for tracheal intubation as well as to help surgical field approach with no need for deep anesthesia ¹.

Pancuronium is a steroid non-depolarizing neuromuscular blocker characterized by long-lasting neuromuscular block and ideal for surgeries lasting more than 4 hours ^2,3.

Atracurium belongs to the benzylisoquinolinic class with shorter duration as compared to pancuronium, with the additional advantage of less dependence on organs for its excretion ⁴.

At intra-abdominal procedure completion, the degree of muscle relaxation in the surgical area is very important for adequate wall closing. Very often, additional neuromuscular blocker doses are needed in this stage of anesthesia to intensify muscle relaxation ⁵. This is particularly important when neuromuscular block is complemented with long-lasting agents. The repetition of non-depolarizing neuromuscular blockers such as pancuronium could, as a function of its long duration, imply longer time for total motor strength and normal ventilatory function recovery. At this point, atracurium, and not pancuronium, to complement pancuronium-induced neuromuscular block could, in theory, result in faster motor function recovery ^6,7.

This study aimed at evaluating during partial pancuronium-induced neuromuscular block recovery, the effect of additional atracurium dose on spontaneous neuromuscular block recovery, as compared to additional pancuronium dose.

METHODS

After the Ethics Committee approval, participated in this study 30 patients of both genders, aged 18 to 65 years, with up to 30% normal weight variation, physical status ASA I or II, with normal serum sodium, potassium, calcium and creatinine. Exclusion criteria were patients with liver or kidney dysfunction and those under drugs which could interfere with neuromuscular block ^8,9. Patients were randomly divided in pancuronium or atracurium group depending on the neuromuscular blocker received to complement initial pancuronium-induced neuromuscular block.

Patients were monitored with noninvasive blood pressure, ECG, pulse oximetry and gases multianalysis. All patients received 1 mg intravenous midazolam after venoclysis. Anesthesia was induced with 2 to 4 mg.kg^-1 propofol and 5 µg.kg^-1 fentanyl. After loss of consciousness, patients were ventilated under mask with 100% oxygen and 0.5% isoflurane (expired fraction). Neuromuscular function was monitored with accelerometry of adductor pollicis muscle using TOF stimulation with supramaximal ulnar nerve stimulation. After stabilization, all patients received 0.08 mg.kg^-1 pancuronium in five seconds to induce neuromuscular block. Anesthesia was maintained with 60% nitrous oxide in oxygen and 0.5% isoflurane (expired fraction). Fentanyl (2 µg.kg^-1) was administered whenever blood pressure rise above 20%, of control. Ventilation was adjusted to maintain P_ETCO₂ between 30 and 35 mmHg. Patients' temperature was controlled by the convection method through a thermal blanket on the chest and upper limbs, to maintain central temperature between 36 and 37 ºC and peripheral temperature above 32 ºC ^8,9.

After 25% T₁ recovery (T₁ = 25%) of the initial pancuronium-induced block (initial duration 25% - ID25%) additional 0.025 mg.kg^-1 pancuronium or 0.20 mg.kg^-1 atracurium was administered to pancuronium and atracurium group, respectively (Figure 1).

Brazilian Journal of Anesthesiology, 2004; 54: 3: 311 - 318

Effect of atracurium on pancuronium-induced neuromuscular block recovery

Luís Fernando Rodrigues Maria; Maria Angela Tardelli; Rita de Cássia Rodrigues

The effect of additional pancuronium or atracurium dose on spontaneous neuromuscular block recovery was evaluated through time elapsed from additional dose administration to first TOF contraction equal 10%, 25%, 75% and fourth to first TOF response ratio (T₄/T₁) equal 0.8. These times after additional dose were called complementary duration (CD), as represented in figure 1.

Blood pressure, heart rate, peripheral and central temperature were recorded, in addition to neuromuscular function monitoring data.

Data were submitted to Chi-square test for contingency 2 X 2 tables, aiming at comparing groups by gender and physical status (ASA). Student's t test was used to compare mean pancuronium and atracurium groups age, weight, height, serum sodium, potassium, calcium and creatinine levels.

Friedman's Analysis of Variance ¹⁰ was used to analyze ID25%, CD10%, CD75%, RI25-75% and CD = 0.8, to compare additional doses deltas for both pancuronium and atracurium groups. Mann-Whitney ¹⁰ test was used to compare pancuronium and atracurium groups in all studied moments, considering significant p < 0.05 or 5%.

RESULTS

Demographics data were homogeneous between groups. There has been predominance of ASA I patients in the atracurium group (Table I).

Brazilian Journal of Anesthesiology, 2004; 54: 3: 311 - 318

Effect of atracurium on pancuronium-induced neuromuscular block recovery

Luís Fernando Rodrigues Maria; Maria Angela Tardelli; Rita de Cássia Rodrigues

Mean time for 25% recovery of first T₁ contraction (ID25%) was similar for pancuronium and atracurium groups, 83.71 ± 28.15 and 94.69 ± 35.91, respectively.

Mean time for 10%, 25% and 75% recovery after complementary pancuronium or atracurium dose was similar for both groups. Recovery index (RI25-75%) was longer for pancuronium group, as well as mean time for T₄/T₁ to reach 0.8 (CD = 0.8) (Table II).

Brazilian Journal of Anesthesiology, 2004; 54: 3: 311 - 318

Effect of atracurium on pancuronium-induced neuromuscular block recovery

Luís Fernando Rodrigues Maria; Maria Angela Tardelli; Rita de Cássia Rodrigues

DISCUSSION

It is known that several available anesthetics when safely administered to patients are inadequate to promote satisfactory muscle relaxation, especially during intra-abdominal procedures. This inconvenient has been overcome by neuromuscular blockers ¹¹.

Pancuronium's DE₉₅ for adductor pollicis muscle block during nitrous oxide anesthesia is approximately 0.06 mg.kg^{-1 12}. Intubation dose between 0.08 and 0.12 mg.kg^-1 allows for laryngoscopy in 2 to 3 minutes. Clinical duration after 0.08 mg.kg^-1 is 86 minutes ¹³. Major pancuronium disadvantage is that 85% of its excretion is performed by kidneys, which may result in prolonged effect in the presence of kidney dysfunction ¹⁴.

Due to its prolonged effect, pancuronium is related to higher incidence of residual neuromuscular block in post-anesthetic recovery units, as compared to shorter duration blockers such as atracurium ¹⁵.

Atracurium's DE₉₅ is 0.17 to 0.33 mg.kg^{-1 16-19}. Intubation dose is 0.4 to 0.5 mg.kg^{-1 3}, and with this dose, clinical duration is 40 to 45 minutes ¹⁸. One advantage of atracurium over pancuronium is shorter clinical duration promoting faster motor strength recovery and being indicated when there is the need for less prolonged muscle relaxation ¹⁵.

Atracurium's weak dependence on organs for excretion and shorter clinical duration, as compared to pancuronium, respond for the lower incidence of postoperative residual blockade; approximately 4.3% and 36.2%, respectively ¹⁵.

Postoperative residual neuromuscular block is related to postoperative morbidity and mortality. The incidence of postoperative pulmonary complications among patients receiving pancuronium is 11%, while among those receiving atracurium it is 3.1% ²⁰. The practice of complementing long-lasting neuromuscular blockers with shorter duration agents has gained interest since the introduction of succinylcholine in the clinical practice in 1951. However, succinylcholine for this purpose has resulted in blockade antagonism or intensification, depending on the recovery stage it was administered ²¹. Considering the difficulties of using succinylcholine for complementation of long-lasting non-depolarizing neuromuscular blockers at surgery completion, and the introduction of atracurium and vecuronium in the clinical practice, it has been proposed that these new agents should replace succinylcholine for this objective ^6,7.

Our study has evaluated the effect of atracurium complementation in spontaneous pancuronium-induced neuromuscular block recovery, evaluating initial recovery (T₁ = 10%, 25% and 75%) and final recovery (T₄/T₁ = 0.8).

During neuromuscular block recovery, muscle response is present as from 10% recovery of T₁, when there is only one TOF contraction. In this stage, 90% of end plate nicotinic receptors are still under the action of neuromuscular blockers. When T₁ recovers to 25%, two to three TOF responses may be observed and 80% of nicotinic receptors are still under the action of neuromuscular blockers. Receptors occupation is still high, approximately 75%, with T₁ recovery = 100%²². So, T₁ recovery to 75% is the initial neuromuscular blocker recovery stage. Clinical duration or duration 25 is the time in minutes elapsed from neuromuscular blocker administration to first TOF response to recover 25% of baseline value ⁸. Time elapsed for T₁ recovery between 25% and 75% of baseline is defined as recovery index (RI25-75%). This measurement has been used to indicate the level of neuromuscular blockers build up ²³.

Values obtained in the first experimental sequence of this study have shown that the methodology was adequate since clinical duration for first pancuronium dose was similar to those described by other studies using total intravenous anesthesia ^5-13.

After complementation with atracurium it has been observed that times during initial spontaneous T₁ recovery to 75% were equal for both groups, in line with the literature ^5,24. The lack of difference in blockade recovery when complemented with pancuronium or atracurium allows the conclusion that there has been atracurium potentiating effect by previous pancuronium administration. One explanation would be that during initial blockade recovery stage, when dose is complemented with shorter duration blocker, most receptors are still occupied by the long duration neuromuscular blocker and blockade has predominantly the characteristics of the first agent. This synergistic and not only additive action with pancuronium may also be attributed to the fact that neuromuscular blockers do not act identically on end plate receptors; there are pharmacokinetic differences among these drugs and the presence of pre and post-synaptic nicotinic receptors, to which neuromuscular blockers have different affinities depending on their chemical class ^25,26. In theory, the concomitant effect of two drugs of different chemical classes would potentiate neuromuscular block.

Our results have shown that, when separately evaluated, times for T₁ to recover 25% (CD25%) and 75% (CD75%) were not significantly different between groups; however RI25-75% was statistically lower for the atracurium group. This result could be attributed to the fact that, although time for T₁ to recover 75% has not been statistically different between groups, there has been a trend to inequalities for atracurium group to present lower value (84.69 ± 16.50 vs. 94.00 ± 28.52). When RI25-75% was evaluated, this inequality has become statistically significant.

Atracurium recovery index after 2DE₉₅ is 13 minutes ¹⁷. In the presence of atracurium-induced neuromuscular block, additional 0.16 mg.kg^-1 doses result in clinical duration of 28.6 minutes without recovery index changes ⁵. In our study, although RI25-75% has been lower in the atracurium group, if its absolute value is considered, 50% increase is observed after 2 DE₉₅.

Increased recovery index and clinical duration, together with no statistical difference between groups in T₁ 10%, 25% and 75% recovery have shown a potentiating effect of pancuronium on complementary atracurium block.

Other studies have shown more intense potentiating effect of pancuronium with recovery indices after complementary atracurium doses of approximately twice the value found with complementary pancuronium ^5,24.

Final neuromuscular block recovery evaluation until T₄/T₁ equals 0.8 is justified because recovery studies aiming at ventilatory control, respiratory mechanics and airway protection suggest that there is no adequate recovery until T₄/T₁ is equal to or above 0.8 ⁸.

In our study, time for T₄/T₁ to reach 0.8 in the atracurium group has been statistically lower as compared to the pancuronium group, which would clinically mean faster final recovery with atracurium. This result is not in line with other studies which have not found differences in final T₄/T₁ recovery to 0.7 between groups ^5,24. Considering that these authors have evaluated T₄/T₁ recovery to 0.7, we cannot assure that final recovery to 0.8 would maintain this same trend.

Studies have shown that time for 25% T₁ recovery until T₄/T₁ = 0.75 after 0.5 mg.kg^-1 atracurium is 28.4 minutes. When atracurium is administered after pancuronium, recovery time from T₁ = 25% to T₄/T₁ = 0.75 is 72.6 minutes ^5,27. In our study, this interval enhanced for T₄/T₁ = 0.80 was 77.3 minutes. Although the atracurium group had final recovery time 20% shorter as compared to pancuronium, when absolute values are compared among studies, these data allow assuming that previous pancuronium administration has potentiated atracurium. So, although complementation with atracurium has promoted faster final recovery of pancuronium-induced neuromuscular block, complementary blockade characteristics were more similar to long duration blockade characteristics.

In the conditions of our study, analysis of results allows stating that complementary atracurium block during partial pancuronium-induced neuromuscular block recovery does not change initial spontaneous recovery and decreases in 20% time for T₄/T₁ to reach 0.8.

REFERENCES

Submitted for publication May 28, 2003

Accepted for publication August 20, 2003

• 01. Griffith HR, Johnson E - The use of curare in general anesthesia. Anesthesiology, 1942;3:418-420.
• 02. Baird WL, Reid AM - The neuromuscular blocking properties of a new steroid compound, pancuronium bromide. A pilot study. Br J Anaesth, 1967;39:775-780.
• 03. Savarese JJ, Miller RD, Lien CA et al - Pharmacology of Muscle Relaxants and their Antagonists, em: Miller RD - Anesthesia. 4^th Ed, New York, Churchill Livingstone, 1994;417-487.
• 04. Hunter JM, Jones RS, Utting JE - Use of atracurium in patients with no renal function. Br J Anaesth, 1982;54:1251-1258.
• 05. Nathan N, Bonada G, Feiss P - Potentiation of atracurium by pancuronium during propofol-fentanyl-N₂O anesthesia. Acta Anaesthesiol Belg, 1996;47:187-193.
• 06. Aps C, Inglis MS - Peritoneal closure and atracurium. Anaesthesia, 1984;39:187.
• 07. Feldman SA - Peritoneal closure and atracurium. Anaesthesia, 1984;39:946.
• 08. Viby-Mogensen J, Engbaek J, Eriksson LI et al - Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents. Acta Anaesthesiol Scand, 1996;40:59-74.
• 09. Heier T, Caldwell JE, Sessler DI et al - The relationship between adductor policis twitch tension and core, skin, and muscle temperature during nitrous oxide-isoflurane anesthesia in humans. Anesthesiology, 1989;71:381-384.
• 10. Siegel S, Castellan Jr NJ - Non Parametric Statistics. 2^nd Ed, New York Mcgraw-Hill, 1988;399.
• 11. Duarte DF - Curarizantes - das suas origens aos dias de hoje. Rev Bras Anestesiol, 2000;50: 330-336.
• 12. Engbaek J, Ording H, Pedersen T et al - Dose-response relationships and neuromuscular blocking effects of vecuronium pancuronium during ketamine anaesthesia; Br J Anaesth. 1984;56:953-957.
• 13. Katz RL - Clinical neuromuscular pharmacology of pancuronium. Anesthesiology, 1971;34:550-556.
• 14. McLeod K, Watson MJ, Rawlins MD - Pharmacokinetics of pancuronium in patients with normal and impaired renal functions. Br J Anaesth, 1976;48:341-345.
• 15. Bevan DR, Smith CE, Donati F - Postoperative neuromuscular blockade: a comparison between atracurium, vecuronium, and pancuronium. Anesthesiology, 1988;69:272-276.
• 16. Payne JP, Hughes R - Evaluation of atracurium in anesthetized man. Br J Anaesth, 1981;53:45-54.
• 17. Basta SJ, Ali HH, Savarese JJ et al - Clinical pharmacology of atracurium besilate (BW33A): a new non-depolarizing muscle relaxant. Anesth Analg, 1982;61:723-729.
• 18. Katz RL, Stirt J, Murray AL et al - Neuromuscular effects of atracurium in man. Anesth Analg, 1982;61:730-734.
• 19. Gramstad L, Lilleaasen P - Dose-response relation of atracurium, ORG NC45 and pancuronium. Br J Anaesth, 1982;54: 647-651.
• 20. Pedersen T, Viby-Mogensen J, Ringsted C - Anaesthetic practice and postoperative pulmonary complications. Acta Anaesthesiol Scand, 1992;36:812-818.
• 21. Rouse JM, Bevan DR - Mixed neuromuscular block. A re-assessment using train-of-four stimulation. Anaesthesia, 1979;34:608-613.
• 22. Tardelli MA - Monitorização do Bloqueio Neuromuscular, em: Sociedade Brasileira de Anestesiologia. Curso de Educação à Distância em Anestesiologia. São Paulo, Office, 2002:177-190.
• 23. Bustamante Bozzo R - Recuperación Espontánea y Revisíon Farmacológica de los Relajantes Musculares, em: Alvarez Gomez JA, González Miranda F, Bustamante Bozzo R - Relajantes Musculares. Madrid, Arám; 2000;129-137.
• 24. Whalley DG, Lewis B, Bedocs NM - Recovery of neuromuscular function after atracurium and pancuronium maintenance of pancuronium block. Can J Anaesth, 1994;41:31-35.
• 25. Waud BE, Waud DR, Phil D - Quantitative examination of the interaction of competitive neuromuscular blocking agents on the indirectly elicited muscle twitch. Anesthesiology, 1994;61: 420-427.
• 26. Amorós Arañó J, Solera Marin J, González Miranda F - Interacciones, em: Alvarez Gomez JA, Gozález Miranda F, Bustamante Bozzo R - Relajantes Musculares en Anestesia y Terapia Intensiva. Madrid, Arán; 2000;165-186.
• 27. Erkola O, Karhunen U, Sandelin-Hellqvist E - Spontaneous recovery of residual neuromuscular blockade after atracurium or vecuronium during isoflurane anaesthesia. Acta Anaesthesiol Scand, 1989;33:290-294.

Correspondence to

Dr. Luís Fernando Rodrigues Maria

Rua Floreal, 395 Agudo Romão

15802-145 Catanduva, SP

*

Received from Hospital São Paulo, SP

Publication Dates

• Publication in this collection
  02 July 2004
• Date of issue
  June 2004

History

• Accepted
  20 Aug 2003
• Received
  28 May 2003