Cardiopulmonary effects and eyeball centralization with low-dose atracurium in spontaneously breathing, anesthetized dogs/Avaliacao cardiopulmonar e da centralizacao do globo ocular em caes com baixas doses de atracurio mantidos em anestesia inalatoria sob ventilacao espontanea.
Neuromuscular blocking agents are commonly utilized as adjuvants to general anesthetics to facilitate ventilation, and in thoracic, orthopedic and intraocular surgeries, in this case to produce centralization of the eyeball (GLOVER & CONSTANTINESCU, 1997), keeping the cornea totally visible and thereby facilitating surgical procedures. However, there is the need of artificial ventilation due to respiratory paralysis.
The action of neuromuscular blocking agents is characterized by flaccid paralysis obtained at different speeds, depending on the body region. Generally, the oculomotor muscles are affected first, followed by the tail, oropharynx and limbs. The intercostals, diaphragm and abdominal muscles are the last ones to follow the sequence of paralysis. In summary, there is a progressive blockade, from the periphery to the center, where recovery occurs in reverse (HEMMERLING & DONATI, 2003).
The choice of low doses of neuromuscular blockers has advantages if a selective paralysis could be achieved, permitting adequate ventilation while the eye is centralized (CARREGARO et al., 2006). This facilitates the performance of intraocular surgeries and diminishes risks to the anesthetized patient. Animals anesthetized on spontaneous breathing maintain cardiovascular function at better baselines than animals on controlled ventilation (HARTSFIELD, 1996), the latter impeding venous return to the right side of the heart, reducing cardiac output and arterial pressure. Besides, the procedure is less expensive because there is no need for specific equipment for the maintenance of ventilation.
Studies have demonstrated the possibility of utilizing low doses of neuromuscular blockers and maintenance of pulmonary function. In the analysis of respiratory depression and muscle relaxation in dogs treated with 10[micro]g [kg.sup.-1] of pancuronium, eyeball centralization was achieved with moderate respiratory depression without however causing apnea and without the need for controlled ventilation in these animals (LEE et al., 1998).
Atracurium at a dose of 250[micro]g [kg.sup.-1] causes total muscle blockade of 15-35min of duration with minimal cardiovascular effects (HUGHES & CHAPPLE, 1981). In a preliminary study (CARREGARO et al., 2006), three doses of atracurium (25, 50 and 75[micro]g [kg.sup.-1]) were tested and found to cause eyeball centralization without complete blockade of the intercostal and diaphragmatic muscles. The time of centralization increased with dose, that was 38, 65 and 78min, respectively. However, there was an increase in end tidal C[O.sub.2] (ETC[O.sub.2]) in the 50[micro]g [kg.sup.-1] group for 5min with a peak near 50mmHg, and a stronger effect in the 75[micro]g [kg.sup.-1] group, with values almost as high as 60mmHg for 20min. The highly elevated ETC[O.sub.2] values obtained indicated a blood gas analysis for the adequate determination of these values.
The aim of this study was to determine the effects of 15 or 30[micro]g [kg.sup.-1] of atracurium on cardiopulmonary parameters and on the duration of eyeball centralization of anesthetized dogs under spontaneous breathing.
MATERIALS AND METHODS
For the study proposed, 18 mixed-breed dogs were utilized, 8 males and 10 females. The animals were considered healthy after performing clinical and ophthalmologic exam and laboratory tests (hemogram, urea, creatinine, alkaline phosphatase and alanine aminotransferase).
After 12h solid and 4h liquid fasting, animals were pre-medicated with 0.1mg [kg.sup.-1] acepromazine (a) and 0.5mg [kg.sup.-1] morphine (b) IM. After 15min, the arms were shaven, and cephalic venopuncture was performed by a 22G catheter, which 0.9% NaCl was administered at a rate of 10mL kg [h.sup.-1] during the whole period of evaluation. Later, the animals were anesthetized with 4mg [kg.sup.-1] Propofol (c) IV, intubated with an orotracheal tube of suitable diameter and maintained under inhalant anesthesia with isoflurane (d) in 1L [min.sup.-1] of 100% [O.sub.2] in a circular valvular circuit. The animals were positioned in sternal recumbency during the period of evaluation. By controlling vaporization, the animals were maintained in stage III/2 of anesthesia, characterized mainly by the total rotation of the eyeball and by the presence of the slight palpebral reflex (MOENS & COPPENS, 2007), which requires a vaporization of 1 to 1.5%. Immediately after the establishment of inhalant anesthesia, instrumentation of the animals was initiated.
The right podal dorsal artery was catheterized using a 22G catheter. This was connected to a 3-way stopcock and a pressure transducer filled with heparinized solution, positioned and zeroed at the level of the heart to measure mean arterial pressure (MAP), systolic arterial pressure (SAP) and diastolic arterial pressure (DAP), in mmHg. The electrodes were positioned in the axillary and the groin regions to determine heart rate (HR) in beats per minute (bpm) and rhythm, based on lead II. Cardiovascular parameters were evaluated by a multiparametric monitor (e).
The ventilometer (f) was connected to the tracheal tube, to measure tidal volume (Vt) and minute volume (Vm), in mL. The respiratory rate (RR) was measured by visualization of the reservoir bag, in breaths per minute (bpm). Body temperature (T[degrees]C) was maintained between 36 and 37[degrees]C for the whole period of evaluation with the aid of a thermal mattress.
After the 30min period for instrumentation and stabilization of the vaporization and physiological parameters, the animals were randomized and equally assigned to one of three treatments (n=6): control (CG) with the administration 1mL 0.9% NaCl IV; and two with atracurium (g) at 15[micro]g [kg.sup.-1] (G15) and 30qg [kg.sup.-1] (G30) IV, diluted in 0.9% NaCl and standardized to a final volume of 1mL. The animals in G15 and G30 were submitted to a surgical procedure for establishing a corneal ulcer model as a part of a different research. In the CG animals, it was not possible to carry out the same surgical procedure since centralization of the eyeball was not achieved.
The physiological parameters were measured by two observers blinded to the treatments. HR, RR, MAP, SAP, DAP, Vt, and Vm were determined immediately before the administration of atracurium (time 0) and every 5min after the administration of the treatment up to 60min. Blood gas analysis was performed at time 0 and every 15min of evaluation. Blood samples (1mL) were anaerobically drawn with a previously heparinized syringe from the podal dorsal artery with the help of a 3-way stopcock connected to the catheter, discarding the first milliliter with another syringe. Arterial C[O.sub.2] pressure (PaC[O.sub.2]), arterial [O.sub.2] pressure (Pa[O.sub.2]), pH, bicarbonate (HC[O.sub.3.sup.-]), bases excess (BE) and hemoglobin oxygen saturation (Sa[O.sub.2]) were obtained immediately after the collection. The eyeball centralization time was determined as the time from initial centralization of the eyeball (after the administration of atracurium) until the eyeball became semi-rotated. At the end of the evaluation period, 0.2mg [kg.sup.-1] meloxicam (h) SC was administered to provide postoperative analgesia.
Statistical analysis was performed using the GraphPad Prism 4 program^ Repeated measure analysis of variance (ANOVA) was used followed by Bonferroni test for comparisons of means within each group in relation to time zero. For comparison between groups, at each time, one-way ANOVA was performed followed by Tukey's test if necessary. For comparisons regarding the time of eyeball centralization, ordinary ANOVA was utilized, followed by the Kruskal-Wallis test. The differences were considered significant when P<0.05. The parametric results are expressed as means [+ or -] standard deviation and the non-parametric as medians and interquartile ranges.
There was no difference in body weight between groups, which CG, G15 and G30 obtained weight of 14.8 [+ or -] 2.2kg, 14.5 [+ or -] 3.1kg and 14.0 [+ or -] 3.1kg, respectively. Eyeball centralization was observed in all the animals of the groups treated with atracurium. There was no significant difference between G15 and G30, where median and interquartile range (IQR) of neuromuscular blockade was 42.5 (10, 60) and 47.5 (20, 60) min, respectively (Figure 1). Both groups differed significantly from CG, which did not show eyeball centralization at any moment.
In relation to the cardiovascular parameters, there were no differences between the groups at any moment, or any group compared to time zero (Figure 2). In addition, no alterations in heart rhythm were observed in any group. There was no statistical difference between groups or in each group when compared to basal levels for RR (Figure 2) and Sa[O.sub.2] (Table 1). Vt in G15 and G30 were statistically lower than in CG up to 15min after drug administration (Figure 2). Similarly, both groups showed a decline in Vt in relation to their baseline values up to 10min. In the analysis of Vm (Figure 2), G15 differed from CG up to 10min and G30 differed from CG up to 25min of evaluation. Both groups differed from zero moment only at 5min.
With regard to pH, there was a decrease in relation to baseline values in CG between 30 and 60min and in G15 and G30, only at 15min (Table 1). G30 also differed from CG at 15 and 30min. In relation to baseline values of PaC[O.sub.2] (Table 1), CG differed between 30 and 60min and G15 differed at 15min. Pa[O.sub.2], bicarbonate and EB showed no differences in any group, in baseline evaluation as well as after the treatments (Table 1).
[FIGURE 1 OMITTED]
[FIGURE 2 OMITTED]
The doses of atracurium utilized were effective in blocking the extrinsic muscles of the eyeball, causing total exposure of the cornea for an adequate period. Because of the time obtained (42.5 and 47.5min), these doses make it possible to carry out various ophthalmic surgeries. The fact that no eyeball centralization occurred in CG demonstrates that centralization requires exclusively the use of a peripheral muscle relaxant, but it can be intensified by the concomitant use of inhalat anesthesia (KASTRUP et al., 2005)
Cardiovascular parameters were maintained within the physiological range. Atracurium causes alterations in these parameters only at high doses, potentially leading to hypotension and tachycardia, due to the release of histamine (MARTINEZ, 1999). Furthermore, neuromuscular blockers cause tachycardia due to an antivagal action (STENLAKE & HUGHES, 1987), but atracurium produces greater cardiovascular stability when compared to other blockers (HACKETT et al., 1989).
In relation to Sa[O.sub.2], all animals showed values over 97%. This parameter does not represent the quantity of [O.sub.2] available to tissues, but permits the determination of arterial oxygenation, which is indicative of alterations that can cause risk of hypoxia for the patient (JONES, 1996). There was no hypoxemia associated with any of the groups studied because the animals were supplemented with 100% oxygen, besides being healthy and without any lung pathology.
Pa[O.sub.2] supplies information on the efficacy of oxygenation of the lungs (HASKINS, 1996). Despite there being no statistical difference among the groups studied in relation to Pa[O.sub.2], CG showed at all times lower values than those considered normal for dogs submitted to inhalant anesthesia in 100% [O.sub.2] with spontaneous breathing (McDONELL, 1996). The groups treated with atracurium showed physiologic levels or very close, as it is anticipated in healthy subjects.
Vt was lower up to 15min in the groups treated with atracurium, when compared to CG, but considering the physiologic range, which is 10 to 20mL [kg.sup.-1] (HASKINS, 1996), this variable showed a decline in G30 from 5 to 45min and in G15 only up to 15min. Since there was a reduction in Vm without occurrence of bradypnea in animals treated with atracurium, mainly in G30, a decrease in respiratory amplitude occurred, with consequent hypercapnia and decrease in pH.
Since C[O.sub.2] diffuses easily through alveolar capillaries, the alveolar C[O.sub.2] tension and PaC[O.sub.2] are essentially the same. As a result, the measure of PaC[O.sub.2] provides direct information on the sufficiency of alveolar ventilation (DIBARTOLA & MORAIS, 1992). Despite that the PaC[O.sub.2] values were higher than physiological levels in all the groups evaluated, there was no significant difference between them, indicating that the administration of atracurium was not the only cause of the elevation of this parameter. Elevated PaC[O.sub.2] caused a reduction in pH, and clinical acidosis was observed in all groups, including CG The results observed in G15 showed acidosis only up to 15min, being equal to CG after on. Those values demonstrate that the inhalant procedure was the most important cause for the acidosis. Inhalant anesthesia is one of the most common causes of respiratory acidosis (ROBERTSON, 1989; MUTOH et al., 1997), that can increase the action of peripheral muscle relaxants (ONO et al., 1988).
It should be pointed out that, although the use of atracurium at low doses does not cause apnea, the reversal of the blockade after doing the procedure is recommended, since the oropharynx muscles are blocked subsequently as the oculomotor muscles, which is associated with an increased risk of aspiration pneumonia. Moreover, the residual neuromuscular blockade is frequently observed after the end of general anesthesia, impairing the recovery of the patient (MURPHY, 2006). Also, the use of controlled or assisted ventilation and monitoring with Train of Four must be considered, to make procedures which use neuromuscular blockers safer.
Both doses of atracurium produced a similar period of eyeball centralization without cardiovascular alterations and bradypnea, but with respiratory acidosis. We suggest that the dose of 15[micro]g [kg.sup.-1] of atracurium is adequate for short corneal procedures in inhalant-anesthetized dogs under spontaneous breathing.
SOURCES AND MANUFACTURERS
(a)--Acepran 1%, Univet Industria Veterinaria S.A., Cambuci, SP, Brazil.
(b)--Dimorf, Cristalia Produtos Quimicos and Farmaceuticos Ltda, Itapira, SP, Brazil.
(c)--Diprivan 1%, AstraZeneca do Brasil, Cotia, SP, Brazil.
(d)--Isoforine, Cristalia Produtos Quimicos and Farmaceuticos Ltda, Itapira, SP, Brazil.
(e)--PM-9000 Express--Mindray[R] Medical Intenational Ltd, Shenzhen, China.
(f)--Ventilometer Narcosul, Narcosul, Porto Alegre, RS, Brazil. g- Tracrium, GlaxoSmithKline Brasil Ltda, Rio de Janeiro, RJ, Brazil.
(h)--Maxicam 0.2%, Ourofino, Ribeirao Preto, SP, Brazil.
(i)--GraphPad Prism, GraphPad Software Inc, San Diego, California, USA.
This work was approved by the Institutional Animal Care Committee, under process number 81-2006.
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Adriano Bonfim Carregaro (I) Gabrielle Coelho Freitas (II) Fernando Silverio Ferreira da Cruz (II) Melissa Machado (II) Guilherme Kanciukaitis Tognoli (III) Ney Luis Pipp (II)
(1) Faculdade de Zootecnia e Engenharia de Alimentos, Universidade de Sao Paulo (USP). Av. Duque de Caxias Norte, 225, 13635900, Pirassununga, SP, Brasil. E-mail: firstname.lastname@example.org. Autor para correspondencia.
(II) Universidade Federal de Santa Maria (UFSM), Santa Maria, RS, Brasil.
(III) Faculdades Integradas do Planalto Central (FACIPLAC), Brasilia, DF, Brasil.
Received 02.22.10 Approved 06.11.10 Returned by the author 06.30.10 CR-3181
Table 1--Blood gas parameters (mean [+ or -] standard deviation) evaluated in dogs (n = 6 each group) maintained on isoflurane anesthesia under spontaneous breathing, treated with saline (CG), 15[micro]g [kg.sup.-1] of atracurium (G15) or 30[micro]g [kg.sup.-1] of atracurium (G30). Time (min) Parameter Group 0 15 pH CG 7.29 [+ or -] 0.03 7.27 [+ or -] 0.03 G15 7.25 [+ or -] 0.05 7.17 [+ or -] 0.13 * G30 7.23 [+ or -] 0.08 7.11 [+ or -] 0.13 * (a) Pa[O.sub.2] CG 376 [+ or -] 50 403 [+ or -] 48 (mmHg) G15 446 [+ or -] 83 427 [+ or -] 75 G30 431 [+ or -] 46 478 [+ or -] 22 PaC[O.sub.2] CG 45 [+ or -] 4 48 [+ or -] 4 (mmHg) G15 51 [+ or -] 7 58 [+ or -] 10 * G30 53 [+ or -] 10 73 [+ or -] 23 HC[O.sub.3 CG 21.3 [+ or -] 1 21.6 [+ or -] 1 .sup.-] (mmol G15 22.1 [+ or -] 1.5 22.9 [+ or -] 1.6 [L.sup.-1]) G30 23.3 [+ or -] 2.5 24.9 [+ or -] 3.7 Sa[O.sub.2] (%) CG 98 [+ or -] 1 99 [+ or -] 0.6 G15 98 [+ or -] 1 98 [+ or -] 1 G30 98 [+ or -] 1 99 [+ or -] 0.3 BE GC -5.2 [+ or -] 0.9 -5.6 [+ or -] 1 G15 -5.1 [+ or -] 1.7 -6.2 [+ or -] 2.4 G30 -4.75 [+ or -] 1.7 -6 [+ or -] 1.2 Time (min) Parameter Group 30 45 pH CG 7.26 [+ or -] 0.03 * 7.26 [+ or -] 0.03 * G15 7.23 [+ or -] 0.06 7.23 [+ or -] 0.04 G30 7.13 [+ or -] 0.14 (a) 7.12 [+ or -] 0.17 Pa[O.sub.2] CG 402 [+ or -] 43 419 [+ or -] 27 (mmHg) G15 467 [+ or -] 96 489 [+ or -] 89 G30 486 [+ or -] 48 479 [+ or -] 48 PaC[O.sub.2] CG 49 [+ or -] 4 * 49 [+ or -] 5 * (mmHg) G15 54 [+ or -] 7 54 [+ or -] 6 G30 63 [+ or -] 16 68 [+ or -] 24 HC[O.sub.3 CG 21.9 [+ or -] 1.2 21.6 [+ or -] 1.4 .sup.-] (mmol G15 22.2 [+ or -] 0.9 22.2 [+ or -] 1.1 [L.sup.-1]) G30 24.1 [+ or -] 3.3 24.9 [+ or -] 3.9 Sa[O.sub.2] (%) CG 99 [+ or -] 0.5 99 [+ or -] 0.4 G15 98 [+ or -] 0.4 99 [+ or -] 0.3 G30 99 [+ or -] 0.3 99 [+ or -] 0.3 BE GC -5.4 [+ or -] 1 -5.7 [+ or -] 1.2 G15 -5.6 [+ or -] 1.5 -5.6 [+ or -] 1.2 G30 -6.5 [+ or -] 1.6 -6 [+ or -] 1.3 Time (min) Parameter Group 60 pH CG 7.25 [+ or -] 0.02 * G15 7.24 [+ or -] 0.05 G30 7.18 [+ or -] 0.08 Pa[O.sub.2] CG 426 [+ or -] 47 (mmHg) G15 442 [+ or -] 68 G30 504 [+ or -] 35 PaC[O.sub.2] CG 50 [+ or -] 3 * (mmHg) G15 53 [+ or -] 8 G30 67 [+ or -] 19 HC[O.sub.3 CG 21.7 [+ or -] 1.3 .sup.-] (mmol G15 22.2 [+ or -] 1.2 [L.sup.-1]) G30 23.9 [+ or -] 2.3 Sa[O.sub.2] (%) CG 98 [+ or -] 1 G15 97 [+ or -] 0.7 G30 99 [+ or -] 0.2 BE GC -5.5 [+ or -] 1.2 G15 -5.3 [+ or -] 1.2 G30 -5.1 [+ or -] 1 * Statistical difference in relation to time 0 (P<0.05). (a) Statistical difference from CG (P<0.05).