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On-line version ISSN 1806-907X
Rev. Bras. Anestesiol. vol.55 no.3 Campinas May/June 2005
Hemodynamic and renal effects of high epidural clonidine doses in dogs*
Efectos hemodinámicos y renales de la inyección de dosis elevadas de clonidina en el espacio peridural del perro
Nilson Camargo Roso, M.D.I; Pedro Thadeu Galvão Vianna, TSA, M.D.II; Yara Marcondes Machado Castiglia, TSA, M.D.II; José Reinaldo Cerqueira Braz, TSA, M.D.II
IPós-Graduando do Programa de Pós-Graduação
em Anestesiologia da FMB-UNESP
IIProfessor Titular do Departamento de Anestesiologia da FMB-UNESP
BACKGROUND AND OBJECTIVES: There are no
studies reporting renal effects promoted by high epidural clonidine doses. This
study aimed at evaluating hemodynamic and renal effects of high epidural clonidine
doses in dogs.
METHODS: This double-blind randomized study involved 20 animals anesthetized with sodium thiopental and fentanyl, which were distributed in two groups: Group 1 or placebo (n = 10), receiving 0.2 mL.kg-1 saline, and Group 2 or clonidine (n = 10), receiving 0.2 mL.kg-1 of a solution with 50 µg.mL-1 clonidine in the epidural space. The following hemodynamic parameters were evaluated: heart rate (HR): beat.min-1; mean blood pressure (MBP): mmHg; pulmonary capillary wedge pressure (PCWP): mmHg; cardiac output (CO): L.min-1; and systolic volume (SV): mL. The following renal function parameters were also evaluated: renal blood flow (RBF) mL.min-1; renal vascular resistance (RVR): mmHg.mL-1; urinary minute volume (UMV): mL.min-1; creatinine clearance (CCr): mL.min-1; para-aminohippurate clearance (CPAH): mL.min-1; filtration fraction (FF); sodium clearance (CNA): mL.min-1; potassium clearance (CK): mL.min-1; sodium fractional excretion (FENA): %; sodium urinary excretion (UNAV): µEq.min-1; potassium urinary excretion (UKV): µEq.min-1. Experiment consisted of three 20-minute moments. Data were collected at 10 minutes of each moment and diuresis was measured in the beginning and end of each moment. At the end of M1, clonidine or saline were epidurally injected. After 20 minutes data were repeated in M2 and M3.
RESULTS: Epidural 10 µg.kg-1 clonidine in dogs has promoted significant changes with decreased heart rate and cardiac output and increased sodium para-aminophurate clearance/cardiac output ratio.
CONCLUSIONS: In our conditions and doses, clonidine has not promoted renal function changes, but has decreased hemodynamic parameters (heart rate and cardiac output).
Key words: ANIMALS: dogs; ANESTHETIC TECHNIQUES, Regional: epidural; DRUGS: clonidine; RENAL SYSTEM: function
JUSTIFICATIVA Y OBJETIVOS: No existen
estudios que relaten las repercusiones renales determinadas por la inyección
de dosis elevadas de clonidina en el espacio peridural. La finalidad del estudio
fue evaluar los efectos hemodinámicos y renales determinados por la inyección
de dosis elevadas de clonidina en el espacio peridural del perro.
MÉTODO: Veinte animales anestesiados con tiopental sódico y fentanil fueron distribuidos eventualmente y de forma doblemente encubierta en dos grupos: Grupo 1 ó placebo (n = 10), que recibió 0,2 mL.kg-1 de solución fisiológica, y Grupo 2 ó clonidina (n = 10), que recibió 0,2 mL.kg-1 de una solución conteniendo 50 µg.mL-1 de clonidina, en el espacio peridural. Fueron evaluados los siguientes parámetros hemodinámicos: frecuencia cardiaca (FC): lat.min-1; presión arterial media (PAM): mmHg; presión de la arteria pulmonar ocluida (PAOP): mmHg; débito cardíaco (DC): L.min-1; volumen sistólico (VS): mL; también, los siguientes parámetros de la función renal fueron evaluados: flujo sanguíneo renal (FSR): mL.min-1; resistencia vascular renal (RVR): mmHg.mL-1.min; volumen urinario minuto (VUM): mL.min-1; depuración de creatinina (DCr): mL.min-1; depuración de para-aminohipurato (DPAH): mL.min-1; fracción de filtración (FF); depuración de sodio (DNa): mL.min-1; depuración de potasio (DK): mL.min-1; excreción fraccionaria de sodio (EFNa): %; excreción urinaria de sodio (UNaV): µEq.min-1; excreción urinaria de potasio (UKV): µEq.min-1. El experimento consistió en tres momentos de 20 minutos cada uno. Los datos fueron colectados a los 10 minutos de cada momento y la diuresis, en el inicio y al final de cada momento. Al término de M1, la clonidina o la solución fisiológica fue administrada en el espacio peridural. Después de un período de 20 minutos en M2 y en seguida en el M3.
RESULTADOS: La clonidina en la dosis de 10 µg.kg-1 en el espacio peridural del perro promovió alteraciones significativas, con disminuciones de la frecuencia cardiaca y del débito cardíaco y aumento de la relación depuración de para-aminohipurato de sodio/débito cardíaco.
CONCLUSIONES: En las condiciones realizadas y en las dosis empleadas, se puede concluir que la clonidina no promovió alteración de la función renal, pero disminuyó valores hemodinámicos (frecuencia y débitos cardíacos).
Epidural clonidine promotes clinically significant actions 1. It is promptly absorbed reaching arterial blood plasma peak concentration within 10 minutes and venous blood plasma peak concentration in 30 to 45 minutes. Analgesia induced by epidural clonidine is a consequence of action on peripheral, supra-spinal and especially spinal sites, including activation of post-synaptic a2 receptors of noradrenergic descending pathways, and cholinergic neurons, in addition to nitric oxide release.
Clonidine renal function effects are complex 2. Clonidine induces diuresis both in humans and animals 3, inhibiting antidiuretic hormone release 4, in addition to antagonizing its action on renal tubule 5 and increasing glomerular filtration rate 6. Diuretic effect is explained by atrial natriuretic factor release 7. If administered in the preoperative period of cardiac surgeries (4 µg.kg-1) it promotes renal protection 8. Epidural clonidine was first reported in 1984 9 and conventional to high doses have been used ever since 10. However, effects of high epidural clonidine doses on renal function are still not known. So, our study aimed at evaluating hemodynamic and renal effects of high epidural clonidine doses (10 µg.kg-1) in dogs.
After the Animal Experiment Ethics Committee, Faculdade de Medicina de Botucatu, UNESP approval, 20 adult male, mixed breed dogs weighing 11 to 20 kg, supplied by the Lab Animals Facility, Universidade Estadual Paulista Julio de Mesquita Filho Botucatu Campus, were evaluated.
This was a randomized double-blind study involving two groups of 10 animals. G1 (placebo) received 0,2 mL.kg-1 epidural saline; G2 (clonidine) received epidural solution with 50 µg.mL-1 (0.2 mL.kg-1 x 50 µg.mL-1 = 10 µg.kg-1 clonidine). Both groups were anesthetized with intravenous 15 mg.kg-1 sodium thiopental and 15 µg.kg-1 fentanyl followed by 40 µg.kg-1.min-1 thiopental and 0,1 µg.kg-1.min-1 fentanyl continuous infusion.
Muscle relaxation was achieved with dialylbisnortoxiferine (alcuronium chloride) in single intravenous dose of 0.2 mg.kg-1 administered after anesthetic induction. Repeated NMB doses (0.06 mg.kg-1) were administered as needed. Animals were submitted to intermittent positive pressure ventilation (IPPV) using Ohmeda device model 7900 monitored by Datex- Engstrom AS/3 device model D-VCN 15-00-02 S/N 763177 (Finland), which would also supply oxygen inspired fraction and CO2 expired fraction (PETCO2), in addition to esophageal and room temperatures.
Arteries and veins were dissected and catheterized. Left femoral vein was used soon after dissection for lactated Ringer's, PAH, creatinine and anesthetic infusions. Left femoral artery was used for mean blood pressure monitoring. Left femoral vein was used for blood sample collection for biochemical and hematological dosages. Right femoral artery was used for arterial blood gases samples collection. External jugular vein was used for Swan-Ganz catheter insertion according to Gouvêa's technique11. After 30 minutes of lactated Ringer's infusion, PAH and creatinine prime (0.4% PAH and 3% creatinine) 12 in the dose of 0.1 mL.kg-1 was administered; then, PAH and creatinine infusion in the dose of 0.1 mg.kg-1.h-1 was started and maintained throughout the experiment; infusion rate was controlled by "Anne" infusion pump (Abbott Laboratories). Both groups had 3 experimental phases (M1, M2 and M3) lasting 20 minutes each, according to the following scheme:
Moment 1 (M1) started 30 minutes after PAH and creatinine infusion (60 minutes after beginning of experiment = 30 minutes of lactated Ringer's + 30 minutes of PAH and creatinine infusion).
At the end of M1 epidural saline or clonidine were injected after epidural puncture. Twenty minutes after epidural puncture hemodynamic and renal function parameters were evaluated in M2 and M3. The following hemodynamic parameters were evaluated in the three moments (M1, M2 and M3): heart rate (HR): beat.min-1; mean blood pressure (MBP): mmHg; pulmonary capillary wedge pressure (PCWP): mmHg; cardiac output (CO): L.min-1; and systolic volume (SV): mL. The following renal function parameters were also evaluated: renal blood flow (RBF) mL.min-1; renal vascular resistance (RVR): mmHg.mL-1; urinary minute volume (UMV): mL.min-1; creatinine clearance (CCr): mL.min-1; para-aminophurate clearance (CPAH): mL.min-1; filtration fraction (FF); sodium clearance (CNA): mL.min-1; potassium clearance (CK): mL.min-1; sodium fractional excretion (FENA): %; sodium urinary excretion (UNAV): µEq.min-1; potassium urinary excretion (UKV): µEq.min-1.
Data were collected at 10 minutes of each moment and diuresis was measured in the beginning and end of each moment. After the experiment, animals still anesthetized were sacrificed with intravenous 19.1% potassium chloride. Since variables were measured in 3 moments for each experimental unit, profile analysis 13 was used for statistical evaluation. In all tested statistical hypotheses, calculated F and p were considered significant when p < 0.05.
Heart rate statistical analysis has shown differences between groups in moments M2 and M3 (Figure 1) and decreased heart rate in G2 as from M2. There have been no heart rate changes in G1 throughout the experiment. There has been no statistically significant difference between groups in M1.
Cardiac output (CO) (Figure 2) values were statistically different between M2 and M3 for G1 and G2 with significant decrease in M2 and M3 for G2. Values were similar for both groups in M1.
Groups had similar profiles between groups and moments in terms of systolic volume, mean blood pressure, pulmonary capillary wedge pressure, renal blood flow, renal vascular resistance, urinary minute volume (Figure 3), creatinine clearance (Figure 4), sodium para-aminohippurate clearance (Figure 5), filtration fraction, sodium and potassium clearance, sodium fractional excretion, sodium urinary excretion and potassium urinary excretion.
There has been statistically significant difference in para-aminophurate clearance/cardiac output ration (CPAH/CO) in M3 between G1 and G2. There has also been significant difference in M2 and M3 for G2 as compared to M1 (Figure 6).
Alpha2-adrenergic agonists may induce heart rate decrease in variable intensity 14. This may be explained by the activation of a2-pre-synaptic adrenoreceptors of peripheral nervous terminations with decreased norepinephrine exocytosis, and by clonidine sympatholytic effect on central nervous system 15.
Clonidine decreases discharges in splancnic nerve sympathetic pre-ganglionic fibers as well as in cardiac nerves post-ganglionic fibers 16. On the other hand, it stimulates parasympathetic flow, which may contribute to decrease heart rate as a consequence of vagal tone increase, as well as to decrease sympathetic impulse 16.
Clonidine-induced heart rate decrease seems to be also promoted by activation of imidazoline receptors located in the nucleus reticularis, probably in nucleus tractus solitarius 17.
By inference, HR decrease observed in moments 2 and 3 in G2 in our experiment was a consequence of epidural clonidine injected in dogs.
HR decrease was observed after clonidine administration. By decreasing sympathetic tone and increasing parasympathetic tone, clonidine may promote decreased heart rate, decreased systemic metabolism, decreased myocardial contractility and decreased systemic vascular resistance resulting in decreased myocardial oxygen need. This might explain its success in treating angina pectoris 18. Decreased HR would be a consequence of vascular post-junctional adrenoreceptors activation 17.
No blood pressure changes were observed with high epidural clonidine doses. This might be explained by clonidine actions in different levels involved in controlling blood pressure. Clonidine has central and medullary actions determining blood pressure decrease, but has also action on peripheral a2-adrenergic receptors located in blood vessels and determining vasoconstriction 14.
This effect is especially important with high clonidine doses. Blood pressure is the result of these opposite effects, and associated bradycardia is an uncommon clonidine complication even in high doses 19. Epidural clonidine-induced hypotension intensity, when present, seems to be associated to the dermatome where it is administered 14.
At low and lumbar thoracic levels, epidural clonidine does not increase the incidence of hypotension 15, but at high thoracic level there is increased incidence of this effect 20. These results may be caused by higher inhibition of pre-ganglionic sympathetic neurons which supply the heart when clonidine is administered in high thoracic level, thus determining deeper changes in blood pressure 14,21. Clonidine decreases norepinephrine plasma concentration and its urinary excretion 22.
Since clonidine was administered in the most distal dermatome of lumbar spine of dogs, the lack of significant MBP changes is understandable.
Pulmonary capillary wedge pressure and systolic volume are among factors determining left ventricular preload. Clinically, left ventricular volume estimate and PCWP measure are used as approximation of left ventricular preload. This is a complex and non-linear correlation 22. Since there has been no significant variation in VS and PCWP in all moments for both groups, the inference was that PCWP profile has followed VS and MBP profiles.
From described factors interfering with CPAH, one may evaluate 12:
a) Renal perfusion pressure (RPP) - there has been no detectable factor able to change RPP during the experiment;
b) Circulating blood volume (extracellular volume) - there has been no factor changing it because there has been no volume loss or detectable factors affecting MBP;
c) Hormonal action on kidneys - hormones were not dosed during the experiment, but it is important to remind that there are different simultaneous factors - IPPV which increases antidiuretic hormone (ADH) production and stimulates rennin-angiotensin-aldosterone system, and clonidine, which inhibits ADH release and antagonizes its action on renal tubule inhibiting rennin release and releasing atrial natriuretic factor;
d) Hematocrit - no changes throughout the experiment;
e) Renal vascular resistance - similar behavior for both groups.
In conclusion, there has been heart rate 14 and cardiac output 15 decrease, however without RBF changes. In percentage, there has been higher renal blood supply when cardiac output decreased. This was well demonstrated when PAH clearance was related to cardiac output (Figure 6). Finally, high epidural clonidine doses have not changed major renal functions.
01. Eisenach J, Detweiler D, Hood D - Hemodynamic and analgesic actions of epidurally administered clonidine. Anesthesiology, 1993;78:277-287. [ Links ]
Submitted for publication October 4, 2004
Accepted for publication February 16, 2005
* Received from Departamento de Anestesiologia da Faculdade de Medicina de Botucatu (FMB-UNESP), Botucatu, SP