Effects of dexmedetomidine on renal system and on vasopressin plasma levels: experimental study in dogs

Abstracts

JUSTIFICATIVA E OBJETIVOS: A insuficiência renal aguda peri-operatória é responsável por elevada taxa de morbidade e mortalidade. Os fármacos alfa2-agonistas aumentam o débito urinário e promovem boa estabilidade hemodinâmica nesse período. O objetivo desta pesquisa foi estudar os efeitos renais e sobre a concentração plasmática do hormônio antidiurético (HAD) provocados pela dexmedetomidina no cão anestesiado. MÉTODO: Trinta e seis cães adultos, anestesiados com propofol, fentanil e isoflurano, foram divididos aleatoriamente em três grupos que receberam, de modo encoberto: G1 - injeção de 20 mL de solução de cloreto de sódio a 0,9%, em 10 minutos, seguida de injeção de 20 mL da mesma solução em uma hora; G2 - injeção de 20 mL de solução de cloreto de sódio a 0,9% contendo dexmedetomidina (1 µg.kg-1), em 10 minutos, seguida de injeção de 20 mL da mesma solução, com a mesma dose de dexmedetomidina (1 µg.kg-1), em uma hora e G3 - injeção de 20 mL de solução de cloreto de sódio a 0,9% contendo dexmedetomidina (2 µg.kg-1) em 10 minutos, seguida de injeção de 20 mL da mesma solução, com a mesma dose de dexmedetomidina (2 µg.kg-1), em uma hora. As variáveis renais, hemodinâmicas e a concentração plasmática do HAD foram estudadas em quatro momentos: M1 (controle) - imediatamente após o período de estabilização; M2 - após a injeção inicial de 20 mL da solução em estudo, em 10 minutos, coincidindo com o início da injeção da mesma solução, em uma hora; M3 - 30 minutos após M2 e M4 - 30 minutos após M3. RESULTADOS: A dexmedetomidina reduziu a freqüência cardíaca e promoveu estabilidade hemodinâmica, mantendo constante o débito cardíaco. Houve elevação do débito urinário no G2 e G3, em comparação com o G1. A osmolalidade urinária no G2 e G3 foi menor no M3 e M4 em relação ao M1 e M2. A depuração de água livre aumentou no G3. A concentração plasmática do HAD diminuiu no G3, apresentando valores mais baixos que os observados no G1 e G2 em M2 e M4. CONCLUSÕES: Os cães anestesiados com baixas doses de dexmedetomidina promovem diurese hídrica por inibir a secreção do hormônio antidiurético, havendo potencial para proteção renal em eventos isquêmicos.

ANIMAIS; DROGAS; DROGAS; SISTEMA RENAL

RESUMEN JUSTIFICATIVA Y OBJETIVOS: La insuficiencia renal aguda peri-operatoria es responsable de la elevada tasa de morbidad y mortalidad. Los fármacos alfa2-agonistas aumentan el débito urinario y promueven buena estabilidad hemodinámica en ese período. El objetivo de esta pesquisa fue estudiar los efectos renales y sobre la concentración plasmática de la hormona antidiurética (HAD) provocados por la dexmedetomidina en un perro anestesiado. MÉTODO: Treinta seis perros adultos, anestesiados con propofol, fentanil e isoflurano, fueron divididos eventualmente en tres grupos que recibieron, de modo encubierto: G1 - inyección de 20 mL de solución de cloruro de sodio a 0,9%, en 10 minutos, seguida de inyección de 20 mL de la misma solución en una hora; G2 - inyección de 20 mL de solución de cloruro de sodio a 0,9% conteniendo dexmedetomidina (1 µg.kg-1), en 10 minutos, seguida de inyección de 20 mL de la misma solución, con la misma dosis de dexmedetomidina (1 µg.kg-1), en una hora y G3 - inyección de 20 mL de solución de cloruro de sodio a 0,9% conteniendo dexmedetomidina (2 µg.kg-1) en 10 minutos, seguida de inyección de 20 mL de la misma solución, con la misma dosis de dexmedetomidina (2 µg.kg-1), en una hora. Las variables renales, hemodinámicas y la concentración plasmática del HAD fueron estudiadas en cuatro momentos: M1 (control) - inmediatamente después del período de estabilización; M2 - después de la inyección inicial de 20 mL de la solución en estudio, en 10 minutos, coincidiendo con el inicio de la inyección de la misma solución, en una hora; M3 - 30 minutos después de M2 y M4 - 30 minutos después de M3. RESULTADOS: La dexmedetomidina redujo la frecuencia cardiaca y promovió estabilidad hemodinámica, manteniendo constante el débito cardíaco. Hubo elevación del débito urinario en el G2 y G3, en comparación con el G1.La osmolalidad urinaria en el G2 y G3 fue menor en el M3 y M4 con relación al M1 y M2. La depuración de agua libre aumentó en el G3. La concentración plasmática del HAD diminuyó en el G3, presentando valores más bajos que los observados en el G1 y G2 en M2 y M4. CONCLUSIONES: Los perros anestesiados con bajas dosis de dexmedetomidina promueven diuresis hídrica por inhibir la secreción de la hormona antidiurética, habiendo potencial para la protección renal en eventos isquémicos.

SCIENTIFIC ARTICLE

Effects of dexmedetomidine on renal system and on vasopressin plasma levels. Experimental study in dogs^*

Efectos de la dexmedetomidina sobre el sistema renal y sobre la concentración plasmática de la hormona antidiurética. Estudio experimental en perros

Nivaldo Ribeiro Villela, M.D.^I; Paulo do Nascimento Júnior, TSA, M.D.^II; Lídia Raquel de Carvalho, M.D.^III; Andrey Teixeira, M.D.^VI

^IDoutor em Anestesiologia pela FMB - UNESP

^IIProfessor Adjunto Livre-Docente do Departamento de Anestesiologia da FMB - UNESP

^IIIProfessora Assistente Doutora do Departamento de Bioestatística do Instituto de Biociências de Botucatu, UNESP

^IVDoutorando em Reprodução Animal da Faculdade de Veterinária de Botucatu, UNESP

^{Correspondence}

SUMMARY

BACKGROUND AND OBJECTIVES: Perioperative acute renal failure increases morbidity and mortality. Alpha₂-adrenergic agonists used in anesthesia increase urinary output and maintain cardiovascular stability. This study aimed at investigating the effects of dexmedetomidine on renal system and on vasopressin plasma levels in anesthetized dogs.

METHODS: This study involved 36 adult mixed-breed dogs anesthetized with propofol, fentanyl, and isoflurane, which were randomly distributed in three groups receiving: G1 -20 mL of 0.9% saline in 10 minutes, followed by 20 mL of the same solution in one hour; G2 -20 mL of 0.9% saline with dexmedetomidine (1 µg.kg^-1) in 10 minutes, followed by 20 mL of the same solution with the same dexmedetomidine dose (1 µg.kg^-1) in one hour; and G3 -20 mL of 0.9% saline with dexmedetomidine (2 µg.kg^-1) in 10 minutes, followed by 20 mL of the same solution with the same dexmedetomidine dose (2 µg.kg^-1) in one hour. Renal and hemodynamic variables and vasopressin plasma levels were studied in four periods: M1 (control) - immediately after the stabilization period; M2 - after initial injection of the solution being studied, coinciding with the beginning of continuous injection of the same solution; M3 - 30 minutes after M2; and M4 - 30 minutes after M3.

RESULTS: Dexmedetomidine has decreased heart rate and maintained adequate cardiovascular stability, as cardiac output was kept constant. Urinary output was increased for G2 and G3 as compared to G1. For G2 and G3, urinary osmolality has decreased in M3 and M4. For G3, values of free water clearance were increased throughout the experiment. Vasopressin plasma levels have decreased for G3, resulting in lower values as compared to G1 and G2 in M2 and M4.

CONCLUSIONS: In anesthetized dogs, low doses of dexmedetomidine inhibit vasopressin secretion, causing aqueous diuresis. These actions might protect kidneys during ischemic events.

Key Words: ANIMALS: dogs, DRUGS: a₂-agonist, dexmedetomidine; RENAL SYSTEM: vasopressin

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: La insuficiencia renal aguda peri-operatoria es responsable de la elevada tasa de morbidad y mortalidad. Los fármacos a₂-agonistas aumentan el débito urinario y promueven buena estabilidad hemodinámica en ese período. El objetivo de esta pesquisa fue estudiar los efectos renales y sobre la concentración plasmática de la hormona antidiurética (HAD) provocados por la dexmedetomidina en un perro anestesiado.

MÉTODO: Treinta seis perros adultos, anestesiados con propofol, fentanil e isoflurano, fueron divididos eventualmente en tres grupos que recibieron, de modo encubierto: G1 - inyección de 20 mL de solución de cloruro de sodio a 0,9%, en 10 minutos, seguida de inyección de 20 mL de la misma solución en una hora; G2 - inyección de 20 mL de solución de cloruro de sodio a 0,9% conteniendo dexmedetomidina (1 µg.kg^-1), en 10 minutos, seguida de inyección de 20 mL de la misma solución, con la misma dosis de dexmedetomidina (1 µg.kg^-1), en una hora y G3 - inyección de 20 mL de solución de cloruro de sodio a 0,9% conteniendo dexmedetomidina (2 µg.kg^-1) en 10 minutos, seguida de inyección de 20 mL de la misma solución, con la misma dosis de dexmedetomidina (2 µg.kg^-1), en una hora. Las variables renales, hemodinámicas y la concentración plasmática del HAD fueron estudiadas en cuatro momentos: M1 (control) - inmediatamente después del período de estabilización; M2 - después de la inyección inicial de 20 mL de la solución en estudio, en 10 minutos, coincidiendo con el inicio de la inyección de la misma solución, en una hora; M3 - 30 minutos después de M2 y M4 - 30 minutos después de M3.

RESULTADOS: La dexmedetomidina redujo la frecuencia cardiaca y promovió estabilidad hemodinámica, manteniendo constante el débito cardíaco. Hubo elevación del débito urinario en el G2 y G3, en comparación con el G1.La osmolalidad urinaria en el G2 y G3 fue menor en el M3 y M4 con relación al M1 y M2. La depuración de agua libre aumentó en el G3. La concentración plasmática del HAD diminuyó en el G3, presentando valores más bajos que los observados en el G1 y G2 en M2 y M4.

CONCLUSIONES: Los perros anestesiados con bajas dosis de dexmedetomidina promueven diuresis hídrica por inhibir la secreción de la hormona antidiurética, habiendo potencial para la protección renal en eventos isquémicos.

INTRODUCTION

Recent decades have witnessed perioperative care advances, however without significant decrease in the incidence of acute renal failure ^1-3. High morbidity and mortality rates associated to perioperative acute renal failure justify efforts and costs incurred in studies attempting to identify preventive mechanisms ⁴.

Hemodynamic and hormonal changes promoted by endocrine-metabolic response to anesthetic-surgical trauma play an important role in triggering acute renal failure ⁵.

Dexmedetomidine decreases catecholamine plasma levels ^6,7, maintains adequate hemodynamic stability ^8,9 and increases urinary output ¹⁰ when administered during surgery, thus being able to decrease renal changes promoted by endocrine-metabolic response to anesthetic-surgical trauma.

There are few experimental studies with dexmedetomidine in conditions and doses similar to those administered in operating rooms. So, this study aimed at evaluating the effects of dexmedetomidine on renal system and on vasopressin plasma levels, in doses similar to those used in clinical anesthesia.

METHODS

This study was approved by the Animal Experiment Ethics Committee, Faculdade de Medicina, Botucatu, UNESP and involved 36 adult mixed-breed dogs of both genders, weighing 18 to 30 kg.

After 12-hour fasting with free access to water, anesthesia was induced with propofol (6 mg.kg^-1) and fentanyl (5 µg.kg^-1). After tracheal intubation, lungs were mechanically ventilated with oxygen (0.8 L.min^-1) and compressed air (1.2 L.min^-1), with tidal volume of 20 mL.kg^-1 and respiratory rate of 12 to 16 movements per minute, aiming at maintaining end tidal CO₂ (P_ETCO₂) between 35 and 45 mmHg, and isoflurane administration was started in expired concentration of 1.7 MAC. Right femoral vein was dissected and catheterized for hydration with lactated Ringer's solution (18 mL.kg^-1.h^-1) followed by rocuronium injection (0.6 mg.kg^-1 and continuous injection of 10 µg.kg^-1.min^-1).

Next, left femoral artery was dissected for continuous mean blood pressure (MBP) monitoring, left femoral vein was dissected for blood collection, and right external jugular vein was dissected for introduction of 7F Swan-Ganz catheter in the pulmonary artery to measure cardiac output by thermodilution and mean diastolic blood pressure (DBP). Normal body temperature for dogs (39 ºC) was maintained with heated air blow (38 to 42 ºC) on the ventral surface and warming of injected solutions.

After surgical preparation, surgical wounds were infiltrated with 0.2% ropivacaine, isoflurane expired concentration was decreased to 0.6 MAC and creatinine (30 mg.kg^-1) and sodium para-aminohipurate (PAH) (4 mg.kg^-1) priming was injected to evaluate renal function. Lactated Ringer's solution was replaced by 0.6% creatinine and 6 mL.kg^-1.h^-1 of 0.24% PAH solution in lactated Ringer's and was administered. Vesical catheter was inserted and a 30-minute stabilization period was started.

After the control moment, animals were randomly and blindly distributed in three groups of 12 dogs:

• G1 (n = 12): 20 mL of 0.9% saline in 10 minutes, followed by 20 mL of the same solution in one hour

• G2 (n = 12): 20 mL of 0.9% saline with dexmedetomidine (1 µg.kg^-1) in 10 minutes, followed by 20 mL of the same solution with the same dexmedetomidine dose (1 µg.kg^-1) in one hour

• G3 (n = 12): 20 mL of 0.9% saline with dexmedetomidine (2 µg.kg^-1) in 10 minutes, followed by 20 mL of the same solution with the same dexmedetomidine dose (2 µg.kg^-1) in one hour.

To control study homogeneity, the following parameters were evaluated: length, weight, body surface area (BSA) and gender. Evaluated hemodynamic parameters were: heart rate (HR), mean blood pressure (MBP), mean diastolic pressure (MDP), cardiac index (CI) and systemic vascular resistance (SVR); blood and renal parameters were: hematocrit (Ht), plasma osmolality (OsmP), urinary output (UO), glomerular filtration rate (GFR) measured by creatinine clearance (CLCr), renal blood flow (RBF - CLPAH/1-Ht), renal vascular resistance (RVR - MBP/RBF), urinary osmolality (OsmU), osmolar clearance (CLOsm = OsmU.UO/OsmP), free water clearance (CLH₂O = UO-CLOsm), filtration fraction (FF = CLCr/ClPAH), sodium fractional excretion (FENa = CLNa.100/CLCr), potassium fractional excretion (FEK = CLK.100/CLCr) and vasopressin plasma levels (VPC).

Parameters were evaluated in 4 moments. Each moment lasted 15 minutes and blood collection and hemodynamic variables evaluation were performed at half this interval. Bladder was emptied in the beginning and end of each moment and urine was collected. Studied moments were:

M1 (control): immediately after the 30-minute stabilization period.

M2: after initial injection, in 10 minutes, of 20 mL of the solution in study, coinciding with the beginning of continuous injection of the solution in study, in one hour.

M3: 30 minutes after M2, coinciding the end of this moment with the end of the injection of the solution in study.

M4: 30 minutes after M3.

To measure vasopressin plasma levels (VPL), 5 mL of venous blood were collected in tubes with heparin, which were centrifuged at 4 ºC for plasma separation. Radioimmunoassay was the technique of choice (kit DSL-1800 Arginine Vasopressin Radioimmunoassay, Texas) with readings by Perkim-Elmer Cobra II Gamma Counter, model E5005 (USA) device. Vasopressin plasma levels were expressed in picograms per mL of plasma.

Profile analysis, followed by Tukey's method for multiple comparisons were used for variables with normal distribution and homogeneity of variances. For variables without normal distribution or homogeneity of variances, Friedman's test was used to compare moments and Kruskal-Wallis test was used to compare groups, followed by multiple comparisons test. Analysis of variance was used to evaluate demographics. Fisher Exact test for frequency analysis was used for gender. Significance level was 5%.

RESULTS

Groups were homogeneous in weight, length, BSA and gender distribution (p > 0.05) (Table I).

Brazilian Journal of Anesthesiology, 2005; 55: 4: 429-440

Effects of dexmedetomidine on renal system and on vasopressin plasma levels. Experimental study in dogs

Nivaldo Ribeiro Villela; Paulo do Nascimento Júnior; Lídia Raquel de Carvalho; Andrey Teixeira

There were no significant differences in MBP and DBP among groups and in different moments within each group (p > 0.05) (Table II).

Brazilian Journal of Anesthesiology, 2005; 55: 4: 429-440

Effects of dexmedetomidine on renal system and on vasopressin plasma levels. Experimental study in dogs

Nivaldo Ribeiro Villela; Paulo do Nascimento Júnior; Lídia Raquel de Carvalho; Andrey Teixeira

HR was lower for G2 and G3 as compared to G1 in M2, M3 and M4 (p < 0.05). For G2, HR has decreased in M2 (p < 0.05), returning to baseline values in M3 and M4. For G3, HR has decreased in M2 and was kept below baseline values in M3 and M4 (p < 0.05). G1 had progressive HR increase (p < 0.05) (Table II).

CI in M4 was lower for G2 and G3 as compared to G1; and for G3 as compared to G2 (p < 0.05). There has been progressive CI increase for G1 throughout the moments (p < 0.05) (Table II).

SVRI was lower for G1 in M2, M3 and M4 as compared to G2 and G3 (p < 0.05). There has been SVRI decrease for G1 in M2, M3 and M4 as compared to M1 (p < 0.05) (Table II).

UO was lower for G1 in M4 (p < 0.05). For G3, UO was lower in M2 as compared to M3 (p < 0.05) (Figure 1).

Brazilian Journal of Anesthesiology, 2005; 55: 4: 429-440

Effects of dexmedetomidine on renal system and on vasopressin plasma levels. Experimental study in dogs

Nivaldo Ribeiro Villela; Paulo do Nascimento Júnior; Lídia Raquel de Carvalho; Andrey Teixeira

FF was lower for G2 as compared to G1 in M1 (p < 0.05). For G2, it was higher in M4 as compared to M1 (p < 0.05) (Table III).

Brazilian Journal of Anesthesiology, 2005; 55: 4: 429-440

Effects of dexmedetomidine on renal system and on vasopressin plasma levels. Experimental study in dogs

Nivaldo Ribeiro Villela; Paulo do Nascimento Júnior; Lídia Raquel de Carvalho; Andrey Teixeira

OsmU was not significantly different among groups. For G2 and G3 it was lower in M3 and M4 (p < 0.05) (Table IV).

Brazilian Journal of Anesthesiology, 2005; 55: 4: 429-440

Effects of dexmedetomidine on renal system and on vasopressin plasma levels. Experimental study in dogs

Nivaldo Ribeiro Villela; Paulo do Nascimento Júnior; Lídia Raquel de Carvalho; Andrey Teixeira

CLH₂O was not significantly different among groups. For G3 it was higher in M2, M3 and M4 as compared to M1 (p < 0.05) (Figure 2).

Brazilian Journal of Anesthesiology, 2005; 55: 4: 429-440

Effects of dexmedetomidine on renal system and on vasopressin plasma levels. Experimental study in dogs

Nivaldo Ribeiro Villela; Paulo do Nascimento Júnior; Lídia Raquel de Carvalho; Andrey Teixeira

Vasopressin plasma level was lower for G3 as compared to G1 and G2, and for G2 as compared to G1, in M2 and M4 (p < 0.05). For G3, it was higher in M1 (p < 0.05) (Figure 3).

Brazilian Journal of Anesthesiology, 2005; 55: 4: 429-440

Effects of dexmedetomidine on renal system and on vasopressin plasma levels. Experimental study in dogs

Nivaldo Ribeiro Villela; Paulo do Nascimento Júnior; Lídia Raquel de Carvalho; Andrey Teixeira

RBF, GFR, RVR (Table III), Ht, OsmP, CLOsm, FENa and FEK (Table IV) were not significantly different among groups and in different moments within each group (p > 0.05).

DISCUSSION

Glomerular filtration rate is a predominantly hemodynamic mechanism and the renal intratubular dynamics suffers hemodynamic and hormonal influences. Some hormones, such as vasopressin, suffer cardiovascular interferences to control their secretion ¹¹. Our experiment has observed that urinary changes promoted by dexmedetomidine were not followed by significant hemodynamic changes. Similar to other studies ^6-10,12, dexmedetomidine has dose-dependently decreased HR and has maintained better hemodynamic stability as compared to control, and the CI was maintained stable throughout the experiment in both groups receiving the drug.

Alpha₂-adrenergic agonists increase urinary output ^12-15. This may be secondary to hemodynamic changes ¹⁶, to vasopressin secretion inhibition ¹⁷ or to its decreased tubular action ¹⁸.

Alpha₂-adrenergic receptors have already been identified in several renal areas of different animals ^19-25. In rats, the activation of these receptors promotes intracellular cAMP inhibition ^26,27, being this one mechanism responsible for vasopressin action inhibition in the collecting duct. In other animals, such as dogs, some investigators have not detected such intracellular cAMP inhibition ¹⁶, suggesting a different mechanism involved in inhibiting collecting duct water absorption by a₂-adrenergic agonists. Reid et al. ¹⁷ have reported that very high clonidine doses, well above those normally used, inhibit vasopressin secretion promoting increased diuresis.

Our study has observed that dexmedetomidine has determined urinary output increase, promoting minor parallel hemodynamic changes. Increased diuresis was followed by decreased urinary osmolality and increased free water clearance. There were no changes in RVR, RBF, GFR, CL Osm, FE Na and FEK, confirming that increased diuresis was secondary to the impairment of water absorption in the collecting duct and not secondary to glomerular filtration increase. This acqueous diuresis was probably secondary to vasopressin secretion inhibition.

Humphrey et al. ²⁸ have associated vasopressin secretion inhibition after clonidine injection to increased MBP. Other possible mechanisms would be no secretion of this hormone due to increased central venous pressure ²⁹ or direct blockade of supraoptic neurosecretory cells ³⁰.

In our experiment, dexmedetomidine has dose-dependently inhibited vasopressin secretion with significant MBP or DBP changes, suggesting direct central inhibition of the drug. In a previous study, Kimura et al. ³¹ have observed decreased vasopressin plasma levels after low clonidine dose injected in the lateral ventricle of dogs, showing that a₂-agonists may promote central vasopressin secretion blockade.

We have observed during control moment that vasopressin plasma levels were close to dogs' physiological values (0 to 5 pg.mL^-1) ³², possibly being result of hydration during surgical preparation and of balanced anesthetic technique with opioids during induction ³³. Other investigators have observed very high vasopressin plasma levels after anesthetic-surgical procedures in dogs ³⁴. There has been decreased vasopressin plasma levels, increased urinary output and low osmolality urine after dexmedetomidine administration in doses close to those used in Anesthesiology ³⁵. There were no hemodynamic changes which could justify decreased vasopressin secretion and higher urine production.

In experimental and clinical trials, blockade of endocrine-metabolic response to anesthetic-surgical trauma associated to clonidine renal effects could prevent or decrease renal injuries secondary to renal ischemia ^36,37.

So, we have concluded that low dexmedetomidine doses in dogs result in aqueous diuresis secondary to central vasopressin secretion inhibition. Based on these actions and on clonidine trials resulting in renal protection against ischemia, it is suggested that dexmedetomidine plays a potential role in protecting kidneys against ischemic events. Experimental renal ischemia models, as well as clinical trials in patients susceptible to renal ischemia, are needed to confirm this hypothesis.

REFERENCES

Submitted for publication November 9, 2004

Accepted for publication March 8, 2005

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*

Received from Departamento de Anestesiologia da Faculdade de Medicina de Botucatu (FMB - UNESP), Botucatu, SP; Financiado pela Fundação de Amparo à Pesquisa do Estado de São Paulo - FAPESP, Processo Auxílio Pesquisa nº 03/01325-9

Publication Dates

• Publication in this collection
  24 Oct 2005
• Date of issue
  Aug 2005

History

• Accepted
  08 Mar 2005
• Received
  09 Nov 2004