Efficacy of 7.5% hypertonic sodium chloride, with and without 6% dextran 70, in renal function preservation of hypovolemic dogs submitted to ischemia-reperfusion

Abstracts

JUSTIFICATIVA E OBJETIVOS: As soluções hipertônicas de cloreto de sódio, associadas ou não a colóides hiperoncóticos, podem ser eficazes em proteger o rim em situações de hipovolemia. O objetivo deste estudo foi verificar, em cães, o real benefício dessas soluções sobre a função renal, em vigência de hipovolemia e isquemia do órgão. MÉTODO: Em 24 cães, anestesiados com pentobarbital sódico, submetidos à nefrectomia direita e à expansão volêmica com solução de Ringer (1 ml.kg-1.min-1), foram observadas possíveis alterações renais morfo-funcionais após hemorragia de 20 ml.kg-1 e trinta minutos de total isquemia renal esquerda, com posterior reperfusão, além da repercussão renal da administração de soluções de cloreto de sódio 7,5% (SH) e esta em dextran 70 a 6% (SHD). Atributos estudados: FC, PAM, pressão de veia cava inferior, fluxo sangüíneo renal, resistência vascular renal, hematócrito, Na+, K+, osmolaridade plasmática, PaO2, PaCO2 e pH, depuração (para-aminohipurato de sódio - PAH-1, creatinina, osmolar, água livre, Na+, K+), fração de filtração, volume e osmolaridade urinários, excreções urinárias e fracionárias de Na+ e K+ e exame histopatológico do rim. Os atributos foram estudados em três grupos (G1, G2 e G3) e em cinco momentos. RESULTADOS: Houve elevação estatisticamente significativa da pressão arterial média em G2 e G3, da resistência vascular renal em G1, do fluxo sangüíneo renal e da depuração de PAH em G3, da excreção fracionária de Na+ em G2 e G3, das depurações de creatinina, osmolar, de água livre e de Na+ e K+, da excreção urinária de Na+ e K+ e do volume urinário em G3. CONCLUSÕES: A SHD administrada 15 minutos após hemorragia moderada e 30 minutos antes de insulto isquêmico de 30 minutos foi eficiente em proteger o rim de cães das repercussões da isquemia-reperfusão. Não foi constatada alteração histopatológica renal à microscopia óptica.

ANIMAL; VOLEMIA; VOLEMIA; VOLEMIA

SCIENTIFIC ARTICLE

Efficacy of 7.5% hypertonic sodium chloride, with and without 6% dextran 70, in renal function preservation of hypovolemic dogs submitted to ischemia-reperfusion

Geraldo Rolim Rodrigues Júnior, TSA, M.D. ^I; José Luiz Gomes do Amaral, TSA, M.D. ^II; Yara Marcondes Machado Castiglia, TSA, M.D. ^III; Mariangela Esther Alencar Marques, M.D. ^IV

^IProfessor Assistente Doutor do Departamento de Anestesiologia da FMB UNESP

^IIProfessor Titular da Disciplina de Anestesiologia, Dor e Terapia Intensiva Cirúrgica da EPM/UNIFESP

^IIIProfessora Titular do Departamento de Anestesiologia da FMB UNESP

^IVProfessora Assistente Doutora do Departamento de Patologia da FMB UNESP

SUMMARY

BACKGROUND AND OBJECTIVES: Sodium chloride hypertonic solutions, with or without hyperoncotic colloids, may be effective in protecting kidney against hypovolemia. This experiment aimed at evaluating, in dogs, the real benefit of these solutions on renal function in the presence of hypovolemia and ischemia.

METHODS: Experiments were performed in 24 mixed-breed dogs anesthetized with sodium pentobarbital, submitted to right nephrectomy and volume expansion with Ringer’s solution (1 ml.kg^-1.min^-1). Renal morphological and physiological changes were studied after 20 ml.kg^-1 hemorrhage and 30 min of total left renal ischemia followed by reperfusion, in addition to renal repercussion of 7.5% NaCl (HS) and 7.5% NaCl in 6% dextran 70 (HSD). The following parameters were studied: HR, MBP, inferior vena cava pressure, renal blood flow, renal vascular resistance, hematocrit, Na⁺, K⁺, plasma osmolarity, PaO₂, PaCO₂ and pH; clearance (para-aminohipuric acid - PAH_-1, creatinine, free water, osmolar, Na⁺ and K⁺), filtration fraction, urine output and osmolarity, sodium and potassium urine and fractionated excretions; rectal temperature; and kidney histopathology. Atributes where studied in five moments in three groups (G1, G2 and G3).

RESULTS: There has been a statistically significant increase in mean blood pressure in G2 and G3. RVR was higher in G1; RBF and PAH clearance were higher in G3; Na⁺ fractionated excretion was increased in G2 and G3; creatinine, free water, osmolar, Na⁺ and K⁺ clearances, diuresis, and urinary excretions of Na⁺ and K⁺ were higher in G3.

CONCLUSIONS: HSD infusion 15 min after mild hemorrhage and 30 min before ischemia was effective in protecting kidney of dogs from ischemia-reperfusion repercussions. There have been no histopathologic changes under optical microscopy.

Key Words: ANIMAL: dog; VOLEMIA: expansion, colloid, 7.5% NaCl solution

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: Las soluciones hipertónicas de cloreto de sodio, asociadas o no a coloides hiperoncóticos, pueden ser eficaces en proteger el riñón en situaciones de hipovolemia. El objetivo de este estudio fue verificar en canes, el real beneficio de esas soluciones sobre la función renal, en vigencia de hipovolemia e isquemia del órgano.

MÉTODO: En 24 canes, anestesiados con pentobarbital sódico, sometidos a nefrectomia derecha y a expansión volémica con solución de Ringer. Fueron observadas posibles alteraciones renales morfo-funcionales después hemorragia de 20 ml.kg^-1 y treinta minutos de total isquemia renal izquierda, con posterior reperfusión, además de la repercusión renal da administración de soluciones de cloreto de sodio 7,5% (SH) y ésta en dextran 70 a 6% (SHD). Atributos estudiados: FC, PAM, presión de vena cava inferior, flujo sanguíneo renal, resistencia vascular renal, hematócrito, Na⁺, K⁺, osmolaridad plasmática, PaO₂, PaCO₂ y pH, depuración (para-aminohipurato de sodio - PAH_-1, creatinina, osmolar, agua libre, Na⁺, K⁺), fracción de filtración, volumen y osmolaridad urinarios, excreciones urinarias y fraccionarias de Na⁺ y K⁺, temperatura rectal y examen histopatológico del riñón. Los atributos fueron estudiados en tres grupos (G1, G2 y G3) y en cinco momentos.

RESULTADOS: Hubo elevación estadísticamente significativa de la presión arterial media en G2 y G3, de la resistencia vascular renal en G1, del flujo sanguíneo renal y de la depuración de PAH en G3, de la excreción fraccionaria de Na⁺ en G2 y G3, de las depuraciones de creatinina, osmolar, de agua libre y de Na⁺ y K⁺, de la excreción urinaria de Na⁺ y K⁺ y del volumen urinario en G3.

CONCLUSIONES: La SHD administrada 15 minutos después de hemorragia moderada y 30 min antes de insulto isquémico de 30 min fue eficiente en proteger el riñón de los canes de las repercusiones de la isquemia-reperfusión. No fue constatada alteración histopatológica renal a la microscópia óptica.

INTRODUCTION

Low doses of hypertonic sodium chloride promptly restore intravascular volume due to water redistribution as from the intracellular compartment. This blood volume increase is transient, but it is earlier observed as compared to isosmotic fluids infusion in the same time period. In addition, such solutions may improve performance of several organs, including the heart, be it by contractility effects, afterload decrease or even for removing myocardial oxygen free radicals. The latter effect is produced by dextran 70 when associated to 7.5% sodium chloride ¹. Although improving perfusion of several organs, including the kidney, such solutions was not widely used due to the short duration of their beneficial effects.

Currently, low volumes of 7.5% hypertonic sodium chloride for treating hypovolemia, hypotension and shock became very popular with the association of 6% dextran 70. This formulation has prolonged solutions effects and maximized beneficial physiological effects of both components ¹. Several animal studies have shown the efficacy of such solutions in attenuating or even reverting many abnormalities caused by hemorrhagic shock and hypovolemia. When facing such situations a major concern is renal preservation because its function, which is fundamental for homeostasis, may be severely affected reaching different failure degrees and impairing patient’s recovery.

Transient renal blood flow interruption causes anatomic and physiological changes which are more severe as a function of ischemia duration. A 30-minute ischemia associated to previous hypovolemia will produce severe renal injury in the absence of treatment or prevention.

Hypertonic sodium chloride, associated or not to hyperoncotic colloids, may be effective in protecting kidneys from such foreseeable situations. Several authors have suggested that the so-called hypertonic resuscitation from hemorrhagic shock certainly reverts renal dysfunction ². Other investigators have stated that 7.5% sodium chloride associated to dextran 70 may revert some noxious ischemia or ischemia/reperfusion-induced effects, especially those caused by capillary perfusion increase ³.

Our study aimed at analyzing the real benefits of 7.5% hypertonic sodium chloride (HS), associated or not to 6% dextran 70 (HSD) on the simulation of abnormal renal function in dogs, caused by hypovolemia associated to 30-minute ischemia.

METHODS

After the Experimental Research Ethics Committee approval, 24 adult mixed-breed dogs with undefined ages, from both sexes and weighing 7 to 33 kg were studied. Animals were anesthetized with 30 mg.kg^-1 intravenous sodium pentobarbital (SP) for induction and 5 mg.kg^-1 for maintenance (105 minutes after priming dose).

Animals were randomly distributed in 3 experimental groups of 8 dogs.

Group 1 (G1) - Animals were submitted to right lombotomy for right kidney removal and left lombotomy for ureter catheterization and left renal artery clamping for 30 minutes. All animals were submitted to approximately 29% to 30% hemorrhage, enough to decrease circulating volume and cause hypovolemia, but not shock.

Group 2 (G2) - The same as G1, followed by intravenous administration of 4 ml.kg^-1 of HS in 3 minutes, 15 minutes after scheduled hemorrhage.

Group 3 (G3) - The same as G1, followed by intravenous administration of HSD in the same dose and speed used for G2.

After a 14-hour fast, animals were anesthetized with sodium pentobarbital and placed in the supine position in a Claude Bernard trough. The following procedures were performed:

1. Tracheal intubation and air controlled ventilation using a K. Takaoka, Mod 850-10 anesthesia machine. Tidal volume was 15 ml.kg^-1 and respiratory rate was 15 movements per minute;

2. Left femoral vein dissection and catheterization for inferior vena cava pressure monitoring with a water pressure gage, initial 0.2 mg.kg^-1 sodium pentobarbital and alcuronium administration and then 0.006 mg.kg^-1 for additional doses, venous blood collection, biochemical dosing and lactated Ringer’s continuous infusion (1 ml.kg^-1.min^-1); right femoral artery dissection and catheterization for mean blood pressure monitoring with a mercury pressure gage and left femoral artery dissection and catheterization for 20 ml.kg^-1 blood volume removal;

3. Left femoral vein dissection and catheterization for PAH priming dose (4 mg.kg^-1) and creatinine (30 mg.kg^-1) in lactated Ringer’s, 30 minutes after Ringer’s solution continuous infusion. Next, continuous PAH (0.06 g%) and creatinine (0.15 g%) in Ringer’s solution infusion was installed and maintained until the end of the experiment in the dose of 0.6 mg creatinine and 0.24 mg PAH per minute, per animal’s kilo (0.4 ml.kg^-1);

4. Right lombotomy for right kidney removal and left lombotomy for ureter catheterization and left renal peduncle dissection; left renal artery exposure, non-traumatic clamp insertion which would remain open until clamping time;

5. Ureter catheterization with 6 or 8 polivynil probe, depending on the animal. Urine, whenever produced, would continuously flow through the probe during the experiment;

6. Placement of rectal alcohol thermometer for temperature readings;

7. Removal of left femoral artery blood 30 minutes after priming injection;

8. Injection of 0.9% sodium chloride in G1, 7.5% in G2 and 7.5% in 6% dextran 70 in G3, 15 minutes after hemorrhage and 45 minutes after priming injection;

9. Left renal artery clamping in all groups and unclamping 30 minutes later;

10. Animals’ euthanasia with 20% intravenous formalin and left kidney removal for histopathologic study.

Attributes were divided in two groups:

a) to control homogeneity: demographics - animal weight (kg), sex and length (m^-1); respiratory rate (mov.min^-1), tidal volume (ml.kg^-1), hematocrit (Ht) (%) and rectal temperature (^oC);

b) to meet research goals: hemodynamic: mean blood pressure (MBP), inferior vena cava pressure (ICP); heart rate (HR); renal plasma flow (measured by PAH clearance - C_{PAH =} U_PAH x V/P_PAH, where V = urine output, U and P = urine and plasma PAH concentration, respectively; renal blood flow (RBF = C_PAH/1-Ht); renal vascular resistance (RVR = MBP/RBF). Renal function: glomerular filtration rate (GFR) (measured by creatinine clearance - C_cr = U_cr x V/P_cr); urine output (V); glomerular filtration (FF = C_cr/C_PAH); plasma osmolarity (P_osm); urine osmolarity (U_osm); osmolar clearance (C_osm = U_osm x V/P_osm); sodium and potassium clearance (C_{Na or K} = U_{Na or K} x V/P_{Na or K}); free water clearance (C_H2O = V - C_osm); sodium urinary excretion (U⁺_{nu x} V = U_Na x V); sodium fractionated excretion ( EF_Na = C_Na/C_cr x 100); potassium urinary excretion (U_KV = K⁺_u x V); potassium fractionated excretion (EF = D_K/C_cr x 100). Left kidney histopathologic study.

These parameters were obtained in the following moments and results were compared among groups. This study has not aimed at measuring hemodynamic variables soon after hemorrhage; rather the aim was evaluating the efficacy of some solutions. To determine the impact, G1 was studied as the control group.

M1 and M2 - obtained 15 and 60 minutes after PAH and creatinine priming injection;

M3 and M4 - obtained 105 and 120 minutes after PAH and creatinine priming injection (immediately and 15 minutes after unclamping, respectively); and M5 - 135 minutes after PAH and creatinine priming injection and 30 minutes after unclamping.

Groups G2 and G3 received 4 ml.kg^-1 of animal’s weight of HS and HSD, respectively, for hemorrhage replacement 15 minutes after blood removal. G1 received the same dose of 0.9% sodium chloride (Chart I).

Histopathological samples were placed in 5% formalin. After being fixed for more than 48 hours, they were cleaned and placed in wax to be further cut and dyed with hematoxylin-eosin and Schiff’s periodic acid (SPA). Samples were labeled and analyzed by an investigator blind to the experimental group they belonged to.

Morrison’s profile analysis was used for all variables and p was determined as 0.05 or 5% (a < or = 0.05); a star (*) was used to highlight significant values. Significance trend was referred when 0.05 < p < 0.10. Tukey’s method was used to compare groups means, by calculating the minimum significant difference for a = 0.05. Demographics were compared by analysis of variance (ANOVA).

RESULTS

Our most significant results are shown in table I, table II and table III and figure 1, figure 2, figure 3 and figure 4.

There has been homogeneity (ANOVA) in weight, length and sex among dogs of the three experimental groups.

U_osm, C_H2O, EF_na, EF_K, PaO₂, PaCO₂, pH, PCI, P_osm, FF, V, C_osm, C_NA, U_NAV, C_K and U_KV were not significantly different within groups and moments studied.

Rectal temperature showed uniform and continuous decrease along the trial in all groups.

Even following every adequate step to identify any lesion visible at optical microscopy, no lesion compatible with acute tubular necrosis was observed.

DISCUSSION

The anesthetic technique used is standard for dogs due to its proven efficacy in reaching an adequate anesthetic depth in a few minutes and for not affecting renal function.

The acute renal ischemia induced in dogs followed a model already developed in a previous study, but this time it was associated to hypovolemia caused by the removal of approximately 29% blood volume, which is a method proved to cause hypovolemia and widely used by several authors ⁵.

Renal function impact determined by the association of hypovolemia and acute ischemia was observed in group 1. In groups 2 and 3 an effective renal function protection against the noxious effects of this association was tested with HS and HSD.

The effects of HS were determined in 1980 by Velasco et al. ⁶, who observed that 7.5% hypertonic sodium chloride, with an osmolarity of approximately 2,400 mOsm.l^-1 and in the dose of 4 ml.kg^-1 would induce maximum plasma expansion at moment zero, similarly to 883 mOsm.l^-1 in a dose of 12 ml.kg^-1. Several authors have shown that other solutions, in concentrations above and below 75%, had neither advantages ⁸ nor increased survival ⁹ even when different sodium salts, chlorides and other electrolyte-free solutions were used ¹⁰.

The association of 6% dextran 70 has prolonged HS hemodynamic effects for more than 30 minutes ¹¹. In a single dose of 4 ml.kg^-1, HSD is effective and virtually free of adverse effects ^12,13.

In post-hemorrhagic situations, HSD restores blood flow to several organs, including the kidney ¹⁴. There is flow improvement and recovery of post-hemorrhage capillary bed narrowing ^15,16. This capillary flow recovery ability of HSD has important clinical implications in treating hemorrhagic shock or ischemia ¹³.

The clinical translation of creatinine clearance is glomerular filtration rate which, in group 3 showed mean results always well above the other groups. This post-hemorrhage moment is followed by a significant glomerular filtration rate decrease ¹⁷ and HSD was able not only to restore initial values but also to go beyond them. In G2, HS produced the same effect, but in a lesser degree and values were always very close to G1, which was the group receiving no treatment.

So, HSD, especially due to plasma volume expansion, increases systemic blood pressure resulting in an increase in glomerular hydrostatic pressure and glomerular filtration rate. In addition, HSD dilates glomerular arterioles by directly acting on their smooth muscles causing an increase in blood perfusion and further favoring glomerular filtration.

This is one of the most apparent results of hypertonic solutions, that is, blood flow increase in several organs ^18,19. Vessels smooth muscle relaxation is a direct hyperosmolarity effect, which is similar to the effect of nitroglycerin on coronary vessels ²⁰. This pre-capillary vasodilation has been observed by several authors ^6,21. Hemodilution-related blood viscosity decrease contributes even further for peripheral vascular resistance decrease.

Osmolarity is defined as an expression of the number of osmotically active particles which attract water through semi-patent membranes until a balance is attained per liter of solvent, while osmolality is a measurement of the number of osmotically active particles per kilogram of solvent. Osmolality is estimated by the following formula (sodium x 2) + (glucose/18) + (urea/2.3) ²².

Although osmols per kilo of water (osmolality) are those determining osmotic pressure, the difference between osmolality and osmolarity for diluted solutions forming body fluids is less than 1%. This allows both terms to be used almost as synonyms. So, in addition to be easier to express body fluids concentration as a function of liters and not of kilograms of water, the practice in almost all physiologic studies is to use osmolarity and not osmolality.

Knowing that hyperosmolarity is present when there is an increased number of osmotically active particles, both uremia and hypernatremia could lead to such state. However, since urea is distributed throughout body water, only an increase in plasma sodium would be able to cause hypertonicity, that is, osmotic redistribution of intracellular water to the extracellular space ²².

Solutions osmotic pressure as compared to plasma is in general called tonicity. So, a fluid with osmotic pressure similar to plasma pressure is called an isotonic fluid. Hypotonic solutions have low osmotic pressure, and hypertonic solutions, such as HS and HSD, have high osmotic pressure. Osmotic pressure is approximately equal to osmolality times 19.3 ²² meaning that each mOsm generates an osmotic pressure of 19.3 mmHg at 37 ºC through an ideal semi-patent membrane ³.

The solutions used in this experiment had an osmolarity of approximately 2,400 mOsm.l^-1, thus being able to generate osmotic pressures around 8 times higher than a solution with osmolarity similar to plasma. In general, such solutions induce mild and transient hyperosmolarity ¹⁸ when used in the recommended bolus doses. Upper osmolarity and plasma sodium concentration accepted levels are still to be defined ²³, but problems with osmolarities below 350 mOms.l^-1 are rare and this value has not been reached by most experiments ^6,24. Reports on high osmolarity values are in general related to high doses or repeated injections ²⁵.

An important increase in osmolar and sodium clearance was observed in groups 2 and 3, meaning more osmotically active substances loss through urine and natriuresis, probably caused by aldosterone secretion inhibition. This HS and HSD-induced inhibition might occur due to the fast hypovolemia correction and the installation of mild plasma hyperosmolarity.

Richards et al. ²⁶ have suggested that atrial natriuretic hormone release would be the cause for this magnitude in diuresis increase. However, no increase in atrial natriuretic peptide serum levels was observed in response to HSD injection ^27,28.

This disproportional diuresis, higher than the volume injected after HS and HSD, is observed even in the presence of hypovolemia and high antidiuretic hormone circulating concentrations. High urine production may even be noxious due to fluid loss and may be responsible for transient hypertonic solution hemodynamic effects ²⁹.

For Rocha e Silva ¹⁸, hypertonic solutions interfere with endocrine secretions in animals with post-hemorrhage hypotension because they rapidly correct hypovolemia which may determine decreased vasopressin, renin and angiotensin circulating concentrations ³⁰. Decreased circulating vasopressin is seen, according to the authors, in spite of the increased osmolarity which, in general, is responsible for its secretion. In this circumstance, the response to osmolarity is overridden by hypovolemia correction, which is a vasopressin-secretion factor ¹⁸.

So, hypertonic solutions determine a significant diuresis increase, which is maintained for hours after the initial injection ¹⁵.

There were similarities among the three groups in free water clearance and urine osmolarity and this shows that groups receiving HS and HSD did not differ from the control group, although with higher diuresis. So, urine osmolarity was significantly decreased with time, but this was not determined by HS or HSD because the same was seen in all groups. There has been no significant differences in free water clearance, representing the excretion of solute-free water, in any moment or group.

Osmolar clearance corresponds to plasma volume released from all osmotically active substances in the time unit, that is, it is equivalent to ion clearance. As a consequence, a significant increase in ion clearance was observed in G3 due to HSD administration. This was identified by the increase in osmolar clearance curve, which initially occurred in M2, moment immediately after HSD injection. Next, there has been a mild decrease but even then it was maintained in a significantly higher level as compared to other groups. On the other hand, in G2, HS injection has determined an increased ion clearance, which was not significant but of biological importance.

The increase seen in groups 2 and 3, which received hypertonic sodium, was possibly due to the interference of such solutions in vasopressin and aldosterone secretion. The decrease in aldosterone blood levels led to a higher osmotically active substance and sodium clearance; and vasopressin decrease has determined more urinary solute-free water loss in those groups.

HS and HSD, which have high sodium content, were responsible for plasma concentration increase of such ion. This concentration is not changed when expansion is obtained with isotonic solutions, due to renal mechanisms which would lead to a higher sodium excretion and lower reabsorbtion in all nephron segments, provided they are healthy. However, two hypertonic solutions exerting higher osmotic pressure than plasma and with a high sodium plasma concentration that goes beyond this rapid excretion ability were administered, determining an increase in this ion plasma concentration. In our experiment, this was observed in M2, which is the moment immediately after hypertonic resuscitation, that is with HS and HSD infusion and, as a consequence, the most susceptible moment for significant sodium plasma concentration increases. With a 4 ml.kg^-1 bolus dose, hypernatremia is mild and transient ³¹.

Similarly to sodium clearance, G3 had significant higher mean values in the urine excretion curve, showing a better ability of HSD in increasing sodium serum levels and clearance.

According to Vincent ³², hypokalemia is frequently observed and probably determined by the increase in urine potassium loss. This may even cause dysrhythmias, especially in patients under digitalis. Decreased potassium serum levels were also observed by other authors ^2,16,33,34. The reasons for such decrease were the absence of potassium in such solutions and the fast intracellular fluid expansion, which decreases extracellular potassium.

In our study, the increase in potassium excretion with time was clearly observed.

Even following every adequate step to identify any renal change visible at electronic microscopy, no lesion compatible with post-ischemia acute tubular necrosis was observed, differently from previous reports by several authors ^35,36. The presence of post-ischemia acute tubular necrosis could have been seen by optic microscopy at least in G1, if the period between the end of the experiment and the removal of the organ for hystopathological study would have been longer because then one could have had enough time for necrosis delimitation.

After statistical analysis of results, it was possible to conclude that 7.5% hypertonic sodium chloride in 6% dextran 70 administered soon after mild hemorrhage and 15 minutes before a 30-minute ischemia challenge was more efficient than 7.5% hypertonic sodium chloride in protecting kidneys against ischemia-reperfussion consequences in dogs.

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^*

Eficacia de la solución de cloreto de sodio a 7,5% con y sin dextran 70 a 6% en la preservación de la función renal de canes hipovolémicos sometidos a isquemia-reperfusión

Correspondence

Publication Dates

• Publication in this collection
  14 Jan 2011
• Date of issue
  Feb 2002

History

• Accepted
  08 Aug 2001
• Received
  29 May 2001