Revista
de la
Universidad
del Zulia
Fundada en 1947
por el Dr. Jesús Enrique Lossada
DEPÓSITO LEGAL ZU2020000153
ISSN 0041-8811
E-ISSN 2665-0428
Ciencias del
Agro
Ingeniería
y Tecnología
Año 12 N° 32
Enero - Abril 2021
Tercera Época
Maracaibo-Venezuela
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DOI: http://dx.doi.org/10.46925//rdluz.32.03
24
Efficiency of the use of perfluorocarbon gas transport drugs for
various forms of anemia in animals
Sergej V. Votrin*
Sergej I. Vorobyev**
Sergey B. Bolevich***
Aleksandra S. Orlova****
Denis D. Gudanovich*****
ABSTRACT
Purpose: The purpose of the article is to determine the effectiveness of the use of
perfluorocarbon gas vehicles in acute, severe anemia in animals caused by external blood loss
and autoimmune intravascular hemolysis. Methodology: The effectiveness of the use of
perfluorocarbon gas transport agents in acute, severe anemia in animals caused by external
blood loss and autoimmune intravascular hemolysis was carried out based on the assessment
of lethality in groups, biochemical criteria that were determined using an automatic
biochemical blood analyzer and an assessment of hematocrit, which was determined using
an automatic an analyzer of a general clinical analysis of blood with an impedance counting
system. Results: The high efficiency of the use of perfluorocarbon gas transport drug -
Perftoran in acute and severe anemia caused by external blood loss and autoimmune
intravascular hemolysis was revealed on the basis of an assessment of the lethality of animals
in groups in comparison with a blood preparation - donor erythrocyte mass. The lethality in
the groups of animals that used the perfluorocarbon gas transport agent was significantly
lower than that in the animals that used the erythrocyte mass, especially in acute and severe
anemia caused by autoimmune intravascular hemolysis.
KEY WORDS: hypoxia, hemolysis, anemia, correction, erythrocyte mass, perfluorocarbon
blood substitute, critical conditions
*Ph.D. student at the human pathology department Sechenov First Moscow State Medical Univesity
(Sechenov Univesity) Moscow, Russia. ORCID: https://orcid.org/0000-0003-1773-1662
**Doctor of Biological Sciences, Professor, the head of the human pathology department Sechenov First
Moscow State Medical Univesity (Sechenov Univesity) Moscow, Russia. ORCID: https://orcid.org/0000-
0003-1383-957X
***MD, Professor, the head of the human pathology department Sechenov First Moscow State Medical
Univesity (Sechenov Univesity) Moscow, Russia. ORCID: https://orcid.org/0000-0002-1574-477X
****PhD in Medicine, associate professor at the human pathology department Sechenov First Moscow State
Medical University (Sechenov University) Moscow, Russia. ORCID: https://orcid.org/ 0000-0001-9725-7491
*****Ph.D. student Sklifosovsky Clinical and Research Institute for Emergency Medicine Moscow, Russia.
ORCID: https://orcid.org/0000-0002-8014-1799
Recibido: 03/08/2020 Aceptado: 05/10/2020
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Eficiencia del uso de fármacos en el transporte de gas
perfluorocarbonado para diversas formas de anemia en animales
RESUMEN
Propósito: El propósito del artículo es determinar la efectividad del uso de vehículos de gas
perfluorocarbonado en la anemia aguda y severa en animales causada por pérdida de sangre
externa y hemólisis intravascular autoinmune. Metodología: La efectividad del uso de agentes
transportadores de gas perfluorocarbonado en la anemia aguda severa en animales causada
por hemorragia externa y hemólisis intravascular autoinmune, se llevó a cabo en base a la
evaluación de la letalidad en grupos, criterios bioquímicos que se determinaron utilizando
una sangre bioquímica automática, y una evaluación del hematocrito, que se determinó
utilizando un analizador automático de análisis clínico general de sangre con un sistema de
recuento de impedancia. Resultados: La alta eficiencia del uso del fármaco de transporte de
gas perfluorocarbonado - Perftoran en la anemia aguda y grave causada por la pérdida de
sangre externa y la hemólisis intravascular autoinmune se reveló sobre la base de una
evaluación de la letalidad de los animales en grupos, en comparación con una preparación de
sangre - masa de eritrocitos del donante. La letalidad en los grupos de animales que usaron el
agente de transporte de gas perfluorocarbonado fue significativamente menor que en los
animales que usaron la masa de eritrocitos, especialmente en la anemia aguda y severa
causada por hemólisis intravascular autoinmune.
PALABRAS CLAVE: hipoxia, hemólisis, anemia, corrección, masa eritrocitaria, sustituto
sanguíneo de perfluorocarbono, condiciones críticas
Introduction
The success of treatment in the complex therapy of any critical conditions in the
animal clinic is determined by the rapid restoration of vital functions, as well as the prompt
elimination of oxygen deficiency in various organs and systems of the body. From this point
of view, the interest shown by researchers from different countries to the use of artificial gas-
transporting blood-substituting drugs for anemia of various genesis is understandable
(Ragimov, 2015; Bialas et al., 2019; Spiess, 2019).
It is known that critical conditions arise both in acute posthemorrhagic anemia
caused by massive external blood loss and in acute autoimmune hemolytic anemia caused by
immune lysis of erythrocytes and can be accompanied by both intravascular and
extravascular hemolysis (Shiffman, 2017).
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Replacement therapy for massive external blood loss should be carried out
immediately to eliminate hypoxia in severe acute posthemorrhagic anemia. However, the
issue of transfusions of blood and its components in the treatment of acute and severe blood
loss is currently ambiguous. It is necessary to avoid unreasonable blood transfusions in an
immune complex recipient (Ragimov, 2015; Vorobyev et al., 2020).
In acute autoimmune hemolytic anemia, the destruction of erythrocytes as a result of
acute autoimmune intravascular hemolysis deserves special attention. Acute autoimmune
intravascular hemolysis is a type of acute pathological hemolysis characterized by the
destruction of erythrocytes in the vascular bed under the influence of antibodies and a
compliment. This is a rapidly developing, autoimmune process, in which the compensatory
forces of the body do not have time to turn on in full (Alekseev, 2004).
Acute autoimmune intravascular hemolysis underlies the pathogenesis of blood
parasitic diseases. Intravascular hemolysis is especially pronounced in its pathological effect
in complicated canine babesiosis. In this disease, erythrocytes are directly damaged by
hemoparasites, and their decay products cause a severe acute autoimmune process,
manifested in the form of intravascular hemolysis (Nimand and Suter, 2004).
With the rapid development of such pathological processes as acute posthemorrhagic
anemia and acute autoimmune hemolytic anemia, the compensatory mechanisms of the body
do not have time to develop sufficient power; accordingly, clinical manifestations, as a rule,
end in a high mortality rate (Shiffman, 2017).
In this regard, the aim of this study is devoted to the correction of critical conditions
(lethality) caused by acute posthemorrhagic anemia and acute autoimmune hemolytic
anemia using a blood-substituting gas transport emulsion of perfluorocarbons of the
Perftoran type (Russia) in comparison with the traditional erythrocyte mass.
1. Materials and methods
In the first block of retrospective studies in acute posthemorrhagic anemia, 41 cats of
both sexes were selected, admitted to the Clinic of Veterinary Medicine of the Scientific
Center for Biological Research in the city of Pushchino with bleeding as a result of various
injuries in the period 2009–2018. Animals were randomized according to the method of
treatment into 3 groups.
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The first control group (n = 17) included animals for the treatment of which traditional
infusion therapy was used, including the use of a colloidal solution “Stabizol” at a dose of 20
ml / kg of body weight (Plumb, 2002).
The second group (n = 13) included animals for the treatment of which traditional
infusion therapy was used on the first day of admission to the clinic, including the use of a
colloidal solution "Stabizol" at a dose of 20 ml / kg body weight; these animals were
transfused with donor EO at a dose of 10 ml / kg body weight one day after injury and bleeding
(Vaden et al., 2013).
The third group (n = 11) included animals for which, in addition to the colloidal
solution "Stabizol", perfluorocarbon blood substitute “Perftoran” was used. The therapeutic
dose was 10 ml / kg body weight, infusion was performed on the first, second, third, fifth, and
seventh day after injury.
Animals with the same criteria were selected into three groups of the first block of
studies: Ht 9-18%, bilirubin 7-11 µMol / L, lactate 2.3-5.4 mMol / L, SpO
2
77-84%, K + 4.1– 5.4
mMol / L. The creatinine level was within the normal range of 80–160 µMol / L. Cats weighing
3–5 kg were selected.
In the second block of retrospective studies to correct hypoxia in acute autoimmune
intravascular hemolysis, 79 dogs of both sexes were used, admitted to the Clinic of Veterinary
Medicine of the Scientific Center for Biological Research in the city of Pushchino in the
period 2009-2018 with a diagnosis of babesiosis complicated by acute autoimmune
intravascular hemolysis.
In this experimental, retrospective, parallel-controlled study, animals were
randomized into 3 treatment groups. Dogs with the same criteria were selected for all three
groups: Ht 9-12%, bilirubin 40-60 μMol / L, lactate 5-6 mMol / L, SpO
2
78-80%, K + 3.6-5.6
mMol / L. The creatinine level was within the reference values - 80–160 mMol / L.
The creatinine level was within the reference values - 80–160 µMol / L. Dogs were selected
whose weight ranged from 15 to 35 kg. These dogs had plasma hemolysis, hemoglobinuria,
anemicity and yellowness of the mucous membranes, microscopy of a blood smear revealed
babesia and agglutination of erythrocytes (ER) in the form of coin bars, plasma was colored red
during blood centrifugation, which confirmed the presence of acute autoimmune intravascular
hemolysis as a result of infection of animals with babesiosis (Alekseev, 2004; Vaden et al., 2013).
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The first control group included 29 dogs for the treatment of which basic therapy
was used, implying: prednisolone intravenously (IV) at a dose of 4 mg/kg once a day for
five days in a row, which is used as an immunosuppressant, as a detoxification solution
IV NaCl 0.9% - 10 ml/kg was injected once a day for five consecutive days, antiprotozoal
therapy was carried out by subcutaneous (sc) administration of Piro-Stop 0.5 ml/10 kg
once. Pyro-Stop is an antiprotozoal drug from the imidazole group. As an active
substance, 1 ml of solution for injection contains 120 mg of imidocarb dipropionate.
Therapeutic dose for dogs is 0.5 ml per 10 kg of animal weight, by subcutaneous
administration, once (Plumb, 2002).
The second group included 28 animals, in which replacement therapy was carried
out in addition to the basic one: to replenish the number of dead erythrocytes as a result
of acute autoimmune intravascular hemolysis, on the first day of treatment, erythrocyte
mass was used, with the help of which the recipient's hematocrit was raised to 20%. To
raise the recipient's Ht by 1%, it takes 1 ml of donor erythrocyte mass with Ht -45% per
kg of the recipient's weight. The erythrocyte mass was used in a 0.9% NaCl dilution in a
1: 1 ratio; in general, the volume of a blood preparation with Ht-10% administered to the
recipient was 20 ml / kg (Vaden et al., 2013; Nimand and Suter, 2004).
The third group included 22 dogs, which were added to the basic therapy with the
introduction of the drug “Perftoran”, at a dose of 10 ml / kg to reduce hypoxia resulting
from acute autoimmune intravascular hemolysis, while the erythrocyte mass of these
animals was not used.
The drug “Perftoran” is a submicron emulsion with an average size of "artificial
erythrocytes" ~ 100 nm with gas transport functions, containing 20% perfluorocarbons
(PFCs): perfluorodecalin - 13 g; perfluoromethylcyclohexylpiperidine - 6.5 g; proxanol - 4 g;
sodium chloride - 0.6 g; magnesium chloride - 0.019 g; potassium chloride - 0.039 g; sodium
bicarbonate - 0.065 g; glucose - 0.2 g; sodium hydrogen phosphate - 0.02 g; water for injection
- up to 100 ml (Vorobiev et al., 2016; Vorobyev et al., 2020).
The drug “Perftoran” was used as follows in the first experimental block of studies for
the relief of hypoxia caused by acute posthemorrhagic anemia in cats: the drug was
administered intravenously at a dose of 10 ml / kg once a day on days 1, 2, 3, 5, 7 of treatment.
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In the second experimental block of studies for the relief of hypoxia caused by acute
autoimmune intravascular hemolysis in dogs, the drug “Perftoran” was used intravenously at
a dose of 10 ml / kg once a day for five consecutive days.
The introduction of the drug “Perftoran” in cats and dogs began with a bioassay,
consisting in a gradual controlled introduction: 0.1 ml of the drug diluted with 0.9% NaCl to
5 ml, the drug was injected slowly intravenously, and then drip with pauses of 60 seconds -
3 , 5, 10, 30 drops, gradually increasing the infusion rate to one drop per second (Votrin et al.,
2018; Votrin and Vorobiev, 2017).
According to the instructions for medical use of the drug “Perftoran”, approved for
clinical use in Russia since 1996 - perfluorocarbon blood substitute is a multifunctional drug
with a wide spectrum of action (Ragimov, 2015).
2. Results and discussion
First block of research. As a result of a retrospective evaluation of the data on animals
(cats) of the first block of studies with acute posthemorrhagic anemia, which were observed
for 5 days, it was found that the lethality of animals in the groups differed significantly in the
control group and in the two main groups, where hypoxia was corrected with the drug
“Perftoran” and donor erythrocyte mass (table 1).
Table 1. Mortality of animals (cats) during the correction of acute blood loss and
posthemorrhagic anemia using the perfluorocarbon drug “Perftoran” and donor
erythrocyte mass (EM) during 5 days of observation
Groups
Initial
number
of
animals
General
mortality
1
2
3
5
1st group
The control
17
3
2
2
1
8 from 17
(47,1 %)
2nd group
Erythrocyte
mass
13
2
1
–
–
3 from 13
(23,1 %)
Group 3
“Perftoran”
11
1
–
–
–
1 from 11
(9,9 %)
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The data obtained show that the highest mortality rate of 47.1% in cats is observed in
the group without correction of hypoxia in the treatment of severe acute posthemorrhagic
anemia. Mostly death was observed in the stage of vascular collapse and in the hydraemic
stage, when hypoxia is most severe. It should be noted that in animals that used donor
erythrocyte mass to correct hypoxia in acute posthemorrhagic anemia, the lethality was
23.1%, which is two times lower than in the control and significantly higher (two or more
times) than in the group. with an artificial blood substitute drug “Perftoran”, where the
mortality rate was 9.9%. It is believed that donor erythrocytes are the best oxygen carriers,
as they dissolve up to 21 vol.% Oxygen (the drug “Perftoran” up to 7 vol.%); however, in
immunocomplex recipients, the decision on transfusion of donor erythrocyte mass is made
on the basis of the hematocrit level, which, in case of external blood loss, is informative 18-20
hours after the lost plasma volume is restored (Ragimov, 2015). That is why on the first day
in the group with erythrocyte mass there is a high mortality rate. In the group with the blood
substitute “Perftoran”, the lowest lethality was observed, which was due to the immediate
use of an artificial oxygen carrier to the immune-complex recipient.
Certain changes in hematocrit, lactate, SpO
2
were revealed on the basis of our
previously obtained experimental data (Votrin and Vorobiev, 2017) on the correction of acute
blood loss and posthemorrhagic anemia in animals using the perfluorocarbon gas transport
drug “Perftoran” and donor erythrocyte mass. We believe that this directly affects the high
mortality rate in the control and erythrocyte mass groups. It should be noted that the
experimental group of animals with posthemorrhagic anemia resulting from blood loss,
which received the drug “Perftoran” as part of the complex therapy, despite significant blood
loss, had indicators: hematocrit, lactate, SpO
2
, characterizing a moderate level of hypoxia,
significantly different from the indicators of animals the control group and the indices of the
animals of the group after transfusion with donor erythrocyte mass (Votrin and Vorobiev,
2017).
Studies have shown that the infusion of the perfluorocarbon gas-transport drug
“Perftoran”, carried out by an injured animal in acute posthemorrhagic anemia to compensate
for the hypoxic state, provides an oxygen reserve and allows the injured body, which has
received serious damage, to stably endure anesthesia, surgery, which together reduces the
mortality rate to 9, nine %.
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Second block of research. As a result of a retrospective assessment of the data on
animals (dogs) of the second block of studies with acute autoimmune hemolytic anemia,
observed for 9 days, it was found that the mortality of animals in the groups differed
significantly in the control group and in the two main groups, where hypoxia was corrected
with the drug “Perftoran” and donor erythrocyte mass (table 2).
Table 2. Mortality of animals (dogs) during the correction of hypoxia caused by
autoimmune intravascular hemolysis using the perfluorocarbon drug “Perftoran” and
donor erythrocyte mass during 9 days of observation
Groups
Initial
number of
animals
Observation time (days)
General
mortality
1
3
5
6
7
8
9
1st group
The control
29
2
6
1
–
2
1
1
13 from 29
(41 %)
2nd group
Erythrocyte
mass
28
1
6
1
2
–
3
2
15 from 28
(53 %)
Group 3
“Perftoran”
22
1
-
1
1
–
–
–
3 from 22
(13 %)
Studies have shown that in the 1st control group without hypoxia correction there is
a high mortality rate as a result of increasing hypoxia up to 41%; in the 2nd group, the main
one, where the animals used the erythrocyte mass for hypoxia correction, the highest
lethality was observed up to 53%; in the 3rd group, the main one, where “Perftoran” was used
for hypoxia correction, the lethality was the lowest, no more than 13% (p <0.05), 3.5-4 times
lower than in the 1st control group and 2nd group with erythrocyte mass (table 2).
Studies have shown that despite various methods of correcting hypoxia, a high
mortality rate in animals occurs in anemia as a result of autoimmune hemolysis. Our early
studies (Votrin et al., 2018) have shown that hyperbilirubinemia, hyperkalemia, acidosis,
hypoxia are of clinical importance in anemia caused by acute autoimmune intravascular
hemolysis. Thus, in the experimental group in animals with anemia caused by acute
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autoimmune intravascular hemolysis, which received donor erythrocyte mass as part of
complex therapy, the level of hypoxia was significantly lower than in the control group.
However, hyperbilirubinemia was noted as a result of increased autoimmune hemolysis, as a
result of which the bilirubin level was significantly higher than in the control group and in
the group with “Perftoran”. The level of hypoxia in the group of animals with anemia, which
received the drug “Perftoran” as part of the complex therapy, was significantly lower than in
the control group, but at the same time the level of bilirubin was significantly lower than in
the group with erythrocyte mass, which proves the absence of increased autoimmune
hemolysis, which directly affects the mortality rate.
The mortality data show that correction of hypoxia in severe autoimmune hemolytic
anemia is necessary, but for this it is necessary to use drugs that do not have immune
aggression, as noted on donor blood preparations. The most effective way to eliminate
hypoxia in severe autoimmune anemia caused by acute autoimmune intravascular hemolysis
is the use of perfluorocarbon gas-transporting blood substitutes of the Perftoran type.
A comparative analysis of animal mortality was carried out between the two blocks of
studies (Fig. 1). Studies have shown that the lowest mortality rate, from 9.9 to 13%, both in
cats and dogs in both blocks of studies, respectively, is observed when hypoxia is corrected
with Perftoran for any type of anemia. However, the use of another gas transport
hemocorrector - erythrocyte mass in the correction of hypoxia in the second block of studies
caused by autoimmune intravascular hemolysis in dogs, showed that the lethality sharply
increases to 53% compared to animals where the red blood cell mass was used for
posthemorrhagic anemia in the first block of studies 23 , 1% in cats. As noted, this is
associated with hyperbilirubinemia as a result of increased autoimmune hemolysis.
Conclusion
The following conclusions can be drawn. Correction with the perfluorocarbon gas
transport drug “Perftoran”, carried out in animals with acute blood loss and acute
autoimmune intravascular hemolysis to compensate for the hypoxic state, provides the
necessary oxygen balance without increasing immune aggression, which ultimately does not
lead to lethal iatrogenic complications.
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Figure 1. Comparative analysis of animal mortality between the two blocks of studies
in the correction of hypoxia caused by posthemorrhagic anemia and autoimmune
intravascular hemolysis. Control is gray. Erythrocyte mass is red. The drug “Perftoran”
is blue color
Correction of hypoxia caused by acute autoimmune intravascular hemolysis with the
help of erythrocyte mass enhances autoimmune hemolysis, thereby causing an increase in
bilirubin and, as a consequence, a high mortality rate. The high clinical efficacy of the
perfluorocarbon gas transport drug “Perftoran” for the correction of hypoxia caused by acute
blood loss and acute autoimmune intravascular hemolysis is associated with its medico-
biological and physicochemical properties: gas transport, rheological, anti-shock, anti-
ischemic, anti-toxic, anti-ischemic.
The use of synthetic gas transport blood substitutes for the correction of various forms
of hypoxia makes it possible to reduce the consumption of donor blood or even to refuse its
use, which reduces the infection and the number of unwanted negative reactions in
recipients.
0
10
20
30
40
50
60
1 Research block 2 Research block
47.1
41
23.1
53
9.9
13
%
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