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THE EFFECTIVENESS OF SODIUM DEOXYRIBONUCLEATE IN THE COMPLEX TREATMENT OF VICTIMS WITH SEVERE ASSOCIATED INJURY: A PROSPECTIVE, RANDOMIZED, PLACEBO-CONTROLLED STUDY
Tulupov A.N., Dulaev A.K., Gromov M.I., Pivovarova L.P., Lapshin V.N., Sinenchenko G.I., Nikitin A.V., Fedorov A.V., Markelova E.V., Osipova I.V., Razumova N.K.
Saint Petersburg I.I. Dzhanelidze Research Institute of Emergency Medicine, Saint Petersburg, Russia
A common feature of the course of severe associated
injury (AI) is insufficiency of immune and hematopoietic system, and cellular
metabolism disorder which develop in the period of acute response to trauma
[1]. The clinical manifestation of such disorders is development of
complications of infectious and non-infectious origin. The incidence of
infectious complications after polytrauma reaches 90 % for pneumonia, and 26-52
% for sepsis [2]. The laboratory findings testify the development of acute
posttraumatic anemia, hypoproteinemia and secondary immune insufficiency [3].
The standard treatment of acute posthemorrhagic anemia
and hypoproteinemia supposes the replacement therapy with donor blood
components. However, such treatment causes the pulmonary vascular
microembolization and immune suppression, is limited by donorship resources and
is hazard due to risk of various viral infections [2].
Various immune modulators were used for correction of
secondary immune deficiency in the associated injury [4]. Recombinant
interleukin-2 [5], and the combination of interleukin-2 and sodium deoxyribonucleate
[6] were efficient for patients with sepsis and lymphocytopenia.
The ability of various nucleic acids for activation of
tissue healing is known from 1960s [7]. A recent experimental study showed that
the use of native fragments of sodium deoxyribonucleate as local application
decreased the edema and injury to the skin in region of bedsores by means of
suppression of local oxidative stress caused by tissue ischemia-reperfusion
[8].
Objective –
to estimate
the effect of deoxyribonucleic acid on the
incidence of complications and the duration of treatment, as well as the state
of immunity and hematopoiesis in victims with severe associated injury.
MATERIALS AND METHODS
Derinat©
(Tekhnomedservis, Russia, registration number No. R N002916/01) presents the
low molecular native fragments of DNA in view of sodium deoxyribonucleate from milt of sturgeons. It realizes
the reparative and immunomodulating action by delivery of bioavailable
polynucleotides to the body. The high accumulation and consumption of the agent
happens in the most actively dividing cells – in bone marrow, the spleen,
lymphatic nodes, the skin and mucosa [7].
The inclusion criteria to the study were the patients’
age of 18-70, traumatic shock of degree 2 or 3, with probable mortality < 50
% and the value of predictive criterion ±Т within the
range from +7.5 to +48 hours [9]. The exclusion criteria were concurrent sexually
transmitted diseases, viral hepatitis, HIV, chronic renal insufficiency,
chronic diseases requiring for anti-inflammatory, hormonal and cytostatic drugs,
chronic alcoholism, drug addiction, pregnancy. The exclusion from the study
group was late identification of the exclusion criteria, and transfer of
patients to other hospitals.
The study design
corresponded to conditions of prospective, double blind, placebo controlled
study. The patients and medical staff did not know where bottles with the
active drugs were or where placebo was. Each patient received the contents of a
flacon (5 ml) designated as Derinat (75 mg) of the same series. The
intramuscular injection was made one time a day during 10 days beginning from
next day post injury. The patients were randomized into two groups according to
generation of 60 random numbers. The even number corresponded to the even
series of the drug, the non-even number was the non-even series of production.
The placebo was of identical appearance and other numbers of production series.
The study included 60
patients (47 men and 13 women at the age of 20-68) with severe closed
associated mechanic injuries who were admitted immediately from Saint Petersburg
I.I. Dzhanelidze Research Institute of Emergency Medicine from May, 2016, to
May, 2018. 83 % of patients were persons of working age. The severity of
injuries was estimated with ISS [10], the severity and the probable outcome of traumatic
shock (+T) – with the formula [9], the severity of organ dysfunction – with
SOFA [11]. Sepsis categories were determined in concordance with the
recommendations of Chicago Consensus Conference [12].
All patients received the clinical, laboratory,
radiologic and instrumental examinations, as well as the treatment in
compliance with the present order for arrangement of medical care for patients
with associated, multiple and single injuries with shock. Additionally, each
patient was estimated for blood levels of mononuclear cells expressing the
receptor of stem cell factor (CD117), and neutrophilic granulocytes (NG), which
contents the antimicrobial peptides of human defensin (def+NG).
The main directions for anti-shock treatment included
the recovery of oxygen transport (infusion, transfusion, cardio- and vasoactive
therapy, respiratory therapy), correction of consequences of hypoxia and
reperfusion (antioxidant and antihypoxant therapy, proteolysis inhibitors),
correction of hemostasis, antibacterial, nutritive and detoxication therapy
[2].
The prognosis (with ±Т criterion) was unclear in
all patients admitted to the anti-shock surgery room. As result, only critical
care operations (primary interventions according to Damage control) and
low-invasive medicodiagnostic procedures were carried out. After anti-shock treatment
and stabilization of vital functions, the early restorative interventions were
realized in full volume in the manner, which allowed performing the procedures
with the first surgical “window of opportunities”, i.e. before formation of
infectious complications, which demonstrate the highest incidence on the days
3-7 after trauma. For the whole period of the treatment in the trauma center,
the patients of the main group received 4 various surgical interventions on
average, the patients of the comparison group – 5.
The complications were considered as life-threatening
and non-life-threatening, and infectious and non-infectious. The condition of erythroid
lineage of hematosis (erythron) was monitored with the data of clinical blood
analysis (Sysmex XT-000i). Protein-synthesis function of cells was monitored
with the level of total protein in blood serum (Cobas c501). The number of days
was calculated when the laboratory signs of anemia and hemoglobin < 100 and
< 90 g/l, and hypoproteinemia with total protein < 60 and < 50 g/l
were registered.
The study protocol was approved by the local ethical committee.
The informed consent for participation in the study was received from each
patient.
The group of healthy individuals (n = 15) of the same
age and gender was used for comparison of erythropoiesis and total protein of
the blood.
The statistical preparation of the data was realized
with Statistica 6.0. The description statistics of the groups is presented by
the average value and error of the mean, and by calculation of percentage
proportions. Non-parametrical tests were used for estimation of quantitative
values: Mann-Whitney’s test – for intergroup comparison, Wilcoxon’s test – for
intragroup comparison. The analysis of nominal data was performed with Fisher’s
exact test. The correlation was analyzed with Pearson’s parametrical method. P value < 0.05 was statistically significant.
The final cohort for analysis included 54 patients
including 27 patients in the main group (with the studied agent), and 27 patients
in the comparison group (placebo). 6 patients were excluded from the study
(transfer to other hospital, pregnancy).
RESULTS AND DISCUSSION
According to the tables 1-3, the patients of both groups did not demonstrate any significant differences in gender, age, ISS, shock severity (±Т), characteristics of injuries, and techniques of surgical and conservative management.
Table 1. General characteristics of patients with associated injury
|
Values |
Main group |
Comparison group |
|
Amount of patients |
27 |
27 |
|
Men (%) |
21 (78 %) |
20 (74 %) |
|
Age, years |
39 (29; 51) |
40 (26; 53) |
|
Road accident (%) |
21 (78 %) |
19 (70 %) |
|
Catatrauma (%) |
5 (19 %) |
6 (22 %) |
|
Industrial injury (%) |
1 (4 %) |
2 (7 %) |
|
Shock of degree 2 (%) |
17 (63 %) |
16 (59 %) |
|
Shock of degree 3 (%) |
10 (37 %) |
11 (41 %) |
|
ISS, points |
26.0 ± 1.2 |
24.7 ± 1.2 |
|
±T, hours |
+12.9 ± 0.9 |
+12.0 ± 0.7 |
|
Total number of hemotransfusion, l |
1.8 ± 0.3 |
1.8 ± 0.2 |
|
ICU stay, days |
5.9 ± 0.9 |
6.2 ± 1.0 |
|
Number of days with SOFA > 0 |
4 3 ± 0.7 |
4.5 ± 0.7 |
Table 2. Incidence of injuries to various regions of the body
|
Region |
Incidence of injuries |
|||||
|
General |
Dominating injuries |
Concurrent injuries |
||||
|
Group |
Group |
Group |
||||
|
Main |
Comparison |
Main |
Comparison |
Main |
Comparison |
|
|
Head |
52 % (14) |
67 % (18) |
14.8 % (4) |
7.4 % (2) |
37 % (10) |
14.8 % (4) |
|
Chest |
52 % (14) |
52 % (14) |
40.7 % (11) |
44.4 % (12) |
14.8 % (4) |
22.2 % (6) |
|
Abdomen |
11 % (3) |
26 % (7) |
7.4 % (2) |
11.1 % (3) |
0 |
11.1 % (3) |
|
Pelvis |
33 % (9) |
30 % (8) |
18.5 % (5) |
18.5 % (5) |
7.4 % (2) |
0 |
|
Spine |
44 % (12) |
37 % (10) |
3.7 % (1) |
0 |
14.8 % (4) |
7.4 % (2) |
|
Extremities |
44 % (12) |
44 % (12) |
14.8 % (4) |
14.8 % (4) |
7.4 % (2) |
7.4 % (2) |
|
2 regions |
15 % (4) |
19 % (5) |
0 |
0 |
14.8 % (4) |
18.5 % (5) |
|
3 and more regions |
85 % (23) |
81 % (22) |
0 |
0 |
0 |
3.7 % (1) |
Table 3. Incidence of injuries to organs and structures in polytrauma in groups
|
Injury pattern |
Group |
|
|
Main |
Comparison |
|
|
Closed traumatic brain injury |
52 % |
67 % |
|
Facial bone fractures |
19 % |
41 % |
|
Lung contusion and laceration |
81 % |
67 % |
|
Multiple rib fractures |
41 % |
59 % |
|
Liver laceration |
2 % |
4 % |
|
Spleen laceration |
11 % |
7 % |
|
Laceration and contusion of small intestine and its mesentery |
7 % |
4 % |
|
Laceration and contusion of colon and its mesentery |
4 % |
2 % |
|
Kidney contusion and laceration |
1 % |
4 % |
|
Urine bladder and urethra laceration |
2 % |
7 % |
|
Pelvis fractures |
33 % |
30 % |
|
Spine fractures |
44 % |
37 % |
|
Humerus fractures |
19 % |
4 % |
|
Forearm fractures |
7 % |
22 % |
|
Hip fractures |
30 % |
22 % |
|
Leg fractures |
37 % |
11 % |
The estimation of severity of patients’ condition
during treatment in ICU showed the absence of differences in mean duration of
organ function disorders (SOFA > 0), and duration of stay in the unit. Also
there were not any differences in average volume of hemotransfusion.
Acute posthemorrhagic anemia of mild degree [13] (normochromic,
normocytic, regeneratory), and hypoproteinemia were registered in both groups
on the following day after trauma (the table 4).Subsequent treatment of polytrauma was analyzed with
consideration of anemia and hypoproteinemia, and various complications within
the whole period of hospital stay.
Table 4. Laboratory characteristics of erythropoiesis and protein level in blood of patients with associated injury (1 day after injury)
|
Values |
Groups |
|||||
|
Healthy |
Main group |
Comparison group |
Р1,2 |
P1,3 |
P2,3 |
|
|
1 |
2 |
3 |
||||
|
Red blood cells, 1012/l |
4.6 ± 0.2 |
3.5 ± 0.1 |
3.3 ± 0.1 |
0.000 |
0.000 |
0.163 |
|
Hemoglobin, g/l |
139 ± 7 |
107 ± 3 |
104 ± 4 |
0.002 |
0.001 |
0.551 |
|
Mean level of hemoglobin in erythrocyte, pg |
29.6 ± 1.0 |
30.7 ± 0.2 |
30.8 ± 0.4 |
0.332 |
0.312 |
0.824 |
|
Reticulocytes, % |
0.94 ± 0.22 |
1.24 ± 0.10 |
1.10 ± 0.10 |
0.223 |
0.512 |
0.327 |
|
Hematocrit, % |
41.8 ± 2.1 |
31.6 ± 0.8 |
31.1 ± 1.1 |
0.001 |
0.001 |
0.715 |
|
Total protein, g/l |
70.8 ± 3.2 |
56.3 ± 1.0 |
53.9 ± 1.5 |
0.000 |
0.000 |
0.189 |
Note: p – reliability of differences according to Mann-Whitney’s test.
First of all, the dependence of laboratory values and
all developed complications was studied in the whole group of patients. As
result, the close positive correlation was found between summary amount of complications
for each patient and duration of anemia and hypoproteinemia (n = 54, r = 0.598, p = 0.009).
Then
the comparative analysis of the main group and the comparison group was
conducted in relation to treatment duration, number of complications, and
outcomes (the table 5). The findings show that the incidence of complications
was 1.8 more seldom in the main group, and the hospital treatment duration was
6.8 days less than in the comparison group. There were not any undesirable
effects after introduction of the drug. The cause of death in the main group
was abdominal sepsis. Two patients died after multiple organ dysfunctions in
the comparison group.There
were not any reliable intergroup differences according to the table 5. However,
some significant differences were found in amount of complications in each
group. Complications did not develop in a half of patients with more mild
conditions (51.9 % in the main group, 48.1 % in the comparison group). Patients
with more severe complications had 21 complications in the main group, and 39
in the comparison group. One or two complications were found in 10 patients in
the main group and in 6 in the comparison group, 3-6 complications – in 2
patients in the main group, and in 7 patients in the comparison group. For
further analysis, both groups were divided into subgroups with absence or
presence of identified complications.
Table 5. Duration of treatment, number of complications and outcomes
|
Values |
Main group |
Comparison group |
p |
|
Mean hospital stay, (M ± m) |
32.8 ± 4.1 |
39.6 ± 6.6 |
0.891 |
|
Mean number of complications in 1 patient, (M ± m) |
0.8 ± 0.2 |
1.4 ± 0.4 |
0.353 |
|
Deceased (%) |
1 (4 %) |
2 (7 %) |
0.618* |
Note: p – reliability of differences according to Mann-Whitney’s test, p* – according to Fisher’s exact test.
The
table 6 shows the results of comparison of subgroups of patients with
complicated course of polytrauma. These subgroups demonstrated higher clinical
and laboratory efficiency of the studied group.
The
table 6 shows the lower (1.9 times) amount of complications in the main group
as compared to the control group. It was mainly determined by a decrease in
number of infectious, non-life-threatening complications.The
analysis of the laboratory values of erythropoiesis and total protein identified
a more favorable correcting effect in the subgroup with sodium deoxyribonucleate.
The duration of acute anemia and hypoproteinemia in
all analyzed ranges of hemoglobin and total protein levels was reliably higher
in the subgroup with complications of the comparison group (2.3-4.9 times) as
compared to patients of the similar subgroup of the main group.
Table 6. Structure of complications and duration of anemia and hypoproteinemia in subgroups with complicated course of associated injury
|
Complications |
Subgroups of patients |
р |
|
|
Main group |
Comparison group |
||
|
All complications, in 1 patient on average |
1.6 ± 0.3 |
3.0 ± 0.4 |
0.014 |
|
- life-threatening infectious complications (severe sepsis, septic shock) |
0.8 ± 0.2 |
0.7 ± 0.3 |
0.579 |
|
- life-threatening non-infectious complications (acute bleeding, arterial thrombosis, pulmonary embolism, lung atelectasis with respiratory failure, fat embolism) |
0.1 ± 0.1 |
0.3 ± 0.2 |
0.511 |
|
- non-life threatening infectious complications (sepsis, focal pneumonia, bronchitis, pleuritis, wound purulence, cystitis, pyelonephritis) |
0 ± 0 |
0.9 ± 0.3 |
0.044 |
|
- non-life threatening non-infectious complications (acute gastrointestinal ulcer, venous thrombosis) |
0.7 ± 0.2 |
1.2 ± 0.2 |
0.186 |
|
Blood hemoglobin < 100 g/l |
7.1 ± 2.1 |
16.0 ± 3.1 |
0.026 |
|
Blood hemoglobin < 90 g/l |
3.2 ± 1.3 |
7.9 ± 2.1 |
0.044 |
|
Total serum protein < 60 g/l |
8.2 ± 2.2 |
19.5 ± 4.1 |
0.034 |
|
Total serum protein < 50 g/l |
1.1 ± 0.5 |
5.4 ± 1.6 |
0.009 |
Note: p – reliability of differences according to Mann-Whitney’s test.
Certainly, for critical states, the significant
importance is related to condition of immune system, i.e. a degree of
mobilization of neutrophils and monocytes providing the immediate
anti-infection protection, and regulation of inflammatory and reparatory
processes. For this reason, the patients with severe associated injury were
analyzed for blood levels of mononucleatyc cells expressing the receptor of
stem cell factor (CD117+) as the value of activation of bone marrow
hematopoesis and mobilization of leukocytes-precursors and tissue cells into
peripheral tissues. The amount of def+NG was estimated for influence
of sodium deoxyribonucleate on bactericidal properties of leukocytes. It is
known that alfa-defensins show the evident cytotoxic activity in relation to
various agents, and promote the regulation of cortisol level and reparation of
damaged tissues [14].
According to the table 7, the patients of the main
group showed an increase in blood monocytes and CD117+ in 7 days
after introduction of the drug. The increase differed from the levels in the
control group. One should consider it as activating influence of the drug on
migration of stem cells from bone marrow into the blood flow and, subsequently,
into tissues, providing the reparative processes in the injury site.
Moreover, the activating influence of sodium deoxyribonucleate
on maturation of functionally mature granulocytes in bone marrow (def+NG),
which contain antimicrobial and regulatory peptides, and on migration into the
blood. It is testified by gradual increase in proportion of def+NG
in the whole population of blood granulocytes in the main group, achieving 26 %
of increase in comparison with the basic level by the day 14 of the follow-up.
The patients of the comparison group demonstrated a gradual decrease by 59 % in
their proportion among granulocytes (the table 7).Besides of deficiency of proteins, fats, carbonhydrates,
aminoacids and microelements, the disadvantage of exogenous bioavailable
nucleotides can influence on severity of the disease course. So, exogenic
introduction of native fragments of DNA significantly improves the activity of
bone marrow in radial disease, and for oncology – after chemotherapy courses
[9]. In the post-shock period of severe associated injury, one can observe the
insufficient activity of functioning of bone marrow and peripheral immune
system [1].
Table 7. Levels of monocytes, mononuclear cells CD117+and def+NG in patients with associated injury
|
Values |
Groups of patients |
Before injection |
After 7 days |
After 14 days |
P1,2 |
P1,3 |
|
1 |
2 |
3 |
||||
|
Monocytes, ×109l |
Main group |
0.56
± 0.05 |
0.89
± 0.07 |
0.65
± 0.07 |
0.004 |
0.681 |
|
Mononuclear cells, CD117+, ×109l |
Main group |
0.46
± 0.05 |
0.81
± 0.07 |
0.46
± 0.05 |
0.014 |
0.237 |
|
Def+NG, % |
Main group |
36 ± 4 |
38 ± 4 |
46 ± 3 |
0.548 |
0.037 |
Note: p – reliability of differences according to Mann-Whitney’s test, P – according to Wilcoxon’s test.
From the first hours after trauma, patients with
associated injury show the high requirement for synthesis of protein and its
preservation in the vascular bed, for recovery and maintenance of higher blood
hemoglobin to exclude the effects of hypoxia and to maintain the sufficient
amount of functionally mature immune cells for realization of antimicrobial
protection and recovery of injured tissues. Insufficient reserves for restoration
of above-mentioned disorders create some premises for development of various
complications, which influence on quality and duration of treatment.
CONCLUSION
The use of sodium deoxyribonucleate for patients with
severe associated injury promotes the recovery of total protein and hemoglobin,
increasing migration of stem cells and NG with antimicrobial peptides into the
blood. Patients with complicated course of associated injury were more
sensitive to the drug. Eventually, 1.8-fold decrease in amount of
complications, and the decrease in treatment by 6.8 days were achieved.
As result of the double blinded study, we can state
that commercial sodium deoxyribonucleate (Derinat) increases the efficiency of
complex treatment of patients with severe associated injury.
The novelty of the study has been protected with
application for the invention (acknowledgement of receipt from December 25,
2018).
Information on financing and conflict of interests
The study was conducted without sponsorship. The authors declare the absence of any clear or potential conflicts of interests relating to publication of this article.
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