CLINICAL EFFICIENCY OF MASSIVE TRANSFUSION THERAPY IN PATIENTS WITH POLYTRAUMA

Sholin I.Yu., Koryachkin V.A., Baryshev A.G., Safin R.R., Pashkova I.A., Zikharev V.A., Filippova E.G., Avetisyan V.A., Ezugbaya B.S., Porkhanov V.A.

Research Institute – Ochapovsky Regional Clinical Hospital No.1, Krasnodar, Russia,
Saint Petersburg State Pediatric Medical University, Saint Petersburg, Russia

 CLINICAL EFFICIENCY OF MASSIVE TRANSFUSION THERAPY IN PATIENTS WITH POLYTRAUMA

According to WHO, the annual mortality after road traffic accidents (RTA) is 1.25 million human lives. About 20-50 million people receive non-fatal injuries with high percentage of disability, including 48 % of all fatal cases after RTA with persons at the age of 15-44 [1]. Injuries take the third place in the general structure of mortality in the population of the Russian Federation. Treatment of patients requires for serious economic costs, with high financial damage for the state if disability or lethal outcome appear [2, 3].
The high rate of mortality and disability requires for future studies and development of medical care algorithm at early prehospital stages [4]. Moreover, considering that hemorrhagic shock is the main cause of potentially reversible death, it is critically important to develop and implement the protocol of massive infusion-transfusion therapy into clinical practice [3, 5].
Objective – clinical evaluation of the effectiveness of massive infusion-transfusion therapy in patients with polytrauma.

MATERIALS AND METHODS

After approval from the local ethical committee (the protocol No.8, 2 October 2015), a study of traumatic disease course was examined in 78 patients in 2015-2018. The patients were urgently admitted to the admission unit of Research Institute – Ochapovsky Regional Clinical Hospital No.1.
All patients were divided into two similar groups (the table 1).

Table 1. Characteristics of examined patients (М ± SD)

Feature

First group
(n = 42)

Second group
(n = 36)

Age (years)

36 ± 5.35

39 ± 4.76

Gender (male/female)

27/15

22/14

weight (kg)

82 ± 3.25

79 ± 4.11

ISS

26.4 ± 1.12

27.1 ± 0.96

Note: ISS – Injury Severity Score.

The first (main) group (n = 42) was treated with our protocol of infusion-transfusion therapy for massive blood loss. The second (control) group (n = 36) received a retrospective analysis of cases of standard infusion-transfusion therapy on the basis of treatment of blood loss of degrees 1-4 (for massive blood loss corresponding to degree 4, the following ratio was used: crystalloids – 20 %, colloids – 25 %, red blood cells – 25 %, FFP – 30 % of total volume of fluid) [6].
The inclusion criteria were: severe associated injury with injuries to thoracic organs and/or abdominal cavity and/or small pelvis (ISS = 16-45), ABC = 2-4, admission within an hour after trauma, a complicated fracture of the spine, pregnancy, severe cardiac pathology with decreased contractility of left ventricle.
At the moment of admission of a patient (the patients of the group 1) with severe associated injury to the admission unit, and after airway management (according to indications of ALV) and making the vascular approach, the infusion of noradrenaline was initiated for supporting the systolic arterial pressure at the level of 80-90 mm Hg, the blood was taken for analysis, the blood group and its individual matching were estimated. The examination was conducted with e-FAST-protocol. If ABC was 2 points and more (a penetrating injury – 1 point, free fluid in abdominal cavity – 1 point, SAP < 90 mm Hg – 1 point, heart rate 102 per min. and more – 1 point) [7], then the massive transfusion protocol (MTP) was initiated: 4 doses of red blood cells, 4 doses of fresh frozen plasma, 1 dose of apheresis platelets or 6 doses of pooled platelets. Since determination of a blood group and its individual compatibility takes about 3-40 minutes, transfusions of red blood cells of O group with negative Rh (1-2 doses) and AB group fresh frozen plasma (1-2 doses) were initiated for life-threatening conditions. Then transfusion of erythrocytic components of the blood, fresh frozen plasma and apheresis platelets with complied blood group with ratio 1:1:1 was initiated. All patients who were admitted within 3 hours from injury moment received 1 g of tranexamic acid with subsequent introduction of 1 g within 8 hours.
In absence of surgical control of bleeding, the laboratory estimation (FBC, acid-base balance, coagulogram) of necessity for recurrence of massive hemotransfusion protocol with the same volume and ratio of components for achievement of surgical hemostasis was initiated.
After transfusion of blood components and bleeding arrest, we performed thromboelastometry and total blood analysis. For CT in INTEM > 240 sec., EXTEM > 80 sec., 4 doses of fresh frozen plasma were transfused. For A10 < 40 mm or ά > 83 o (INTEM or EXTEM) + A10 > 10 mm FIBTEM, 1 dose of apheresis platelets was transfused. For A10 < 40 mm or ά > 83 o (INTEM or EXTEM) + А10 < 10 mm FIBTEM, 10 doses of cryoprecipitate were transfused. For B APTEM with the change in values by 15 % as compared to EXTEM, anti-fibrinolytic agents were administered. Transfusion of erythrocytic suspension was performed for hemoglobin < 90 g/l.
After achievement of targeted levels of coagulation and hemoglobin, infusion therapy was conducted with control of MAP, tissue perfusion markers and with measurement of diameter and the index of inferior vena cava collapse. MAP was maintained at the level of 65 mm Hg and higher. Noradrenaline infusion was continued for hypotonia. Saturation of central venous blood (ScvO2), venoarterial difference in CO2 partial stress (Pv-aCO2)  and measurement of diameter and the inferior vena cava collapse index (IVC-CI) were estimated in case of hyperlactatemia (> 2.5 mmol/l) and dynamic increasing.
Ultrasonic identification of the signs of necessity for decreasing rate of transfusion therapy was carried out in normalization of metabolic marker of perfusion (ScvO2 – 70 %, lactate < 2.5 mmol/l, Pv-aCO2 < 6 mm Hg), absence of necessity for continuous infusion therapy and with hemodynamic stability (noradrenaline < 0.3 µg/kg/min.). These signs included dIVC ≥ 2 cm, increasing dIVC ≥ 0.5 cm over 12 h, IVC-CI ≤ 13 % (with ALV) or IVC-CI ≤ 20 % (in spontaneous breathing), В-line ≥ 1 region) [8].
In case of preserved function of kidneys, a decrease in infusion rate was realized with continuous intravenous introduction of diuretic agents (furosemide 40-100 mg per day). A daily negative balance was up to -1,000-1,500 ml. Extracorporeal ultrafiltration (24-48 hours) was performed for acute renal injury or chronic renal failure.
The patients of the second group initially received the infusion of crystalloid and colloid solutions with volume of 20-30 ml/kg. Hemotransfusion was performed for decreasing hemoglobin level below 90 g/l (patients older 55) or lower 70 g/l (patients younger 55). Transfusion of fresh frozen plasma was conducted for 1.5-fold (and more) increase in APPT and included 10-15 ml/kg. The indication for transfusion of platelet suspension was a decrease in level of platelets below 50×109/l. Cryoprecipitate was introduced for level of fibrinogen < 1 g/l. The agent of choice for arterial hypotonia was continuous intravenous infusion of adrenaline. The control group received the infusion therapy according to level of central venous pressure (up to achievement of 60-80 mm Hg), systemic hemodynamics (MAP > 65 mm Hg) and diuresis rate (at least 0.5 ml/kg/h) [9].
The volume of transfused blood components was registered: erythrocytic suspension, fresh frozen plasma and volume of infusion of crystalloid solutions within three days in ICU. The duration of ALV in ICU, organ dysfunction according to MODS on the third day [10] and mortality were estimated.
The blood lactate, venoarterial difference in Pv-aCO2, and central venous blood saturation (ScvO2) were measured with the gas analyzer ABL800 FLEX.
Siemens ACUSON S2000 was used for ultrasonic diagnosis.
Intraabdominal pressure (IAP) was measured with low pressure tonometer TN-01 Triton (Triton Electronic, Ekaterinburg, Russia).
Statistical analysis of the digital data was performed with the standard methods with PC Microsoft Excel 13 and Statistica 6.0. The received results were tested for normalcy of distribution. Considering the pattern of distribution, non-parametrical statistical methods were used. The results were presented as the mean and standard deviation (M ± σ).

RESULTS

Within the first day, the volume of transfused blood components was reliably higher (p < 0.05) than in the first group as compared to the second one. Therefore, the volume of infusion of crystalloid solutions was statistically higher (p < 0.05) in the second group (Fig. 1).
By the third day, the volume of transfused packed red blood cells and fresh frozen plasma was reliably higher as compared to the first group (Fig. 2). The volume of crystalloid solution increased significantly.
The second group demonstrated the high volumes of crystalloid solutions: 1,900 ± 340 ml in the first day, 3,600 ± 300 ml in the third day (p < 0.05).
The plasma lactate level (Fig. 3) achieved 9.4 ± 2.2 mmol/l in the first group, 9.9 ± 3 mmol/l in the second group (p > 0.05) at admission. The level of lactate decreased in all patients within the first day at the background of intensive care: up to 2.5 ± 0.8 mmol in the first group, up to 3.8 ± 1.4 mmol/l in the second group (p < 0.05) in the first day at the background of intensive care. On the second day, the trend to decreasing lactate was observed. However a difference in the value was significant: 1.8 ± 1.0 mmol/l and 2.9 ± 1.1 mmol/l (р < 0.05).
At admission, Pv-aCO2 was significantly higher than the normal values in both groups. At the background of therapy, the first group showed the normalization of this value within 24 hours as compared to the second group, where normalization appeared only on the third day. The time course of Pv-aCO2 is shown in the figure 4.

Figure 1. Volume of infusion-transfusion therapy in the first day. EC – erythrocytic components of the blood, FFP – fresh frozen plasma, Cryst. – crystalloids.




Note:* – р < 0.05 as compared to the first group according to Mann-Whitney test.

Figure 2. Volume of infusion-transfusion therapy on the third day.
EC – erythrocytic components of the blood, FFP – fresh frozen plasma, Cryst. – crystalloids.

Note:* – р < 0.05 as compared to the first group according to Mann-Whitney test.

Figure 3. Time course of lactate (mmol/l) in blood plasma

Note:* – р < 0.05 as compared to the first group according to Mann-Whitney test.

Figure 4. Time course of Pv-aCO2 of mm Hg

Note: *– р < 0.05 as compared to the first group according to Mann-Whitney test.

ScvO2 also decreased in both groups at admission – 54.1 ± 5.2 % and 55.4 ± 7.1 % (р > 0.05) correspondingly. After 24 hours, the first group showed ScvO2 of 69.4 ± 4.4 %, the second group – 59.3 ± 6.6 % (р < 0.05). On the second day, the values of ScvO2 normalized without statistical difference between them.
On the third day, IAP was 11.2 ± 2.6 mm Hg in the first group, and 18.7 ± 1.5 mm Hg in the second group (p > 0.05).
The duration of ALV was 2.1 ± 1.8 days in the first group, and 7.8 ± 2.4 days in the second group (p < 0.05, Pearson’s χ2 p-criterion). A similar trend was observed in relation to ICU stay: 5.4 ± 2.6 days, and 9.6 ± 2.1 days (p < 0.05, Pearson’s χ2 p-criterion) correspondingly.
Estimation of intensity of organ dysfunction showed that MODS up to 4 points was more often observed in the first group on the third day, as compared to the second one – 73.8 % and 50 % (p < 0.05) correspondingly (the table 2). More intense statistically significant organ dysfunction (MODS = 5-12) was noted in the second group (p < 0.05). The most intense organ dysfunction (MODS = 9-12) was registered in 4 (11 %) patients in the second group and in only 2 (4.8 %) patients in the first group (p < 0.05).
Two patients of the first group (4.76 %) died in ICU. Their MODS values were 9 and 10 points. Five patients (13.88 %) died in the second group. The severity of the injuries was 8, 9, 10, 10 and 12 according to MODS correspondingly (Fig. 5).

Table 2. Intensity of organ dysfunction according to MODS on the third day

MODS, points

First group
(n = 42)

Second group
(n = 36)

1-4 балла / points

31 (73.8 %)

18 (50 %)*

5-8 баллов / points

9 (21.4 %)

14 (38.9 %)*

9-12 баллов / points

2 (4.8 %)

4 (11.1 %)*

Note:* – р < 0.05 as compared to the first group (p-test Pearson χ2).

Figure 5. Mortality in the groups 1 and 2

Note:* – р < 0.05 as compared to the first group according to Mann-Whitney test (p-test, χ2 test).

DISCUSSION

Generally, our results comply with the data in recent publications [15], which show that timely initiation of massive transfusion therapy makes a positive influence on the course of traumatic disease.
According to damage control resuscitation, a necessary component of hemostasis control is hypotonic resuscitation with maintenance of systolic arterial pressure at the level of 80-90 mm Hg. Noradrenaline was the agent of choice for intense arterial hypotonia. Infusion of noradrenaline can reduce the volume of blood loss in uncontrolled bleeding [11].
The study by S. Lui et al. [7] showed the decrease in the risk of death after massive transfusion.
Infusion of crystalloids (> 500 ml) for patients without arterial hypotonia increased the risk of 30-day mortality [12]. S. Kind et al. (2013) showed some disadvantages of infusion solutions such as coagulopathy worsening [13]. The use of hydroxyethyl starches is also undesirable since these agents increase the risk of acute kidney injury and require for renal replacement therapy.
Realization of the massive transfusion protocol allowed rapid stabilization of condition and, as most importantly, high improvement in perfusion of organs and tissues.
The elevated level of lactate in patient with polytrauma indicated the hypoperfusion, tissue hypoxia, and intensity of hemorrhagic shock, and it was associated with increasing risk of postsurgical, and mainly infectious, complications [14]. Moreover, the increase in blood lactate is associated with increasing mortality in trauma patients and predicts a need for massive blood transfusion [15]. The decrease in blood lactate at the background of intensive care was a good value of its adequacy.
Pv-aCO2 is a value of tissue perfusion adequacy. G. Ospina-Tascón et al. (2013) showed that a persistent (more than 6 hours) high level of Pv-aCO2 was associated with more severe organ dysfunction in patients with septic shock. The use of massive infusion-transfusion therapy allowed normalizing Pv-aCO2 within the first 24 hour [16].
A cause of venous blood desaturation is disordered perfusion due to decreasing cardiac output as result of disordered pump function of the heart and/or hypovolemia [17]. T. Kowalenko et al. [18] and T. Scalea et al. [19] showed that patients with trauma and hemorrhagic shock showed ScvO2 < 65 % after primary resuscitation measures, and they more often needed for additional therapy and surgical interventions. A. Filippo et al. [20] showed a study of patients with concomitant injury. They found that the value of ScvO2 < 65 % during the first 24 hours was associated with higher incidence of lethal outcomes and influenced on duration of stay in ICU and hospital. Diagnostic, therapeutic and predictive significance of venous saturation monitoring was demonstrated in various critical conditions [21]. The use of massive transfusion therapy allowed normalizing ScvO2 within the first 24 hours.
The predictors of abdominal hypertension syndrome are hypothermia, hemoglobin < 80 g/l, deficiency of bases < 8 mmol/l, infusion of crystalloids > 3,000 ml, and hemotransfusion > 3 doses of erythrocytic suspension [14]. We performed successful correction of anemia and metabolic acidosis in our patients.
Our results confirm the opinion by A. Agalaryan [22] that adequate therapy of polytrauma reduces the duration of ALV, with the results similar with the findings by K. Almahmoud et al. [23] who showed the decrease in duration of ALV from 10 days to 5.9 days over 10 years of the study (35,232 patients). We performed ALV with high pressure mode in the end of respiration. At that, faster hemodynamic stabilization, normalization of markers of organ and tissue perfusion, and, finally, earlier termination of shock, resulting in a decrease in ALV duration, were noted.
Another factor influencing on ALV duration is decreasing volume of introduced crystalloid solutions in the main group. It is well-known that use of crystalloid solutions causes lung injury in 70 % of patients. Moreover, crystalloid solutions were developed for increase in volume of interstitial space, but not for volume of circulating blood, since only 20 % of isotonic solution of natrium chloride remains in vascular bed after 25 minutes [24]. Transition of water into interstitial space favors an injury to lung parenchyma and development of distress-syndrome [25].
Management of patients with polytrauma requires for coordinated efforts of the medical team and the blood bank for provision of appropriate management of use of blood components. The understanding of complex pathophysiology of massive blood loss and blood replacement has the important significance for making the decisions. Development of local and concrete recommendations with clinical, laboratory and logistical answers is a key to the successful result.

CONCLUSION

Realization of massive infusion-transfusion therapy protocol stabilized the patients’ condition, significantly reduced the volume of crystalloid solutions, improved the tissue perfusion, prevented the development of abdominal hypertension syndrome, reduced the duration of artificial lung ventilation and ICU stay, and promoted the decrease in hospital mortality.

Information on financing and conflict of interests

The study was conducted without sponsorship.
The authors declare the absence of any clear and potential conflict of interests relating to publication of this article.

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