Article, Hematology

The effect of fibrinogen concentrate and fresh frozen plasma on the outcome of patients with acute traumatic coagulopathy: A quasi-experimental study

a b s t r a c t

Introduction: The debate on replacing coagulation factors and its effect on the final outcome of the patients with acute traumatic coagulopathy (ATC) in need of transfusion is still ongoing. Therefore, the present study is de- signed with the aim of comparing the outcome of patients with acute traumatic coagulopathies receiving fibrin- ogen and fresh frozen plasma .

Methods: In this quasi-experimental randomized controlled study, patients with severe blunt trauma (ISS N 16) and in need of packed cells transfusion were divided into 3 groups of receiving fibrinogen, receiving FFP, and con- trol, and their final outcome was compared.

Results: 90 patients with the mean age of 33.16 +- 16.32 years were randomly allocated to one of the 3 study groups (82.2% male). The 3 groups were similar regarding baseline characteristics. Patients receiving fibrinogen needed significantly less packed cells (p = 0.044) and intravenous fluid in the initial 24 h of hospitalization (p = 0.022). In addition, mortality rate (p = 0.029), need for admission to intensive care unit (p = 0.020) and duration of hospitalization (p = 0.045) were also lower in the group receiving fibrinogen. The number of sepsis cases in patients receiving fibrinogen and control group was lower than those who received FFP (p = 0.001). The number of multiple organ failure cases in patients receiving fibrinogen was about one fourth of the other 2 groups (p = 0.106), and a fewer number of them needed mechanical ventilation (p = 0.191). No case of venous thrombosis was detected in any of the 3 groups.

Conclusion: Multiple trauma patients in need of transfusion who received fibrinogen along with packed cells had significantly better outcomes regarding mortality, sepsis, need for admission to the intensive care unit, need for receiving packed cells, need for receiving intravenous fluids in the initial 24 h, and duration of hospitalization.

Introduction

Prevalence of acute coagulopathy following trauma is considerable and it is deemed an independent factor affecting the outcome of pa- tients [1,2]. The frequency of acute traumatic coagulopathies (ATC) has been estimated to vary between 2% and 34% based on its definition [3,4].

Numerous factors such as loss of coagulation factors following bleed- ing, decrease in the concentration of coagulation factors due to fluid therapy and blood transfusion, dysfunction of coagulation proteases fol- lowing hypothermia and acidemia, and finally tissue hypoperfusion and direct tissue trauma have been thought to be responsible for causing

* Corresponding author at: Department of Emergency Medicine, Imam Hossein Hospital, Madani Street, P.O. Box: 193955487, Tehran, Iran.

E-mail address: [email protected] (H. Hatamabadi).

these dysfunctions [5,6]. It seems that severity of coagulopathies is a di- rect function of trauma severity, rate of bleeding, and rate of resuscita- tion with liquid and blood [7].

Treatment is usually done with the aim of replacing key components of coagulation via transfusion of allogeneic blood products. Fibrinogen is the first coagulation factor that drops to the minimum suboptimal level at the time of bleeding and progressive coagulopathy [8,9]. The findings of studies are indicative of the fact that the tendency to bleed increases with decrease in the Blood concentration of fibrinogen dropping to b150-200 mg/dl [10-12]. Until now, 3 sources for replacing fibrinogen have been proposed including fibrinogen concentrate, Fresh frozen plasma and cryoprecipitate.

Fibrinogen has potential superiorities to the other two products and is the only product that can also be used outside of the hospital. This product lacks any unwanted side effects related to allogeneic blood products including acute lung injury and ABO incompatibility. In

https://doi.org/10.1016/j.ajem.2018.02.018

1948 E. Akbari et al. / American Journal of Emergency Medicine 36 (2018) 1947-1950

addition, with a small volume of this product, a high concentration of fi- brinogen can be given to the patient, however using cryoprecipitate or FFP provide a lower level of fibrinogen for the body and the accurate amount of fibrinogen prescribed via these 2 products cannot be known [8,12].

Currently, the debate on using various products for replacing this factor and their effects on the final outcome of the patients with ATC in need of massive transfusion is still ongoing [8,13,14]. Therefore, the present study is designed with the aim of comparing the outcome of ATC patients receiving fibrinogen and FFP.

Methods

Study design and setting

In this quasi-experimental study, patients with severe blunt trauma who visited the emergency department (ED) of Imam Hossein, Shohadaye Tajrish and Loghmane Hakim Hospitals in Tehran and Shahid Rajaee Hospital in Shiraz, Iran, during April 2015 to December 2016, and were in need of blood transfusion were studied. Patients were divided into 3 groups, which received fibrinogen with packed cells, FFP along with packed cells, or packed cells alone and their final outcome was compared. The study was approved by the ethics commit- tee of Shahid Beheshti University of Medical Sciences under the number IR.SBMU.MSP.REC.1396.313 and the researchers adhered to principles of ethics in performing biomedical studies and keeping patient data confidential throughout the study. Informed consent was obtained from the patients or their relatives for inclusion in the study. All the ad- ditional charges inflicted on the patients were paid by the researchers.

Participants

The participants of the present study consisted of patients with se- vere blunt multiple trauma (ISS N 16), aged equal to or N18 years, in need of receiving concentrated red blood cells and with a fibrinogen blood level b200 mg/dl, which were selected via consecutive non-prob- ability sampling. Eligible patients were consecutively randomized. All cases of penetrating trauma, those with ISS b16, patients with known history of Liver dysfunction or coagulation disorders and those who did not give consent for participation were excluded from the study.

Data gathering

A checklist consisting of demographic data (age, sex), level of con- sciousness (based on Glasgow coma scale) and vital signs on admission to ED (blood pressure, heart rate, respiratory rate, and oxygen satura- tion percentage), trauma severity (based on Injury Severity Score (ISS)), hemoglobin and Fibrinogen level of the patient, the number of packed cells units received, fluids received before and during the initial 24 h of admission to ED, time interval between trauma incidence and reaching the ED and finally, the outcome of the patients were recorded by a senior emergency medicine resident for all the patients. The person responsible for data gathering was aware of the clinical data of the pa- tients and type of treatment received.

Outcomes

Mortality (throughout hospital stay), amount of blood and liquid needed in the first 24 h, need for admission to intensive care unit, need for mechanical ventilation, rate of multiple organ failure, sepsis and thrombosis during hospitalization, and finally, duration of hospital- ization were the outcomes assessed in the present study.

Statistical analysis

Required sample size for the present study considering 95% confi- dence interval (CI), 80% power, 35% decreased risk of mortality with fi- brinogen concentrate [15] and 2.9% per unit decreased risk of mortality with FFP [16] was estimated as 30 patients for each group. Ultimately all patient data were entered to SPSS 21 software and underwent statistical analysis. To compare means of the 3 groups, ANOVA test and for com- paring qualitative variables between the groups, chi-square test were used. Findings were reported using tables, calculation of frequency and percentage or mean +- standard deviation. Maximum acceptable type 1 error for all the comparisons was considered 0.05.

Table 1

Baseline characteristics of the patients based on study groups

Variable	Groups			P
	Fibrinogen	FFP	Control
Sex
Male	26 (86.7)	23 (76.7)	25 (83.3)	0.587
Female	4 (13.3)	7 (23.3)	5 (16.7)
Age (year)
18-39.9	22 (73.4)	23 (76.7)	22 (73.4)	0.950
40-59.9	3 (10.0)	4 (13.3)	4 (13.3)
>=60	5 (16.6)	3 (10.0)	4 (13.3)
Consciousness level (GCS)
>=14	2 (6.7)	3 (10.0)	3 (10.0)	0.204
8-14	8 (26.7)	10 (33.3)	16 (53.3)
b8	20 (66.7)	17 (56.7)	11 (36.7)
Vital signs on admission
Systolic blood pressure	96.4 +- 16.6	97.1 +- 16.6	93.0 +- 13.8	0.563
(mmHg)

Procedure

After admission of the patients to ED, for patients with blunt multi- ple trauma, who were aged over 18 years and were deemed in need of blood transfusion based on clinical evidence and vital signs, in addition to starting diagnostic and treatment measures based on advanced trauma life support (ATLS) protocol, a blood sample was drawn and sent to the lab for measurement of fibrinogen level. Immediately, con- centrated red blood cells were ordered for all the patients and injected as soon as they were prepared. Then if fibrinogen level of the patient was reported to be b200 mg/dl, the patient would be allocated to one

Diastolic blood pressure (mmHg)

64.7 +- 9.4 67.9 +- 12.7 63.8 +- 6.8 0.247

of the following 3 groups using block randomization. For the first

Heart rate (/min) 114.7 +-

13.7

109.3 +-

14.3

111.0 +-

25.4

0.529

group, 2 g fibrinogen (Haemocomplettan P; CSL Behring, Marburg, Ger- many) was infused, for the second group at least 2 units of FFP was

Respiratory rate (/min) 24.7 +- 4.5 23.1 +- 4.8 25.9 +- 13.4 0.446

Oxygen saturation (%) 92.3 +- 7.7 92.3 +- 4.0 89.9 +- 8.0 0.292

injected and for the third group, as the control group, no product other than concentrated red blood cells was injected.

Time before reaching ED (min)	35.6 +- 14.4	25.7 +- 12.7	26.5 +- 14.8	0.126
Fluid before reaching ED (cc)	633 +- 224	600 +- 203	215 +- 616	0.835
Trauma severity (ISS)	19.3 +- 4.4	17.2 +- 3.1	19.0 +- 4.3	0.009
Fibrinogen level (mg/dl)	106.4 +-	120.0 +-	123.2 +-	0.018
	24.6	22.4	24.4

The person responsible for selecting the patients was a senior (3rd year) emergency medicine resident with consultation of a senior (4th year) surgery resident under supervision of an emergency medicine specialist. Patients in need of blood transfusion were selected based

Hemoglobin on admission (mg/dl)

8.81 +- 0.81 8.59 +- 0.90 9.1 +- 1.2 0.178

on the clinical decision of the physician in charge of the patient and he- moglobin level measurement, as a helping tool.

FFP: fresh frozen plasma; GCS: Glasgow coma scale; ED: emergency department; ISS: in- jury severity score; Data are presented as frequency (%) or mean +- standard deviation.

E. Akbari et al. / American Journal of Emergency Medicine 36 (2018) 1947-1950 1949

Results

Baseline characteristics

90 patients with the mean age of 33.16 +- 16.32 (18-85) years were randomly allocated to one of the 3 study groups (82.2% male). Table 1 compares the baseline characteristics of the 3 studied groups. The mean age of patients was 34.93 +- 16.94 years in fibrinogen group,

30.63 +- 13.21 years in FFP group and 33.90 +- 18.57 years in the control

group (p = 0.572). The 3 groups were not significantly different regard- ing baseline characteristics such as vital signs and level of consciousness on admission, time interval between trauma incidence and reaching ED and amount of fluids received before reaching ED. None of the patients had received blood before reaching ED. Mean level of fibrinogen in the studied patients was 116.6 +- 24.6 (72-175) mg/dl.

Outcome

Table 2 has compared the outcome of patients between the 3 studied groups. Patients receiving fibrinogen needed significantly less concen- trated red blood cells (p = 0.044) and intravenous fluid in the initial 24 h of hospitalization (p = 0.022). In addition, mortality rate (p = 0.029), need for admission to intensive care unit (p = 0.020) and dura- tion of hospitalization (p = 0.045) were also lower in the group receiv- ing fibrinogen. The number of sepsis cases in patients receiving fibrinogen and control group was lower than those who received FFP (p = 0.001). Although the number of multiple organ failure cases in pa- tients receiving fibrinogen was about one fourth of the other 2 groups, this difference was not statistically significant (p = 0.106). A fewer number of patients receiving fibrinogen needed mechanical ventilation (p = 0.191). No case of venous thrombosis was detected either in pa- tients receiving fibrinogen or the other 2 groups.

Discussion

Based on the findings of the present study multiple trauma patients in need of transfusion who received fibrinogen along with concentrated red blood cells had a significantly lower mortality rate and shorter dura- tion of hospitalization compared to those who received FFP and the con- trol group. Additionally, the rates of admission to the intensive care unit, being affected with sepsis, and receiving packed cells and intravenous fluid in the initial 24 h were also lower in these patients. Although the rate of multiple organ failure and need for mechanical ventilation was lower in these patients, the difference was not statistically significant.

Schlimp et al. in a study in 2016 showed that prescription of 1 to 4 g of fibrinogen can significantly reduce the need for blood transfusion compared to control group [17]. Decrease in need for blood transfusion in those receiving fibrinogen compounds was also confirmed in a study by Curry et al. [18]. The findings are in line with the results of the

Table 2

Outcome of the studied patients.

Variable	Groups			P
	Fibrinogen	FFP	Control
Blood received in the initial 24 h	2.04 +-	2.66 +-	2.88 +-	0.044
(unit)	1.14	0.65	0.88
Fluid received in the initial 24 h (L)	3.4 +- 0.8	4.0 +- 1.1	4.1 +- 1.0	0.022
Need for ICU admission	19 (63.3)	28 (93.3)	22 (73.3)	0.020
Need for mechanical ventilation	10 (33.3)	14 (46.7)	17 (56.7)	0.191
Multiple organ failure	2 (6.7)	8 (26.7)	7 (23.3)	0.106
Sepsis	5 (16.6)	16 (53.3)	4 (13.3)	0.001
Duration of hospitalization (days)	11.0 +- 6.1	10.4 +-	14.8 +-	0.045
		8.2	7.6
Mortality	3 (10.0)	11 (36.7)	11 (36.7)	0.029

FFP: fresh frozen plasma; ICU: intensive care unit; Data are presented as frequency (%) or mean +- standard deviation.

present study, which showed that patients receiving fibrinogen needed an average of 600 and 800 cm³ less blood for resuscitation compared to FFP and control groups, respectively.

Meanwhile, Wilhelmi et al. showed that injection of FFP had no ef- fect on decreasing bleeding during and after open heart surgery [19]. This finding was confirmed in studies by Menges et al. and Noddeland et al. [20,21].

The prevalence of sepsis in this study was significantly higher in the group receiving FFP compared to the other 2 groups. However, manifes- tation of multiple organ failure did not vary significantly between the 3 groups. Bochicchio et al. showed that prescription of FFP in addition to concentrated red blood cells leads to increase in rate of infection com- pared to the control group [22].

In the present study, duration of hospitalization in fibrinogen and FFP groups was significantly shorter that the control group. Meanwhile, in Bochicchio and Silliman studies, contrary to this study, prescription of blood and its products had led to an increase in duration of hospitaliza- tion and in Schlimp et al. study no significant difference was detected between the groups in this regard [22-24].

In this study patients receiving fibrinogen had a significantly lower rate of mortality compared to those receiving FFP and the control group (about one third of the other 2 groups). Schlimp et al. in their study in 2016 showed that the rate of mortality was significantly lower in patients with severe trauma who received fibrinogen along with concentrated red blood cells [17]. Meanwhile, assessing the correlation of mortality and in- jection of FFP in trauma patients has shown its reverse effect on the final outcome in various studies [22,25]. Bochicchio et al. showed that the risk of mortality in trauma patients hospitalized in the critical care unit in- creases 3.5 times with each unit of FFP received [22]. However, Duchesne et al. showed that decrease in the ratio of FFP injection to concentrated red blood cells leads to an increase in mortality rate of trauma patients [26]. They introduced 1 to 1 ratio as the best ratio for injection of FFP to packed cells in patients in need of massive transfusion.

As can be seen, various studies still have significant contradictions regarding the effect of injecting blood and other blood products on dif- ferent outcomes of trauma patients. These differences may be caused by the differences in types of studies, studied populations, and different Treatment protocols in various centers. It seems that performing a sys- tematic review and meta-analysis in this regard can be of help.

Limitations

In the present study, double dummy blinding was not applied and the person who allocated patients to various groups was the same as the one gathering data. Therefore, the person gathering data was completely aware of the drugs received and the patients’ clinical status, which can lead to bias regarding selecting and gathering patient data. Small number of studied cases was another limitation.

Conclusion

Multiple trauma patients in need of blood transfusion who received fibrinogen along with concentrated red blood cells had a significantly better outcome regarding mortality, sepsis, need for intensive care unit admission, need for receiving packed cells, need for receiving intra- venous fluids in the initial 24 h, and duration of hospitalization. Al- though the rate of multiple organ failure and need for mechanical ventilation was lower in these patients, the difference was not statisti- cally significant.

Acknowledgement

We are grateful to all of the emergency staff of teaching hospitals affil- iated with Shahid Beheshti University of Medical Sciences in Tehran and Rajaee Hospital in Shiraz for their cooperation throughout the study.

1950 E. Akbari et al. / American Journal of Emergency Medicine 36 (2018) 1947-1950

Author contribution

All the authors meet the standard criteria of authorship based on the recommendations of international committee of medical journal editors.

Conflict of interest

The authors declare that there is no conflict of interest regarding the various phases of performing the study.

Funding

This present article is financially supported by Research Department of the School of Medicine, Shahid Beheshti University of Medical Sci- ences, Tehran, Iran, under grant number 11003.

References

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