Abstract

Background: Postoperative fibrinogen deficiency after surgical removal of a brain tumor can cause potentially serious complications, such as intracranial hematoma, and worsen the patient’s outcome. Our study aimed to determine the prevalence of hypofibrinogenemia after resection of intracranial tumor, to identify the risk factors for this abnormality, and to evaluate the prognosis of patients with this hemostasis disorder.

Methods: We conducted a prospective, descriptive study including 120 patients who presented for brain tumor resection without preoperative fibrinogen deficiency and had given their consent to participate in the study. We determined the fibrinogen level the day before the procedure, at 1 h and 24 h postoperatively. We determined the prevalence of postoperative fibrinogen deficiency. Postoperative complications, neurological status of the patient, and mortality at 3 months were subsequently recorded.

Results: Forty-eight patients presented postoperative fibrinogen deficiency with a high prevalence of 40%. Our study identified three predictive independent risk factors of fibrinogen deficiency after surgical resection of brain tumor: histological type of meningioma (P = 0.015), prolonged duration of surgery (more than 195 min) (P = 0.045), and use of surgicel as a hemostatic product intraoperatively (P = 0.009). Postoperative hematoma and sensory-motor deficit were significantly associated with postoperative fibrinogen deficiency (P

Conclusion: We found a high prevalence of hypofibrinogenemia after brain tumor resection (40%). This anomaly increases the risk of intracranial hematoma. It, therefore, deserves the attention of the practitioner to correct it rapidly and avoid its potentially serious complications.

Keywords: Brain tumors, Hemostasis disorders, Hypofibrinogenemia, Neurosurgery

INTRODUCTION

Hemostasis disorders in neurosurgery are an undisputed cause of postoperative bleeding with devastating consequences.[ 13 , 17 ] Indeed, the brain is located in an inextensible skull, and any intracranial bleeding can, therefore, be the cause of intracranial hypertension through pressure imbalance of the intracranial contents.[ 1 ] Most studies have focused on hemostasis disorders in the context of isolated head trauma. They have shown an increase in mortality in the presence of these abnormalities.[ 4 , 8 , 10 , 11 , 20 ] In the case of intracranial tumors, good control of hemostasis, both surgically and biologically, is essential to avoid potentially fatal postoperative hemorrhagic complications. Hemostasis disorders remain a major cause of postoperative morbidity and mortality in intracranial tumor surgery, and fibrinogen deficiency is at the forefront of these disorders.[ 19 ] Postoperative fibrinogen deficiency following brain tumor resection may increase the risk of intracranial hematoma[ 5 ] and subsequently compromise the patient’s prognosis.[ 2 , 19 ]

The aim of our work was, therefore, to study the prevalence of hypofibrinogenemia post brain tumor resection, to identify the risk factors for this anomaly, and to help the practitioner prevent it in order to reduce the risk of its potentially serious complications.

MATERIALS AND METHODS

Study design

We conducted a monocentric, prospective, descriptive and analytical study at the neurosurgery department, traumatology, and severe burn center in Tunisia.

Sample size calculation

The sample size calculation was based on a prevalence of 10% reported in the literature, with a required precision of 5% and a power of 85%. The sample size was estimated to be 120 patients.

Study population

We included subjects aged 18 years old and over, proposed for brain tumor resection in the context of urgent or scheduled surgery. All patients who participated in our study were followed up for 3 months. We did not include in our study patients who refused to be included in the study, pregnant women, patients with preoperative fibrinogen deficiency, patients with an acquired or constitutional hemostasis disorder, and patients with hepatocellular failure.

We excluded from our study patients who received fibrinogen transfusion or died during the surgery.

Study protocol

A hemostasis test was systematically requested the day before the operation for scheduled surgeries or on patient admission for urgent surgeries. It included complete blood count, prothrombin time (PT), activated partial thromboplastin time, and fibrinogenemia. For the fibrinogenemia assay, samples were taken in a citrated tube. The same tests were conducted only twice (Regardless of fibrinogen levels found) at 1 h and 24 h postoperatively to determine the prevalence of hypofibrinogenemia after brain tumor resection. Normal fibrinogen levels are between 2 and 4 g/L in adults and between 1.5 and 3.5 g/L in children. Fibrinogen deficiency is defined as a plasma level <2 g/L.[ 6 ]

A unique dose of fibrinogen (3 g) was administered to any patient with postoperative fibrinogen deficiency of <1.5 g/L.

The prevalence of hypofibrinogenemia after brain tumor resection was determined by calculating the ratio of the number of patients with hypofibrinogenemia at 1 h or 24 h postoperatively to the total number of patients.

Anesthetic management

In the operating room, the patient was placed on a surgical table and monitored by five-lead electrocardiography, heart rate, respiratory rate, pulsed oxygen saturation, and noninvasive blood pressure. A peripheral venous catheter is placed at the upper limb. General anesthesia was chosen as the main anesthetic technique. After verifying the vital constants of the patient, anesthetic induction was performed using remifentanil (1 μg/kg over 2 min), propofol (3 mg/kg), and cisatracurium (0.15 mg/kg). After intubation, mechanical ventilation was adjusted to have the end-tidal carbon dioxide between 30 and 35 mmHg. An ultrasound-guided central venous catheter in the supraclavicular area, a radial arterial catheter (monitoring invasive blood pressure), a thermal probe, and a bladder catheter were placed. Anesthesia was maintained using propofol (6 kg/h), remifentanil (0.1–0.5 μg/kg/min), and cisatracurium (0.12 mg/kg/h). We then monitored the depth of anesthesia using a bispectral index.

Measurements of blood loss, fluid therapy, and transfusion strategy

Intraoperative bleeding was estimated by quantifying blood in a suction bottle and weighing compresses and drapes. We noted any hemostatic products used (absorbable hemostatic compresses [surgicel, fibrillar surgicel] and hemostatic gel [surgiflo]). Fluid therapy consists of the administration of isotonic crystalloids and colloids guided by monitoring mean arterial pressure and urine output. Perioperative transfusion trigger for red blood cells was a hemoglobin concentration <8 g/dL. Fresh frozen plasma was transfused at PT <60%, and platelet concentrate was transfused at platelet count <100,000/mm³.

Postoperative care

Patients were kept under surveillance for a minimum of 24 h, barring complications, in the neurosurgical intensive care unit (ICU). Laboratory investigations were performed (Hemoglobin, electrolytes, PT, fibrinogen, and platelet count) at 1 h and 24 h postoperatively, and the decision to extubate or elective ventilation was based on the assessment of both consultant anesthesiologist and surgeon. Cerebral computed tomography was performed to evaluate tumor resection and hematoma formation. Postoperative complications, such as intracranial bleeding or convulsive seizure, were noted during hospitalization and 3 months later. The Extended Glasgow Outcome-Scale (GOS-E) (which is a scale ranging from 1 (deceased) to 8 (complete neurological recovery) for patients with brain injuries such as traumatic brain injury, which groups patients according to the objective degree of neurological recovery) was evaluated at the time of discharge of the patient from the hospital and 3 months. The duration of ICU and hospital stay was recorded.

Outcomes

The primary outcome was set as the prevalence of hypofibrinogenemia after surgical removal of intracranial tumor. Secondary outcomes were mortality and postoperative complications in patients operated on for brain tumors with postoperative hypofibrinogenemia.

Statistics

Statistical analysis was performed with the Statistical Package for the Social Sciences statistical software version 25. The Kolmogorov-Smirnov statistic was used for testing normality for continuous variables. Qualitative variables were expressed as simple frequencies and relative frequencies (percentages). We calculated means and standard deviations and determined the extreme values for quantitative variables. A comparison of means was performed using Student’s t-test. Pearson’s Chi-square test was used to compare qualitative variables. When this test was not valid, Fisher’s exact test was used. We conducted a multivariate analysis using stepwise descending binary logistic regression. (All factors with P-values below 0.05 in the univariate analysis were included). This logistic regression allowed us to calculate an adjusted odds ratio for each factor, measuring the specific role of each. A 95% confidence interval was used. The significance level (P) was set at 5% for all statistical tests. Patient survival at 3 months from inclusion was studied according to the Kaplan–Meier model.

RESULTS

During the study period, 138 patients underwent surgery for intracranial tumors. Twelve patients did not meet the inclusion criteria (preoperative fibrinogen deficiency). Six patients were excluded. In the end, 120 patients were retained.

Figure 1 shows the flowchart of patient selection.

Figure 1:

Patient flowchart.

Demographics

There were 63 female patients and 57 male patients presented in the study. The mean age was 51 ± 14 years. All patients’ characteristics are shown in Table 1 .

Table 1:

Patients’ characteristics

There was no significant difference in preoperative laboratory parameters.

The most common histological types of tumors are as follows: meningioma (30%), gliomas (astrocytoma and glioblastoma) (22.5%), metastases (15%), pituitary adenomas (12.5%), and acoustic neuroma (10%). Tumors characteristics are shown in Table 2 .

Table 2:

tumors’ characteristics

Six patients (5% of the study population) required blood transfusion, and no patient received fresh frozen plasma or platelets. The mean duration of surgery was 211 min, with extremes ranging from 60 to 360 min. The shortest duration was reserved for transsphenoidal pituitary adenoma resection, with an average of 100 min, while the longest duration was reserved for acoustic neuroma resection, with an average duration of 290 min. Intraoperative blood loss, transfusion requirements, and other surgery characteristics are summarized in Table 3 .

Table 3:

Surgery

Prevalence

Our study showed that 40% of patients (48) had an immediate postoperative fibrinogen deficit (within the 1^st postoperative h). Of these patients, 90% (43) retained this deficit after 24 h postoperatively.

Risk factors

Among patient-related epidemiological, clinical, and biological parameters, none was significantly associated with postoperative fibrinogen deficiency [ Table 4 ]. With regard to tumor-related factors, histological type meningioma and acoustic neuroma, frontal lobe and cerebellopontine angle location, and narrow vascular relationship were significantly associated with postoperative fibrinogen deficiency [ Table 5 ]. Among surgery related factors, we found that the prolonged duration of the procedure (over 195 min), the high quantity of crystalloids used (over 2150 mL) and the use of surgicel as hemostatic products were significantly associated with postoperative fibrinogen deficiency [ Table 6 ].

Table 4:

Patients’ related factors, predictive of postoperative fibrinogen deficiency

Table 5:

Tumors’ related factors, predictive of postoperative fibrinogen deficiency

Table 6:

Surgery related factors, predictive of postoperative fibrinogen deficiency

All factors showing a significant association with postoperative fibrinogen deficiency in univariate analysis (P < 0.05) were subsequently included for multivariate analysis in logistic regression. Three factors emerged as independent predictors of postoperative fibrinogen deficiency following brain tumor resection: histological type meningioma, prolonged duration of surgery (over 195 min), and intraoperative use of surgicel [ Table 7 ].

Table 7:

Independent risk factors of fibrinogen deficiency after surgical removal of intracranial tumors

Prognosis

When studying postoperative complications, we found that postoperative fibrinogen deficiency was significantly associated with a high occurrence of intracranial hematoma, as well as with sensory-motor deficit [ Table 8 ]. Furthermore, patients with postoperative hypofibrinogenemia had worse GOS-E scores at discharge and after three months than those with normal fibrinogen levels [ Tables 9 and 10 , Figures 2 and 3 ]. Nonetheless, postoperative hypofibrinogenemia after intracranial tumor removal was not associated with increased postoperative ICU stay, prolonged duration of mechanical ventilation, or prolonged total postoperative hospital stay.

Table 8:

Postoperative Complications

Table 9:

GOS-E at discharge

Table 10:

GOS-E after three months

Figure 2:

Stacked bar chart of extended Glasgow Outcome-scale scale at discharge.

Figure 3:

Stacked bar chart of extended Glasgow Outcome-scale scale after 3 months.

Survival study

At the end of the 3-month follow-up period, 111 patients (92%) were still alive.

Kaplan–Meier survival curves are shown in Figures 4 and 5 . Our study showed no significant difference in overall survival between the two groups: those with postoperative fibrinogen deficiency and those with normal fibrinogen levels.

Figure 4:

Overall survival curve.

Figure 5:

Overall survival curve in relation to postoperative fibrinogen deficiency.

Postoperative fibrinogen deficiency after surgical removal of the intracranial tumor was not significantly associated with increased postoperative mortality at 3 months [ Figure 5 ].

DISCUSSION

Fibrinogen is a glycoprotein synthesized by the liver.[ 15 ] It is the final substrate in the coagulation cascade. It is an essential component of the primary and secondary hemostasis processes.[ 5 ] Its conversion to fibrin and the formation of an insoluble thrombus is the final substrate of the coagulation cascade.[ 18 ] Fibrinogen deficiency is a direct cause of coagulopathy. It can result in uncontrolled bleeding.[ 12 ] A minimum level of 2 g/L is required to ensure satisfactory effective hemostasis.[ 5 ]

Our prospective descriptive study, including 120 patients, aimed to determine the prevalence of hypofibrinogenemia post brain tumor resection, identify risk factors for this abnormality, and assess the prognosis of patients who presented with postoperative hypofibrinogenemia. We found a high prevalence of hypofibrinogenemia post brain tumor resection, equal to 40% (48 patients), with a mean fibrinogen level of 3.08 ± 1.23 g/L (2; 7.54).

Regarding predictive factors for this abnormality, we found that meningioma histological type, prolonged duration of surgery (>195 min), and the use of surgicel as a hemostatic product intraoperatively were independent predictors of postoperative fibrinogen deficiency following brain tumor resection. With regard to Surgicel, several hypotheses can be considered: procoagulant effect and increased fibrinogen consumption, interaction with fibrinolysis, and local inflammatory response. It requires further investigation to prove the association between the use of surgicel and low postoperative fibrinogen levels. Studying the prognosis of patients who experienced hypofibrinogenemia following brain tumor resection, we concluded that they had poorer neurological outcomes, with more impaired GOS-E scores compared to patients with normal postoperative fibrinogen levels. However, there was no increase in the duration of hospital stay or postoperative mechanical ventilation. Furthermore, our study found that hypofibrinogenemia after brain tumor resection did not increase mortality after 3 months. Several other risk factors for hypofibrinemia following brain tumor resection have been identified in previous studies. Plasma fibrinogen levels have been shown to be directly associated with patient body mass index (BMI).[ 3 , 9 , 16 ] Mertens confirmed the existence of disturbed hemostasis and fibrinolysis in obese subjects[ 14 ], while Wei et al. showed that BMI is proportionally associated with intraoperative fibrinogen consumption during intracranial tumor surgery.[ 19 ] Obesity may, therefore, be a risk factor for hypofibrinogenemia after brain tumor resection.

Another study by Hiippala et al. showed that coagulation factors concentration (including fibrinogen) decreases postoperatively as a result of bleeding and hemodilution.[ 7 ] Regarding patient’s prognosis, Wei et al. supported our findings in their study and found that patients who developed hypofibrinogenemia following brain tumor surgery had a worse prognosis compared to other patients. This included a higher risk of postoperative intracranial hematoma, a lower GOS-E score, a longer hospital stay, and higher hospital expenses.[ 19 ]

CONCLUSION

Our study highlighted the role of hypofibrinogenemia in the occurrence of postoperative bleeding after intracranial tumor surgery. We therefore recommend systematic postoperative fibrinogen dosing, especially for at-risk patients, to enable early detection and treatment of this abnormality and to prevent its potentially serious complications.

Ethical approval:

The Institutional Review Board approval is not required as it is a descriptive observational study that does not involve any intervention or deviation from standard clinical practice.

Declaration of patient consent:

The authors certify that they have obtained all appropriate patient consent.

Financial support and sponsorship:

Nil.

Conflicts of interest:

There are no conflicts of interest.

Use of artificial intelligence (AI)-assisted technology for manuscript preparation:

The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.

Disclaimer

The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Journal or its management. The information contained in this article should not be considered to be medical advice; patients should consult their own physicians for advice as to their specific medical needs.

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