Risk Factors and Neurologic Outcomes in Patients With Traumatic Brain Injury and Coagulopathy Within 72 Hours Post-operatively

Abstract

Background There are few studies on the development and effect of coagulopathy in patients with a traumatic brain injury (TBI) during the early post-operative period. We determined the risk factors and neurologic outcomes of in patients with a TBI and coagulopathy diagnosed by routine laboratory tests within 72 hours post-operatively. 

Methods The baseline characteristics, intra-operative management, and follow-up results of 462 patients with TBIs were obtained and retrospectively analyzed by multivariate logistic regression from January 2015 to June 2019. Coagulopathy was defined as an activated partial thromboplastin time > 40 seconds, international normalized ratio >1.4, or a platelet count < 100×10⁹ /L.

Results Multivariate logistic regression analysis revealed that the Glasgow Coma Scale (GCS) at the time of admission, Injury Severity Score (ISS) at the time of admission, pupil mydriasis, duration of surgery, intra-operative blood loss, and intra-operative crystalloid resuscitation were independent risk factors for patients who developed a coagulopathy post-operatively. There were statistical differences in mortality (p = 0.049), the Glasgow Outcome Scale-Extended (GCS-E; p = 0.024), and the modified Rankin Scale (p = 0.043) between patients with and without coagulopathy 1 week after surgery. Coagulopathy within 72 h after surgery revealed a trend for higher mortality at 1 week (66.7%), 3 months (71.4%), and 6 months (76.2%). Furthermore, coagulopathy and contusion expansion in the early post-operative period were independent risk factors for TBI mortality after surgery. Intra-operative crystalloid resuscitation had a substantial diagnostic accuracy in predicting coagulopathy within 72 h post-operatively (area under the curve [AUC] = 0.972).

Conclusion Coagulopathy within 72 h post-operatively in patients with a TBI predicted worse disease progression and unfavorable neurologic outcomes. Hence, we should take practical and reasonable measures to manage these risk factors, which may protect patients with a TBI from post-operative coagulopathy. 

Introduction

The prevalence of coagulopathy in patients with a traumatic brain injury (TBI) on arrival at the emergency room is 7%-63% and > 60% in patients with a severe TBI [1, 2]. The overall mortality of TBI-associated coagulopathy is 17%-86%, approximately 34% occurring within 24 h after injury [3–5]. The main challenge for management is to address the risk of hypo-coagulopathy, which is associated with prolonged bleeding or progression of hemorrhagic lesions, and this pathologic phenomenon may persist at least 48 h after injury [6].

The injury can induce a massive release of tissue factor into the systemic circulation, which leads to the activation of the extrinsic coagulation pathway. In addition, platelet dysfunction, endogenous anticoagulation, endothelial activation, fibrinogen modification, inflammation, and hyperfibrinolysis can elicit increased and potentially severe bleeding [7, 8], and play a critical role in coagulopathy after a TBI.

There are few studies focusing on the development and effect of coagulopathy in patients with a TBI during the early post-operative period. The present study investigated the risk factors and neurologic outcomes of coagulopathy in these patients within 72 h post-operatively.

Methods

Results

In the cohort of 462 patients with TBIs, the incidence of coagulopathy within 72 h post-operatively was 30.9%. Patients who developed a coagulopathy had a lower GCS on admission (p < 0.001), a higher ISS on admission (p = 0.006), unilateral mydriasis (p < 0.001), bilateral mydriasis (p = 0.005), duration of surgery (p = 0.046), contusion expansion within 24 h post-operatively (p = 0.014), length of hospital stay (p < 0.001), intra-operative blood loss (p < 0.001), and intra-operative crystalloid resuscitation (p < 0.001) than patients without a coagulopathy after surgery (Tables 1 & 2).

Multivariate logistic regression analysis revealed an association between patients who developed a coagulopathy post-operatively and GCS on admission (OR = 0.748; 95% CI = 0.647–0.866; p < 0.001), ISS on admission (OR = 1.058; 95% CI = 1.016–1.102; p = 0.007), unilateral pupil mydriasis (OR = 3.405; 95% CI = 2.032–5.703; p < 0.001), bilateral pupil mydriasis (OR = 4.947; 95% CI = 1.751–13.978; p = 0.003), duration of surgery (OR = 2.199; 95% CI = 1.853–2.610; p < 0.001), intra-operative blood loss (OR = 1.002; 95% CI = 1.001–1.002; p < 0.001), and intra-operative crystalloid resuscitation (OR = 1.004; 95% CI = 1.003–1.005; p < 0.001; Table 3).

There were statistical differences in mortality (p = 0.049), GOS-E (p = 0.024), and mRS (p = 0.043) between patients who developed a coagulopathy and without a coagulopathy 1 week after surgery (Table 4). Coagulopathy within 72 h post-operatively revealed a trend for higher mortality at 1 week (66.7%), 3 months (71.4%), and 6 months (76.2%; Table 5). Furthermore, univariate and multivariate analyses showed that a coagulopathy within 72 h post-operatively (OR = 2.438; 95% CI = 1.190–4.994; p = 0.015), contusion expansion within 24 h (OR = 16.643; 95% CI = 7.528–36.795; p < 0.001), between 24 and 72 h (OR = 8.365; 95% CI = 1.976–35.404; p = 0.004), and > 72 h (OR = 5.813; 95% CI = 2.025–16.684; p = 0.001) were independent risk factors for mortality in patients with a TBI post-operatively (Tables 6 & 7).

The AUC value for predicting the incidence of post-operative coagulopathy was 0.719 (95% CI = 0.676–0.760; p < 0.001) with a cut-off of 6.5 for GCS on admission, 0.589 (95% CI = 0.535–0.644; p = 0.002) with a cut-off of 11.5 for ISS on admission, 0.815 (95% CI = 0.773–0.856; p < 0.001) with a cut-off of 3.79 for duration of surgery, 0.972 (95% CI = 0.957–0.986; p < 0.001) with a cut-off of 1650 ml for intra-operative crystalloid resuscitation, and 0.774 (95% CI = 0.732–0.817; p < 0.001) with a cut-off of 835 ml for intra-operative blood loss (Fig. 1). There were statistical differences in the AUC values between intra-operative crystalloid resuscitation and GCS on admission (Z = 9.634, p < 0.001), ISS on admission (Z = 13.511, p < 0.001), duration of surgery (Z = 6.913, p < 0.001), and intra-operative blood loss (Z = 8.633, p < 0.001).

Discussion

Mounting evidence has identified the following independent risk factors for the development of acute coagulopathy after a TBI, including a GCS ≤ 8, pre-hospital intravenous fluid infusion ≥ 2000 ml, subarachnoid hemorrhage, and a midline shift on CT images [1, 2]. In addition, patients with a penetrating TBI had a higher incidence of coagulopathy and a higher mortality rate than patients with a closed craniocerebral injury [12]. Intravenous mannitol and hypertonic saline are routinely used to control intracranial hypertension in patients with a severe TBI; however, the impact of a single bolus infusion of hypertonic fluids could worsen hypocoagulability and hyperfibrinolysis in patients with hemorrhagic shock trauma [4]. The present study demonstrated that some risk factors, such as GCS on admission, ISS on admission, and abnormal pupil size, could be used to assess the severity of brain injury after trauma and predict the occurrence of coagulopathy for patients with a TBI within 72 h post-operatively. Notably, bilateral mydriasis pre-operatively was a strong predictor. Nevertheless, whether complicated by a coagulopathy or not, patients with a severe TBI, pupil mydriasis, and no light reflex, despite undergoing decompressive craniectomy, could have high mortality and disability rates.

In the setting of trauma or emergency surgery, intra-operative bleeding can be minimized with optimal pre-operative preparation, but cannot be prevented completely. In this study, duration of surgery (OR = 2.199) and intra-operative blood loss (OR = 1.002) were independent risk factors for post-operative coagulopathy. It has been confirmed that shortening the duration of surgery, avoiding unnecessary blood loss, and reducing blood transfusion may help save medical resources, reduce medical costs, and decrease the mortality rate [13, 14].

The main goals of fluid therapy for patients with a TBI are to optimize cerebral perfusion and maintain adequate cerebral oxygenation. The anesthesiologist may prefer rapid intra-operative fluid infusion to maintain blood pressure and cerebral blood flow stability when blood pressure decreases markedly after the induction of general anesthesia or relief of intracranial hypertension. Although this study confirmed that a large volume of intra-operative crystalloid resuscitation is an independent risk factor for patients who developed a coagulopathy in the early post-operative period (OR = 1.004), there is still considerable controversy about fluid resuscitation for trauma patients. Shin et al. [15] reported that the volume of intra-operative fluid administration (900–1100 ml) is consistently associated with optimal 30-day mortality, respiratory complications, acute kidney injury, and post-operative length of stay in adults undergoing non-cardiac surgery. Hahn et al. [16] recommended the intra-operative administration of 3–5 ml/kg/h of crystalloids; however, additional fluid should be administered to patients who have more bleeding during surgery. Crystalloid resuscitation (> 2000 ml) for patients with a TBI is associated with increased mortality; thus, limited resuscitation before and after surgery may be indicated [17, 18].

A coagulopathy in patients with a TBI has been strongly associated with progressive hemorrhagic injury. Approximately one-half of TBI patients with a coagulopathy could subsequently exhibit hemorrhagic progression of the initial brain contusions within 48 h [1]. There were statistical differences in contusion expansion within 24 h (p = 0.014) between patients who did and did not develop a coagulopathy 1 week after surgery based on our research. Furthermore, a coagulopathy within 72 h post-operatively and contusion expansion during the early post-operative period were independent risk factors for non-survival of patients with a TBI. The research results conclusively prove that coagulopathy alone and contusion expansion secondary to a coagulopathy may be associated with increased mortality.

At different onset times, a coagulopathy could lead to different mortality rates, and a coagulopathy with early onset after injury and long duration is a marker of increased morbidity and poor outcomes [19]. Carrick et al. [6] implied that coagulopathy increased from 21–41% from the 1st day to the 3rd day in patients with a TBI. Finally, the mortality rate was 62%, and the length of stay was increased by 1 day (p = 0.14) in such patients. In agreement with Solla et al. [21] and Corbett [22], we reported that coagulopathy within 72 h post-operatively may portend a higher mortality rate, whether 1 week, 3 months, or 6 months. Therefore, it is essential to prevent coagulopathy and shorten the duration of the coagulopathy to improve clinical neurologic outcomes.

We have been cautious in interpreting these findings because of the limitations in our study. First, a retrospective clinical study has a significant selection bias that might influence the results. Second, these data, including osmotic/diuretic drugs, fluid resuscitation, severe hypoxia or asphyxia, and blood loss in the pre-hospital emergency care, were not uniformly available for us to incorporate into the subgroup analysis. Third, traditional blood coagulation tests, as the most commonly used method to detect coagulation abnormalities, did not provide the status of platelets, fibrinogen function, and fibrinolysis in coagulation cascades. Indeed, thromboelastography could play an essential role in accurately diagnosing platelet dysfunction, fibrinogen deficiency, and hyperfibrinolysis.

Conclusion

Among patients with a TBI who develop coagulopathy within 72 h post-operatively, worse disease progression and unfavorable neurologic outcomes are likely during the early post-operative period. Moreover, a coagulopathy of long duration after surgery is associated with a high mortality rate at different post-operative periods. Hence, we should implement practical and reasonable measures to prevent and manage risk factors, which may protect patients with a TBI from developing a coagulopathy post-operatively.

Abbreviations

TBI, traumatic brain injury; GCS, Glasgow Coma Scale; AIS, Abbreviated Injury Scale; APTT, activated partial thromboplastin time; INR, International Normalized Ratio; GOS-E, Glasgow Outcome Scale-Extended; mRS, modified Rankin Scale; IQR, interquartile range; ISS, Injury Severity Score

Declarations

Acknowledgments

This study was completed in the Intensive Care Unit of the Second Affiliated Hospital of Air Force Medical University.

Funding

This work was supported by the General Program of National Natural Science Foundation of China.[Grant number: 81971186]

Availability of data and materials

No

Authors’ contributions

T C collected the data and drafted the manuscript. YL Y, GQ F, and QB G revised the language and grammar of the manuscript. T C, Z Q, XX T, and QB G provided the clinical data and searched the literature. LH L conceived and designed the experiments. All authors read and agreed to the final manuscript.

Ethics approval and consent to participate

All procedures performed in the study were in accordance with the ethical standards and approved by the Medical Ethics Committee of the Second Affiliated Hospital of Air Force Medical University (Grant number: 20194651).

Consent for publication

We have obtained consent from all patients or their legal guardians.

Competing interests

The authors declare that they have no competing interests.

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