Effect of Minimally Invasive Drainage for Intracerebral Hemorrhage and Other Factors on Clinical Prognosis of Patients with Severe Brainstem Hemorrhage and Survival Analysis

Abstract

Objective: This study primarily aimed to evaluate the impact of minimally invasive surgery and other contributing factors on the clinical prognosis of severe primary brainstem hemorrhage (PBSH).

Methods: A retrospective analysis was conducted on the clinical data of 152 severe PBSH patients admitted to the neurological intensive care unit of Linyi People’s Hospital from 2020 to 2023.

Results: Univariate Cox regression analysis identified significant correlations between prognosis and factors including surgery (modified-frameless stereotactic minimally invasive drainage for intracerebral hemorrhage [ICH]), smoking history, homocysteine levels, cardiac arrest, mechanical ventilation, brainstem hemorrhage volume, and spontaneous breathing at discharge (all p < 0.05).Surgery (HR = 0.583, 95% CI: 0.345–0.986) and spontaneous breathing at discharge (HR = 0.355, 95% CI: 0.196–0.645) were identified as independent protective factors, while brainstem hemorrhage volume (HR = 1.049, 95% CI: 1.012–1.088) and cardiac arrest (HR = 1.882, 95% CI: 1.135–3.12) were independent risk factors (all p < 0.05). Kaplan-Meier indicated the surgical group had a significantly higher 180-day survival rate than the non-surgical group (p < 0.05).

Conclusion: Surgery (modified-frameless stereotactic minimally invasive drainage for ICH) and spontaneous breathing at discharge have been identified as independent protective factors for the survival of patients with severe PBSH. The brainstem hemorrhage volume and cardiac arrest serve as independent risk factors.

Graphical abstract

Keywords

primary brainstem hemorrhage / severe / minimally invasive drainage for intracerebral hemorrhage / prognostic factors / survival analysis

Hemorrhagic stroke, also known as spontaneous intracerebral hemorrhage (ICH), constitutes 20%–30% of all stroke cases, primarily arising from hypertension, intracranial aneurysm, or vascular malformation or rupture. It is distinguished by acute onset, rapid progression, and elevated disability and mortality rates. Given that ICH predominantly occurs in the cerebral hemisphere (~80%), brainstem hemorrhage is relatively infrequent[1].

Primary brainstem hemorrhage (PBSH) represents the most lethal subtype of hypertensive ICH, constituting 6%–10% of cases[2]. PBSH manifests with acute onset and rapid progression, exhibiting an overall mortality rate between 25% and 90%[3]. Historically, PBSH was deemed unsuitable for surgical intervention, with conservative treatment being the standard approach. However, in moderate or severe PBSH cases, conservative treatment alone often fails to enhance prognosis[4]. Minimally invasive puncture and drainage have demonstrated efficacy in reducing ICH mortality rates[5], though their effectiveness specifically in brainstem hemorrhage remains debated. Moreover, existing research, both domestic and international, presents conflicting findings regarding factors influencing PBSH prognosis. This study retrospectively examined the clinical data of severe PBSH patients admitted to the neurological intensive care unit (NICU) of Linyi People’s Hospital from May 1, 2020 to June 30, 2023, with long-term follow-up to assess survival outcomes. The impact of minimally invasive surgery and other prognostic factors were evaluated, and survival analysis was conducted to inform the development and implementation of improved treatment strategies for high-risk patients.

Materials and methods

Study patients

A total of 232 severe PBSH patients admitted to the NICU of Linyi People’s Hospital from May 1, 2020 to June 30, 2023, were continuously enrolled. Based on the inclusion and exclusion criteria, 152 patients were deemed eligible, including 114 males (75%) and 38 females (25%), with a median age of 51 (44, 58) years. This retrospective case series study obtained informed consent from all patients’ families and received approval from the Ethics Committee of Linyi People’s Hospital (Approval No. 202311-H-062).

Inclusion and exclusion criteria

Inclusion criteria: (1) imaging-confirmed brainstem hemorrhage; (2) brainstem hemorrhage volume > 3 mL or hematoma diameter ≥ 2 cm; (3) Glasgow Coma Scale (GCS) ≤ 8 points at discharge[6]; (4) complete clinical and follow-up data; (5) provision of written informed consent.

Exclusion criteria: (1) trauma, cerebrovascular malformation, aneurysm, hematological disease-induced brainstem hemorrhage; (2) brainstem failure upon admission; (3) loss to follow-up; (4) family refusal to provide written informed consent; (5) incomplete clinical data.

Data collection

Patient information, encompassing basic details and clinical data, was gathered through the Linyi People’s Hospital Ruimei Laboratory Information System and medical record system platform. Specific data comprised: (1) baseline data: name, sex, age, inpatient number, history of hypertension, ICH, cerebral infarction, diabetes, coronary heart disease, smoking, alcohol consumption, blood pressure at discharge, GCS score at discharge, and time from onset to hospital admission (h); (2) clinical laboratory test indices: random blood glucose, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglyceride (TG), homocysteine (HCY), and procalcitonin (PCT); (3) outcome measures during hospitalization: fever, cardiac arrest, tracheal intubation, mechanical ventilation, modified-frameless stereotactic minimally invasive drainage for ICH, spontaneous breathing at discharge, and in-hospital death; and (4) imaging results: brainstem hemorrhage volume (mL), hemorrhage involving ventricles, and hemorrhage at other sites.

Allocation

Patients with severe PBSH were categorized into death and survival groups based on their 180-day post-onset survival outcomes. Variables influencing these outcomes underwent statistical analysis. Additionally, patients were divided into surgical and non-surgical groups to assess relevant variables and median survival time.

Calculation of hemorrhage volume

Brainstem hemorrhage volume was determined using the Coniglobus formula[7] (hematoma volume = A × B × C/2), where A is the maximum diameter of the hematoma in the axial plane, B is the maximum diameter perpendicular to A in the same plane, and C is the number of 5-mm slices showing the hematoma.

Surgical procedures

The patient was positioned laterally on the unaffected side, with the head slightly bent toward the sternum to expose the affected area, ensuring the midsagittal line remained parallel to the bed surface. The preoperative puncture point was identified and the surgical site disinfected. The limiter of the bone awl was set to 3.0–3.5 cm, adjusted according to scalp thickness at the puncture site. The skull bradawl was used to puncture the scalp, penetrate the skull, and breach the dura mater. A catheter was then inserted through a guide steel needle, aligned with both the lateral and frontal projection lines. The catheter depth was determined by preoperative computed tomography measurements. The guide steel needle was carefully withdrawn, and a 5-mL empty needle was attached to aspirate old blood, confirming correct catheter placement. The three-way valve was connected, followed by attachment of a disposable craniocerebral external drainage device. The scalp was sutured, and the drainage catheter secured. Bandaging was applied, and the drip pot of the drainage device was suspended for positive pressure drainage.

Survival outcome

The outcome variable was the survival status of severe PBSH patients at 180 days post-onset (death or survival).

Statistical methods

Statistical analyses utilized SPSS 26.0 software. Normally distributed measurement data were reported as mean ± standard deviation (\overline{x} ± s), and analyzed using the two independent-samples t-test. Non-normally distributed measurement data were reported as median (Q1, Q3) and analyzed with the Mann-Whitney U test. Enumeration data were presented as N (%) and analyzed via the chi-square test. This study conducted follow-up assessments and performed univariate and multivariate Cox regression analyses to identify risk factors influencing the prognosis of severe PBSH patients. The Log-rank test was employed to compare survival rates between the surgical and non-surgical groups. And p < 0.05 was considered statistically significant.

Results

Descriptive statistics of basic data of severe PBSH patients

This study included 152 severe PBSH patients with a median age of 51 (44, 58) years, comprising 114 males (75%) and 38 females (25%). The median time from onset to hospital admission was 1.43 (0.93, 2.88) hours. The median brainstem hemorrhage volume was 5.84 (4.09, 9.31) mL. Blood pressure at discharge was abnormal in 141 patients (92.76%), with 11 patients (7.24%) being normotensive. Patients were categorized into the surgical group (modified-stereotactic soft-channel drainage of intracranial hematoma, n = 40, 26.32%) and the non-surgical group (n = 112, 73.68%). At 180 days post-onset, there were 105 deaths (69.08%) and 47 survivors (30.92%). The descriptive statistics indicated that the patients were relatively young, predominantly male, with few underlying conditions, significant brainstem hemorrhage, and abnormal blood pressure at discharge. During hospitalization, a high incidence of fever, tracheal intubation, and mechanical ventilation was observed, along with a high overall mortality rate. Detailed descriptive analysis of severe PBSH patients was presented in Tables 1 and 2.

Univariate Cox regression analysis of severe PBSH

Univariate Cox analysis identified significant associations between prognosis and variables including surgery (modified-stereotactic soft-channel minimally invasive drainage for intracranial hematoma), smoking history, HCY, cardiac arrest, mechanical ventilation, hemorrhage volume, and spontaneous breathing at discharge (p < 0.05). Conversely, factors such as sex, age, and past medical history showed no significant correlation with prognosis (p > 0.05), as detailed in Table 3.

Multivariate Cox regression analysis of severe PBSH

Indices significantly associated with prognosis in the univariate Cox regression analysis, along with those clinically deemed likely to affect prognosis, were incorporated into the multivariate Cox regression analysis. Results indicated that variables such as surgery, brainstem hemorrhage volume, cardiac arrest, and spontaneous breathing at discharge substantially influenced mortality risk. Surgery (HR = 0.583, 95% CI: 0.345–0.986) and spontaneous breathing at discharge (HR = 0.355, 95% CI: 0.196–0.645) emerged as independent protective factors. Conversely, the brainstem hemorrhage volume (HR = 1.049, 95% CI: 1.012–1.088) and cardiac arrest (HR = 1.882, 95% CI: 1.135–3.120) were identified as independent risk factors (all p < 0.05), as detailed in Table 4.

ROC curve analysis of independent prognostic factors in severe PBSH patients

Receiver operating characteristic (ROC) curve analysis demonstrated that the area under the curve (AUC) for surgery in predicting patient prognosis was 0.587 (sensitivity 79.0%, specificity 38.3%). The AUC for cardiac arrest was 0.610 (sensitivity 21%, specificity 100%). The AUC for brainstem hemorrhage volume was 0.728 (sensitivity 57.1%, specificity 85.1%). The AUC for spontaneous breathing at discharge was 0.768 (sensitivity 79.0%, specificity 74.5%). The combined diagnosis with independent factors yielded an AUC of 0.838 (sensitivity 75.2%, specificity 83.0%). These results indicated that surgery, cardiac arrest, brainstem hemorrhage volume, and spontaneous breathing at discharge each held predictive value for prognosis. The combined diagnosis, exhibiting a higher AUC than single factors, suggested a superior predictive capability, as illustrated in Table 5 and Figure 1.

Survival analysis in the surgical and non-surgical groups

Univariate analysis of various indices in both groups

Following the K-S normality test, all indices failed to meet the normal distribution criteria (p < 0.05). Consequently, the Mann-Whitney U test was employed to compare the differences between the two groups. The results indicated no significant differences in age, sex, and past medical history between the groups (p > 0.05), as presented in Table 6. Similarly, no statistical significance was found in the clinical indices (p > 0.05), as shown in Table 7. This suggested that the baseline data between the groups were balanced and comparable, ensuring that subsequent comparative analysis was not influenced by demographic characteristics, past medical history, or clinical indices.

Comparison of survival time between two groups

The log-rank test on survival curves demonstrated a statistically significant difference in survival time between the two groups at 180 days post-onset (p < 0.05), as presented in Table 8. The mean survival time was 52 days for the non-surgical group and 96 days for the surgical group, with median survival times of 3 days and 58 days, respectively. The surgical group exhibited a markedly longer survival time compared to the non-surgical group, as illustrated in Table 9 and Figure 2.

Discussion

PBSH is characterized by acute onset, rapid progression, severe clinical symptoms, and a high overall mortality rate[3]. The MISTIE III study reported a higher incidence of PBSH in men compared to women, accounting for 61.12% (305/499) of cases, with an onset age of 62 (52, 71) years[8]. This study identified that severe PBSH had a 75% (114/152) incidence in men, surpassing that of supratentorial ICH. The onset age of PBSH in this study was 51 (44, 58) years, indicating a relatively younger population compared to those with supratentorial ICH. Additionally, the incidence of underlying conditions in severe PBSH patients was lower than in those with supratentorial ICH[8].

Despite a lower incidence, severe PBSH has significantly higher mortality and disability rates compared to other ICH types[9]. Therefore, it is imperative to identify prognostic parameters for severe PBSH patients and develop individualized treatment strategies. Clinically significant variables in both univariate and multivariate Cox regression analyses included surgery (modified-frameless stereotactic minimally invasive drainage for ICH), brainstem hemorrhage volume, cardiac arrest, and spontaneous breathing at discharge. Variables significant in univariate Cox regression but not in multivariate analysis included smoking history, HCY levels, and mechanical ventilation.

Large-scale studies have indicated the effectiveness of minimally invasive surgery for supratentorial hemorrhage[8]. However, the brainstem, due to its intricate anatomical structure, challenging treatment, and high risk, has traditionally been deemed a surgical taboo. Data on PBSH-related surgeries are limited. The 2015 American Heart Association (AHA)/American Stroke Association (ASA) guidelines for managing spontaneous ICH do not endorse surgical intervention for brainstem hemorrhage[10]. Recent advancements in neuroimaging and artificial intelligence have facilitated the use of microsurgery, robot-assisted stereotactic surgery, and neuroendoscopy for brainstem hemorrhage treatment, rendering severe PBSH no longer an absolute surgical contraindication[9,11,12]. Current studies demonstrate that minimally invasive techniques for brainstem hemorrhage significantly reduce mortality rates compared to conservative treatment[12–16]. These minimally invasive procedures, in contrast to traditional stereotactic surgery, streamline surgical processes, minimize trauma, and enhance accurate positioning, effective fluidization, and complete hematoma removal, thus markedly improving patient outcomes. Multivariate Cox regression analysis in this study identified surgical treatment as an independent protective factor for the prognosis of severe PBSH; with no baseline level differences between groups, the median survival time in the surgical group surpassed that of the non-surgical group, highlighting the safety and efficacy of this procedure.

Pathological injury in brainstem hemorrhage is closely associated with brainstem hemorrhage volume. This study identified brainstem hemorrhage volume as an independent risk factor for the prognosis of severe PBSH, suggesting its potential as a valuable parameter for optimizing treatment strategies. Furthermore, brainstem hemorrhage volume has been shown to independently affect mortality in patients with severe hypertensive brainstem hemorrhage[17]. Given the brainstem’s critical role in brain function, a larger hemorrhage volume implies more severe damage, a higher likelihood of poor prognosis, and an increased risk of mortality[18]. Additionally, prognosis is influenced by the hemorrhagic site; hematomas closer to the midline, which are typically larger, are associated with worse prognosis[19].

The center of cardiovascular function resides in the brainstem[20]. Severe brainstem hemorrhage can induce cardiac arrest, with its incidence positively correlated with the volume of ICH. This study identified cardiac arrest as an independent prognostic risk factor for severe PBSH. Following cardiac arrest, cerebral blood circulation ceases, leading to loss of consciousness within seconds, glycogen depletion, mitochondrial dysfunction, and subsequent neuronal degeneration and death[21]. The extent and duration of cerebral ischemia determine the severity of primary neural damage[21]. Post-cardiopulmonary resuscitation, blood flow reperfusion induces secondary neural damage in brain tissue[21,22]. Contributing factors include hypoxemia, refractory hypotension-induced insufficient cerebral perfusion pressure, cerebral edema, intracranial hypertension, and clinical or subclinical seizures, all exacerbating secondary brain injury. Despite resuscitation efforts, primary and secondary brain tissue damage persists during arrest, with severity ranging from mild damage to brain death[21]. Consequently, PBSH-induced brainstem injury leads to cardiac arrest, further compounding brain injury. This bidirectional causation results in a poor prognosis for PBSH patients experiencing cardiac arrest, thereby underscoring cardiac arrest as an independent risk factor for PBSH.

In this study, spontaneous breathing was identified as an independent protective factor for PBSH patients. Brainstem hemorrhage frequently impacts the respiratory center, particularly in critically ill individuals. Consequently, patients experiencing respiratory failure due to PBSH necessitate early tracheal intubation and mechanical ventilation support. Evidence indicates that severe hemorrhagic stroke patients requiring invasive mechanical ventilation face a heightened mortality risk and poor prognosis[23]. Early tracheotomy within three days post-intubation significantly reduces mechanical ventilation duration and mortality[24]. In this study, 37.5% (57/152) of patients exhibited spontaneous breathing at discharge, of whom 68.4% (39/57) had undergone early tracheotomy following intubation. A total of 76 patients (76/152) received early tracheotomy after intubation, with a mean interval of 3.14 ± 2.16 days from intubation to tracheotomy; over half (39/76) of these patients achieved spontaneous breathing by discharge. Early tracheotomy, compared to tracheal intubation, reduces airway resistance during mechanical ventilation, enhances airway management, and enables earlier ventilator weaning, thereby promoting the restoration of spontaneous breathing and improving long-term prognosis. Furthermore, early recovery of spontaneous breathing decreases the incidence of ventilator-associated pneumonia and shortens hospital stay.

This study found that while cigarette smoking and high HCY levels were not independent risk factors for ICH, they significantly influenced its prognosis. Toxic substances in tobacco increase the incidence of spontaneous ICH, exacerbate hematoma expansion, and elevate post-ICH mortality risk[25,26]. The mechanisms include: a transient rise in blood pressure and sympathetic nervous system activation, which increases heart rate and blood pressure via the nicotinic acetylcholine receptor[27]; long-term nicotine exposure raises circulating tumor necrosis factor levels, compromising blood-brain barrier integrity through phosphorylation of platelet endothelial cell adhesion molecule-1[28]; cigarette smoke exposure enhances reactive oxygen and nitrogen release[29]; and activation of pro-inflammatory pathways exacerbates mitochondrial dysfunction[30]. These combined mechanisms worsen post-ICH brain injury. Consequently, smoking cessation can reduce the risk of ICH and hematoma enlargement in both active and passive smokers. High HCY levels cause endothelial and vascular dysfunction and promote chronic inflammation by releasing damage-associated molecular patterns, leading to cerebral atherosclerosis. Multiple factors contribute to cerebral atherosclerosis rupture and subsequent hemorrhage[31]. This study indicated that elevated HCY levels increased the risk of severe PBSH, aligning with previous findings. Therefore, modulating HCY levels can reduce ICH incidence.

This study has several limitations. The small sample size of patients undergoing brainstem hemorrhage surgery with modified-frameless stereotactic technology may reduce the statistical power and limit the generalizability of the findings. Additionally, the small sample size precluded random sampling. As a single-center study, it also has regional and ethnic constraints. Future research should consider multicenter collaboration or expanding the study’s scope to include a broader patient population and additional outcome measures for more comprehensive and in-depth analysis.

In summary, this study demonstrates that surgery (modified-frameless stereotactic minimally invasive drainage for ICH) and spontaneous breathing at discharge are independent protective factors influencing survival in patients with severe PBSH, whereas the brainstem hemorrhage volume and cardiac arrest are independent risk factors for disease progression. In clinical practice, patients with severe PBSH who exhibit substantial brainstem hemorrhage and have experienced cardiac arrest require vigilant monitoring. These two indices can be utilized for risk stratification in severe PBSH patients to identify high-risk individuals and guide personalized management strategies. Given the limited sample size of brainstem hemorrhage cases treated surgically in China, multi-center studies are essential to evaluate the efficacy and safety of surgical interventions for severe PBSH patients, thereby providing significant clinical and societal benefits.

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