Surgery for Intracerebral Hemorrhage

Key Points

Surgery for spontaneous supratentorial intracerebral hemorrhage (ICH) remains controversial.
Surgical evacuation of cerebellar ICH is recommended for clots that are large or causing brainstem compression.
There is good rationale and strong preclinical data to suggest that surgical evacuation would be beneficial to patients.
Studies evaluating minimally invasive evacuation strategies have produced positive results but require further evaluation in well-designed, rigorous randomized clinical trials.
The Minimally Invasive Surgery with Thrombolysis in Intracerebral Hemorrhage Evacuation (MISTIE) III study was negative for the primary end point of functional outcome at 1 year, but prespecified secondary end points suggested that effective hematoma removal (≤15 mL at end of treatment) may result in improved function compared with medical management at 1 year.

Introduction

Intracerebral hemorrhage (ICH) is the most devastating subtype of stroke, with 40% of patients dead at 1 month and 75% of patients dead or severely disabled 6 months after the hemorrhage. At 15% of all strokes, ICH is fairly common, with 2 million hemorrhages occurring globally each year. Major risk factors for ICH include old age, male sex, hypertension, excessive drug or alcohol consumption, a high-salt diet, and genetic factors that affect endothelial integrity. Patients taking oral anticoagulative drugs comprise 12%–20% of ICH cases. The incidence of ICH due to anticoagulants is rising with increased aging populations and more common use of antiplatelet therapy as a treatment paradigm for the prevention of thromboembolic cardiovascular disease.

The role of surgery in the treatment of spontaneous ICH remains controversial. Major trials evaluating the role of surgery in various forms have not demonstrated a direct benefit to surgery. However, secondary outcomes and meta-analyses have suggested some patients may benefit in some cases, which has led to continued interest in evaluating the role of surgery in ICH. Numerous surgical clinical trials are ongoing at the time of writing of this text. The most current American Heart Association (AHA) guidelines from 2015 on the management of ICH conclude that “for most patients with supratentorial ICH, the usefulness of surgery is not well established.” Surgery for supratentorial ICH may be considered as a life-saving measure in a deteriorating patient. Regarding the role of surgery in patients with cerebellar ICH, the authors conclude that early surgery is appropriate for patients with brainstem compression and/or hydrocephalus from ventricular obstruction.

The backbone of the history of surgery for ICH consists of three major randomized clinical trials evaluating different forms of surgery on different groups of patients: the Surgical Trial for Intracerebral Hemorrhage I (STICH I) completed in 2005, the STICH II published in 2013, and the Minimally Invasive Surgery with Thrombolysis in Intracerebral Hemorrhage Evacuation III (MISTIE III) published in 2019. Although these trials were each negative for their primary outcomes, they revealed valuable information about the types of patients who may benefit from surgery, contributed to setting evidence-based measures of surgical success, and advanced the field of surgical training, proctoring, quality assessment, and quality maintenance for all surgical trials in any field of medicine.

Advances in technology have empowered the medical system to improve all aspects of the care pathway of the surgical ICH patient. Improvements in patient imaging modalities, artificial intelligence–driven rapid assessment of imaging, interdisciplinary communication, neuronavigation, devices for minimally invasive evacuation, noninvasive hematoma morcellation, intensive care management, and neurorehabilitation all contribute to a higher likelihood of improving functional outcome in this challenging patient population. Surgery for ICH currently plays a major role in subgroups of patients, and investigations to broaden that role will continue given that surgery for ICH has a strong pathophysiologic reasoning, preclinical experimental support, and evidence from randomized clinical trials that certain groups are likely to benefit. With additional advancements in knowledge about the disease and technology to aid the management of these patients, surgery for ICH is poised to play a prominent role in ICH patient management in the future.

Pathophysiologic Rationale for Surgical Evacuation

The effort to identify an effective surgical strategy in the management of ICH is driven by pathophysiologic reasoning and preclinical studies. Bleeding in the parenchyma of the brain due to spontaneous ICH often results from a single point of hemorrhage that creates a volume of clot expressing force outward radially counteracted by the spring force or noncompliance of the surrounding brain. When the outward force of the hemorrhage is balanced by the inward force of the perihematomal brain matter, the hematoma stabilizes and clotting of the bleeding source occurs.

This sudden development of a blood clot in the parenchyma of the brain initiates a biphasic process of injury. The primary injury occurs on the scale of minutes to hours after the hemorrhage and results from the mechanical injury associated with the mass effect of the expanding hematoma resulting in excitotoxicity and apoptosis of the perihematomal region. Theoretically, evacuation of the blood clot will remove the intracranial mass of the blood and reduce the mechanical forces on the perihematomal brain. Preclinical studies injecting agarose into the rat caudate with and without hemoglobin supported the paradigm that initial injury occurs from the mass effect alone then additional inflammatory injury occurs from the presence of the blood itself.

Secondary injury then follows on a scale of days to weeks. The degree of secondary injury correlates with the initial hematoma volume and is therefore considered to result from the initial damage caused by the expanding hematoma and the direct contact of blood products with the brain parenchyma. This delayed phase of injury is known to consist of multiple parallel pathologic pathways including hematotoxicity, hypermetabolism, excitotoxicity, spreading depression, and oxidative stress leading to blood-brain barrier breakdown, edema, dysfunction, and cell death. This process is described radiographically as perihematomal edema, which correlates with poor outcome and has been shown to decrease with hematoma evacuation. There is some evidence that removal of a hematoma can in part mitigate secondary injury by reducing perihematomaledema. More so, reduction in perihematomal edema correlates with the surgical reduction in hematoma volume.

In vitro and in vivo preclinical data strongly suggest a link between early hematoma removal and improved outcomes. Despite strong preclinical data and physiologic rationale, the role of early evacuation in humans remains controversial. An earlier study inflating a microballoon in the rat caudate for 10 minutes then deflating it versus allowing it to remain in place for 24 hours demonstrated that early, rapid removal of the mass effect was able to improve local cerebral blood flow and neurologic outcome. Additional ICH evacuation studies in rabbits and dogs with evacuation at 6, 12, 18, and 24 hours demonstrate a time-dependent improvement in neurologic outcome and mitigation of perihematomal pathologic processes. Moving to clinical evidence that early surgical evacuation of ICH improves outcomes, a patient-level meta-analysis of randomized control trial (RCT) data including both open and minimally invasive evacuation trials suggested that evacuation within 8 hours improved clinical outcomes among patients in those trials while evacuation after 8 hours did not. However, there may be increased risk with early evacuation clinically. A clinical trial studying ultra-early evacuation within 4 hours versus evacuation within 12 hours was stopped early after rebleeding occurred in four patients in the ultra-early group, three of whom died, suggesting challenges with hemostasis at that early time point. In addition, time-dependent outcomes were not observed in the three major surgical trials STICH, STICH II, and MISTIE III. Modern minimally invasive evacuation techniques theoretically may improve intracavitary visibility and hemostasis, but that remains to be proven.

A Brief History of Surgery for Intracerebral Hemorrhage

Much like the landscape of trials evaluating any intervention in ICH, the history of surgery for ICH over the past 60 years has been largely characterized by negative studies. Studies exploring the benefits of open or minimally invasive surgery for ICH date back to the 1960s and 1980s, respectively. The first controlled study of craniotomy for supratentorial hematoma drainage was reported by McKissock in 1961. McKissock et al. conducted an RCT of 180 patients randomized to craniotomy for hematoma evacuation or conservative management. The authors concluded that there was no demonstrated benefit to surgery in regards to mortality or morbidity. The first RCT for minimally invasive surgery for ICH was published in 1989 by Auer et al. This study compared endoscopic hematoma evacuation to conservative management in 100 spontaneous ICH patients. At 6 months, lower mortality (42 vs. 70%, P < .01) and higher rates of favorable outcome (40 vs. 25%, P < .01) were observed in the surgical group, specifically in patients with subcortical hemorrhages who were alert perioperatively.

A landmark meta-analysis of surgical treatment for ICH by Prasad et al. in 1997 analyzed 373 articles with four randomized trials. The meta-analysis concluded that endoscopic evacuation was a promising intervention for patients with primary supratentorial intracerebral hematoma but necessitated a rigorous randomized trial. In 2003 the SICHPA trial of stereotactic aspiration failed to show improved outcome from thrombolytically assisted aspiration. ^,

In 2005, STICH I demonstrated that there was no functional benefit overall to the paradigm of early surgery over medical management. This large, international RCT randomized 1033 patients from 83 centers in 27 countries into early surgery versus initial conservative treatment for ICH stratified by good or poor prognosis. A favorable outcome in the good prognosis group was defined as good recovery or moderate disability on the Glasgow Outcome Scale obtained by postal questionnaires at 6 months. For the poor prognosis group, a favorable outcome also included the upper level of severe disability. Of 468 remaining patients randomized to early surgery, 122 (26%) had a favorable outcome compared with 118 (24%) of 496 randomized to initial conservative treatment (odds ratio [OR], 0.89; 95% confidence interval [CI], 0.66–1.19; P = .414). These findings concluded that early surgery for spontaneous supratentorial ICH showed no overall benefit compared with initial conservative treatment. Subgroup analyses from this study identified multiple presenting clinical characteristics that appeared to correlate with improved outcome in STICH I including Glasgow Coma Scale (GCS) greater than 9 and hematoma location 1 cm or less from the cortical surface.

From the insights gained in STICH I, a follow-up study STICH II was designed. This study, published in 2013, randomized 601 patients from 78 centers in 27 countries to early surgical hematoma evacuation plus medical treatment or initial conservative treatment for conscious patients with superficial lobar ICH. In this study, 174 (59%) of 297 patients included in the early surgery group had an unfavorable outcome compared with 178 (62%) of 286 patients in the initial conservative treatment group (absolute difference, 3.7% [95% CI −4.3 to 11.6]; OR, 0.86 [0.62–1.20]; P = .367) resulting in a negative study for the primary outcome focusing on function. The authors of this study concluded that early surgery had a small but clinically important survival advantage for patients with spontaneous superficial ICH.

Derived from success in single-center minimally invasive trials and the negative outcome of STICH I, the MISTIE trials investigated stereotactic aspiration and thrombolysis as a surgical strategy. In 2016, MISTIE II (Minimally Invasive Surgery Plus Rt-PA for ICH Evacuation) showed encouraging preliminary data suggesting an effect size of approximately 16% improvement in functional outcome in the surgical arm over the medical arm. ^, The endoscopic evacuation arm of MISTIE II, called Intraoperative Stereotactic Computed Tomography-Guided Endoscopic Surgery (ICES), demonstrated promising safety data as well. However, the fully powered MISTIE III trial found no functional benefit for the MISTIE procedure in selected patients. However, multiple prespecified secondary outcomes were positive, including a suggested mortality benefit to the MISTIE procedure, and improved 1-year outcome in patients with more complete evacuation (≤15 mL residual hematoma remaining after the procedure). ^, Estimated all-cause mortality differed by 6%–8% over 1 year and was significantly lower in the MISTIE group than the standard medical care group (severity Cox proportional hazard ratio, 0.67; 95% CI, 0.45–0.98; P = .037). The extent of removal was correlated with modified Rankin Scale (mRS) scores 0–3 (OR, 0.68 [95% CI 0.59–0.78; P < .0001]) and the as-treated analysis comparing the proportion of patients who achieved the surgical aim of 15 mL or less remaining at the end of treatment showed a 10.5% increase in risk difference (95% CI, 1.0–20.0; P = .03) in mRS scores or 0–3 at 365 days. The authors caution that these secondary analyses are exploratory.

Other forms of minimally invasive ICH evacuation have been developed over the years that may provide increased ability to maximize the evacuation percentage and functional outcome relationship suggested by the MISTIE III results. In contrast to the prolonged thrombolytic drainage required in MISTIE, active evacuation techniques have the potential to achieve immediate hematoma evacuation during the procedure and does not require tissue plasminogen activator (tPA) administration. Because these techniques permit the ability to rapidly relieve mass effect and address bleeding, there may not be a need to confirm that a hematoma is “stable,” thereby increasing the number of patients eligible to undergo surgical evacuation. Mitigation of hematoma expansion by early surgery may rescue some patients from expanding and thereby suffering significant clinical worsening. Series of early and ultra-early evacuation of ICH in different subsets of patients suggesting that minimally invasive ICH evacuation can be performed safely in the ultra-early patient population, although this remains to be definitely proven in a controlled trial.

Modern Minimally Invasive Evacuation Techniques

Meta-Analyses of Trials Evaluating Minimally Invasive Evacuation Techniques

Since 1989, there have been 16 randomized clinical trials evaluating various minimally invasive methods for ICH evacuation, producing a variety of results. Some studies have demonstrated a functional and/or mortality benefit to ICH evacuation under certain conditions while others have not. Here in this section we will therefore focus on the meta-analysis of minimally invasive evacuation studies that have helped to shape the structure of subsequent clinical trials.

In 2009, Gregson et al. reported a patient-level meta-analysis of data from eight published trials of surgery for ICH, some of which included data on minimally invasive surgery (MIS) evacuation for a combined total of 2186 patients. The authors analyzed hematoma location, presence of intraventricular hemorrhage, volume, GCS on presentation, and age. They found that patients evacuated within 8 hours (OR, 0.59; 95% CI, 0.42–0.84), age 50–69 (OR, 0.71; 95% CI, 0.54–0.94), presenting with GCS of 9 or greater (OR, 0.54; 95% CI, 0.37–0.77), and volume 20–50 mL (OR, 0.69; 95% CI, 0.54–0.89) were less likely to suffer death or dependence at the study time point.

In 2012, Zhou et al. performed a study-level meta-analysis looking only at trials that focused on or included patients specifically undergoing MIS ICH evacuation. The authors identified 12 RCTs involving 1955 patients who underwent MIS evacuation for ICH. The OR for the primary outcome of dependency or death by the trial end point was 0.54 (95% CI, 0.39–0.76). The authors performed subgroup analyses based on the inclusion criteria of the individual RCTs, specifically looking at age, hematoma volume, GCS on presentation, and time to evacuation. They demonstrated that the benefit of MIS evacuation appeared to apply to age older than 30 years, hematoma 40 mL or less and 25 mL or greater, GCS 9 or greater, and across all studied times to evacuation. These subgroup meta-analyses were limited by the heterogeneity of the inclusion and exclusion criteria of the individual studies.

In 2018, Xia et al. performed a systematic review and meta-analysis of RCTs comparing conventional craniotomy and MIS ICH evacuation. This study demonstrated a functional benefit for MIS ICH evacuation over conventional craniotomy (OR, 1.99; 95% CI, 1.21–3.28) but interestingly also demonstrated a decreased incidence of rebleeding in MIS ICH cases over conventional craniotomy (OR, 0.43; 95% CI, 0.26–0.72). This decreased incidence of rebleeding may be one of the advantages of MIS ICH evacuation over conventional craniotomy.

Scaggiante et al. updated the meta-analysis performed by Zhou et al. by adding the five randomized controlled trials that have occurred comparing MIS ICH evacuation to medical management since 2012. This study found a calculated composite OR of 0.46 (CI, 0.36–0.57) for the primary outcome of death or moderate/severe disability. Authors were also able to perform subgroup analyses demonstrating that endoscopic evacuation and stereotactic thrombolysis both decrease the odds of death or disability with ORs, respectively, of 0.40 (CI, 0.25–0.66) and 0.47 (CI, 0.29–67). They also showed that the treatment effect occurred in both studies performed with time to evacuation less than 24 hours and less than 72 hours.

In summary, these meta-analyses demonstrate a robust signal across 15 RCTs that MIS ICH evacuation improves the chance of functional independence over medical management by approximately 2.2 times. MIS evacuation also improves the chance of functional independence over craniotomy by a factor of 2.3 times. In Scaggiante et al., both stereotactic thrombolysis and endoscopic evacuation independently improved outcome over medical management and treatment effect persisted in both evacuations performed within 24 hours and those performed within 72 hours.

A Brief Description of Modern Minimally Invasive Techniques

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