Safety and technical efficacy of early minimally invasive endoscopy-guided surgery for intracerebral haemorrhage: the Dutch Intracerebral haemorrhage Surgery Trial pilot study

Spontaneous intracerebral haemorrhage (ICH) accounts for 16–19% of all strokes in the Western world and for 28–32% in low- and middle-income countries [12, 24]. ICH contributes profoundly to stroke-related disability and 30-day case fatality is around 40% [38, 48]. Survival and functional outcome after spontaneous ICH are independently predicted by age, Glasgow Coma Scale (GCS) score, haematoma volume, the presence of intraventricular haemorrhage (IVH) [38], and hematoma growth [9, 40]. Around 20% of patients with ICH show growth of hematoma, mainly within the first 3 h after symptom onset [3]. Neurotoxicity, caused by blood degradation products and plasma-derived components such as thrombin, and inflammation, may lead to the development of perihematomal oedema (PHO). This process starts already within 3 to 4 h after symptom onset [4, 20]. Reduction of the hematoma volume in an early stage may not only alleviate the direct mass effect of the ICH, but may also prevent hematoma growth and development of PHO [35, 51]. Theoretically, this could result in better functional outcome [2, 35]. Increasing evidence including recent narrative [8, 14] and systematic reviews [43, 44] of randomised controlled trials (RCTs) suggests that surgical hematoma evacuation may reduce mortality and improve functional outcome [13, 43, 44, 55]. However, large high-quality RCTs have not established this presumed beneficial effect of surgery [15, 16, 30, 31, 44]. Besides evacuation by means of a craniotomy, several minimally invasive techniques are available to remove the hematoma [2, 17, 36, 41, 55]. Recent case series suggest that endoscopy-guided minimally invasive evacuation by means of aspiration is promising and safe and effectively reduces haemorrhage volume, with few complications [1, 11, 19, 23, 27, 41, 45, 46, 53]. The MISTIE III trial recently failed to demonstrate a beneficial effect on functional outcome of minimally invasive surgery with local application of alteplase followed by hematoma aspiration up to 72 h [16]. The relatively long median time from symptom onset to surgery in MISTIE III (59 h) [16] and in the other large, multicentre, high-quality studies of conventional surgery STICH (30 h) [30] and STICH-II (26 h) [31] might in part explain the lack of a treatment effect. An individual patient data meta-analysis of RCTs found that outcome improved after surgery compared to standard medical management, if surgery was performed within 8 h [13]. However, one study showed that ultra-early surgery (within 4 h) was associated with rebleeding [34], whilst other studies have shown that ultra-early surgery (<4–6 h) is safe [25, 26]. In addition, a recent study showed that for every hour that patients were operated earlier, there was a 5% increase in the odds of good functional outcome at 6 months [22].

Well-designed RCTs are needed to provide definitive and guideline changing evidence whether or not early minimally invasive and endoscopy-guided surgical evacuation would reduce mortality after sICH and improves functional outcome [43]. As a prelude to such a large randomised clinical trial, the aim of the Dutch ICH Surgery Trial (DIST) pilot study was to investigate safety and technical efficacy of minimally invasive endoscopy-guided surgery for the treatment of spontaneous supratentorial ICH within 8h after symptom onset.

Forty patients were included between March 2019 and January 2021. We experienced delays at the start due to limited availability of the surgical devices, and during the study because of the COVID-19 pandemic with temporary halting of clinical research activities and limited availability of operation room capacity and ICU beds. Demographics and baseline characteristics are summarised in Table 1. Median ICH volume at baseline was 47.7mL (IQR 29.4–72.0mL; 2 patients had a baseline ICH volume <15mL). Median time from symptom onset to the start of the surgery (first incision) was 6 h and 43 min (IQR 5 h 26 min–7 h 56 min). Median duration of the procedure (first incision to skin closure) was 68 min (IQR 55–106 min). Median ICH volume after 24 h was 10.5mL (IQR 5.1–23.8mL). Further details of the surgical procedures are summarised in Table 2. Online resource table 2 shows the baseline characteristics and technical outcome parameters according to baseline ICH volume subgroups (<30mL and ≥30mL). An illustrative case is shown in Fig. 1. Twelve patients had a CTA spot sign, of whom five had active bleeding during surgery. Of a total of 19 patients with active bleeding during surgery (Table 2), 14 did not have a spot sign at baseline.

In the DIST pilot study, minimally invasive endoscopy-guided surgery within 8 h of symptom onset in patients with a spontaneous supratentorial ICH appeared safe and could be performed with good technical results. Technical efficacy tended to become better in the second half of the study, suggesting a learning curve for the procedure.

Our study differs from previous studies in that all patients had minimally invasive endoscopy-guided hematoma evacuation within the time window of 8 h after symptom onset. Previous non-randomised studies of endoscopy-guided minimally invasive surgery included patients up to 16 days after symptom onset with a median time to surgery of 19 h to 2.3 days [23, 46, 50]. In these studies, only a minority of patients was operated on within 8 h after symptom onset. The optimal timing of surgical evacuation is still a topic for debate. In a systematic review and meta-regression analysis, we recently showed that surgery seemed to be more effective when performed earlier after symptom onset [44]. Another review of 15 high-quality studies including 2152 patients found no difference in the risk of death or dependence between minimally invasive surgery performed within 24 h (OR 0.49, 95% CI 0.38–0.63, five studies) or within 72 h (OR 0.57, 95% CI 0.43–0.76, 12 studies) as compared with medical care or conventional craniotomy [43]. In both reviews, analyses were based on study level data and not on individual patient data. In addition, only one of the included studies restricted inclusion to patients in whom surgery could be started within 8 h after symptom onset [37]. In an observational study in 59 patients without a spot sign on CTA, the authors found no difference in rebleeding rates after stereotactic aspiration within 6 h or after 6 h after symptom onset [26]. In contrast, a small pilot study that assessed hematoma evacuation by means of a craniotomy within 4 h after symptom onset was stopped early because rebleeding occurred in four of 11 patients within 24 h after surgery [34]. In our study, a rebleed did not occur in the three patients in whom surgery was started within 4 h after symptom onset, and occurred in only one of 21 patients in whom surgery was started within 6 h. In MISTIE III (median time between symptom onset and start of surgery 58 h), six of 255 patients (2%) had a symptomatic bleeding within 72 h, and 81 patients (32%) an asymptomatic bleeding [16]. In the ICES study [50] (median time between symptom onset and start of surgery 30 h), three of 14 patients (21%) had an asymptomatic bleeding within 72 h, defined as an increase of at least 5mL and less than 2 points increase on the GCS motor score. Although a previous cohort study in 143 patients with spontaneous ICH who underwent endoscopic hematoma evacuation found no association between hypertension and postoperative rebleeding [32], we cannot exclude that elevated blood pressure after surgery may have contributed to rebleeding in one of the patients in our study. In practice, we strive for a systolic blood pressure of <160 mmHg. We could not confirm the findings of previous studies that the CTA spot sign is associated with postoperative rebleeding [32, 33]. In addition, we found no association between the presence of a CTA spot sign and intra-operative active bleeding, in contrast to what has previously been suggested by others [33]. In that study, 23% of patients were operated within 8 h, and could also have infratentorial ICH, and more frequently had a coagulopathy [33] than in our study. Based on our results, we suggest that patients with a CTA spot sign should not be excluded from future trials. Our 30-day case fatality of 10% is similar to that of 9–14% found in MISTIE III [16], as well as in ICES [50] (7%, 95% CI 1.8–33.9%) and other prospective studies investigating minimally invasive endoscopy-guided surgery [23, 46], in which patients were operated on at a median of 30 h to 3.2 days after symptom onset [16, 23, 46, 50].

The low percentage of intracranial infection (n=1; 2.5%) in this study was similar to that in MISTIE III (n=2/255; 1%) [16], ICES (n=0/14) [50], and another prospective study investigating minimally invasive endoscopy-guided surgery (n=2/49; 4%) [53].

The technical efficacy in our study was similar to the 54 to 97% postoperative ICH volume reduction reported in other studies of various minimally invasive techniques performed at later times after symptom onset (median time between symptom onset to surgery ranging from 19 h to 2.3 days) [23, 28, 46, 47, 50]. Hence, technical efficacy appears no reason to defer surgery to later time-points.

Previous studies on endoscopic surgery have shown that the evacuation rate improves with more experience [5, 28, 50], and that better technical results are associated with improved functional outcomes [16]. In our study, there also appeared to be a learning curve, with a suggestion of slightly better technical results in the second part of the study (albeit with overlapping 95% confidence intervals). In MISTIE -III, a threshold of four patients per surgeon and seven per centre was found, after which no patient had poor end of treatment volumes [16]. This learning curve is important to take into account in the design of future studies. The IDEAL recommendations for the design and reporting of studies on surgical and interventional therapy innovations [29] advise to monitor the quality of the intervention, including pre-operative care, surgery, and post-operative care. For RCTs these recommendations additionally advise to evaluate the learning curve, ideally with Bayesian hierarchical models, and to minimise potential harms by mentoring and training, and to demonstrate that the technique can be widely adopted by surgeons [7, 29]. Because of the small sample size, we refrained from formal analysis of the learning curve.

Based on the results of this study and those of others, we conclude that high-quality RCTs are needed to investigate whether minimally invasive surgery improves functional outcome in patients with spontaneous supratentorial ICH. It remains to be determined whether the timing is indeed a key factor in the success of this treatment [44, 52], but ‘time is brain’ may also hold true for ICH [21, 39]. The existence of a learning curve should be taken into account in the design of such trials.

Several RCTs comparing minimally invasive endoscopy-guided surgery with standard medical management in different time windows are ongoing: MIND (NCT03342664) investigates minimally invasive surgery with the Artemis^TM device within 72 h after symptom onset, ENRICH (NCT02880878) investigates minimally invasive surgery with the Brainpath® device by NICO Corporation (Indianapolis, Indiana, USA) within 24 h after symptom onset, and EVACUATE (NCT04434807) is investigating minimally invasive aspiration by the Aurora Surgiscope® by Rebound Therapeutics® (Irvine, California, USA) within 8 h after symptom onset. In the Dutch Intracerebral Haemorrhage Surgery Trial (DIST, NCT05460793), we will investigate whether treatment with minimally invasive endoscopy-guided surgery within 8 hours after symptom onset in addition to medical management improves functional outcome after 6 months in comparison with medical management alone. DIST has started in October 2022 and is estimated to be completed in 2027. Strengths of the DIST pilot study are its prospective, multicentre design and the broad inclusion criteria, without limitations for age, GCS, or the presence of a CTA spot sign, following a standardised surgical protocol. In addition, all imaging to determine technical efficacy was centrally assessed by an independent neuroradiologist, blinded for baseline characteristics and outcomes. Furthermore, we assessed the difference in technical efficacy between the first half and second half of patients, highlighting the importance of training.

Our study also has some limitations. First, the sample size was small. Second, we were not able to report on the effect of early minimally invasive endoscopy-guided surgery on functional outcome. Third, we did not keep screening logs. Furthermore, results might not be generalisable to other countries than the Netherlands. In particular, the distance to a neurosurgical centre in the Netherlands is small in comparison with other countries.

This study shows that in patients with supratentorial ICH, minimally invasive endoscopy-guided surgery within 8 h after symptom onset appears safe and technically effective. An RCT is needed to assess whether this intervention improves functional outcome.