Pharmacological targeting of secondary brain damage following ischemic or hemorrhagic stroke, traumatic brain injury, and bacterial meningitis - a systematic review and meta-analysis

The term ‘secondary brain damage (SBD)’ refers to delayed detrimental functional and structural sequelae after various types of acute cerebral injury. The underlying mechanisms are triggered by the primary ictus, such as ischemic or hemorrhagic stroke (aneurysmal subarachnoid, aSAH or intracerebral hemorrhage, ICH) or traumatic brain injury (TBI) and intracranial infections [1‐4]. Numerous mechanisms contributing to the pathogenesis of SBD following the aforementioned acute cerebral events have been identified over the past decades, which subsequently led to the development and clinical investigation of numerous experimental pharmacological treatments focused on different SBD mechanisms. SBD mechanisms include impairment of cerebral flood flow and cerebral autoregulation, metabolic dysfunction, edema formation, oxidative stress, disruption of the blood brain barrier and inflammation [1‐4].

While some SBD pathomechanisms are specific for ischemic and hemorrhagic stroke, TBI and intracranial infections, other mechanisms are a rather unspecific reaction of the injured brain, such as edema and delayed ischemia. At the present time it remains unclear whether a pharmacological strategy targeting one specific pathomechanism could result in a beneficial effect on outcome [5, 6]. Moreover, the relevance of targeted treatment of SBD, in addition to established general measures of critical care, e.g. avoidance of arterial hypotension, increased intracranial pressure, hyperthermia, and hypoxemia, is uncertain [7‐11]. We performed a systematic review and meta-analysis to summarize the currently available randomized clinical trials exclusively targeting specific pathomechanisms of SBD with the aim to improve clinical outcome following ischemic stroke, ICH, SAH, TBI, and bacterial meningitis. In order to obtain practically useful information we grouped the available phase III randomized clinical trials according to addressed pathomechanisms.

For this systematic review we used the Cochrane Collaboration format [12] and followed the PRISMA checklist [13].

Out of a total of 5299 reports, ultimately data from 123 studies targeting specific pathomechanisms of SBD fulfilled the specified criteria and the corresponding data on a total of 66,561 patients was included in the analysis (Fig. 1). The corresponding references for the included studies as well as the complete risk of bias assessment are provided in the online supplementary information (Additional file 1). Data on poor outcome was available in 67% of the included studies.

While previous meta-analyses have investigated the effects of various experimental pharmacological or surgical treatments for specific cerebral diseases on different outcome measures [30‐34], the present meta-analysis explores the efficacy of pharmacological treatments solely targeting specific SBD mechanisms across the various underlying entities. All entities analyzed in the present study are considered to share at least partially some common mechanisms of SBD [35‐37]. In contrast to the initial ictus, e.g. aSAH, the mechanisms causing SBD are considered amenable for therapeutic intervention and have therefore been subject of considerable scientific efforts.

Our pooled analyses for the main pathological groups provided risk ratios of poor outcome or death for the experimental groups in a relatively narrow range from 0.86 to 1.03. For the subgroups of addressed pathways the risk ratios scattered somewhat wider with a range from 0.57 to 2.0. Since in such a pooled analysis the effect of positive concepts and result is diluted by a larger number of negative attempts, the relatively narrow range of the pooled results is not surprising.

For ischemic stroke, TBI and ICH the pooled risk ratios for the experimental groups were close to one, which leads to the conclusion that addressing SBD could not be confirmed as a relevant therapeutic target. There were only 3 outliers in these groups, trials showing a statistically significant benefit for the experimental group: the study by Mayer et al. [22] on the use of recombinant activated factor VII for ICH, the study of Rockswold et al. [23] on the use of hyperbaric oxygen for TBI and the controversial study of Cruz et al. [24] on the use of high dose mannitol for TBI with mydriasis. Unfortunately, the benefit of recombinant activated factor VII for ICH could not be confirmed in two later trials and both trials on TBI were not devoid of the risk of bias. The study of Cruz et al. is subject to ongoing scientific debate due to suspicion of data manipulation or fabrication [24]. However, the use of mannitol is widely established and represents a slightly different concept than blocking a metabolic pathway or suppressing an active reaction of the organism. Patients with TBI entered into the trial were on the verge of brain herniation due to cerebral edema and high dose mannitol helped the physiological measures of compensation. In this context the recently published RESCUE-ICP trial using decompressive craniectomy provided similar results [38]. Nonetheless, based on all the trials it appears doubtful that addressing SBD can be maintained as a generally valid treatment concept for ischemic stroke, TBI and ICH.

For aSAH the pooled risk ratio for poor outcome in the experimental groups was with 0.94 clearly below 1. A study on nimodipine showed a statistically significant benefit and the subgroup analysis showed a tendency towards a beneficial effect for the effector mechanism category “oxidative metabolism/stress”. Therefore it can be assumed that the concept of SBD as a therapeutic target has some value for the management of aSAH in the current setting.

Why does aSAH differ from ischemic stroke, TBI and ICH? A possible explanation could be that during the natural course after aSAH secondary processes are well balanced to allow for the best possible recovery, i.e. minimizing the chance of rebleed and ischemic damage by vasospasm. The data of the Cooperative Study [39] showed that during the natural course after aSAH rebleeds were less frequent in case of vasospasm, in other words that vasospasm protected to some degree against re-rupture. Since the introduction of early aneurysm elimination, the protective effect of vasospasm is no longer needed and only the negative side effects remain, i.e. delayed cerebral ischemia. Therefore, in the case of aSAH and eliminated source of bleeding, blocking physiological reactions might make some sense.

Methylprednisolone showed a marginally significant benefit for aSAH in one study [21], while corticosteroids were shown to be ineffective or even toxic for TBI and ICH. In the light of the above remarks regarding calcium antagonists it appears that corticosteroids likely benefit patients after aSAH, but corticosteroids have not been appropriately evaluated for aSAH.

Dexamethasone was shown in a number of, although marginally powered, studies to reduce the chance of death or poor outcome in patients with bacterial meningitis. The setting of meningitis is interesting. Similar to aSAH, the current setting with antibiotic treatment differ widely from the natural course and the natural secondary reactions of the immune system are not optimally adapted to the current situation, or in other words, the natural defense and clean-up mechanisms may become activated more than necessary under antibiotic treatment and therefore lead to unnecessary harm.

While the actual analysis could confirm a beneficial effect of pharmacological treatment of SBD only for aSAH and intracranial infection, cohort and population-based studies have clearly demonstrated a distinct reduction of overall mortality across all stroke entities and even TBI over the past decades [32, 38, 39]. In view of the absent or very limited effect of SBD directed treatments for ischemic stroke, ICH and TBI, it must be concluded that the positive time-trends during the last decades were mainly achieved by more aggressive early management and improved general measures of critical care [40]. Furthermore, treatments targeting the primary cause of brain damage, e.g. thrombectomy for ischemic stroke, seem to be generally more efficacious than studies focusing on sole neuroprotection or targeted reduction of specific SBD mechanisms [41‐46]. It must be assumed that the extent of primary brain injury per se is by far the dominant prognostic factor. This causality seems to be especially valid for aSAH and ICH but also for ischemic stroke or TBI [44‐50].

Our study has several limitations: First, a pooled analysis of treatment effects among different entities may certainly be controversial due to heterogeneous studies or therapeutic interventions per se. Nevertheless, the aim of this study was to illustrate the status quo of the overall effect of specific treatment of SBD for each entity and to highlight some potential explanations. Second, we primarily focused on death as a robust outcome event, since there were heterogeneous definitions for poor functional outcome in the majority of the underlying trials. However, both of these endpoints are not specific for SBD. We accounted for this by excluding trials that target both primary and secondary causes of brain injury. We cannot state with absolute certainty that we did not exclude by this an effective treatment concept actually working on SBD rather than the primary cause. Moreover, variations in outcome severity distribution might be inherent to the underlying conditions: While the mortality rate in patients undergoing endovascular thrombectomy for large-vessel stroke is 15%, the mortality for aSAH can be as high as 44% and for TBI as high as 72%, depending on regional or age-related factors, respectively [51‐53]. Accordingly, in conditions with a relatively small proportion of fatal and poor outcomes, our approach might underestimate relatively subtle treatment effects on good or excellent outcomes. Third, with regard to the validity of SBD as a useful target of treatment we cannot exclude that the modern generally accepted critical care concepts also used within the clinical trials contributed to the general reduction of SBD [7‐11, 54]. This may partially explain why more specific or targeted experimental treatments have failed to additionally improve outcome. However, methodological problems, such as imbalances in major baseline variables or prognostic factors, insufficient patient numbers as well as errors, noise or inconsistencies in outcome assessment, offer an alternative explanation why studies on SBD might fail to detect moderate treatment effects that could nevertheless be clinically relevant. This issue could be addressed by methodological improvements of future randomized trials, but also by focusing more on common data elements to facilitate meta-analyses, or even by contributing individual patient data for pooled analyses [55‐57]. Additionally, assuming that SBD is a useful target of treatment, negative results of a methodologically sound trial might be related to the compound being tested, e.g. its effectiveness for the intended mechanism, or the pharmacokinetics and pharmacodynamics, e.g. dosing and timing. Finally, the strict selection criteria of included trials (only randomized, controlled trials) might have somewhat biased the results due to exclusion of some larger non-randomized observational studies.

In summary, our meta-analysis on targeted treatment of specific SBD mechanisms following acute cerebral injury showed that a few selected SBD directed medications are likely to reduce the rate of poor outcome and death following aSAH, bacterial meningitis and maybe TBI, while no evidence for the usefulness of SBD directed medications was found in ischemic stroke and ICH. The result should lead to a new perspective of secondary reactions following cerebral injury. These processes should not be seen as suicide mechanisms that need to be fought. They should be rather seen as well orchestrated clean-up mechanisms that may today be somewhat too active in a few very specific constellations, such as meningitis under antibiotic treatment and aSAH after aneurysm elimination. Furthermore, these results should stimulate increased focus on methodological and reporting aspects of future trials.