Curr Treat Options Neurol (2016) 18:9 DOI 10.1007/s11940-015-0392-z
Critical Care Neurology (K Sheth, Section Editor)
Treatment of Edema Associated With Intracerebral Hemorrhage Audrey Leasure, BS1,* W. Taylor Kimberly, MD, PhD2 Lauren H. Sansing, MD, MS1 Kristopher T. Kahle, MD, PhD3 Golo Kronenberg, MD4 Hagen Kunte, MD4 J. Marc Simard, MD, PhD5 Kevin N. Sheth, MD1 Address *,1 Department of Neurology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA Email: [email protected] 2 Department of Neurology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA 3 Yale Program on Neurogenetics, Department of Neurosurgery and Pediatrics, 333 Cedar Street, New Haven, CT, 06510, USA 4 Department of Neurology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany 5 Department of Neurosurgery, University of Maryland School of Medicine, 22 South Greene Street, Baltimore, MD, 21201-1559, USA
* Springer Science+Business Media New York 2016
This article is part of the Topical Collection on Critical Care Neurology Keywords Intracerebral hemorrhage I Perihematomal edema I Secondary brain injury I Hyperosmolar therapy I ICP
Opinion statement Cerebral edema (i.e., Bbrain swelling^) is a common complication following intracerebral hemorrhage (ICH) and is associated with worse clinical outcomes. Perihematomal edema (PHE) accumulates during the first 72 h after hemorrhage, and during this period, patients are at risk of clinical deterioration due to the resulting tissue shifts and brain herniation. First-line medical therapies for patients symptomatic of PHE include osmotic agents, such as mannitol in low- or high-dose bolus form, or boluses of hypertonic saline (HTS) at varied concentrations with or without subsequent continuous infusion. Decompressive craniectomy may be required for symptomatic edema refractory to osmotherapy. Other
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strategies that reduce PHE such as hypothermia and minimally invasive surgery have shown promise in pilot studies and are currently being evaluated in larger clinical trials. Ongoing basic, translational, and clinical research seek to better elucidate the pathophysiology of PHE to identify novel strategies to prevent edema formation as a next major advance in the treatment of ICH.
Introduction Intracerebral hemorrhage (ICH) remains a devastating disease with limited treatment options. The 30-day mortality rate for spontaneous ICH is as high as 50 %, and only 20 % of those surviving regain functional independence [1]. There are several potential mechanisms by which ICH leads to acute brain injury. The main focus of recent randomized controlled trials has been on reversing or attenuating the mechanical effects of the hematoma by limiting hematoma growth or evacuating the hematoma entirely. The Surgical Trial in Intracerebral Hemorrhage (STICH) trials tested whether hematoma evacuation through an open neurosurgical approach would reduce disability, but there was no beneficial effect on the outcome [2, 3]. Similarly, the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage (INTERACT) trials aiming to prevent hematoma expansion were inconclusive [4]. While INTERACT1 showed reduced hematoma growth after intensive blood pressure lowering, the larger INTERACT2 trial failed to show a reduction in death or disability [5, 6]. Although a promising clinical efficacy signal was present in INTERACT2, it was not mediated by hematoma growth, and the effect size was small. The North American counterpart of the INTERACT trials, Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) II, has recently stopped and the results are awaited [7]. However, hematoma expansion through hypertension may not be a robust treatment target, and it is unknown if blood pressure reduction in the field will improve clinical outcomes. As such, an investigation of new treatment options is warranted. In addition to ongoing investigations into attenuating the mechanical effects of ICH, a more recently recognized form of secondary injury after ICH that has therapeutic potential is perihematomal edema (PHE). PHE is initiated by the brain’s physiologic response to the primary injury [8] and develops in the days to weeks following ICH, providing a wider window for intervention than primary injury [9]. Patients who develop edema are at risk of neurologic deterioration and may benefit from therapies directed at preventing edema
formation [10•]. However, PHE does not occur in isolation. Indeed, many of the processes contributing to, and resulting from, edema may also cause hydrocephalus, mass effect, midline shift, and increased intracranial pressure (ICP), as depicted in Fig. 1. As such, treatment strategies to prevent and manage edema may also modulate ICP, hydrocephalus, or other related pathologic processes. Current strategies for management of edema after ICH focus on treating elevated ICP. However, the incidence of elevated ICP after ICH and the outcomes of treatment are uncertain. One retrospective study found that episodes of elevated ICP were common among ICH patients receiving ICP monitoring, but that there was no association between the frequency of these events and the functional outcome at 1 year [11]. Based on current evidence, the decision to monitor and treat ICP after ICH remains unclear. However, increasing evidence suggests that PHE has an independent association with a poor outcome and targeted edema treatment strategies should be investigated [12•, 13•, 14••]. Progressive edema in the days after injury contributes to the mass effect of the hematoma, resulting in tissue shifts and herniation, which are responsible for delayed neurologic deterioration and increased mortality [13•].
Fig.1. Relationships between processes contributing to and resulting from edema.
Curr Treat Options Neurol (2016) 18:9 Independent of mass effect, edema as demonstrated on CT or MRI is a useful surrogate marker of secondary brain injury that may impede functional recovery. The volume of PHE is suggested to reflect the extent of secondary brain damage caused by inflammatory processes [8, 15, 16] and therefore may be a useful endpoint in clinical trials. Novel methods of quantifying edema, such as edema
Page 3 of 14 9 expansion rate [15, 17•] and edema extension distance [18], may facilitate phase II clinical trials that focus on reduction of edema, potentially with smaller sample sizes. These new methods of measuring PHE, coupled with an improved understanding of the molecular pathophysiology of edema, have created a unique opportunity to develop innovative treatment strategies
PHE and outcome: why focus on PHE as a therapeutic target? With the development of new therapies directed at edema, the question of whether edema has an effect on the clinical outcome is important. Retrospective studies have produced conflicting results, with some arguing that edema is an independent predictor of a poor outcome and others suggesting that edema has no effect, or even a positive effect, on the outcome [19–23]. Variations in study populations, edema measurement techniques, or the time course used to evaluate edema may account for these differences. The largest study to report no association between PHE growth and the 90day outcome was a retrospective study in 2009 of 270 subjects in the INTERACT1 cohort [24]. This study found a significant association between absolute and relative edema growth and death or dependency at 90 days, but this association did not persist after adjustment for baseline hematoma volume [24]. However, in 2015 the same group conducted a larger analysis of 1138 INTERACT1 and INTERACT2 cohort subjects with small to moderate, deep ICH [14••]. The absolute growth in PHE volume during the first 24 h after ICH was significantly associated with death or dependency at 90 days, defined as a modified Rankin scale (mRS) of 3–6, after adjustment for prognostic factors (1.17; 95 % confidence interval, 1.02–1.33 per 5 mL increase from baseline; P = 0.025) [14••]. The prognostic significance of edema growth is further supported by a recent review of 596 ICH patients that explored the association between iPHE, defined as PHE volume expansion within the first 72 h after ICH, and the functional outcome at 90 days [12•]. This study found that the odds of a poor outcome (mRS ≥ 3) increased with iPHE (OR 1.78; CI 1.12–2.64 per mL increase) [12•]. A subgroup analysis of these data by baseline ICH volume corroborates previous findings that iPHE was related only to poor functional outcomes in small (G30 mL) ICH [19]. Interestingly, this study also suggested that ICH location may influence the relationship between PHE and the outcome. A significant association was found between iPHE and functional outcomes in basal ganglia ICH, but not in lobar ICH [12•]. A similar relationship has been observed between PHE and the functional outcome at discharge. A recent review of 220 subjects with a mean admission ICH volume of 22.7 cm3 showed a negative effect of peak absolute PHE volume on the functional outcome at discharge (OR 0.977; 95 % CI 0.957–0.998, P = 0.03) [13•]. The odds of a poor outcome were found to increase by 2 % for every additional millimeter of PHE [13•].
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In light of these new findings that demonstrate an association between edema and poorer outcome, PHE requires further investigation as a therapeutic target for ICH.
Pathophysiology of edema formation PHE is a result of many inflammatory pathways activated in response to injury, and new therapies to ameliorate PHE may act at various stages during edema development. Immediately after ICH, the process of clot retraction extrudes serum proteins from the hematoma into the interstitium. This movement of osmoles produces an osmotic gradient that draws water into the interstitium prior to any blood-brain barrier (BBB) disruption [9]. Following this phase of ionic edema, three intersecting pathways of secondary injury contribute to vasogenic edema: inflammation, thrombin production, and erythrocyte lysis [9, 25].
&
&
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Neutrophils and macrophages infiltrate the perihematomal tissue after ICH and trigger a robust inflammatory response [26]. Upregulated NF-κB stimulates the production of inflammatory cytokines that mediate the progressive breakdown of the BBB and induce the formation of vasogenic edema, the fluid movement out of the intravascular space into the surrounding tissue [9]. NF-κB activation is closely related to the clinical outcome at 6 months post-ICH in humans [27]. However, the full effects of inflammation are still unknown, as some have theorized that early inflammation and edema may promote brain recovery and improve outcomes [28]. Thrombin is activated in the area of injury soon after hemorrhage to limit bleeding and is thought to be neuroprotective at low concentrations [8]. However, thrombin is also a potent proinflammatory agent, and at the high concentrations present after ICH, it may promote BBB disruption, neuronal damage, and inflammatory cell infiltration [16]. The activation of the coagulation cascade in the surrounding tissue then activates resident microglia that secrete inflammatory factors and contribute to PHE [8]. Thrombin also mediates secondary injury through activation of protease-activated receptors (PARs), which are upregulated after ICH and may play a role in edema formation [29, 30]. The role of thrombin in edema formation is further supported by the finding that warfarin-related ICH results in less edema than spontaneous ICH [31]. Complement cascade proteins also enter the perihematomal tissue through the disrupted BBB [8]. The activation of these proteins, in part by thrombin, causes microglial activation, erythrocyte lysis, and the release of hemoglobin and iron into the surrounding tissue [32, 33]. Iron and hemoglobin degradation products are neurotoxic and promote secondary injury. Iron’s toxicity is thought to be mediated
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through the generation of free radicals, leading to further BBB disruption and edema [8].
Medical therapies Hyperosmolar therapy is the main medical strategy in the treatment of edema. Hypertonic solutions establish an osmotic gradient between the interstitial fluid and the vascular compartments, drawing water out of the brain and into the vasculature to reduce cerebral volume. Mannitol and HTS are the osmotic agents of choice as they do not readily cross an intact BBB [34]. These agents can be given in various solutions as boluses for rapid ICP reduction or, in the case of hypertonic saline, as a continuous infusion to mitigate edema formation, although there is a relative paucity of data on the comparative efficacy of various administration strategies [34]. Common methods of administration are summarized in Table 1. The rapid effects of bolus therapy are well supported. Mannitol has been shown to work in a dose- and location-dependent manner, with the greatest ICP reductions in patients with supratentorial hemorrhages [35]. Retrospective cohorts have even shown the ability of 23.4 % HTS boluses to reverse transtentorial herniation after a nontraumatic brain injury [36]. The indication is less clear for continuous infusion of HTS. In theory, the therapeutic effects of hyperosmolar therapy are expected to be transient due to the brain’s adaptation to osmotic gradients [37]. However, one study demonstrated that early continuous infusion of 3 % HTS reduced both relative and absolute edema after large ICH for up to 14 days compared to controls [38]. The retrospective nature and small sample size (26 subjects receiving HTS) of this study limit the generalizability of the results. Although the short-term effects of mannitol and HTS are well established, their ultimate effects on the clinical outcome are unclear. A recent review of the INTERACT2 cohort of 2526 ICH subjects concluded that mannitol therapy does not affect the poor outcome at 90 days, defined as a modified Rankin scale score of 3–6 [39•]. Interestingly, a trend toward better outcomes in those with larger hematoma volumes was seen, suggesting that there may still be a relevant therapeutic effect on the outcome in certain patient populations [39•].
Table 1. Hypertonic solutions Solution
Dose administration
Access
Indications
Mannitol 20 %
Bolus of 0.25–1.0 g/kg body weight as a single dose of repeated boluses q4-6 h
Peripheral IV
Saline 1.5 %
Continuous infusion with a target plasma sodium of 145–155 mmol/L 150-mL bolus or continuous infusion with a target plasma sodium of 145–155 mmol/L 30-mL bolus
Peripheral IV
Management of elevated ICP, emergent ICP reduction, herniation reversal Prevent serum hyposmolarity
Saline 3 % Saline 23.4 %
Central line Central line
Maintain serum hyperosmolarity, decrease edema formation Emergent ICP reduction, ICP refractory to mannitol, herniation reversal
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Curr Treat Options Neurol (2016) 18:9 A trend has emerged in neurocritical care favoring HTS over mannitol, but this preference is based on limited evidence. A retrospective meta-analysis performed in 2011 concluded that subjects receiving HTS have a 1.16 times better chance of ICP control than those receiving equimolar doses of mannitol, an absolute difference in ICP of only 2 mmHg [40]. If there is indeed a benefit to using HTS over mannitol, the effect size is very small. Safety, rather than limited data comparing mannitol to HTS, should be the paramount concern when choosing an osmotic agent for an individual patient. The side effect profiles of mannitol and hypertonic saline, along with the patient’s medical history, should be considered. For example, patients with congestive heart failure or poor cardiac output should receive mannitol, whereas HTS may be used to avoid dehydration in elderly or diabetic patients [34].
Surgical therapies Although the surgical trials of ICH have not shown clinical benefit, preclinical data have suggested that minimally invasive evacuation of blood products after ICH could reduce secondary injury and improve outcomes. A recent review of the Minimally Invasive Surgery Plus Rt-PA for ICH Evacuation (MISTIE) II cohort revealed that edema volume after intervention was significantly smaller in the surgical group than in the medical group [41••]. Furthermore, a positive correlation was identified between the percentage of ICH removed and the reduction in PHE, providing strong evidence that hematoma removal prevents edema development [41••]. The study also concluded that PHE does not seem to be exacerbated by Rt-PA and that it may be useful in clot removal [41••]. MISTIE III, a 500-patient phase III randomized clinical trial, is ongoing [42]. For life-threatening edema that is refractory to osmotherapy, decompressive craniectomy (DC) may be considered. After the results of the DESTINY, DECIMAL, and HAMLET trials, DC has been accepted as a lifesaving intervention for malignant edema after ischemic stroke [43]. The same quality of evidence does not yet exist for DC after ICH, but some observational studies have shown reduced mortality in patients receiving DC without clot removal [44–47]. The experience in malignant edema after ischemic stroke has informed the design of a large randomized control trial, Swiss Trial of Decompressive Craniectomy Versus Best Medical Treatment of Spontaneous Supratentorial Intracerebral Hemorrhage (SWITCH) [48]. This study will compare DC within 72 h of ICH to the best medical management in 300 subjects with large basal ganglia hemorrhages (≥30 and ≤100 mL). The primary endpoint is mRS at 6 months, where a poor outcome is defined as mRS ≥ 5. The potential limitations of this study include a broad population of very large basal ganglia and thalamic ICHs that may extend into the cerebral lobes, the ventricles, or the subarachnoid space. Initial hemorrhage volume is the most powerful predictor of outcome and may mask the effects of decompression [1]. As such, the decision to perform DC in clinical practice
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would remain unclear and would need to be guided by thoughtful discussions among physicians and patients and families.
Therapeutic hypothermia Therapeutic hypothermia may treat edema by modulating the inflammatory pathways following ICH. Fever and hyperthermia after ICH are associated with early neurologic deterioration and a worse outcome [10•]. This led to the hypothesis that reducing the body temperature may lead to better outcomes. In support of this principle, a review of 250 ICH patients in the INTERACT1 cohort found a positive association between ambient temperature and perihematomal edema volume [49]. Experimental evidence has shown that hypothermia may be neuroprotective in animal models of brain injury [50, 51]. These results were corroborated in a case-control study of 12 patients with large ICH who received therapeutic cooling to 35 °C for 10 days by endovascular cooling [52]. The results show that mild hypothermia may prevent edema progression after ICH compared to controls (P = 0.035) and may further reduce mortality in the acute phase and also at 1 year [53]. A similar study of 25 patients with large ICH treated with mild hypothermia also demonstrated slowed edema progression, reduced mortality, and improved functional recovery at 1 year [54]. Pneumonia was a common adverse event in these studies but was manageable in all cases. The promising results of these pilot studies prompted the development of two randomized clinical trials assessing the safety and efficacy of therapeutic hypothermia and targeted temperature management after ICH. In 2013, Cooling in Intracerebral Hemorrhage (CINCH) completed enrollment and randomization of 50 subjects to either mild hypothermia (35 °C) for 8 days or conventional temperature management [55]. The results have not yet been released. Targeted Temperature Management After ICH (TTM-ICH) began enrolling in 2014 and is designed to randomize 50 subjects to either moderate hypothermia (32–34 °C) for 72 h or targeted temperature management to normothermia (36–37 °C) using endovascular or surface cooling [56]. Results from these trials will be forthcoming.
Anti-inflammatory therapies Experimental studies have led to advances in our understanding of the etiology of PHE and have identified several agents that appear capable of modulating brain inflammation in response to ICH and thereby ameliorating the development of PHE. Many of these therapies reflect the ongoing shift in ICH research from reactive to preventative therapies. New treatments that prevent edema formation aim to avoid further deterioration, ICP crisis, and the need for interventions such as osmotic therapy or surgical decompression. These agents and other preventative therapies are currently being evaluated in clinical trials are summarized in Table 2. Deferoxamine Deferoxamine is an iron chelator that has been shown to reduce edema and improve outcomes in experimental models of ICH [16, 57, 58]. A meta-analysis
Pioglitazone
Minimally invasive surgery plus tPA for hematoma removal Mild hypothermia (35 °C for 8 days) Moderate hypothermia (32–34 °C for 72 h) Normothermia
Decompressive craniectomy
Decompressive craniectomy after hematoma removal
Minocycline (400 mg for 5 days)
August 2009
December 2013
January 2013
March 2014
October 2014
October 2014
February 2013
January 2011
Deferoxamine
October 2014
IntracerebralHemorrhage Deferoxamine (iDEF) Phase II [59] Safety of Pioglitazone for Hematoma Resolution in Intracerebral Hemorrhage (SHRINC) Phase II [68] Minimally Invasive Surgery plus Tt-PA for ICH Evacuation (MISTIE III) Phase III [42] Cooling in Intracerebral Hemorrhage (CINCH)108 Phase II [55] Targeted Temperature Management After ICH (TTM-ICH) Phase II [56] Systemic Normothermia in Intracerebral Hemorrhage (SNICH) [74] Decompressive Hemicraniectomy in Intracerebral Hemorrhage (SWITCH) [48] Decompressive Craniectomy After Removing Hematoma to Treat Intracerebral Hemorrhage (CARICH) [75] A Pilot Study of Minocycline in Intracerebral Hemorrhage Patients (MACH) [76]
Intervention
Start date
Trial
Table 2. Ongoing clinical trials targeting edema or secondary injury after ICH
ICH volume
180 day mRS (poor outcome ≥4)
Occurrence of second surgery
90-day mRS (poor outcome ≥ 3)
Safety
Mortality, functional outcomes, quality of life
180-day mRS (poor outcome ≥ 5)
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90 day mRS
Functional and cognitive outcomes, serum cytokines
Functional outcome, hematoma and PHO growth
Relative PHE growth from baseline to day 5
Serious adverse events
30-day mortality, ICH and PHE volume
Safety, functional outcome
Safety, early vs late treatment, cognitive function, PHE growth Safety, functional outcome, PHE and ICH resolution
90-day mRS (poor outcome ≥ 3)
Mortality at discharge
Secondary endpoints
Primary endpoint
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Page 9 of 14 9 of deferoxamine treatment in animal models of ICH showed a reduction in brain water content by 85.7 % and improved neurobehavioral scores. Deferoxamine was most efficacious when administered early after ICH, but the benefit remained for up to 24 h postinjury [57]. Deferoxamine is currently being evaluated for ICH in the Intracerebral Hemorrhage Deferoxamine (iDEF) clinical trial, in which the primary endpoint is the proportion of subjects with an mRS of 0–2 at 90 days [59]. iDEF aims to randomize 324 patients with spontaneous ICH to either deferoxamine or placebo within 24 h of ICH onset.
Fingolimod
Fingolimod inhibits the egress of lymphocytes from peripheral lymphoid tissues and prevents their recirculation, decreasing the amount of circulating immune cells available to enter the brain [60]. Fingolimod also has a direct effect on astrocytes, which play an important role in the inflammatory response to ICH [61, 62]. Modulation of the inflammatory response following ICH by fingolimod may be a promising therapy to reduce PHE and improve the outcome. A pilot RCT of 23 subjects with small to moderate ICH showed that fingolimod is safe, may reduce PHE at day 7 (47 vs 108 mL, P = 0.04), and may attenuate neurologic deficits at 90 days, as measured by the percentage of subjects with an mRS of 0–1 (63 vs 0 %; P = 0.001) [60, 63].
Celecoxib
Celecoxib is a selective COX2 inhibitor that is used widely for its antiinflammatory properties. Celecoxib has been shown to reduce PHE and promote functional recovery in experimental models of ICH [64]. A case-control study in 2009 showed that celecoxib given within 48 h of spontaneous ICH reduced edema volume (P = 0.027) [65]. A pilot RCT (ACE-ICH) of 44 subjects showed that treatment with celecoxib within 24 h of ICH is associated with a smaller number of patients with expansion of PHE from baseline to 7 days [66]. Larger studies are needed to corroborate these findings.
Pioglitazone
Pioglitazone is a PPAR-γ agonist found in microglia and macrophages that plays a role in promoting phagocytosis. Pioglitazone may downregulate inflammatory mediators and reduce tissue damage arising from the generation of reactive oxygen species. Preclinical data have shown that PPAR-γ agonists may promote hematoma resolution through stimulated phagocytosis as well as reduce edema [67]. A prospective, randomized safety study evaluating Pioglitazone for ICH (Safety of Pioglitazone for Hematoma Resolution in Intracerebral Hemorrhage [SHRINC]) is ongoing [68].
Statins
A number of retrospective studies have implicated statins as a neuroprotective agent in the setting of ICH. It has been suggested that statins play a role in stabilizing the BBB and may decrease edema [69]. A retrospective study found that prior statin use is associated with a reduction in perihematomal edema associated with ICH [69]. Furthermore, a nonrandomized clinical pilot study indicated that the use of statins during the acute phase of ICH could be associated with a better outcome [70]. A recent meta-analysis of 17 studies evaluating the outcomes in patients with ICH and statin use reports a risk reduction of acute mortality in subjects exposed to statins (OR 0.73; 95 % CI 0.54–0.97) [71]. A reduction in mortality with continuation of statin use after ICH has also been suggested (OR 0.14; 95 % CI 0.1–0.2) [71]. Randomized controlled trials are needed to further investigate the effects of statin use for ICH.
However, as was the case with many neuroprotectant trials for ischemic stroke, it still remains a question if the anti-inflammatory agents proposed for ICH can be clinically tested in a way that will demonstrate significant benefit [72]. The pleiotropic and partially overlapping nature of the processes contributing to the development of secondary injury associated with ICH makes it
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unlikely that interventions targeting one molecule or pathway will have a significant impact on the outcome after ICH. However, further research into the timing of the molecular pathophysiology of edema formation may improve our ability to identify new targets and treatment strategies. For example, the progressive stages of edema formation may have different molecular drivers, and, therefore, different therapies may work optimally at distinct time intervals [21, 28, 73]. The results of ongoing clinical trials such as iDEF and SHRINC should provide insights into optimal trial design and the choice of outcome measures to best show the true effects of these drugs.
Conclusions There is increasing evidence that PHE after ICH has an impact on the clinical outcome and therefore is a potential target for pharmacotherapeutic intervention. The current management of PHE almost exclusively relies on osmotic therapies despite a lack of evidence that using these agents improves clinical outcomes. Advances in basic and translational research have identified novel genes and pathways that, when targeted, might limit the development of PHE. Hemorrhagic stroke still awaits a similar golden age of research that has benefitted ischemic stroke; however, recent investigations of PHE are promising as new approaches for treatment have shifted from reactive to protective measures. Novel therapies that aim to reduce PHE, and thereby ameliorate secondary injury and promote functional recovery, may be the next major advances in the treatment of ICH.
Acknowledgments A special thank you is given to Dr. Myrna Rosenfeld for taking the time to review this paper.
Compliance with Ethical Standards Conflict of Interest Audrey Leasure, Kristopher T. Kahle, and Golo Kronenberg each declare no potential conflicts of interest. W. Taylor Kimberly reports grants from the National Institutes of Health-NINDS, American Heart Association, and Remedy Pharmaceuticals, Inc. Lauren H. Sansing reports grants from the National Institutes of Health. Hagen Kunte reports personal compensation for speaking from Bayer, Biogen, Genzyme, Novartis, Merck Serono, and Teva. J. Marc Simard has Patent 7,285,574 with royalties paid by Remedy Pharmaceuticals. Kevin N. Sheth reports grants from Remedy Pharmaceuticals, Inc. Dr. Sheth is a section editor of Current Treatment Options in Neurology. Human and Animal Rights and Informed Consent This article does not contain any studies with human participants or animals performed by any of the authors.
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References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.
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10.•
Lord AS, Gilmore E, Choi HA, Mayer SA. Time course and predictors of neurological deterioration after intracerebral hemorrhage. Stroke. 2015;46(3):647–52. doi:10.1161/strokeaha.114.007704. This study implicates edema as a driver of neurologic deterioration after ICH in the 24–72 h window. 11. Kamel H, Hemphill 3rd JC. Characteristics and sequelae of intracranial hypertension after intracerebral hemorrhage. Neurocrit Care. 2012;17(2):172–6. doi:10.1007/s12028-012-97447. 12.• Murthy SB, Moradiya Y, Dawson J, Lees KR, Hanley DF, Ziai WC. Perihematomal edema and functional outcomes in intracerebral hemorrhage: influence of hematoma volume and location. Stroke. 2015;46(11):3088–92. doi:10.1161/strokeaha.115. 010054. This study uses a large sample size to demonstrate that PHE expansion in the first 72 hours after ICH is associated with worse outcomes in basal ganglia ICH after adjusting for hematoma volume. This study corroborates previous findings and strengthens the argument that PHE has a clinically significant impact on outcome and is a potential target for therapeutic intervention. 13.• Volbers B, Willfarth W, Kuramatsu JB, Struffert T, Dorfler A, Huttner HB et al. Impact of perihemorrhagic edema on short-term outcome after intracerebral hemorrhage. Neurocritical Care. 2015. doi:10.1007/ s12028-015-0185-y. This study demonstrates, in a large sample size and over a longer period of follow-up, that peak PHE volume, rather than PHE growth, may be a predictor of short-term functional outcome at discharge. These findings corroborate data supporting the role of PHE in determining outcomes after ICH and argues that PHE may be a clinically relevant treatment target. 14.•• Yang J, Arima H, Wu G, Heeley E, Delcourt C, Zhou J, et al. Prognostic significance of perihematomal edema in acute intracerebral hemorrhage: pooled analysis from the intensive blood pressure reduction in acute cerebral hemorrhage trial studies. Stroke. 2015;46D4]:1009–13. doi:10.1161/strokeaha.114. 007154. This large study provides evidence of an independent association between the growth of edema after ICH and a poor outcome. Together with 12 and 13, this paper helps to clarify the impact of edema on the outcome and strengthens the argument for the investigation of strategies for attenuating PHE growth. 15. Urday S, Beslow LA, Goldstein DW, Vashkevich A, Ayres AM, Battey TW, et al. Measurement of
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perihematomal edema in intracerebral hemorrhage. Stroke. 2015;46(4):1116–9. doi:10.1161/strokeaha. 114.007565. 16. Ziai WC. Hematology and inflammatory signaling of intracerebral hemorrhage. Stroke. 2013;44(6 Suppl 1):S74–8. doi:10.1161/strokeaha.111.000662. 17.• Urday S BL, Dai F, Zheng F, Battey TWK, Vashkevich A, Ayres A, Selim MH, Simard JM, Rosand J, Kimberly WT, Sheth KN. Rate of peri-hematomal edema expansion predicts outcome after intracerebral hemorrhage. In Press. 2015. This paper provides a new index of edema, PHE expansion rate, and shows that PHE expansion rate predicts the outcome after ICH. Along with 12, 13, and 14, the data from this paper support PHE as an independent predictor of the outcome in the controversial debate on the role of edema in ICH. 18. Parry-Jones AR, Wang X, Sato S, Mould WA, Vail A, Anderson CS, et al. Edema extension distance: outcome measure for phase II clinical trials targeting edema after intracerebral hemorrhage. Stroke. 2015;46(6):e137– 40. doi:10.1161/strokeaha.115.008818. 19. Appelboom G. Volume-dependent effect of perihaematomal oedema on outcome for spontaneous intracerebral haemorrhages. J Neurol Neurosurg Psychiatry. 2013;84:488–93. 20. Sun W, Pan W, Kranz PG, Hailey CE, Williamson RA, Sun W, et al. Predictors of late neurological deterioration after spontaneous intracerebral hemorrhage. Neurocrit Care. 2013;19(3):299–305. doi:10.1007/ s12028-013-9894-2. 21. Staykov D. Natural course of perihemorrhagic edema after intracerebral hemorrhage. Stroke. 2011;42:2625–9. 22. Sansing LH, Messe SR, Cucchiara BL, Lyden PD, Kasner SE. Anti-adrenergic medications and edema development after intracerebral hemorrhage. Neurocrit Care. 2011;14:395–400. 23. Li YH, Wang JB, Li MH, Li WB, Wang D. Quantification of brain edema and hemorrhage by MRI after experimental traumatic brain injury in rabbits predicts subsequent functional outcome. Neurol Sci. 2012;33(4):731–40. doi:10.1007/s10072-011-0768-0. 24. Arima H. Significance of perihematomal edema in acute intracerebral hemorrhage: the INTERACT trial. Neurology. 2009;73:1963–8. 25. Ziai W, Moullaali T, Nekoovaght-Tak S, Ullman N, Brooks JS, Morgan TC, et al. No exacerbation of perihematomal edema with intraventricular tissue plasminogen activator in patients with spontaneous intraventricular hemorrhage. Neurocrit Care. 2013;18(3):354–61. doi:10.1007/s12028-013-9826-1. 26. Zhao X, Zhang Y, Strong R, Zhang J, Grotta JC, Aronowski J. Distinct patterns of intracerebral hemorrhage-induced alterations in NF-kappaB subunit, iNOS, and COX-2 expression. J Neurochem. 2007;101(3):652–63. doi:10.1111/j.1471-4159.2006. 04414.x. 27. Zhang ZL, Liu YG, Huang QB, Wang HW, Song Y, Xu ZK, et al. Nuclear factor-kappaB activation in perihematomal brain tissue correlates with
Curr Treat Options Neurol (2016) 18:9 outcome in patients with intracerebral hemorrhage. J Neuroinflammation. 2015;12:53. doi:10. 1186/s12974-015-0277-9. 28. Gebel Jr JM. Relative edema volume is a predictor of outcome in patients with hyperacute spontaneous intracerebral hemorrhage. Stroke. 2002;33:2636–41. 29. Babu R, Bagley JH, Di C, Friedman AH, Adamson C. Thrombin and hemin as central factors in the mechanisms of intracerebral hemorrhage-induced secondary brain injury and as potential targets for intervention. Neurosurg Focus. 2012;32(4):E8. doi:10.3171/2012.1. focus11366. 30. Zheng GQ. Long-time course of protease-activated receptor-1 expression after intracerebral hemorrhage in rats. Neurosci Lett. 2009;459:62–5. 31. Gebel JM. Decreased perihematomal edema in thrombolysis-related intracerebral hemorrhage compared with spontaneous intracerebral hemorrhage. Stroke. 2000;31:596–600. 32. Xi G, Hua Y, Keep RF, Younger JG, Hoff JT. Systemic complement depletion diminishes perihematomal brain edema in rats. Stroke. 2001;32(1):162–7. 33. Zhou Y, Wang Y, Wang J, Anne Stetler R, Yang QW. Inflammation in intracerebral hemorrhage: from mechanisms to clinical translation. Prog Neurobiol. 2014;115:25–44. doi:10.1016/j.pneurobio.2013.11.003. 34. Ropper AH. Management of raised intracranial pressure and hyperosmolar therapy. Pract Neurol. 2014;14(3):152–8. doi:10.1136/practneurol-2014000811. 35. Tan G, Zhou J, Yuan D, Sun S. Formula for use of mannitol in patients with intracerebral haemorrhage and high intracranial pressure. Clin Drug Investig. 2008;28(2):81–7. 36. Koenig MA, Bryan M, Lewin 3rd JL, Mirski MA, Geocadin RG, Stevens RD. Reversal of transtentorial herniation with hypertonic saline. Neurology. 2008;70(13):1023–9. doi:10.1212/01.wnl. 0000304042.05557.60. 37. Diringer MN. New trends in hyperosmolar therapy? Curr Opin Crit Care. 2013;19(2):77–82. doi:10.1097/ MCC.0b013e32835eba30. 38. Wagner I. Effects of continuous hypertonic saline infusion on perihemorrhagic edema evolution. Stroke. 2011;42:1540–5. 39.• Wang X, Arima H, Yang J, Zhang S, Wu G, Woodward M et al. Mannitol and outcome in intracerebral hemorrhage: propensity score and multivariable Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 2 results. Stroke. 2015. doi:10.1161/ strokeaha.115.009357. This study found no significant difference in poor outcome between ICH patients who received mannitol and those who did not. This study shows that the most commonly used treatment strategy for edema is not associated with better outcomes and highlights the lack of evidence-based strategies for treatment of edema and ICP. 40. Kamel H, Navi BB, Nakagawa K, Hemphill 3rd JC, Ko NU. Hypertonic saline versus mannitol for the treatment
Curr Treat Options Neurol (2016) 18:9 of elevated intracranial pressure: a meta-analysis of randomized clinical trials. Crit Care Med. 2011;39(3):554– 9. doi:10.1097/CCM.0b013e318206b9be. 41.•• Mould WA. Minimally invasive surgery plus recombinant tissue-type plasminogen activator for intracerebral hemorrhage evacuation decreases perihematomal edema. Stroke. 2013;44:627–34. This study shows that minimally invasive surgery for hematomal evacuation significantly reduces PHE. 42. Barnes B, Hanley DF, Carhuapoma JR. Minimally invasive surgery for intracerebral haemorrhage. Curr Opin Crit Care. 2014;20(2):148–52. doi:10.1097/mcc. 0000000000000077. 43. Wijdicks EF, Sheth KN, Carter BS, Greer DM, Kasner SE, Kimberly WT, et al. Recommendations for the management of cerebral and cerebellar infarction with swelling: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45(4):1222–38. doi:10.1161/ 01.str.0000441965.15164.d6. 44. Ramnarayan R, Anto D, Anilkumar TV, Nayar R. Decompressive hemicraniectomy in large putaminal hematomas: An Indian experience. J Stroke Cerebrovasc Dis. 2009;18(1):1–10. doi:10.1016/j. jstrokecerebrovasdis.2008.09.001. 45. Fung C, Murek M, Z’Graggen WJ, Krahenbuhl AK, Gautschi OP, Schucht P, et al. Decompressive hemicraniectomy in patients with supratentorial intracerebral hemorrhage. Stroke. 2012;43(12):3207–11. doi:10.1161/strokeaha.112.666537. 46. Heuts SG, Bruce SS, Zacharia BE, Hickman ZL, Kellner CP, Sussman ES, et al. Decompressive hemicraniectomy without clot evacuation in dominant-sided intracerebral hemorrhage with ICP crisis. Neurosurg Focus. 2013;34(5), E4. doi:10.3171/ 2013.2.focus1326. 47. Esquenazi Y, Savitz SI, El Khoury R, McIntosh MA, Grotta JC, Tandon N. Decompressive hemicraniectomy with or without clot evacuation for large spontaneous supratentorial intracerebral hemorrhages. Clin Neurol Neurosurg. 2015;128:117–22. doi:10.1016/j.clineuro. 2014.11.015. 48. Beck J. Decompressive Hemicraniectomy in Intracerebral Hemorrhage (SWITCH). ClinicalTrials.gov. 2014. https://clinicaltrials.gov/ ct2/show/NCT02258919. 49. Zheng D, Arima H, Heeley E, Karpin A, Yang J, Chalmers J, et al. Ambient temperature and volume of perihematomal edema in acute intracerebral haemorrhage: the INTERACT1 study. Int J Stroke. 2015;10(1):25–7. doi:10.1111/ijs.12389. 50. Kawanishi M, Kawai N, Nakamura T, Luo C, Tamiya T, Nagao S. Effect of delayed mild brain hypothermia on edema formation after intracerebral hemorrhage in rats. J Stroke Cerebrovasc Dis. 2008;17(4):187–95. doi:10.1016/j.jstrokecerebrovasdis.2008.01.003. 51. Wei S, Sun J, Li J, Wang L, Hall CL, Dix TA, et al. Acute and delayed protective effects of pharmacologically induced hypothermia in an intracerebral hemorrhage
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Critical Care Neurology (K Sheth, Section Editor)
Treatment of Edema Associated With Intracerebral Hemorrhage Audrey Leasure, BS1,* W. Taylor Kimberly, MD, PhD2 Lauren H. Sansing, MD, MS1 Kristopher T. Kahle, MD, PhD3 Golo Kronenberg, MD4 Hagen Kunte, MD4 J. Marc Simard, MD, PhD5 Kevin N. Sheth, MD1 Address *,1 Department of Neurology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA Email: [email protected] 2 Department of Neurology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA 3 Yale Program on Neurogenetics, Department of Neurosurgery and Pediatrics, 333 Cedar Street, New Haven, CT, 06510, USA 4 Department of Neurology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany 5 Department of Neurosurgery, University of Maryland School of Medicine, 22 South Greene Street, Baltimore, MD, 21201-1559, USA
* Springer Science+Business Media New York 2016
This article is part of the Topical Collection on Critical Care Neurology Keywords Intracerebral hemorrhage I Perihematomal edema I Secondary brain injury I Hyperosmolar therapy I ICP
Opinion statement Cerebral edema (i.e., Bbrain swelling^) is a common complication following intracerebral hemorrhage (ICH) and is associated with worse clinical outcomes. Perihematomal edema (PHE) accumulates during the first 72 h after hemorrhage, and during this period, patients are at risk of clinical deterioration due to the resulting tissue shifts and brain herniation. First-line medical therapies for patients symptomatic of PHE include osmotic agents, such as mannitol in low- or high-dose bolus form, or boluses of hypertonic saline (HTS) at varied concentrations with or without subsequent continuous infusion. Decompressive craniectomy may be required for symptomatic edema refractory to osmotherapy. Other
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strategies that reduce PHE such as hypothermia and minimally invasive surgery have shown promise in pilot studies and are currently being evaluated in larger clinical trials. Ongoing basic, translational, and clinical research seek to better elucidate the pathophysiology of PHE to identify novel strategies to prevent edema formation as a next major advance in the treatment of ICH.
Introduction Intracerebral hemorrhage (ICH) remains a devastating disease with limited treatment options. The 30-day mortality rate for spontaneous ICH is as high as 50 %, and only 20 % of those surviving regain functional independence [1]. There are several potential mechanisms by which ICH leads to acute brain injury. The main focus of recent randomized controlled trials has been on reversing or attenuating the mechanical effects of the hematoma by limiting hematoma growth or evacuating the hematoma entirely. The Surgical Trial in Intracerebral Hemorrhage (STICH) trials tested whether hematoma evacuation through an open neurosurgical approach would reduce disability, but there was no beneficial effect on the outcome [2, 3]. Similarly, the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage (INTERACT) trials aiming to prevent hematoma expansion were inconclusive [4]. While INTERACT1 showed reduced hematoma growth after intensive blood pressure lowering, the larger INTERACT2 trial failed to show a reduction in death or disability [5, 6]. Although a promising clinical efficacy signal was present in INTERACT2, it was not mediated by hematoma growth, and the effect size was small. The North American counterpart of the INTERACT trials, Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) II, has recently stopped and the results are awaited [7]. However, hematoma expansion through hypertension may not be a robust treatment target, and it is unknown if blood pressure reduction in the field will improve clinical outcomes. As such, an investigation of new treatment options is warranted. In addition to ongoing investigations into attenuating the mechanical effects of ICH, a more recently recognized form of secondary injury after ICH that has therapeutic potential is perihematomal edema (PHE). PHE is initiated by the brain’s physiologic response to the primary injury [8] and develops in the days to weeks following ICH, providing a wider window for intervention than primary injury [9]. Patients who develop edema are at risk of neurologic deterioration and may benefit from therapies directed at preventing edema
formation [10•]. However, PHE does not occur in isolation. Indeed, many of the processes contributing to, and resulting from, edema may also cause hydrocephalus, mass effect, midline shift, and increased intracranial pressure (ICP), as depicted in Fig. 1. As such, treatment strategies to prevent and manage edema may also modulate ICP, hydrocephalus, or other related pathologic processes. Current strategies for management of edema after ICH focus on treating elevated ICP. However, the incidence of elevated ICP after ICH and the outcomes of treatment are uncertain. One retrospective study found that episodes of elevated ICP were common among ICH patients receiving ICP monitoring, but that there was no association between the frequency of these events and the functional outcome at 1 year [11]. Based on current evidence, the decision to monitor and treat ICP after ICH remains unclear. However, increasing evidence suggests that PHE has an independent association with a poor outcome and targeted edema treatment strategies should be investigated [12•, 13•, 14••]. Progressive edema in the days after injury contributes to the mass effect of the hematoma, resulting in tissue shifts and herniation, which are responsible for delayed neurologic deterioration and increased mortality [13•].
Fig.1. Relationships between processes contributing to and resulting from edema.
Curr Treat Options Neurol (2016) 18:9 Independent of mass effect, edema as demonstrated on CT or MRI is a useful surrogate marker of secondary brain injury that may impede functional recovery. The volume of PHE is suggested to reflect the extent of secondary brain damage caused by inflammatory processes [8, 15, 16] and therefore may be a useful endpoint in clinical trials. Novel methods of quantifying edema, such as edema
Page 3 of 14 9 expansion rate [15, 17•] and edema extension distance [18], may facilitate phase II clinical trials that focus on reduction of edema, potentially with smaller sample sizes. These new methods of measuring PHE, coupled with an improved understanding of the molecular pathophysiology of edema, have created a unique opportunity to develop innovative treatment strategies
PHE and outcome: why focus on PHE as a therapeutic target? With the development of new therapies directed at edema, the question of whether edema has an effect on the clinical outcome is important. Retrospective studies have produced conflicting results, with some arguing that edema is an independent predictor of a poor outcome and others suggesting that edema has no effect, or even a positive effect, on the outcome [19–23]. Variations in study populations, edema measurement techniques, or the time course used to evaluate edema may account for these differences. The largest study to report no association between PHE growth and the 90day outcome was a retrospective study in 2009 of 270 subjects in the INTERACT1 cohort [24]. This study found a significant association between absolute and relative edema growth and death or dependency at 90 days, but this association did not persist after adjustment for baseline hematoma volume [24]. However, in 2015 the same group conducted a larger analysis of 1138 INTERACT1 and INTERACT2 cohort subjects with small to moderate, deep ICH [14••]. The absolute growth in PHE volume during the first 24 h after ICH was significantly associated with death or dependency at 90 days, defined as a modified Rankin scale (mRS) of 3–6, after adjustment for prognostic factors (1.17; 95 % confidence interval, 1.02–1.33 per 5 mL increase from baseline; P = 0.025) [14••]. The prognostic significance of edema growth is further supported by a recent review of 596 ICH patients that explored the association between iPHE, defined as PHE volume expansion within the first 72 h after ICH, and the functional outcome at 90 days [12•]. This study found that the odds of a poor outcome (mRS ≥ 3) increased with iPHE (OR 1.78; CI 1.12–2.64 per mL increase) [12•]. A subgroup analysis of these data by baseline ICH volume corroborates previous findings that iPHE was related only to poor functional outcomes in small (G30 mL) ICH [19]. Interestingly, this study also suggested that ICH location may influence the relationship between PHE and the outcome. A significant association was found between iPHE and functional outcomes in basal ganglia ICH, but not in lobar ICH [12•]. A similar relationship has been observed between PHE and the functional outcome at discharge. A recent review of 220 subjects with a mean admission ICH volume of 22.7 cm3 showed a negative effect of peak absolute PHE volume on the functional outcome at discharge (OR 0.977; 95 % CI 0.957–0.998, P = 0.03) [13•]. The odds of a poor outcome were found to increase by 2 % for every additional millimeter of PHE [13•].
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In light of these new findings that demonstrate an association between edema and poorer outcome, PHE requires further investigation as a therapeutic target for ICH.
Pathophysiology of edema formation PHE is a result of many inflammatory pathways activated in response to injury, and new therapies to ameliorate PHE may act at various stages during edema development. Immediately after ICH, the process of clot retraction extrudes serum proteins from the hematoma into the interstitium. This movement of osmoles produces an osmotic gradient that draws water into the interstitium prior to any blood-brain barrier (BBB) disruption [9]. Following this phase of ionic edema, three intersecting pathways of secondary injury contribute to vasogenic edema: inflammation, thrombin production, and erythrocyte lysis [9, 25].
&
&
&
Neutrophils and macrophages infiltrate the perihematomal tissue after ICH and trigger a robust inflammatory response [26]. Upregulated NF-κB stimulates the production of inflammatory cytokines that mediate the progressive breakdown of the BBB and induce the formation of vasogenic edema, the fluid movement out of the intravascular space into the surrounding tissue [9]. NF-κB activation is closely related to the clinical outcome at 6 months post-ICH in humans [27]. However, the full effects of inflammation are still unknown, as some have theorized that early inflammation and edema may promote brain recovery and improve outcomes [28]. Thrombin is activated in the area of injury soon after hemorrhage to limit bleeding and is thought to be neuroprotective at low concentrations [8]. However, thrombin is also a potent proinflammatory agent, and at the high concentrations present after ICH, it may promote BBB disruption, neuronal damage, and inflammatory cell infiltration [16]. The activation of the coagulation cascade in the surrounding tissue then activates resident microglia that secrete inflammatory factors and contribute to PHE [8]. Thrombin also mediates secondary injury through activation of protease-activated receptors (PARs), which are upregulated after ICH and may play a role in edema formation [29, 30]. The role of thrombin in edema formation is further supported by the finding that warfarin-related ICH results in less edema than spontaneous ICH [31]. Complement cascade proteins also enter the perihematomal tissue through the disrupted BBB [8]. The activation of these proteins, in part by thrombin, causes microglial activation, erythrocyte lysis, and the release of hemoglobin and iron into the surrounding tissue [32, 33]. Iron and hemoglobin degradation products are neurotoxic and promote secondary injury. Iron’s toxicity is thought to be mediated
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through the generation of free radicals, leading to further BBB disruption and edema [8].
Medical therapies Hyperosmolar therapy is the main medical strategy in the treatment of edema. Hypertonic solutions establish an osmotic gradient between the interstitial fluid and the vascular compartments, drawing water out of the brain and into the vasculature to reduce cerebral volume. Mannitol and HTS are the osmotic agents of choice as they do not readily cross an intact BBB [34]. These agents can be given in various solutions as boluses for rapid ICP reduction or, in the case of hypertonic saline, as a continuous infusion to mitigate edema formation, although there is a relative paucity of data on the comparative efficacy of various administration strategies [34]. Common methods of administration are summarized in Table 1. The rapid effects of bolus therapy are well supported. Mannitol has been shown to work in a dose- and location-dependent manner, with the greatest ICP reductions in patients with supratentorial hemorrhages [35]. Retrospective cohorts have even shown the ability of 23.4 % HTS boluses to reverse transtentorial herniation after a nontraumatic brain injury [36]. The indication is less clear for continuous infusion of HTS. In theory, the therapeutic effects of hyperosmolar therapy are expected to be transient due to the brain’s adaptation to osmotic gradients [37]. However, one study demonstrated that early continuous infusion of 3 % HTS reduced both relative and absolute edema after large ICH for up to 14 days compared to controls [38]. The retrospective nature and small sample size (26 subjects receiving HTS) of this study limit the generalizability of the results. Although the short-term effects of mannitol and HTS are well established, their ultimate effects on the clinical outcome are unclear. A recent review of the INTERACT2 cohort of 2526 ICH subjects concluded that mannitol therapy does not affect the poor outcome at 90 days, defined as a modified Rankin scale score of 3–6 [39•]. Interestingly, a trend toward better outcomes in those with larger hematoma volumes was seen, suggesting that there may still be a relevant therapeutic effect on the outcome in certain patient populations [39•].
Table 1. Hypertonic solutions Solution
Dose administration
Access
Indications
Mannitol 20 %
Bolus of 0.25–1.0 g/kg body weight as a single dose of repeated boluses q4-6 h
Peripheral IV
Saline 1.5 %
Continuous infusion with a target plasma sodium of 145–155 mmol/L 150-mL bolus or continuous infusion with a target plasma sodium of 145–155 mmol/L 30-mL bolus
Peripheral IV
Management of elevated ICP, emergent ICP reduction, herniation reversal Prevent serum hyposmolarity
Saline 3 % Saline 23.4 %
Central line Central line
Maintain serum hyperosmolarity, decrease edema formation Emergent ICP reduction, ICP refractory to mannitol, herniation reversal
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Curr Treat Options Neurol (2016) 18:9 A trend has emerged in neurocritical care favoring HTS over mannitol, but this preference is based on limited evidence. A retrospective meta-analysis performed in 2011 concluded that subjects receiving HTS have a 1.16 times better chance of ICP control than those receiving equimolar doses of mannitol, an absolute difference in ICP of only 2 mmHg [40]. If there is indeed a benefit to using HTS over mannitol, the effect size is very small. Safety, rather than limited data comparing mannitol to HTS, should be the paramount concern when choosing an osmotic agent for an individual patient. The side effect profiles of mannitol and hypertonic saline, along with the patient’s medical history, should be considered. For example, patients with congestive heart failure or poor cardiac output should receive mannitol, whereas HTS may be used to avoid dehydration in elderly or diabetic patients [34].
Surgical therapies Although the surgical trials of ICH have not shown clinical benefit, preclinical data have suggested that minimally invasive evacuation of blood products after ICH could reduce secondary injury and improve outcomes. A recent review of the Minimally Invasive Surgery Plus Rt-PA for ICH Evacuation (MISTIE) II cohort revealed that edema volume after intervention was significantly smaller in the surgical group than in the medical group [41••]. Furthermore, a positive correlation was identified between the percentage of ICH removed and the reduction in PHE, providing strong evidence that hematoma removal prevents edema development [41••]. The study also concluded that PHE does not seem to be exacerbated by Rt-PA and that it may be useful in clot removal [41••]. MISTIE III, a 500-patient phase III randomized clinical trial, is ongoing [42]. For life-threatening edema that is refractory to osmotherapy, decompressive craniectomy (DC) may be considered. After the results of the DESTINY, DECIMAL, and HAMLET trials, DC has been accepted as a lifesaving intervention for malignant edema after ischemic stroke [43]. The same quality of evidence does not yet exist for DC after ICH, but some observational studies have shown reduced mortality in patients receiving DC without clot removal [44–47]. The experience in malignant edema after ischemic stroke has informed the design of a large randomized control trial, Swiss Trial of Decompressive Craniectomy Versus Best Medical Treatment of Spontaneous Supratentorial Intracerebral Hemorrhage (SWITCH) [48]. This study will compare DC within 72 h of ICH to the best medical management in 300 subjects with large basal ganglia hemorrhages (≥30 and ≤100 mL). The primary endpoint is mRS at 6 months, where a poor outcome is defined as mRS ≥ 5. The potential limitations of this study include a broad population of very large basal ganglia and thalamic ICHs that may extend into the cerebral lobes, the ventricles, or the subarachnoid space. Initial hemorrhage volume is the most powerful predictor of outcome and may mask the effects of decompression [1]. As such, the decision to perform DC in clinical practice
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would remain unclear and would need to be guided by thoughtful discussions among physicians and patients and families.
Therapeutic hypothermia Therapeutic hypothermia may treat edema by modulating the inflammatory pathways following ICH. Fever and hyperthermia after ICH are associated with early neurologic deterioration and a worse outcome [10•]. This led to the hypothesis that reducing the body temperature may lead to better outcomes. In support of this principle, a review of 250 ICH patients in the INTERACT1 cohort found a positive association between ambient temperature and perihematomal edema volume [49]. Experimental evidence has shown that hypothermia may be neuroprotective in animal models of brain injury [50, 51]. These results were corroborated in a case-control study of 12 patients with large ICH who received therapeutic cooling to 35 °C for 10 days by endovascular cooling [52]. The results show that mild hypothermia may prevent edema progression after ICH compared to controls (P = 0.035) and may further reduce mortality in the acute phase and also at 1 year [53]. A similar study of 25 patients with large ICH treated with mild hypothermia also demonstrated slowed edema progression, reduced mortality, and improved functional recovery at 1 year [54]. Pneumonia was a common adverse event in these studies but was manageable in all cases. The promising results of these pilot studies prompted the development of two randomized clinical trials assessing the safety and efficacy of therapeutic hypothermia and targeted temperature management after ICH. In 2013, Cooling in Intracerebral Hemorrhage (CINCH) completed enrollment and randomization of 50 subjects to either mild hypothermia (35 °C) for 8 days or conventional temperature management [55]. The results have not yet been released. Targeted Temperature Management After ICH (TTM-ICH) began enrolling in 2014 and is designed to randomize 50 subjects to either moderate hypothermia (32–34 °C) for 72 h or targeted temperature management to normothermia (36–37 °C) using endovascular or surface cooling [56]. Results from these trials will be forthcoming.
Anti-inflammatory therapies Experimental studies have led to advances in our understanding of the etiology of PHE and have identified several agents that appear capable of modulating brain inflammation in response to ICH and thereby ameliorating the development of PHE. Many of these therapies reflect the ongoing shift in ICH research from reactive to preventative therapies. New treatments that prevent edema formation aim to avoid further deterioration, ICP crisis, and the need for interventions such as osmotic therapy or surgical decompression. These agents and other preventative therapies are currently being evaluated in clinical trials are summarized in Table 2. Deferoxamine Deferoxamine is an iron chelator that has been shown to reduce edema and improve outcomes in experimental models of ICH [16, 57, 58]. A meta-analysis
Pioglitazone
Minimally invasive surgery plus tPA for hematoma removal Mild hypothermia (35 °C for 8 days) Moderate hypothermia (32–34 °C for 72 h) Normothermia
Decompressive craniectomy
Decompressive craniectomy after hematoma removal
Minocycline (400 mg for 5 days)
August 2009
December 2013
January 2013
March 2014
October 2014
October 2014
February 2013
January 2011
Deferoxamine
October 2014
IntracerebralHemorrhage Deferoxamine (iDEF) Phase II [59] Safety of Pioglitazone for Hematoma Resolution in Intracerebral Hemorrhage (SHRINC) Phase II [68] Minimally Invasive Surgery plus Tt-PA for ICH Evacuation (MISTIE III) Phase III [42] Cooling in Intracerebral Hemorrhage (CINCH)108 Phase II [55] Targeted Temperature Management After ICH (TTM-ICH) Phase II [56] Systemic Normothermia in Intracerebral Hemorrhage (SNICH) [74] Decompressive Hemicraniectomy in Intracerebral Hemorrhage (SWITCH) [48] Decompressive Craniectomy After Removing Hematoma to Treat Intracerebral Hemorrhage (CARICH) [75] A Pilot Study of Minocycline in Intracerebral Hemorrhage Patients (MACH) [76]
Intervention
Start date
Trial
Table 2. Ongoing clinical trials targeting edema or secondary injury after ICH
ICH volume
180 day mRS (poor outcome ≥4)
Occurrence of second surgery
90-day mRS (poor outcome ≥ 3)
Safety
Mortality, functional outcomes, quality of life
180-day mRS (poor outcome ≥ 5)
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90 day mRS
Functional and cognitive outcomes, serum cytokines
Functional outcome, hematoma and PHO growth
Relative PHE growth from baseline to day 5
Serious adverse events
30-day mortality, ICH and PHE volume
Safety, functional outcome
Safety, early vs late treatment, cognitive function, PHE growth Safety, functional outcome, PHE and ICH resolution
90-day mRS (poor outcome ≥ 3)
Mortality at discharge
Secondary endpoints
Primary endpoint
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Page 9 of 14 9 of deferoxamine treatment in animal models of ICH showed a reduction in brain water content by 85.7 % and improved neurobehavioral scores. Deferoxamine was most efficacious when administered early after ICH, but the benefit remained for up to 24 h postinjury [57]. Deferoxamine is currently being evaluated for ICH in the Intracerebral Hemorrhage Deferoxamine (iDEF) clinical trial, in which the primary endpoint is the proportion of subjects with an mRS of 0–2 at 90 days [59]. iDEF aims to randomize 324 patients with spontaneous ICH to either deferoxamine or placebo within 24 h of ICH onset.
Fingolimod
Fingolimod inhibits the egress of lymphocytes from peripheral lymphoid tissues and prevents their recirculation, decreasing the amount of circulating immune cells available to enter the brain [60]. Fingolimod also has a direct effect on astrocytes, which play an important role in the inflammatory response to ICH [61, 62]. Modulation of the inflammatory response following ICH by fingolimod may be a promising therapy to reduce PHE and improve the outcome. A pilot RCT of 23 subjects with small to moderate ICH showed that fingolimod is safe, may reduce PHE at day 7 (47 vs 108 mL, P = 0.04), and may attenuate neurologic deficits at 90 days, as measured by the percentage of subjects with an mRS of 0–1 (63 vs 0 %; P = 0.001) [60, 63].
Celecoxib
Celecoxib is a selective COX2 inhibitor that is used widely for its antiinflammatory properties. Celecoxib has been shown to reduce PHE and promote functional recovery in experimental models of ICH [64]. A case-control study in 2009 showed that celecoxib given within 48 h of spontaneous ICH reduced edema volume (P = 0.027) [65]. A pilot RCT (ACE-ICH) of 44 subjects showed that treatment with celecoxib within 24 h of ICH is associated with a smaller number of patients with expansion of PHE from baseline to 7 days [66]. Larger studies are needed to corroborate these findings.
Pioglitazone
Pioglitazone is a PPAR-γ agonist found in microglia and macrophages that plays a role in promoting phagocytosis. Pioglitazone may downregulate inflammatory mediators and reduce tissue damage arising from the generation of reactive oxygen species. Preclinical data have shown that PPAR-γ agonists may promote hematoma resolution through stimulated phagocytosis as well as reduce edema [67]. A prospective, randomized safety study evaluating Pioglitazone for ICH (Safety of Pioglitazone for Hematoma Resolution in Intracerebral Hemorrhage [SHRINC]) is ongoing [68].
Statins
A number of retrospective studies have implicated statins as a neuroprotective agent in the setting of ICH. It has been suggested that statins play a role in stabilizing the BBB and may decrease edema [69]. A retrospective study found that prior statin use is associated with a reduction in perihematomal edema associated with ICH [69]. Furthermore, a nonrandomized clinical pilot study indicated that the use of statins during the acute phase of ICH could be associated with a better outcome [70]. A recent meta-analysis of 17 studies evaluating the outcomes in patients with ICH and statin use reports a risk reduction of acute mortality in subjects exposed to statins (OR 0.73; 95 % CI 0.54–0.97) [71]. A reduction in mortality with continuation of statin use after ICH has also been suggested (OR 0.14; 95 % CI 0.1–0.2) [71]. Randomized controlled trials are needed to further investigate the effects of statin use for ICH.
However, as was the case with many neuroprotectant trials for ischemic stroke, it still remains a question if the anti-inflammatory agents proposed for ICH can be clinically tested in a way that will demonstrate significant benefit [72]. The pleiotropic and partially overlapping nature of the processes contributing to the development of secondary injury associated with ICH makes it
9
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unlikely that interventions targeting one molecule or pathway will have a significant impact on the outcome after ICH. However, further research into the timing of the molecular pathophysiology of edema formation may improve our ability to identify new targets and treatment strategies. For example, the progressive stages of edema formation may have different molecular drivers, and, therefore, different therapies may work optimally at distinct time intervals [21, 28, 73]. The results of ongoing clinical trials such as iDEF and SHRINC should provide insights into optimal trial design and the choice of outcome measures to best show the true effects of these drugs.
Conclusions There is increasing evidence that PHE after ICH has an impact on the clinical outcome and therefore is a potential target for pharmacotherapeutic intervention. The current management of PHE almost exclusively relies on osmotic therapies despite a lack of evidence that using these agents improves clinical outcomes. Advances in basic and translational research have identified novel genes and pathways that, when targeted, might limit the development of PHE. Hemorrhagic stroke still awaits a similar golden age of research that has benefitted ischemic stroke; however, recent investigations of PHE are promising as new approaches for treatment have shifted from reactive to protective measures. Novel therapies that aim to reduce PHE, and thereby ameliorate secondary injury and promote functional recovery, may be the next major advances in the treatment of ICH.
Acknowledgments A special thank you is given to Dr. Myrna Rosenfeld for taking the time to review this paper.
Compliance with Ethical Standards Conflict of Interest Audrey Leasure, Kristopher T. Kahle, and Golo Kronenberg each declare no potential conflicts of interest. W. Taylor Kimberly reports grants from the National Institutes of Health-NINDS, American Heart Association, and Remedy Pharmaceuticals, Inc. Lauren H. Sansing reports grants from the National Institutes of Health. Hagen Kunte reports personal compensation for speaking from Bayer, Biogen, Genzyme, Novartis, Merck Serono, and Teva. J. Marc Simard has Patent 7,285,574 with royalties paid by Remedy Pharmaceuticals. Kevin N. Sheth reports grants from Remedy Pharmaceuticals, Inc. Dr. Sheth is a section editor of Current Treatment Options in Neurology. Human and Animal Rights and Informed Consent This article does not contain any studies with human participants or animals performed by any of the authors.
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