Abstract
Background and Purpose:
Hematoma volume (HV) is a powerful determinant of outcome after intracerebral hemorrhage (ICH). We examined whether the effect of the iron chelator, deferoxamine, on functional outcome varied depending on HV in the i-DEF trial.
Methods:
A post-hoc analysis of the i-DEF trial; participants were classified according to baseline HV (small <10 mL, moderate 10–30 mL, and large >30 mL). Favorable outcome was defined as modified Rankin Scale (mRS) 0–2 at day-180; secondarily at day-90.Logistic regression was used to evaluate the differential treatment effect according to HV.
Results:
291 subjects were included in the as-treated analysis; 121 with small, 114 moderate, and 56 large HV. Day-180 mRS scores were available for 270/291 subjects (111 with small, 105 moderate, and 54 large HV).There was a differential effect of treatment according to HV on day-180 outcomes (p-for-interaction =0.0077); 50% (27/54) of deferoxamine-treated patients with moderate HV had favorable outcome compared with 25.5% (13/51) of placebo-treated subjects (adjusted OR 2.7; 95% CI 1.13–6.27; p=0.0258). Treatment effect was not significant for small (aOR 1.37; 95% CI 0.62–3.02) or large (aOR 0.12; 95% CI 0.01–1.05) HV. Results for day-90 outcomes were comparable (p-for-interaction =0.0617). Sensitivity analyses yielded similar results.
Conclusions:
Among patients with moderate HV, a greater proportion of deferoxamine- than placebo-treated patients achieved mRS 0–2. The treatment effect was not significant for small or large HVs. These findings have important trial-design and therapeutic implications.
Registration:
URL: http://www.clinicaltrials.gov. Unique identifier: NCT02175225
Keywords: ICH, Hematoma, Volume, Outcome, Deferoxamine, i-DEF
Graphical Abstract
Introduction
Intracerebral hemorrhage (ICH) is a devastating condition. The estimated case fatality rate of ICH approaches 17% at discharge and 30% at 12 months.1 Hematoma volume (HV) is a powerful determinant of mortality and functional outcome after ICH.2, 3Large HV emerges as a consistent and independent predictor of poor outcome in several epidemiological and clinical studies. In one study, while patients with HV less than 30 mL had good potential for survival and recovery, over 98% of patients with HV greater than 30 mL were functionally dependent at 30 days, and the 30-day mortality of patients with HV greater than 60 mL was 93% for deep ICH and 71% for lobar ICH.2
Hematoma volume is potentially modifiable via two therapeutic strategies: hematoma evacuation and/or rapid prevention of hematoma expansion. Previous studies suggest that therapeutic strategies’ efficacy in ICH may vary according to HV. For example, patients with large HV might derive benefit from hematoma evacuation, while the potential benefit may be outweighed by surgical risk in patients with small HV.4–7 Improved patient selection in ICH trials improves the likelihood of detecting a clinical benefit, adequate evaluation of safety, and has implications for the overall wider applicability of the trial results. While attempting to prevent hematoma expansion in patients presenting with small ICH seems sensible, an argument can be made that patients with very large HV in whom medical therapy alone is unlikely to result in a clinically meaningful difference should probably be excluded from ICH trials of medical interventions.
The intracerebral hemorrhage deferoxamine (i-DEF) trial investigated whether treatment with deferoxamine mesylate, an iron chelator that targets the secondary injury after ICH but not HV, could improve outcomes after spontaneous ICH.8 We hypothesized that patients with small or large HV who participated in i-DEF had little potential to benefit from deferoxamine and that their inclusion may have lessened the observed treatment effect. We performed this post-hoc analysis of the i-DEF trial to investigate whether the effects of treatment with deferoxamine varied based on HV.
Methods
This study is performed in agreement with the AHA Journals’ implementation of the Transparency and Openness Promotion Guidelines. The data that support the findings of this study will be provided to researchers from upon reasonable request.
Study Design And Participants:
The i-DEF trial was a multicenter, randomized, placebo-controlled, double-blind, futility-design, phase 2 clinical trial in the United States and Canada. The trial was funded by the National Institute of Neurological Disorders and Stroke (U01 NS074425) and approved by the US Food and Drug Administration (IND #77306) and Health Canada (CTA #160713). Details of study design, methods, and results have been previously published.8 Briefly, patients aged 18–80 years with primary, spontaneous, supratentorial ICH were recruited and randomly assigned to receive deferoxamine (32 mg/kg per day) or placebo (saline) infusions for 3 consecutive days within 24 hours of ICH onset. The modified Rankin Scale (mRS) was assessed at 90 and 180 days. All assessments were done by qualified investigators who were certified in mRS administration and masked to treatment assignment. Good outcome was defined as a dichotomized mRS score of 0–2. The trial was approved by the Institutional Review Board at each participating site, and written informed consent was obtained from each participant or legally authorized representative according to local regulations.
A total of 294 patients were randomized in the i-DEF trial. The key randomization covariates were clinical site, baseline ICH score (<3 vs.≥3)9, ICH-onset-to-treatment time (≤12 h vs.>12 h), warfarin use at ICH onset (yes vs.no), National Institute of Health Stroke Scale (NIHSS) score (≤10 vs.>10), and volume of ICH (<10 mL vs.≥10 mL) at presentation. The study infusions were initiated in 291 of 294 participants, of whom 147 were randomized to placebo and 144 to deferoxamine. However, 145 actually received placebo and 146 received deferoxamine due to a randomization error.
Hematoma Volume Measurement:
Brain computed tomography (CT) scans were performed at baseline and the images were sent to the i-DEF core imaging laboratory (Beth Israel Deaconess Medical Center, Boston, MA, USA) for central review. Experienced assessors, who were masked to clinical data and treatment assignment, determined the location of ICH and performed quantitative measurements of ICH and intraventricular hemorrhage (IVH) volumes using an imaging analysis software (Analyze 11.0 Visualization and Analysis Software for Medical Imaging; AnalyzeDirect, Overland Park, KS,USA). In this post hoc analysis, we stratified patients according to baseline ICH volume assessed by central readers, which was classified as small (<10 mL), moderate (10–30 mL), and large HV (>30 mL). The rationale for these volume thresholds was based on the ICH volume threshold (<10 mL vs. ≥ 10 mL) used in the randomization scheme and epidemiological data indicating that HV >30 mL commonly portends poor prognosis.2, 9 We used HV as a categorical instead of a continuous variable because of concerns about non-linearity between absolute HV and outcomes.
Statistical analyses:
Analyses were performed on the as treated population, in which participants were analyzed according to the actual treatment received. Baseline characteristics were evaluated for differences related to HV group and treatment via generalized linear model. Table 1 shows the interaction p-value, indicating whether the difference between treatment arms varied according to the HV group; where the interaction term is not significant, the p-value corresponding to the HV effect is also shown. The primary outcome measure was good clinical outcome, which was defined as a dichotomized mRS score of 0–2 at day 180 (±30 days). Good clinical outcome at day 90 was examined in secondary analyses. This was based on the main results of i-DEF, which showed that patients in both the placebo- and deferoxamine-treated groups continued to improve between days 90 and 180, and other data suggesting that recovery after ICH is protracted and occurs beyond 3 months.1, 8, 10 The potential for differential treatment effect according to HV category was evaluated in a logistic regression model focused on the interaction between treatment and HV subgroup and adjusted for the randomization covariates. A sensitivity analysis was performed with adjustment for additional prognostic factors including age (as a continuous variable), NIHSS score (as a continuous variable), history of diabetes, IVH volume (as a continuous variable), ICH location (lobar vs deep thalamic vs deep non-thalamic), and intubation (yes vs no). The potential for different treatment effect on mortality was evaluated via Cox proportional hazard model with covariates as in the logistic regression model. A two-sided 0.05 level of significance was applied for all analyses. All statistical analyses were performed with SPSS 22.0 (IBM), SAS software version 9.4 (SAS Institute Inc., Cary, NC, USA), and GraphPad Prism 7.0 (GraphPad Software Inc.).
Table 1:
Baseline and Clinical Characteristics by Treatment and Hematoma Volume.
| Characteristics | Hematoma volume <10 ml | Hematoma volume 10–30 ml | Hematoma volume >30 ml | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| DFO (n=63) | Placebo (n=58) | All | DFO (n=58) | Placebo (n=56) | All | DFO (n=25) | Placebo (n=31) | All | HV by Treatment Interaction p-value | HV p-value from main effect model | |
| Age, years | 58.87±11.26 | 62.07±11.36 | 60.40±11.37 | 58.47±13.35 | 58.27±10.25 | 58.37±11.87 | 65.80±11.56 | 62.58±13.72 | 64.02±12.79 | 0.2161 | 0.0151 |
| Female sex | 26 (41.3) | 24 (41.4) | 50 (41.3) | 22 (37.9) | 19 (33.9) | 41 (36.0) | 9 (36.0) | 12 (38.7) | 21 (37.5) | 0.9001 | 0.6932 |
| Medical history | |||||||||||
| Hyperlipidemia | 27 (42.9) | 31 (53.4) | 58 (47.9) | 15 (25.9) | 19 (33.9) | 34 (29.8) | 11 (44.0) | 8 (25.8) | 19 (33.9) | 0.1530 | 0.0123 |
| Hypertension | 56 (88.9) | 53 (91.4) | 109 (90.1) | 40 (69.0) | 48 (85.7) | 88 (77.2) | 17 (68.0) | 23 (74.2) | 40 (71.4) | 0.5447 | 0.0022 |
| Diabetes mellitus | 17 (27.0) | 19 (32.8) | 36 (29.8) | 8 (13.8) | 19 (33.9) | 27 (23.7) | 7 (28.0) | 5 (16.1) | 12 (21.4) | 0.0583 | 0.3667 |
| Cardiac disease | 10 (15.9) | 7 (12.1) | 17 (14.0) | 2 (3.4) | 6 (10.7) | 8 (7.0) | 3 (12.0) | 1 (3.2) | 4 (7.1) | 0.1116 | 0.1519 |
| Pulmonary disease | 13 (20.6) | 15 (25.9) | 28 (23.1) | 9 (15.5) | 7 (12.5) | 16 (14.0) | 8 (32.0) | 5 (16.1) | 13 (23.2) | 0.2956 | 0.1481 |
| Previous ICH | 4 (6.3) | 0 | 4 (3.3) | 2 (3.4) | 1 (1.8) | 3 (2.6) | 1 (4.0) | 2 (6.5) | 3 (5.4) | 0.1336 | 0.6342 |
| Previous ischemic stroke/TIA | 6 (9.5) | 10 (17.2) | 16 (13.2) | 2 (3.4) | 3 (5.4) | 5 (4.4) | 2 (8.0) | 3 (9.7) | 5 (8.9) | 0.9085 | 0.0491 |
| Pre-ICH mRS score = 1# | 9 (14.3) | 9 (15.5) | 18 (14.9) | 2 (3.4) | 5 (8.9) | 7 (6.1) | 3 (12.0) | 3 (9.7) | 6 (10.7) | 0.5332 | 0.0858 |
| Severity Scores | |||||||||||
| GCS score | 15 (14–15) | 15 (14–15) | 15 (14–15) | 13 (12–15) | 13 (11–14) | 13 (12–15) | 13 (10–14) | 12 (9–13) | 13 (10–14) | 0.4299 | <.0001 |
| NIHSS score | 9 (7–13) | 9 (7–12) | 9 (7–12.5) | 14 (8–17) | 17 (12–20) | 15 (10–19) | 18 (15–20) | 16 (12–19) | 17 (14–19) | 0.0162 | NA |
| ICH score>21 | 0 | 0 | 0 | 0 | 0 | 0 | 6 (24.0) | 8 (25.8) | 14 (25.0) | ||
| Laboratory and Imaging Data | |||||||||||
| Blood glucose2, mg/dL | 151.70± 62.33 | 154.59± 60.44 | 153.09± 61.19 | 136.55± 38.51 | 157.50± 74.63 | 146.84± 59.74 | 148.47± 31.90 | 150.93± 43.30 | 149.83± 38.32 | 0.6509 | 0.3692 |
| ICH Location: Lobar Deep (thalamic) Deep (non-thalamic) | |||||||||||
| 1 (1.6) | 4 (6.9) | 5 (4.1) | 13 (22.4) | 8 (14.3) | 21 (18.4) | 12 (48.0) | 21 (67.7) | 33 (58.9) | 0.0703 | <.0001 | |
| 32 (50.8) | 34 (58.6) | 66 (54.5) | 13 (22.4) | 23 (41.1) | 36 (31.6) | 1 (4.0) | 3 (9.7) | 4 (7.1) | 0.5651 | <.0001 | |
| 30 (47.6) | 20 (34.5) | 50 (41.3) | 32 (55.2) | 25 (44.6) | 57 (50.0) | 12 (48.0) | 7 (22.6) | 19 (33.9) | 0.5638 | 0.1314 | |
| ICH volume3, mL | 5.47 (2.89–7.94) | 5.99 (3.86–7.71) | 5.78 (3.51–7.72) | 17.67 (13.97–23.48) | 16.23 (13.01–20.51) | 17.05 (13.04–21.77) | 49.70 (38.32–59.22) | 52.52 (36.41–67.12) | 51.63 (36.88–62.49) | ||
| Presence of IVH | 23 (36.5) | 28 (48.3) | 51 (42.1) | 19 (32.8) | 27 (48.2) | 46 (40.4) | 10 (40.0) | 13 (41.9) | 23 (41.1) | 0.6981 | 0.9466 |
| IVH volume4, mL | 0.00 (0.00–4.52) | 0.00 (0.00–6.06) | 0.00 (0.00–4.67) | 0.00 (0.00–1.34) | 0.00 (0.00–9.14) | 0.00 (0.00–5.43) | 0.00 (0.00–0.23) | 0.00 (0.00–1.17) | 0.00 (0.00–0.97) | ||
| Intubation | 7 (11.1) | 4 (6.9) | 11 (9.1) | 10 (17.2) | 20 (35.7) | 30 (26.3) | 8 (32.0) | 13 (41.9) | 21 (37.5) | 0.1524 | <.0001 |
Only patients with pre-ICH mRS score 0–1 were recruited into the iDEF trial.
p-values not provided for ICH score due to data sparsity.
p-values based on inverse transformation of blood glucose to correct non-normality of residuals.
p-values not provided for ICH volume due to collinearity with hematoma volume category.
p-values not provided for continuous IVH volumne due to non-normaility of residuals.
DFO = Deferoxamine
Results
A total of 291 patients received study infusions in i-DEF; 146 received deferoxamine and 145 placebo. The mean age (±SD) was 60.3±12.0years, and 179 patients (61.5%) were men. One hundred twenty-one patients presented with small (63 deferoxamine and 58 placebo), 114 moderate (58 deferoxamine and 56 placebo), and 56 large HV (25 deferoxamine and 31 placebo). Table 1 summarizes the baseline and clinical characteristics of patients with different HV, overall and by treatment within each HV subgroup. Patients with large HV were older and more likely to have been intubated. Patients with small HV had a higher prevalence of hypertension and deep ICH. The demographic and clinical characteristics within each HV subgroup were overall similar between patients in the two treatment arms (deferoxamine vs. placebo).
Figure 1 shows the full distribution of mRS scores at 180 (A) and 90 (B) days in different subgroups of HV. Figure 2 shows treatment effects on mRS 0–2 at 180 and 90 days by hematoma volume. The overall proportions of patients with favorable outcome decreased with increasing HV. The mRS scores at 180 days were available for 270 of the 291 patients: 111 with small, 105 moderate and 54 large HV. At 180 days, 54.1% of patients with small HV, 38.1% with moderate HV, and 16.7% with large HV had mRS 0–2. At 90 days, 44.5% of patients with small HV, 32.4% with moderate HV, and 12.5% with large HV had mRS 0–2.
Figure 1:
The mRS scores at 180 days (A) and 90 days (B) in different HV subgroups. Data are presented only for patients in whom a mRS score was obtained. DFO = deferoxamine.
Figure 2:
Treatment effects on mRs 0–2 at 180 and 90 days by hematoma volume, adjusted for remaining randomization covariates (onset to treatment time and NIHSS)
There was a significant interaction between treatment and HV on favorable outcomes at day-180 (p-for-interaction=0.0077; p-for-interaction =0.0617 at day-90). The adjusted odds ratio for deferoxamine treatment effect on good outcome in patients with moderate HV at day-180 was 2.7 (95% CI 1.13–6.27) vs. 1.37 (95% CI 0.62–3.02) in patients with small HV and 0.12 (95% CI 0.01–1.05) with large HV. At day-90, the adjusted OR for treatment effect on favorable outcome was 1.84 (95% CI 0.75–4.54) for patients with moderate HV, 0.81 (95% CI 0.36–1.82) for patients with small HV, and 0.15 (95% CI 0.02–1.47) in patients with large HV. Sensitivity analyses adjusting for additional prognostic factors yielded similar results (Supplemental Table 1).
Figure 3 depicts survival curves and mortality. Overall, 3 of 121 (2.5%) of patients with small HV, 9of 114 (7.9%) with moderate HV, and 12 of 56 (21.4%) with large HV had died by day-180. The risk of death at 180 days did not significantly differ by treatment in any HV group. The hazard ratio for death in the deferoxamine arm compared to placebo was 1.564 (95% CI:0.141–17.312) in patients with small HV, 1.387 (95% CI 0.370–5.192) with moderate HV, and0.925 (95% CI 0.293–2.915) with large HV.
Figure 3:
Survival curves of mortality at 180 days.
Discussion
This post-hoc analysis of the i-DEF trial demonstrates that the treatment effect of deferoxamine on long-term functional outcome at 180 days after ICH varied according to HV. Among patients with moderate HV, a greater proportion of deferoxamine-treated patients compared with placebo achieved mRS 0–2 after adjustment for several prognostic factors. On the other hand, patients with small HV had little potential to benefit from treatment with deferoxamine, and fewer deferoxamine-treated patients with large HV achieved favorable outcome compared to their placebo-treated counterparts.
Previous studies showed a strong association between baseline HV and the 30-day morbidity and mortality. 2, 3, 9 In the present study, we found that the cumulative mortality rates at 180 days progressively increased with increasing HV and favorable functional outcome rates decreased with increased HV at both 90 and 180 days. These results indicate that HV is also an important predictor of longer-term outcomes after ICH.
The differential effects of treatment based on HV have been examined in subgroup analyses of previous randomized controlled trials of other therapeutic interventions for ICH.11–13 However, there was considerable heterogeneity in the HV thresholds used in these subgroup analyses. For example, in two trials of intensive blood pressure reduction, the subgroups were defined as HV <15 ml versus ≥15 ml in one study11 and <30 ml versus ≥30 ml in another.12 Analyses of primary outcome according to HV subgroups did not reveal significant differences between the intervention and control subgroups in these trials. In the Tranexamic acid for hyperacute primary IntraCerebral Hemorrhage (TICH-2) trial13, HV was sub-grouped into 3 categories (<30 ml, 30–60 ml and>60 ml). Again, no significant differences between the intervention and control arms were noted among any of these subgroups. The disparities of these results from those of the current analyses may be attributed to differences in HV thresholds used, lumping of a wide range of HVs into only 2 categories, differences in the therapeutic targets of the various interventions, or true lack of efficacy of the studied interventions. We used 10 ml as the cut-off to define small HV and 30 ml as the cut-off for large HV. There are data to support the use of these thresholds. In one study, only one of 71 patients with HV >30 mL achieved functional independence at 30 days2, and HV ≥30 mL is a component of the ICH score, which is widely used to predict outcome after ICH.9 Also, only 15 patients in the i-DEF trial presented with HV >60 ml. Therefore, we included all patients with HV >30 ml into one subgroup to minimize the drawbacks of small sample size. The median HV in the i-DEF trial was 12.95 ml. Since a HV <10 ml was pre-defined as a small HV in the trial and included as a variable in the randomization scheme, we elected to use this cut-off to define small HV in this analysis.
Our findings that the beneficial effects of deferoxamine on outcome seem to vary depending on HV, and are mostly noted in patients with moderate HV, are logical. The breakdown of hemoglobin after ICH results in iron overload, which contributes to secondary injury.14 Deferoxamine, which is an iron chelator, has multiple neuroprotective effects after ICH.15 The contribution of hemoglobin-degradation products, including iron, to secondary neuronal injury in ICH and its severity may depend on HV. It is intuitive to posit that small ICH results in less brain iron load compared with moderate or large HV, and that the proportional contribution from iron to neurological injury may be less pronounced in patients with small HV. Furthermore, patients with small HV tend to have a favorable prognosis overall. Therefore, the efficacy of deferoxamine may be masked by a ceiling effect particularly when using the mRS as the primary outcome. To the contrary, brain iron load may be too high in patients with large HV, overwhelming the capability of adequate chelation by deferoxamine alone. In addition, the mechanical consequences of large ICH, in particular early mass effect of the hematoma and increased intracranial pressure, may eclipse the effect of iron as the main drivers of neurological injury. These patients demonstrate high early mortality and morbidity, and medical interventions targeting iron toxicity alone may be futile in such patients.
Patient selection in ICH trials influences the detection of a possible benefit and has implications for the overall wider applicability of the trial results. In this regard, our findings have potentially important clinical trial design and therapeutic implications. First, they suggest that large variation in HV among study participants may result in dilution of treatment effect in clinical trials of medical therapies targeting secondary injury after ICH. If this finding is validated, future studies may consider exclusion of those with large HV, enriching the study population with moderate HV, or adaptive designs which allow for subgroup selection according to HV while the trial is ongoing. Although such exclusion could slow down recruitment and prolong clinical trials and related costs, it is possible that focus on those most likely to benefit from therapy could result in an overall smaller sample size which could counterbalance these challenges. Second, our findings open an intriguing possibility for a new avenue in the search for effective therapy for ICH; utilizing minimally invasive techniques to reduce large HV to a moderate volume amenable to subsequent medical therapy with deferoxamine or other treatments targeting the secondary injury to maximize treatment effect. In exploratory analyses of MISTIE III trial, hematoma reduction to 15 ml was associated with improved functional outcomes, but the ability to reduce HV to this target was only achieved in 58% of patients16. The use of deferoxamine as an adjunctive rescue therapy for patients with large HV after undergoing hematoma evacuation to improve their overall outcome is an appealing and exciting concept.
Our study has some limitations. In this post-hoc analysis, we did not apply a correction to the level of significance to account for multiple testing. As this trial was not designed to detect a clinically relevant treatment by HV interaction, such an adjustment would further reduce the power available to detect a clinically relevant interaction. The potential impact of multiplicity on reported findings cannot be ruled out, and these results are therefore considered hypothesis generating. We only collected data on mRS and mortality at 180 days. We did not collect other outcomes to corroborate our findings. Lastly, a higher percentage of placebo-treated patients with moderate HV had history of hypertension, diabetes, hyperlipidemia, and cardiac disease; thalamic and intraventricular hemorrhages; and were intubated. These imbalances in baseline prognostic characteristics may have contributed to poorer outcomes in the placebo group. However, sensitivity analyses adjusting for most of these confounders did not alter the overall results. We found that a greater proportion of placebo-treated patients than deferoxamine achieved favorable outcomes among patients with large HV. This finding is surprising because there is no biological reasoning to explain why deferoxamine would worsen outcome in this subset of patients and the treatment-related adverse events did not differ between deferoxamine and placebo-treated patients.8 Only 56 patients with large HV were included in the i-DEF trial, and the impact of the small sample size in this subgroup on our findings cannot be excluded.
Summary/Conclusion
We found a differential effect for treatment with deferoxamine on long-term favorable outcome based on baseline HV in the i-DEF trial. The beneficial effects of deferoxamine were predominantly noted in patients with moderate HV (>10 ml to 30 ml). These findings could have important trial-design and therapeutic implications, and they raise the question as to whether patients with small or large HV should be excluded from future trials of therapies targeting the secondary injury after ICH to maximize the chances for detecting a possible benefit.
Supplementary Material
Sources of Funding
The iDEF trial was funded by the NIH/NINDS (U01 NS074425). Dr. Selim receives funding from the NIH/NINDS (U01 NS102289). Dr. Wei was supported by the China Scholarship Council and the National Natural Science Foundation of China (81620108009).
Disclosures
Dr. Yeatts receives grant funding from the NINDS (related to and outside of the current submission) and NHLBI (outside of the current submission); compensation for editorial position with Stroke; and from Bard and Emory for DSMB service. Dr.Mocco receives research grant support from Stryker Neurovascular, Microvention, and Penumbra. He is an investor in: Cerebrotech, Imperative Care, Endostream, Viseon, BlinkTBI, Serenity, Vastrax, NTI, RIST, Viz.ai, Synchron, and Truvic. He serves, or has recently served, as a consultant for: Cerebrotech, Viseon, Endostream, Vastrax, RIST, Synchron, Viz.ai, Perflow, and CVAid. Dr. Selim receives grant funding from the NINDS (related to and outside of the current work), royalties from Up to Date and Cambridge University Press. He serves on the Advisory Board of MedRhythms Inc.
Non-standard Abbreviations and Acronyms
- HV
Hematoma volume
- ICH
Intracerebral hemorrhage
- i-DEF
The intracerebral hemorrhage deferoxamine trial
- IVH
Intraventricular hemorrhage
- mRS
Modified Rankin Scale
- ml
Milliliter
Footnotes
References
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