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Deferoxamine in intracerebral hemorrhage: Systematic review and meta-analysis
Sun T, Zhao YY, Xiao QX, Wu M, Luo MY
Clinical neurology and neurosurgery. 2023;227:107634
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Editor's Choice
Abstract
BACKGROUND Intracerebral hemorrhage (ICH) is a stroke with a high morbidity and mortality rate. Deferoxamine (DFX) is thought to be effective in treating Intracerebral Hemorrhage. In our study, we performed a meta-analysis to evaluate the treatment effects of DFX. METHODS We systematically searched PubMed, Embase, Web of Science, the Cochrane Central Register of Controlled Trials, and Chinese Biomedical Literature Database in Jan 2022 for studies on DFX for ICH patients. Outcome measures included relative hematoma volume, relative edema volume, good neurological functional outcome and adverse events. Odds risk (OR) and weighted mean difference (WMD) were used to evaluate clinical outcomes. RESULTS After searching 636 articles, 4 RCTs, 2 NRCTs, and 1cohort study were included. We found that DFX was effective in hematoma absorption on day 7 after onset, but the difference was not significant on day 14. DFX could suppress edema expansion on days 3, 7, and 14 after onset. DFX did not contribute to better outcomes after 3 and 6 months when used the modified Rankin Scale and the Glasgow Outcome Scale to evaluate neurological prognosis. The pooled results showed no statistically significant difference in Serious adverse events between the experimental and control groups. CONCLUSIONS DFX could limit edema expansion on days 3, 7, and 14 after commencement and facilitate hematoma absorption at week 1 without significantly increasing the risk of adverse events, but it did not improve neurological prognosis.
PICO Summary
Population
Patients with intracerebral haemorrhage (n= 7 studies).
Intervention
Deferoxamine (DFX).
Comparison
Placebo.
Outcome
Outcome measures included relative haematoma volume, relative oedema volume, good neurological functional outcome and adverse events. DFX was effective in haematoma absorption on day 7 after onset, but the difference was not significant on day 14. DFX could suppress oedema expansion on days 3, 7, and 14 after onset. DFX did not contribute to better outcomes after 3 and 6 months when used the modified Rankin Scale and the Glasgow Outcome Scale to evaluate neurological prognosis. The pooled results showed no statistically significant difference in serious adverse events between the experimental and control groups.
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Neuroendoscopic evacuation improves outcomes compared to external ventricular drainage in patients with spontaneous intraventricular hemorrhage: a systematic review with meta-analyses
Mezzacappa FM, Weisbrod LJ, Schmidt CM, Surdell D
World neurosurgery. 2023
Abstract
BACKGROUND Spontaneous intraventricular hemorrhage (IVH) is a cause of significant morbidity and mortality. Treatment for the resulting obstructive hydrocephalus has traditionally been via an external ventricular drain (EVD). We aimed to compare patient outcomes after neuroendoscopic surgery (NES) evacuation of IVH versus EVD management. METHODS MEDLINE, EMBASE, and the Cochrane Library were searched on October 8, 2022, with adherence to PRISMA guidelines. Of the 252 records remaining after removal of duplicates, 12 met the study's inclusion criteria. After extraction of outcomes data, fixed-effects and random-effects models were used to establish odds-ratios with 95% confidence intervals (CIs) for intensive care-unit (ICU) length-of-stay (LOS), rate of permanent cerebrospinal fluid (CSF) diversion, Glasgow Outcomes Scale (GOS) score, and mortality rate. RESULTS The results of the pooled analysis showed that ICU LOS was shorter (OR -2.61 [95% CI -5.02, -0.19]; I(2)=97.76%; p=0.034), permanent CSF diversion was less likely (OR -0.79 [95% CI -1.17, -0.41]; I(2)=46.96%; p<0.001), higher GOS was more likely (OR 0.48 [95% CI 0.04, 0.93]; I(2)=60.12%; p=0.032), and all-cause mortality was less likely (OR -1.11 [95% CI -1.79, -0.44]; I(2)=0%; p=0.001) in the NES evacuation group compared to the EVD group. CONCLUSIONS NES for evacuation of spontaneous IVH results in reduced ICU LOS, reduced permanent CSF diversion rates, improved GOS, and reduced mortality when compared with EVD. More robust prospective, randomized studies are necessary to help inform the safety and utility of NES for IVH.
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Time Course of Early Hematoma Expansion in Acute Spot-Sign Positive Intracerebral Hemorrhage: Prespecified Analysis of the SPOTLIGHT Randomized Clinical Trial
Al-Ajlan FS, Gladstone DJ, Song D, Thorpe KE, Swartz RH, Butcher KS, Del Campo M, Dowlatshahi D, Gensicke H, Lee GJ, et al
Stroke. 2023
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Editor's Choice
Abstract
BACKGROUND In the SPOTLIGHT trial (Spot Sign Selection of Intracerebral Hemorrhage to Guide Hemostatic Therapy), patients with a computed tomography (CT) angiography spot-sign positive acute intracerebral hemorrhage were randomized to rFVIIa (recombinant activated factor VIIa; 80 μg/kg) or placebo within 6 hours of onset, aiming to limit hematoma expansion. Administration of rFVIIa did not significantly reduce hematoma expansion. In this prespecified analysis, we aimed to investigate the impact of delays from baseline imaging to study drug administration on hematoma expansion. METHODS Hematoma volumes were measured on the baseline CT, early post-dose CT, and 24 hours CT scans. Total hematoma volume (intracerebral hemorrhage+intraventricular hemorrhage) change between the 3 scans was calculated as an estimate of how much hematoma expansion occurred before and after studying drug administration. RESULTS Of the 50 patients included in the trial, 44 had an early post-dose CT scan. Median time (interquartile range) from onset to baseline CT was 1.4 hours (1.2-2.6). Median time from baseline CT to study drug was 62.5 (55-80) minutes, and from study drug to early post-dose CT was 19 (14.5-30) minutes. Median (interquartile range) total hematoma volume increased from baseline CT to early post-dose CT by 10.0 mL (-0.7 to 18.5) in the rFVIIa arm and 5.4 mL (1.8-8.3) in the placebo arm (P=0.96). Median volume change between the early post-dose CT and follow-up scan was 0.6 mL (-2.6 to 8.3) in the rFVIIa arm and 0.7 mL (-1.6 to 2.1) in the placebo arm (P=0.98). Total hematoma volume decreased between the early post-dose CT and 24-hour scan in 44.2% of cases (rFVIIa 38.9% and placebo 48%). The adjusted hematoma growth in volume immediately post dose for FVIIa was 0.998 times that of placebo ([95% CI, 0.71-1.43]; P=0.99). The hourly growth in FFVIIa was 0.998 times that for placebo ([95% CI, 0.994-1.003]; P=0.50; Table 3). CONCLUSIONS In the SPOTLIGHT trial, the adjusted hematoma volume growth was not associated with Factor VIIa treatment. Most hematoma expansion occurred between the baseline CT and the early post-dose CT, limiting any potential treatment effect of hemostatic therapy. Future hemostatic trials must treat intracerebral hemorrhage patients earlier from onset, with minimal delay between baseline CT and drug administration. REGISTRATION URL: https://www. CLINICALTRIALS gov; Unique identifier: NCT01359202.
PICO Summary
Population
Patients with a computed tomography (CT) angiography spot-sign positive acute intracerebral haemorrhage (ICH) enrolled in the SPOTLIGHT trial (n= 50).
Intervention
Recombinant activated factor VIIa (n= 19).
Comparison
Placebo (n= 25).
Outcome
This prespecified analysis aimed to investigate the impact of delays from baseline imaging to study drug administration on haematoma expansion. Haematoma volumes were measured on the baseline CT, early post-dose CT, and 24 hours CT scans. Total haematoma volume (intracerebral haemorrhage + intraventricular haemorrhage) change between the 3 scans was calculated as an estimate of how much haematoma expansion occurred before and after studying drug administration. Of the 50 patients included in the trial, 44 had an early post-dose CT scan. Median time (interquartile range) from onset to baseline CT was 1.4 hours (1.2 - 2.6). Median time from baseline CT to study drug was 62.5 (55 - 80) minutes, and from study drug to early post-dose CT was 19 (14.5 - 30) minutes. Median (interquartile range) total haematoma volume increased from baseline CT to early post-dose CT by 10.0 mL (-0.7 to 18.5) in the rFVIIa arm and 5.4 mL (1.8 - 8.3) in the placebo arm. Median volume change between the early post-dose CT and follow-up scan was 0.6 mL (-2.6 to 8.3) in the rFVIIa arm and 0.7 mL (-1.6 to 2.1) in the placebo arm. Total haematoma volume decreased between the early post-dose CT and 24-hour scan in 44.2% of cases (rFVIIa 38.9% and placebo 48%). The adjusted haematoma growth in volume immediately post dose for FVIIa was 0.998 times that of placebo ([95% CI: 0.71 - 1.43]). The hourly growth in FFVIIa was 0.998 times that for placebo ([95% CI: 0.994 - 1.003]).
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Efficacy and safety of tranexamic acid in intracranial haemorrhage: A meta-analysis
Xiong Y, Guo X, Huang X, Kang X, Zhou J, Chen C, Pan Z, Wang L, Goldbrunner R, Stavrinou L, et al
PloS one. 2023;18(3):e0282726
Abstract
BACKGROUND Although some studies have shown that tranexamic acid is beneficial to patients with intracranial haemorrhage, the efficacy and safety of tranexamic acid for intracranial haemorrhage remain controversial. METHOD The PubMed, EMBASE, and Cochrane Library databases were systematically searched. The review followed PRISMA guidelines. Data were analyzed using the random-effects model. RESULTS Twenty-five randomized controlled trials were included. Tranexamic acid significantly inhibited hematoma growth in intracranial hemorrhage (ICH) and traumatic brain injury (TBI) patients. (ICH: mean difference -1.76, 95%CI -2.78 to -0.79, I2 = 0%, P < .001; TBI: MD -4.82, 95%CI -8.06 to -1.58, I2 = 0%, P = .004). For subarachnoid hemorrhage (SAH) patients, it significantly decreased the risk of hydrocephalus (OR 1.23, 95%CI 1.01 to 1.50, I2 = 0%, P = .04) and rebleeding (OR, 0.52, 95%CI 0.35 to 0.79, I2 = 56% P = .002). There was no significance in modified Rankin Scale, Glasgow Outcome Scale 3-5, mortality, deep vein thrombosis, pulmonary embolism, or ischemic stroke/transient ischemic. CONCLUSION Tranexamic acid can significantly reduce the risk of intracranial haemorrhage growth in patients with ICH and TBI. Tranexamic acid can reduce the incidence of complications (hydrocephalus, rebleeding) in patients with SAH, which can indirectly improve the quality of life of patients with intracranial haemorrhage.
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A systematic review on viscoelastic testing in subarachnoid haemorrhage patients
Tjerkstra, M. A., Wolfs, A. E., Verbaan, D., Vandertop, W. P., Horn, J., Müller, M. C. A., Juffermans, N. P.
World Neurosurgery. 2023
Abstract
OBJECTIVES Bleeding and thromboembolic complications frequently occur following subarachnoid haemorrhage (SAH) and substantially contribute to poor outcome. Viscoelastic testing could be used for detection of coagulopathies following SAH. This review summarizes literature on the utility of viscoelastic testing to detect coagulopathy in SAH patients and explores whether viscoelastic parameters are associated with SAH-related complications and clinical outcome. MATERIALS AND METHODS PUBMED, EMBASE and Google Scholar were systematically searched on August 18(th), 2022. Two authors independently selected studies which performed viscoelastic testing in SAH patients and assessed the quality of studies using the Newcastle Ottawa Scale or a previously published framework for quality assessment. Data was meta-analysed if methodologically possible. RESULTS The search yielded 19 studies (1160 SAH patients). Pooling of data including all relevant studies was not possible for any of the outcome measurements due to methodological differences. Thirteen of 19 studies evaluated the association of coagulation profiles and SAH, of which 11 studies showed a hypercoagulable profile. Rebleeding was associated with platelet dysfunction, deep venous thrombosis was associated with faster clot initiation and both delayed cerebral ischemia and poor outcome were associated with increased clot strength. CONCLUSIONS This explorative review shows that SAH patients frequently have a hypercoagulable profile. TEG- and ROTEM-parameters are associated with rebleeding, delayed cerebral ischemia, deep venous thrombosis and poor clinical outcome after SAH, however more research on the subject is needed. Future studies should focus on determining the optimal time frame and cut-off values for TEG or ROTEM to predict these complications.
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The outcomes of combined endoscopic surgery and fibrinolytic treatment protocol for intraventricular hemorrhage: a randomized controlled trial
Noiphithak R, Ratanavinitkul W, Yindeedej V, Nimmannitya P, Yodwisithsak P
World neurosurgery. 2023
Abstract
BACKGROUND Intraventricular fibrinolysis (IVF) and endoscopic surgery (ES) are the new promising treatment strategies to enhance the rate of hematoma clearance which might improve functional outcome. This study investigated and compared the outcomes among these interventions. METHODS A randomized (1:1) double-blinded trial was carried out between August 2018 and December 2021. The intervention and control groups comprised patients receiving IVF and/or ES, and external ventricular drainage (EVD), respectively. All participants had experienced primary or secondary IVH from spontaneous intracerebral hemorrhage with obstructive hydrocephalus complications. The primary outcome was modified Rankin scale (mRS) score at 180 days post-treatment. Interim assessments were planned for every 50 participants enrolled to ensure safety and efficacy. RESULTS After enrollment of 110 participants (55 participants in each group), there was the difference in 30-day mortality (2 [3.6%] vs 13 [32.7%] in EVD group, p = 0.002), reaching the predetermined boundaries for the termination of the trial. We demonstrated a better favorable outcome (mRS 0-3) at 180 days in the intervention group, compared to control group (35 [63.6%] vs. 24 [43.6%], p = 0.04). Participants in the intervention group experienced a higher IVH removal rate (91% [9.0] vs. 69.5% [38.0], p < 0.01), and had lower shunt conversion (1 [1.8%] vs. 16 [29.3%], p < 0.01). Treatment complications were comparable between the two groups. CONCLUSIONS This study demonstrated that combined ES and IVF is safe and effective for the treatment of IVH. In addition, it concluded that aggressive but safe procedures used to remove IVH could improve clinical outcome in patients with IVH.
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Tranexamic Acid After Aneurysmal Subarachnoid Hemorrhage: Post-Hoc Analysis of the ULTRA Trial
Tjerkstra MA, Post R, Germans MR, Vergouwen MDI, Jellema K, Koot RW, Kruyt ND, Willems PWA, Wolfs JFC, de Beer FC, et al
Neurology. 2022
Abstract
BACKGROUND AND OBJECTIVES The ULTRA-trial showed that ultra-early and short-term tranexamic acid treatment after subarachnoid hemorrhage did not improve clinical outcome at six months. An expected proportion of the included patients had non-aneurysmal subarachnoid hemorrhage In this post-hoc study, we will investigate whether ultra-early and short-term tranexamic acid treatment in patients with aneurysmal subarachnoid hemorrhage improves clinical outcome at six months. METHODS The ULTRA-trial is a multicenter, prospective, randomized, controlled, open-label trial with blinded outcome assessment, conducted between July 24, 2013 and January 20, 2020. After confirmation of subarachnoid hemorrhage on non-contrast computer tomography, patients were allocated to either ultra-early and short-term tranexamic acid treatment with usual care, or usual care only. In this post-hoc analysis, we included all ULTRA-participants with a confirmed aneurysm on CT angiography and/or digital subtraction angiography. The primary endpoint was clinical outcome at six months, assessed by the modified Rankin Scale, dichotomized into good (0-3) and poor (4-6) outcome. RESULTS Of the 813 ULTRA-trial patients who had an aneurysmal subarachnoid hemorrhage, 409 (50%) were assigned to the tranexamic acid group and 404 (50%) to the control group. In the intention-to-treat analysis, 233 of 405 (58%) patients in the tranexamic acid group and 238 of 399 (60%) patients in the control group had a good clinical outcome (adjusted odds ratio (aOR) 0·92; 95% confidence interval (C.I.) 0·69 to 1·24). None of the secondary outcomes showed significant differences between the treatment groups: excellent clinical outcome (mRS 0-2) aOR 0.76, 95% C.I. 0.57-1.03, all-cause mortality at 30 days aOR 0.91, 95% C.I. 0.65-1.28), all-cause mortality at six months aOR 1.10 (95% C.I. 0.80-1.52). DISCUSSION Ultra-early and short-term tranexamic acid treatment did not improve clinical outcome at six months in patients with aneurysmal subarachnoid hemorrhage and therefore, cannot be recommended. TRIAL REGISTRATION ClinicalTrials.gov (NCT02684812; submission date February 18, 2016, first patient enrollment on July 24(th), 2013). CLASSIFICATION OF EVIDENCE This study provides Class II evidence that tranexamic acid does not improve outcomes in patients presenting with aneurysmal subarachnoid hemorrhage.
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Systematic Review of Resource Utilization and Costs in the Hospital Management of Intracerebral Hemorrhage
Thomas SM, Reindorp Y, Christophe BR, Connolly ES Jr
World neurosurgery. 2022
Abstract
BACKGROUND While clinical guidelines provide a framework for hospital management of spontaneous intracerebral hemorrhage (ICH), variation in the resource utilization and costs of these services exist. OBJECTIVES Perform a systematic literature review to assess the evidence on hospital resource utilization and costs associated with management of adult ICH patients, as well as identify factors that impact variation in such hospital resource utilization and costs, regarding clinical characteristics and delivery of services. METHODS A systematic literature review was performed using PubMed, Cochrane Central Register of Controlled Trials, and Ovid MEDLINE(R) 1946 to Present. Articles were assessed against inclusion and exclusion criteria. Study design, ICH sample size, population, setting, objective, hospital characteristics, hospital resource utilization and cost data, and main study findings were abstracted. RESULTS 43 studies met the inclusion criteria. Pertinent clinical characteristics that increased hospital resource use included presence of comorbidities and baseline ICH severity. Aspects of service delivery that greatly impacted hospital resource consumption included ICU length of stay and performance of surgical procedures and intensive care procedures. CONCLUSION Hospital resource utilization and costs for ICH patients were high and differed widely across studies. Making concrete conclusions on hospital resources and costs for ICH care was constrained given methodological and patient variation in the studies. Future research should evaluate the long-term cost-effectiveness of ICH treatment interventions and use specific economic evaluation guidelines and common data elements to mitigate study variation.
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Tranexamic acid for patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis of 2991 patients
Ghaith HS, Gabra MD, Ebada MA, Dada OE, Al-Shami H, Bahbah EI, Swed S, Ghaith AK, Kanmounye US, Esene IN, et al
The International journal of neuroscience. 2022;:1-14
Abstract
OBJECTIVE We aimed to synthesize evidence from published clinical trials on the efficacy and safety of tranexamic acid (TXA) administration in patients with aneurysmal subarachnoid hemorrhage (aSAH). METHODS We followed the standard methods of the Cochrane Handbook of Systematic Reviews for interventions and the PRISMA statement guidelines 2020 when conducting and reporting this study. A computer literature search of PubMed, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials was conducted from inception until 1 January 2022. We selected observational studies and clinical trials comparing TXA versus no TXA in aSAH patients. Data of all outcomes were pooled as the risk ratio (RR) with the corresponding 95% confidence intervals in the meta-analysis models. RESULTS Thirteen studies with a total of 2991 patients were included in the analysis. TXA could significantly cut the risk of rebleeding (RR 0.56, 95% CI 0.44 to 0.72) and mortality from rebleeding (RR 0.60, 95% CI 0.39 to 0.92, p = 0.02). However, TXA did not significantly improve the overall mortality, neurological outcome, delayed cerebral ischemia, or hydrocephalus (all p > 0.05). In terms of safety, no significant adverse events were reported. No statistical heterogeneity or publication bias was found in all outcomes. CONCLUSION In patients with aSAH, TXA significantly reduces the incidence of rebleeding and mortality from rebleeding. However, current evidence does not support any benefits in overall mortality, neurological outcome, delayed cerebral ischemia, or hydrocephalus.
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A New Nomogram for Predicting the Risk of Intracranial Hemorrhage in Acute Ischemic Stroke Patients After Intravenous Thrombolysis
Weng ZA, Huang XX, Deng D, Yang ZG, Li SY, Zang JK, Li YF, Liu YF, Wu YS, Zhang TY, et al
Frontiers in neurology. 2022;13:774654
Abstract
BACKGROUND We aimed to develop and validate a new nomogram for predicting the risk of intracranial hemorrhage (ICH) in patients with acute ischemic stroke (AIS) after intravenous thrombolysis (IVT). METHODS A retrospective study enrolled 553 patients with AIS treated with IVT. The patients were randomly divided into two cohorts: the training set (70%, n = 387) and the testing set (30%, n = 166). The factors in the predictive nomogram were filtered using multivariable logistic regression analysis. The performance of the nomogram was assessed based on the area under the receiver operating characteristic curve (AUC-ROC), calibration plots, and decision curve analysis (DCA). RESULTS After multivariable logistic regression analysis, certain factors, such as smoking, National Institutes of Health of Stroke Scale (NIHSS) score, blood urea nitrogen-to-creatinine ratio (BUN/Cr), and neutrophil-to-lymphocyte ratio (NLR), were found to be independent predictors of ICH and were used to construct a nomogram. The AUC-ROC values of the nomogram were 0.887 (95% CI: 0.842-0.933) and 0.776 (95% CI: 0.681-0.872) in the training and testing sets, respectively. The AUC-ROC of the nomogram was higher than that of the Multicenter Stroke Survey (MSS), Glucose, Race, Age, Sex, Systolic blood Pressure, and Severity of stroke (GRASPS), and stroke prognostication using age and NIH Stroke Scale-100 positive index (SPAN-100) scores for predicting ICH in both the training and testing sets (p < 0.05). The calibration plot demonstrated good agreement in both the training and testing sets. DCA indicated that the nomogram was clinically useful. CONCLUSIONS The new nomogram, which included smoking, NIHSS, BUN/Cr, and NLR as variables, had the potential for predicting the risk of ICH in patients with AIS after IVT.
