How to Talk Like a Neurologist

Written by: Saabir Kaskar, MD (NUEM ‘23) Edited by: Nick Wleklinski (NUEM ‘22)
Expert Commentary by: Fan Caprio, MD

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Neurology Scores: LVO, NIHSS, and ICH

As first line providers, being able to effectively communicate with ancillary services and specialties is key to advancing patient care within the emergency department. When patients present with symptoms concerning for ischemic or hemorrhagic stroke, there are a variety of clinical decision tools available to help direct interventions and predict patient outcomes.  Having a basic understanding of these scoring systems helps ED providers communicate more effectively with our neurology colleagues. This post highlights indications, strengths, and limitations of common stroke assessment scales used in the prehospital and hospital setting.  

Cincinnati Prehospital Stroke Scale (CPSS)

The Cincinnati Prehospital Stroke Scale is a simple, easy to teach, three-part evaluation and is the most cited scale in statewide EMS protocols. Patients with one of these three findings, as a new event, will have 72% probability of ischemic stroke. If they have three of these deficits, that probability increases to 85%. Further, those scoring higher on this scale are more likely to have a large vessel occlusion (LVO) and warrant transfer to a comprehensive stroke center. One major limitation is that the CPSS does not identify features of posterior circulation strokes.

Figure 1: Cincinnati Prehospital Stroke Scale components

Predicting Large Vessel Occlusion 

There are many stroke severity scales that are useful in predicting large vessel occlusion (LVO) in the pre-hospital setting. Early LVO detection is useful as these patients have better outcomes if transported to comprehensive stroke centers (CSCs) which have endovascular interventions, such as thrombectomy, readily available. Such interventions are not available at primary stroke centers (PSC). LVO screening tools include the Rapid Arterial Occlusion Evaluation Scale (RACE), the Cincinnati Prehospital Stroke Severity Scale (CP-SSS/C-STAT), the Los Angeles Motor Scale (LAMS), and the Emergent Large Vessel Occlusion Scale (ELVO). While these scales are good, none have achieved an optimal sensitivity/specificity combination which is why there is no “gold standard” test per the most recent 2019 AHA guidelines (Powers et al. Guidelines for Early Mgmt of Patients with AIS. Stroke 2019). 

The Rapid Arterial Occlusion Evaluation Scale (RACE), for example, is one of these severity scales that predicts stroke caused by large vessel occlusion. It is based on the NIHSS but provides quicker assessment in the pre-hospital environment. It focuses on facial palsy, extremity motor function, head deviation, gaze deviation and aphasia or agnosia. The scale ranges from 0-9 with scores ≥ 5 being associated with detection of an LVO. RACE has a sensitivity of 85% and specificity of 68% for LVO at scores ≥ 5. 

Another example of a LVO screening tool is the Cincinnati Prehospital Stroke Severity Scale (CP-SSS/CSTAT) which is important to differentiate from the CPSS outlined above.  CSTAT focuses on gaze deviation, level of consciousness and arm weakness. Both RACE and CSTAT are validated in the prehospital setting and with external data sets. However, CSTAT is more convenient with fewer items to score. 

EMS protocol in Chicago (Region XI), utilizes a two-tier system that first involves the Cincinnati Stroke Scale and finger to nose test. If either aspect is abnormal, then stroke severity is assessed with the 3-Item Stroke Scale (3I-SS) which assesses level of consciousness, gaze preference and motor function, scored from 0-6. If the 3I-SS score is ≥4 and the last known normal is ≤6 hours ago then the patient is transported to the closest CSC instead of the closest primary stroke center (PSC), as long as the added transport time is not >15 minutes.  

National Institutes of Health Stroke Scale (NIHSS)

The NIHSS is a 11-part scoring tool and is the gold standard when assessing stroke patients in hospital (figure 3). Higher scores indicate a more severe stroke and usually correlate with infarct size on CT and MRI. Taken within the first 48 hours of acute stroke, the NIHSS helps predict three month and one-year clinical outcomes. For example, patients with a NIHSS of 1-4 have a high likelihood of functional independence and favorable outcome regardless of treatment. The NIHSS does not serve as the primary clinical guide in determining tPA administration. However, given that higher scores correlate with larger infarct size, caution is advised when considering tPA in patients with a NIHSS >22 as there is a higher risk of hemorrhagic conversion (see figure 2 for full tPA exclusion criteria). Analysis from subjects of the NINDS trials show that a NIHSS of >20 was associated with a 17% rate of intracranial hemorrhage with tPA when compared to 3% hemorrhage rate in patients with a score of <10.

Figure 2: Contraindications for tPA administration

Overall, the NIHSS is a reliable scoring tool to quicky assess the effects of stroke. Medical providers and nurses have been shown to have similar levels of accuracy when trained. Limitations include assessing posterior circulation stroke that involve gait abnormality, dizziness, or diplopia.

Figure 3: NIHSS, adopted from the American Stroke Association

Intracerebral Hemorrhage Score (ICH Score)

The ICH score is an important tool when evaluating a hemorrhagic stroke. This score was developed to standardize clinical grading of ICH and to improve communication between providers. This five-component scoring system (Figure 4) helps quantify ICH severity and subsequently 30-day mortality  (Figure 6) with a sensitivity of 66%. It is not used to determine treatment modality. This score helps universalize the grading of ICH severity, providing a standardized language that can be used between EM providers, neurologists, and neurosurgeons. Further, this score can help providers guide goals of care conversations with patient’s families and determine appropriate level of care or transfer.

Figure 4: ICH score, adapted from the American Stroke Association

Figure 5: Mortality rates based on ICH score

*No patients in the study scored 6, but estimated 100% mortality

Conclusion

In summary, it is important to understand how to utilize these scoring tools for ischemic and hemorrhagic stroke. Knowing how to interpret pre-hospital stroke scores and how to calculate a NIHSS score accurately and quickly is helpful in not only quantifying severity but also in improving communication between providers. Improved understanding and effective use of these tools can help better advance care of our stroke patients efficiently. These tools can also remind us of the severity of the neurologic deficit we observe on clinical exam. Subsequently, this can be helpful in guiding discussions with patients and their families regarding the severity of their condition.

References

Adams HP Jr, Davis PH, Leira EC, et al. Baseline NIH Stroke Scale score strongly predicts outcome after stroke: A report of the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Neurology 1999; 53:126.

Goldstein, L. (2019). Use and utility of stroke scales and grading systems. Up To Date

Goldstein L, Bertels C, Davis JN. Interrater reliability of the NIH stroke scale. Arch Neurol 1989; 46:660.

Generalized efficacy of t-PA for acute stroke. Subgroup analysis of the NINDS t-PA Stroke Trial. Stroke 1997; 28:2119.

Hemphill JC 3rd, Bonovich DC, Besmertis L, Manley GT, Johnston SC. The ICH score: a simple, reliable grading scale for intracerebral hemorrhage. Stroke. 2001 Apr;32(4):891-7. PubMed PMID: 11283388.

Kothari RU, Pancioli A, Liu T, et al. Cincinnati Prehospital Stroke Scale: reproducibility and validity. Ann Emerg Med 1999; 33:373.

Pérez de la Ossa N, Carrera D, Gorchs M, et al. Design and validation of a prehospital stroke scale to predict large arterial occlusion: the rapid arterial occlusion evaluation scale. Stroke 2014; 45:87.

Schlemm L, Ebinger M, Nolte CH, Endres M. Impact of Prehospital Triage Scales to Detect Large Vessel Occlusion on Resource Utilization and Time to Treatment. Stroke 2018; 49:439.

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Expert Commentary

Thanks for writing this comprehensive summary of common screening tools used in stroke patients. Having a good handle on these tools will allow you to quickly and effectively communicate with comanaging care providers. It is also important to understand how and why each scale was developed, so they can be used in the appropriate setting to expedite care in extremely time-sensitive neurologic emergencies.

Keep in mind that scales are merely screening tools and are not meant to give a definitive diagnosis. No scale is perfect, but you have highlighted some that yield the highest sensitivity and specificity for identifying a potential stroke patient. In addition to leaning on these scales as decision support tools, always use your clinical judgement. A few things to remember in addition to the neurologic symptoms:

* Strokes are potentially intervenable within the first 24 hours:

1. Up to 4.5 hours – IV-TPA / tenecteplase.

2. Up to 6 hours – Thrombectomy with LVO on vessel imaging.

3. Up to 24 hours – Thrombectomy with LVO + favorable penumbra on perfusion imaging.

* Last known normal (LKN) starts the timer to when stroke patients are eligible for intervention (not to be confused with time of symptom discovery!)

* Strokes typically cause a sudden loss of function (in contrast to positive phenomena such as convulsive movements, tingling sensation, sparkling vision, which can point away from a stroke diagnosis)

* In patients with prior deficits, ask which symptoms are new or different in comparison to their baseline.

The NIHSS is widely accepted as THE stroke severity scale, and it has many strengths and some pitfalls. The NIHSS was initially developed to be used in research, and, as mentioned here, was designed to be reproducible between various groups – physicians, nurses, research staff. Higher scores correlate with bigger infarct volume. The NIHSS is not an accurate scale in that it does not necessarily capture each patient’s deficits, omitting brain functions such as gait, distal limb dexterity, and cognition. It also scores higher for dominant (L) hemispheric functions as many points depend on language function.

When screening for large vessel occlusion, remember key brain structures and functions from the L MCA, R MCA, and posterior circulation. Looking for cortical signs can be very helpful to identify larger stroke syndromes: aphasia, neglect, gaze deviation, visual field deficit.

Last but not least, keep in mind that hemorrhagic strokes (intracerebral hemorrhage, subarachnoid hemorrhage) account for about 15% of all strokes. The same screening tools for acute neurologic symptoms can be used to identify these patients, though they more often have concurrent headache or LOC than ischemic strokes (due to increased ICP and irritation from blood products). For SAH, two scales are commonly used to describe the clinical and radiographic severities: Hunt-Hess (surgical risk index) and modified Fisher scales (risk index for developing vasospasm).

Figure 1: Hunt-Hess Scale

Figure 2: Modified Fisher Scale

Fan Caprio, MD

Assistant Professor of Neurology (Stroke)

Department of Neurology

Northwestern Memorial Hospital

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How To Cite This Post:

[Peer-Reviewed, Web Publication] Kaskar, S. Wleklinski, N. (2021, Oct 25). How to Talk Like a Neurologist. [NUEM Blog. Expert Commentary by Caprio, F]. Retrieved from http://www.nuemblog.com/blog/neuro-scores

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The PATCH Trial

Written by:  Andrew Berg, MD (NUEM PGY-3) Edited by: Ryan Huebinger, MD, (NUEM Grad 2017) Expert commentary by:  Stephen Trevick, MD

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Intro:

Hemorrhagic strokes, while accounting for less than 20% of incident strokes, contribute to half of all stroke-related deaths and long-term disability, totaling up to 47 million life-years lost [1]. Unlike ischemic strokes which have the potential to be intervened upon, non-surgical treatment of hemorrhagic stroke is limited. Hemorrhagic stroke associated with the use of non-reversible antiplatelet agents can be problematic, and the goal should be to try to limit the extent of the hemorrhage. In this day and age of increasing myocardial ischemia, percutaneous coronary intervention, and ischemic stroke leading to increasing antiplatelet usage, the attempted reversal of antiplatelet agents with platelet transfusion seems like a logical step. However, it is unclear if this is efficacious (both in the short and long-term) or if there are potential harms as studies are limited. The PATCH Trial looked at the use of platelet transfusion after acute spontaneous intracerebral hemorrhage in people taking antiplatelet therapy to determine if there was any impact on long-term functional outcomes.

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The Study:

Baharoglu, M. Irem, et al. "Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial." The Lancet 387.10038 (2016): 2605-2613. 

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Study Design:

This was a 6-year multicenter (60 hospitals in Europe), parallel-group trial that randomized 190 patients with non-traumatic supratentorial intracerebral hemorrhage while on antiplatelet therapy to standard care or standard care plus platelet transfusion and performed both an intention-to-treat and as-treated analysis of the outcomes.

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Population: 

Inclusion criteria:

1. 18 years or older with non-traumatic supratentorial intracerebral hemorrhage confirmed by brain imaging
2. Glasgow Coma Scale ≥ 8
3. Platelet transfusion could potentially be initiated within 6 hours of symptom onset and within 90 minutes of brain imaging
4.  On antiplatelet therapy with either a COX inhibitor (aspirin or carbasalate), ADP receptor inhibitor (clopidogrel) or an adenosine-reuptake inhibitor (dipyridamole) for at least 7 days prior to the ICH.
5. Pre-ICH mRS (modified Rankin Score) score of 0 or 1 only, suggesting no prior disability.

Exclusion criteria:

1. Imaging findings suggestive of epidural or subdural hematoma or those needing surgery within the next 24 hrs of admission
2.  Imaging suggesting underlying aneurysm or AVM
3.  Prior adverse reaction to platelets
4.  Use of a vitamin K antagonist
5.  Known coagulopathy
6. Imminent death

Patient selection flow chart: 

Intervention protocol: 

The patients were randomized to either standard care or standard care plus platelet transfusion. Both groups had a repeat brain imaging 24 hours after intervention.

Standard care was not defined in the protocol, but was assumed to be given according to contemporary European and national guidelines.

Platelet transfusions were initiated within 6hrs of intracerebral hemorrhage symptom onset and within 90 min of diagnostic brain imaging.  Those patients on clopidogrel received 2 units of platelets, all others received one unit as determined by in-vitro experiments. 

Outcome Measures

The primary endpoint was difference in functional outcome at 3 months after randomization scored with the mRS, as was done for the inclusion criteria, which was scored by a physician or nurse not involved with the medical treatment. Secondary clinical endpoints further stratified these outcomes into survival, poor outcome defined as mRS of 4-6 and poor outcome defined as mRS of 3-6. Another secondary outcome was median absolute intracerebral hemorrhage growth in mL after 24 hours on brain imaging. Safety outcomes and other serious adverse events were also recorded.

Results

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For the primary endpoint of functional outcome difference at 3 months, there was an increase in odds toward death or dependence at 3 months in those that received platelet transfusions, both adjusted and unadjusted (adjusted common OR 2.05, CI 1.18-3.56, p=0.0114). Secondary analysis and serious adverse events are listed in the following graphs:

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Interpretation

For the primary outcome, there was increased odds of a poorer functional outcome after 3 months among those who received platelet transfusions compared to those who just received standard care. In the secondary analysis (which stratifies these functional outcomes further into smaller categories), showed there was a significant poorer outcome at 3 months within the mRS 4-6 category (higher disability) for those that received platelets. All the other subcategories were insignificant. Median ICH growth did not differ significantly between the two groups at 24 hours. Among the serious adverse events, the only minimally significant difference was an increased odds of an adverse event due to ICH as a whole in the platelet transfusion group, though this may be explained by differences in the baseline characteristics of the different arms of the study.

Strengths

• While there was some crossover between the two study arms, there was an intention-to-treat analysis as well as an as-treated analysis.
• Follow-up was strong without attrition.
• The physician/nurse that performed the mRS after 3 months was blinded to randomization.
• Their intended inclusion/exclusion criteria were strong.

Weaknesses

• Looking at the baseline characteristics, there were several patients included in the trial that should have been excluded by criteria (GCS <8, infratentorial ICH location, etc).  
• Even though the paper states that the baseline patient characteristics were balanced between the two arms, it appeared that as a whole, the patients who were randomized to receive platelets were sicker (lower GCS, more patients with ICH volume >30mL, both the infratentorial ICH patients).
• The majority of patients were on a COX inhibitor (>90% of patients), with very little representation of the other antiplatelet agents
• This study could have been strengthened with platelet function testing to evaluate for modified treatment effect.

Internal/external validity

External validity could be questioned as this study presumably included only European patients (although race was not specifically mentioned). This study also likely cannot be generalized to non-COX inhibitors given how few patients were on ADP inhibitors, such as clopidogrel.

Internal validity is questioned with the inclusion of patients who met exclusion criteria and should have been excluded. The authors comment on this being an issue for several emergency-department studies given situational urgency.

Future Directions

Given the high prevalence in use of Plavix or Ticagrelor, there should be a study that includes more ADP inhibitors.

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Summary: 

• This was a European multi-center randomized trial comparing the functional outcomes of patients with spontaneous intracerebral hemorrhage on antiplatelet therapy, when they received either standard care or standard care plus platelet transfusion.
•  The study included 190 patients from either Netherlands, UK or France.
•  Their results indicated that platelet transfusion did not benefit patients from a functional outcome after 3 months, and in fact, may be associated with worse outcomes. Although there were several weaknesses in the study’s execution, these results seem to be significant enough to have some validity.
• There was no difference in reported/observed immediate (<24 hour) outcomes on imaging between the two groups

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Expert Commentary:

ICH is a devastating disease, and often one which we often must watch powerlessly, despite the acuity of presentation.  One of the first goals in ICH management is to prevent further bleeding.  Platelets for aspirin reversal seemed promising, since it has been documented that patients on aspirin have more hematoma expansion and worse outcomes, as well as clear anecdotal evidence from surgeons that platelet infusion in aspirin users makes an overt difference intra-op.  So why should PATCH have been negative?

Given the complexity of factors leading to hematoma expansion and subsequent hospitalization, it is hard to drive outcomes with any one intervention.  However, even the rate of hematoma expansion was unchanged.  Even though the irreversible binding of Aspirin usually takes many days to wash out, serum half-life is about 15-20 minutes (with active metabolites lingering a few hours).  One thing to remember is that transfused platelets themselves can have time-limited efficacy due to immune-related consumption and inactivation.  While even a temporarily effective transfusion can help stop brief bleeding such as in the OR or during acute stabilization, it is unlikely to prevent the stuttering hematomal expansion of ICH.

Platelets, unlike other blood products, must be stored at room temperature.  Therefore, platelet transfusions are associated with high risks of transfusion reactions.  It is theorized that some platelets may become activated prior to transfusion and can therefore also be associated with a risk of pathological clotting.  These factors could blunt any potential benefit of treatment.

Intracerebral hemorrhage is a rarer and more heterogenous illness than stroke or MI.  This trial is as high of quality as we are likely to obtain on the topic.  When applying the results of the PATCH trial, it is important to remember that no patients with platelet counts below 100k were enrolled, so transfusions to meet that goal may still be performed.  Also, it is still acceptable to transfuse for procedures or surgery.  The study did not explore any sort of functional assays, namely Platelet Function Assay (PFA) or Platelet Aspirin Assay (PAA). 

Stephen Trevick, MD

Neurocritical Care Fellow, NUEM

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How to cite this post

[Peer-Reviewed, Web Publication]  Berg A,   Huebinger A  (2018, May 14 ). The PATCH Trial.  [NUEM Blog. Expert Commentary by Trevick, S]. Retrieved from http://www.nuemblog.com/blog/PATCH

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Resources

1. Feigin VL, Krishnamurthi RV, Parmar P, et al. Update on the global burden of ischemic and hemorrhagic stroke in 1990–2013:the GBD 2013 Study. Neuroepidemiology 2015; 45: 161–76.

The ATACH-2 Trial: Blood Pressure Control in ICH

Written by: Jessica Bode, MD (NUEM PGY-3) Edited by: Michael Macias, MD,  (NUEM class of 2017) Expert Commentary by: Andrew Naidech, MD, MSPH

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Introduction

Hemorrhagic stroke is the second-leading cause of strokes (behind ischemic strokes). The 30-day mortality from intracerebral hemorrhage (ICH) ranges from 35 to 52 percent, with one-half of these deaths occurring within the first two days[1]. A 2010 systematic review estimated that only between 12 and 39 percent of patients go on to achieve independent function[2]. Somewhat intuitively it has long been thought that aggressive blood pressure (BP) control may improve outcomes by limited hemorrhage expansion.

The INTERACT2 study examined the efficacy of intensive systolic blood pressure (SBP) reduction to a goal of <140 mmHg over the course of 1 hour and within a 6 hour window of symptom onset as measured by death and disability. While initially touted as a positive study further examination of the methodology revealed significant differences in the two arms only with ordinal analysis. When comparing this aggressive intervention to the standard treatment SBP goal of <180, the 2013 study found no significant difference between treatment arms. [3]

The 2016 ATACH-2 study sought to reexamine this question: Does aggressively lowering blood pressure lead to decreased death or disability at 90 days?

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Study

Qureshi AI et al. Intensive blood-pressure lowering in patients with acute cerebral hemorrhage (ATACH-2 Trial). NEJM 2016. PMID: 2726234

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Study Design

• Randomized, multicenter, two-group, open-label trial (took place in 110 sites in the US, Japan, China, Taiwan, South Korea and Germany)

Population

• Age 18-90
• Intracerebral hemorrhage (< 60 cm3) seen on CT scan with NIHSS score 4 or greater
•  GCS ≥5 
•  Presenting within 4.5 hours of symptom onset (initially within 3 hours but later extended)
• At least one reading of SBP of 180 mmHg or more between symptom onset and the initiation of intravenous antihypertensive treatment

Exclusion Criteria

• Time of symptom onset not reliably established
• Previously known AVM, neoplasm or aneurysm
•  Intracerebral hematoma considered to be related to trauma.
• lCH located in infratentorial regions such as pons or cerebellum
•  IVH associated with intraparenchymal hemorrhage and blood completely fills one lateral ventricle or more than half of both ventricles
• Subject is considered a candidate for immediate surgical intervention by the neurosurgery service
• Pregnancy or parturition within previous 30 days or active lactation
•  Any history of bleeding diathesis or coagulopathy
• Use of warfarin within the last 5 day
• A platelet count less than 50,000/mm3
• Known sensitivity to nicardipine
• Pre-morbid mRS of 4 or greater
• Subject’s living will precludes aggressive ICU management

Ultimately 8532 patients were screened, 1000 were randomized

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Intervention Protocol

Patients were assigned to aggressive (SBP goal <140) or standard (SBP goal <180) arms with BP control achieved via nicardipine or, alternatively, via labetalol or diltiazem. Strict control within these parameters was maintained for 24 hours.

Outcome Measures

Primary

• Modified Rankin scale of 4-6 (death or disability) at 3 months after randomization

Secondary

• European Quality of Life–5 Dimensions (EQ-5D) scores at 3 months
• Visual-analogue scale (VAS) at 3 months
• Proportion of patients with 33% or more expansion in volume of hematoma on 24h delta scan
• Safety outcomes (fall in GCS by 2 or increase of NIH Stroke Score by 4)
• Incidence of serious adverse events within 72 hours

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Results

“In conclusion, our results do not support the notion that acute reduction to a target systolic blood pressure of 110 to 139 mmHg in patients with intracerebral hemorrhage is more effective in improving functional outcomes than a reduction to a target systolic blood pressure of 140 to 179 mm Hg.”

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Aggressive SBP reduction to a target of 110-139 mmHg did not result in lower rate of death or disability compared to the standard treatment goal of 140-179 mmHg. There was no difference between groups in mRS of 4-6 at 3 months (38.7% in intervention arm, 37.7% in control arm).

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Interpretation

 Strengths

•   Multi-centered trial
•  Clinically meaningful outcomes

 Weaknesses

• During the trial, ATACH-2 expanded enrollment from patients who presented within 3 hours to those who presented within 4.5 hours. As the authors acknowledge in the paper, this could mask a time-dependent loss of benefit but they deem this unlikely as subgroup analyses of INTERACT2 data did not demonstrate this phenomenon.
• Intracerebral hemorrhage grouped as a single entity
• Primary treatment failure (inability to achieve target BP within 2 hours) was seen in 12.2% of patients in the intensive-treatment group vs just 0.8% in the standard-treatment group. It’s difficult to interpret its impact on treatment effect.
• 56.2% of patients were Asian making it difficult to generalize to primarily European populations though when subgroups extracted out again no clinically significant benefit to aggressive therapy was found.

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The Bottom Line

As mentioned above, ATACH-2 serves as a rebuttal to the purported positive results of the INTERACT2 trial. On further analysis, the interpretation of INTERACT2 results was somewhat flawed and many experts have ultimately come to view it as a negative trial, consistent with ATACH-2. Dr. Rory Spiegel discusses this in more depth here.

As it stands, decisions should be made in conjunction with neurology and neurosurgery at your institution, but the literature at present does not support aggressive BP control and in fact this practice may lead to harm in the form of decreased cerebral perfusion. Standard SBP target of <180 mmHg should probably be maintained.

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Expert Commentary

Intracerebral hemorrhage (ICH) is the most deadly form of stroke and has no FDA approved treatment . This is not to say nothing can be done, and the lack of specific therapies has heightened the importance of optimizing the management. Protocols to improve diagnosis, obtain appropriate imaging, obtain subspecialty care, screen for dysphagia, ensure rehabilitation assessments and accredit Stroke Centers are important. Within these broad strokes, hypotheses about which specific management strategies are likely to improve biomarkers and, subsequently, patient outcomes, can be rigorously tested.

Severe hypertension is both a risk factor and a cause of ICH. Hypertension is plausibly linked to growth of the hematoma, a proximate cause of worse patient outcomes. Thus, it is reasonable to test the hypothesis that lowering blood pressure reduces hematoma growth and, subsequently, improves patient outcomes.

INTERACT2 was negative for its primary endpoint of improved odds of good outcome with a dichotomous ordinal scale, while statistically significant for ordinal regression (a method to determine if there is a shift along the score) and health-related quality of life (HRQoL). ATACH-2 found no evidence of overall benefit to rapid blood pressure lowering, and an increased rate of renal failure. There was no evidence that rapid lowering of blood pressure reduced hematoma growth, which makes the potential mechanism of improved outcomes conjectural.

These studies highlight another problem: Outcomes assessment in clinical trials may be too crude to show meaningful differences between groups. Since INTERACT2 and ATACH-2 were designed, NIH has created, normed, and distributed new benchmarks for HRQoL, the Patient Reported Outcomes Measurement Information System (PROMIS) and Neuro-QOL. We have previously validated PROMIS and Neuro-QOL against ordinal scales, and found they highlight facets of HRQoL that are important, but not as well measured by ordinal scales while being more statistically powerful [4].  They are now generally accepted as pivotal outcomes for clinical research [5]. 

Aggressive blood pressure lowering is likely to be of some benefit; a target of 140 – 160 mm Hg systolic is reasonable for patients with systolic blood pressure <220 mm Hg pending the next update of evidence based guidelines. Going forward, accurate assessment of patient outcomes with sensitive, powerful scales will make clinical trials more meaningful, and more likely to be positive.

Andrew Naidech, MD, MSPH

Professor of Neurology (Stroke and Neurocritical Care), Anesthesiology, Medical School Sciences, Neurological Surgery, and Preventive Medicine (Health and Biomedical Informatics), Northwestern University

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References

1. Flaherty ML, Haverbusch M, Sekar P, et al. Long-term mortality after intracerebral hemorrhage. Neurology 2006; 66:1182.
2. van Asch CJ, Luitse MJ, Rinkel GJ, et al. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol 2010; 9:167.
3. Anderson CS, Heeley E, Huang Y, et al. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med 2013; 368:2355.
4. Naidech AM, Beaumont JL, Berman M, Francis B, Liotta E, Maas MB, Prabhakaran S, Holl J, Cella D.Dichotomous "Good Outcome" Indicates Mobility More Than Cognitive or Social Quality of Life.  Crit Care Med. 2015 Aug;43(8):1654-9. doi: 10.1097/CCM.000000000000108
5. Salinas J, Sprinkhuizen SM, Ackerson T, Bernhardt J, Davie C, George MG, Gething S, Kelly AG, Lindsay P, Liu L, Martins SC, Morgan L, Norrving B, Ribbers GM, Silver FL, Smith EE, Williams LS, Schwamm LH.An International Standard Set of Patient-Centered Outcome Measures After Stroke.  Stroke. 2016 Jan;47(1):180-6. doi: 10.1161/STROKEAHA.115.010898. Epub 2015 Nov 24.

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