Keynote Address: The Importance of Time
James C. Grotta, M.D.
University of Texas Medical School Houston
Recent progress in the treatment of acute ischemic stroke is to a great extent the result of two major basic research themes evolving over the past 20 years: (a) our ability to measure cerebral blood flow (CBF) and metabolism and the resultant observation that the first minutes to hours after a stroke is a period of dynamic (and potentially reversible) change, and (b) the development of appropriate animal models of stroke that allowed us to explore the components and duration of this dynamic.
Studies of CBF and metabolism. Most methods of measuring CBF are based on the Kety-Schmidt principle that the flow of a nonmetabolized and diffusible tracer is proportional to its wash-out from the organ. Using radiolabeled xenon or hydrogen clearance, it was soon learned that flow in brain regions supplied by an occluded artery is variably reduced depending in part on the distance of the region from the stroke epicenter, and that flow in much of these regions was sufficient to maintain viability for some period of time as evidenced by correlative measurements of oxygen or glucose metabolism in the same regions. The brain regions that were threatened but viable were termed the "ischemic penumbra," and the time this penumbra could remain viable was termed the "therapeutic time window." It was also appreciated that flow usually is restored spontaneously (and may even become greater than normal [hyperemic]) in most penumbral brain regions after a stroke, but that this did not result in tissue survival unless reperfusion occurred within the therapeutic time window. Finally, we learned that the more profound the reduction of blood flow, the briefer this window became; with flow reduced to essentially zero, as after cardiac arrest, tissue death became inevitable after 10 minutes, whereas flow of about 15 cc/100 gm of brain tissue/minute such as is measured after focal stroke could be tolerated for substantially longer.
Stroke models. Animal models of stroke were needed to allow us to identify which pathophysiological events are set in motion by the occlusion of an artery supplying the brain, and how these events lead to cellular destruction. While our knowledge is still incomplete, numerous therapeutic strategies aimed at rectifying or reversing steps along this "ischemic cascade" have been shown to reduce ischemic damage in these models and are under development and in various stages of clinical evaluation (1,2). It is likely that combinations of such strategies will be most successful. Animal models have also allowed us to study the therapeutic time window for each of these strategies.
Scientists have developed numerous animal models, including rodents, that allow reperfusion after variable durations of middle cerebral artery occlusion. Most studies in these models have consistently shown that reperfusion within 3 hours of arterial occlusion will limit to some extent the size of the resulting infarct and improve other measures of outcome as well (3,4). These studies also show, however, that reperfusion after the 3-hour time point will have little or no benefit or may make things worse (5). In fact, understanding the pathophysiology of such "reperfusion injury" now assumes greater importance since some patients treated with t-PA even within the 3-hour time window will develop cerebral edema and/or hemorrhage (6), and others may harbor less obvious consequences of reperfusion at the cellular level which negate the benefits of re-establishing adequate blood flow. If we can work out the important components of the phenomenon of reperfusion injury, we may make thrombolytic therapy both safer and applicable to a larger number of patients treated beyond the 3-hour time point.
Animal models have also shown that, at least within the first few minutes to hours after the onset of ischemia, the ultimate fate of tissue after reperfusion is dependent on two main variables: the duration and the depth of hypoperfusion (3). Consequently, effectively and safely selecting patients for thrombolysis depends on knowing both of these variables. To date, clinical studies have used only the stopwatch without an on-line measurement of cerebral hypoperfusion. Until we better understand reperfusion injury and find a way to measure CBF and tissue viability acutely, we must recognize that the only conclusively positive clinical study of reperfusion (7) was exactly predicted by animal models: patients must be treated within 3 hours.
Animal models also provide us with clues about which neuroprotective strategies might work and how to apply them. These studies suggest that in the first minutes after the onset of ischemia, the release of glutamate and rising intracellular calcium play pivotal roles in the fate of tissue in the ischemic penumbra, that other "downstream" events may also be important especially in reperfusion injury, and that combination therapy using two or more neuroprotective strategies is better than monotherapy. It is particularly important to emphasize to laboratory researchers working with animal models that the biology of neuronal repair and recovery is still very poorly understood. Much more attention must be focused on this aspect of experimental ischemic injury in order to design therapies that may be useful if started in the subacute or chronic stages of stroke.
The lessons to clinical investigators from these animal data are that:
1. Neuroprotective therapy targeting neurotransmitter release and intracellular calcium-mediated events must be started very early after focal ischemia (the exact time window is unknown but none of these strategies has been effective in reducing infarct volume after middle cerebral artery occlusion in animals when started beyond 1-2 hours after the onset of ischemia), so prehospital treatment or prophylactic therapy of high-risk patients (i.e., those scheduled to receive coronary artery bypass or carotid endarterectomy) should be considered in the design of clinical trials.
2. If the target is penumbral regions, the clinical benefit may be modest and not very dramatic, mandating an adequate sample size and careful long-term follow up and outcome assessment.
More than lip service needs to be paid to the idea of combination therapies. At least within the first 3 hours of stroke, neuroprotective therapies will now have to be tested in combination with t-PA for those patients meeting the criteria for thrombolytic therapy. It is possible that a neuroprotective monotherapy will be effective if started beyond this time point and several such trials are presently under way. However, animal studies (and clinical experience) predict that neuroprotective trials of extended time window monotherapy will be negative or equivocal. After that, we hope that instead of giving up on the concept of neuroprotection, we will overcome the practical obstacles and carry out prophylactic or prehospital trials of rational combination therapy.
Despite the biologic considerations indicating the "need for speed" in evaluating and treating acute stroke patients, current recognition and treatment of stroke patients is usually too slow to allow therapy within the therapeutic time window. This is due to many factors, including lack of public awareness of stroke symptoms and the importance of early recognition and treatment; "neglect" of important neurological deficits by the patient due to involvement of sensory brain regions; unrecognized onset of symptoms during sleep; unavailability of family or friends to provide help in seeking rapid medical attention; unavailability or underuse of the 911 system for immediate stroke transport; lack of prioritization for rapid transport of stroke patients by prehospital emergency medical services (EMS) systems; lack of prioritization or an efficient system for stroke triage, diagnosis (especially brain CT to exclude hemorrhage), and treatment within the emergency department (ED); lack of knowledge among emergency medical care providers about acute stroke and its treatment; and lack of neurological expertise in the acute ED setting (8). These factors pose an immense "systems" problem, but solutions have been achieved for other conditions such as trauma and heart attack (9).
For medical personnel, it is most expedient to focus efforts on improving the EMS, ED, and physician response to patients with acute stroke (10). In conducting a trial of thrombolysis for acute stroke in our community, we studied the existing state of EMS and emergency stroke management at eight participating hospitals, focusing particularly on system delays (11). We then evaluated the impact of a dedicated "stroke team" on our ability to complete the transport, triage, diagnosis, and treatment of patients within the therapeutic time window. The hospitals included a large fully affiliated private medical school teaching hospital, large and small private community hospitals with variable teaching roles, and a public urban teaching institution. They ranged in bed capacity from 175 to 979. Our stroke team consisted of neurologists and registered nurses who specialize in acute stroke therapy. One physician and one nurse were on call 24 hours a day, 7 days a week. Inservicing of the Houston Fire Department EMS personnel was carried out by the stroke team with specific instructions to rapidly transport all acute stroke patients and to immediately notify the stroke team. A communications system was set up with a dedicated beeper activated by EMS or the ED triage nurse and worn by both the stroke team physician and nurse on call for any acute stroke patient transported to or arriving at a participating hospital ED. Stroke team personnel were equipped with cellular phones and appropriate lists of key personnel such as CT technicians who would be notified and activated while the team was en route. Patient, pharmacy, laboratory, and radiographic (CT) movement and procedures were flow-charted within each ED and algorithms and guidelines were developed to speed assessment and treatment.
In the total population of acute stroke patients arriving at participating EDs within 6 hours of symptom onset, the mean time from onset of stroke symptoms to arrival at the ED was 115 minutes; there was no difference between patients arriving by ambulance or private vehicle. The mean interval from ED arrival to placement in an ED room was 11 minutes.
In the absence of the stroke team, patients were seen by a physician a mean of 28 minutes after arrival at the ED. Patients arriving by ambulance were examined by the ED physician more rapidly (20 minutes) than those arriving by car (48 minutes). Stroke patients were in the ED for a mean of 123 minutes before they were seen by a neurologist, and 100 minutes before a brain CT scan was performed. While vital signs were obtained within 7 minutes, drawing blood took 48 minutes and obtaining an electrocardiogram took 61 minutes. Patients stayed in the ED from arrival to disposition for a mean of 324 minutes. These intervals were not substantially different among the different hospitals regardless of type or size except that the public hospital was slightly slower and the smaller community hospitals had less documentation of neurological findings and slower access to neurological consultation.
All intervals were shortened when the stroke team was activated. For example, in the teaching hospital, the mean interval from ED arrival to completion of the entire evaluation of the patient including CT (i.e., "door to needle time") was reduced from 139 to 50 minutes.
We conclude that EMS, triage, CT scanning, neurological consultation, and medical attention for most acute stroke patients is too slow to allow treatment within the therapeutic time window. Upgrading EMS transport from Code I (nonurgent) or II (emergent) to Code III (life-threatening) might help. Selection of patients for potentially dangerous stroke therapies may be problematic in smaller community hospitals if neurological consultation is not available. Rapid availability of CT scanning is essential since 25% of our patients had intracerebral hemorrhage or non-ischemic cause for their acute stroke symptoms, yet the interval was 2 hours between ED arrival and CT scanning. Despite these findings, most EMS and ED stroke management problems can be corrected by faster patient transport and medical evaluation, the availability of an acute stroke team, and education of ED physicians and nurses.
1. The International Nimodipine Study Group. Meta-analysis of nimodipine trials in acute ischemic stroke. Stroke 1992;23:148.
2. Lenzi GL, Grigoletto F, Gent M, et al (including the Early Stroke Trial Group). Early treatment of stroke with monosialoganglioside GM-1: Efficacy and safety results of the early stroke trial. Stroke 1994;25:1552-1558.
3. Jones TH, Morawetz RB, Crowell RM, et al. Thresholds of focal cerebral ischemia in awake monkeys. J Neurosurgery 1981;54:773-782.
4. Kaplan B, Brint S, Tanabe J, et al. Temporal thresholds for neocortical infarction in rats subjected to reversible focal cerebral ischemia. Stroke 1991;22:1032-1039.
5. Yang G, and Betz L. Reperfusion-induced injury to the blood-brain barrier after middle cerebral artery occlusion in rats. Stroke 1994;25:1658-1665.
6. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. JAMA 1995;42:976-982.
7. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;333:1581-1587.
8. Feldmann E, Gordon N, Brooks J, et al. Factors associated with early presentation of acute stroke. Stroke 1993;24:1805-1810.
9. National Heart Attack Alert Program Coordinating Committee. Emergency department: Rapid identification and treatment of patients with acute myocardial infarction. Ann Emerg Med 1994;23:311-329.
10. Malik M, Gomez C, Tulyapronchote R, et al. Delay between emergency room arrival and stroke consultation. J Stroke Cerebrovasc Dis 1993;3:177-180.
11. Bratina P, Greenberg L, Pasteur W, et al. Current emergency department management of stroke in Houston, Texas. Stroke 1995;26:409-414.
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National Institute of Neurological Disorders and Stroke
National Institutes of Health
Bethesda, MD 20892
Last Modified May 17, 2011