Our goal is to introduce the concept of emergency brain resuscitation. We propose that it be used in a manner similar to that of cardiopulmonary resuscitation and that it be used for patients who have strokes either in or out of the hospital. Our immediate goals are to increase awareness among medical personnel of the emergent nature of stroke; to rapidly identify, diagnose, and stabilize patients with stroke; and to facilitate the study of therapies for acute stroke. Long-term goals are to decrease morbidity after stroke and to improve long-term functional outcome. An understanding of the importance of emergency brain resuscitation is vital for non-neurologists because most patients with stroke in the United States are not cared for primarily by neurologists. We review the scientific and clinical basis for emergency brain resuscitation and make specific recommendations forming pilot programs.

Scientific Basis for Emergency Brain Resuscitation

The brain of the normal adult human has a cerebral blood flow ranging from 30 to 70 mL/100 g per minute [6, 7]. When the cerebral blood flow decreases to less than 20 mL/100 g per minute, compensatory mechanisms such as vasodilation and increased oxygen extraction are insufficient to meet the metabolic needs of neurons and neurologic dysfunction occurs [6-9]. A cerebral blood flow of less than 12 mL/100 g per minute is probably sufficient to produce cerebral infarction if it is not rapidly reversed [10]. If some collateral flow develops and increases the local cerebral blood flow, then the onset of infarction can be delayed and the therapeutic window can be prolonged.

In some cases of stroke, a region of marginally viable but dysfunctional brain tissue probably surrounds the core of infarcted tissue. This has been termed the "ischemic penumbra" [6-11]. In studies using positron emission tomography and magnetic resonance spectroscopy, the visualization of a region that has some of the characteristics of an ischemic penumbra has been reported Figure 1 [12, 13]. The concept of salvaging injured but viable neurons within the penumbra forms the basis for many new interventions for acute stroke [1, 5, 14]. Other factors that may influence neuronal survival during cerebral ischemia include hyperglycemia [15-19], cerebral perfusion pressure [20-22], and brain temperature [23-25].

Surprisingly few reports have addressed the duration of focal ischemia required to produce irreversible neuronal damage [26-28]. A few studies have rigorously investigated the relation between the duration and degree of ischemia (which most closely approximates clinical stroke) in unanesthetized animal models. Some permanent damage may be produced within 15 to 30 minutes of a focal ischemic insult [29]. In some models, damage in the entire distribution of the occluded vessel does not become irreversible until approximately 4 to 6 hours after vascular occlusion [2, 5, 28, 30].

The relevance of these times to stroke in humans is complicated by all of the factors discussed above and by interspecies differences in metabolism and anatomy that may affect the degree of ischemia [29, 31]. The probable relation between duration of ischemia and neuronal injury is shown in Figure 2. Even if cerebral circulation is restored rapidly, data suggest that additional damage may occur, possibly because of the production of neurotoxic free radicals [32].

View larger version (13K): [in this window] [in a new window]   Figure 2. Relation between neurologic injury and duration of cerebral ischemia. A brief period of ischemia followed by restoration of blood flow results in complete neurologic recovery (point CR), as seen in transient ischemic attacks. Episodes of increased ischemia lead to progressively more damage until injury is complete. At this point, further ischemia cannot produce any measurable increase in damage. Point NR defines the extent of ischemia after which no recovery is possible and the maximum window of opportunity for a therapy for an acute stroke. There are no scale markings on the x-axis because these times are now uncertain. Data suggest that the duration of ischemia associated with CR is several minutes and that several hours will produce NR. The time points will be altered (prolonged) in cases of incomplete ischemia. The shape of the curve will differ for some individual brain regions.

The conclusion from numerous animal studies is that rapid reversal of focal cerebral ischemia or early treatment with neuroprotective agents, or both, are the key factors associated with the reversal or limitation of cerebral damage [2, 5, 33-35]. Most of the data supports the concept that the rapid initiation of therapy would be beneficial in many cases of stroke in humans.

Clinical Basis for Emergency Brain Resuscitation

Several studies have shown that patients having a stroke outside the hospital may not rapidly seek or receive medical care (Table 1). Intense educational efforts at some medical centers have helped to reduce delays [37, 38]. The most striking success has been that of the trial of thrombolysis sponsored by the National Institutes of Health, which has been able to enroll large numbers of patients within 90 to 180 minutes of stroke onset [37, 42, 43]. In many other cases, patients with stroke are not rapidly evaluated or treated when they reach a hospital. Some are sent home, only to return hours later when their deficit worsens. Even patients having a stroke in the hospital are not evaluated rapidly. A recent study examined the time profiles for patients who had had a stroke while hospitalized for other reasons [39]; the mean and median delays between onset of symptoms and a neurologic evaluation were 14.5 and 2.5 hours, respectively. At least 35 000 patients per year have strokes in the hospital; they compose an important pool of patients to consider for rapid therapy [36].

It has been argued that this approach will become practical and popular only after an effective acute therapy for stroke is identified. We feel that this is circular reasoning because without such an approach, enrolling large numbers of patients with stroke and validating new therapies will be challenging. A recent trial of thrombolytic therapy in myocardial infarction enrolled more than 40 000 patients in a single study [44]. This is more than 10 times as many patients as have been enrolled in all of the thrombolytic trials for stroke published to date [45]. In addition, the presence and activities of a team would provide positive reinforcement of the need for rapid therapy, which might help change the nihilistic attitudes of some health care providers.

Organization of the Emergency Brain Resuscitation Team

The team should include at least the following personnel: a neurologist or neurosurgeon, preferably one with expertise in cerebrovascular disease; a nurse, nurse clinician, or physician's assistant trained in cerebrovascular disease; a respiratory therapist; members of the cardiac code team; and a phlebotomist. In some cases, a pharmacist and an electrocardiography technician would be helpful. Inclusion of a neuroradiologist or a radiology technician, or both, may be appropriate in certain settings. In academic medical centers, senior members of the neurology or neurosurgical housestaff or fellows could serve in a rotation as the neurologist or neurosurgeon on the team.

Community-based and rural hospitals without housestaffs might find it problematic to have a neurologist or neurosurgeon in the hospital and on call 24 hours a day. Two alternatives are possible: Train a small pool of emergency department physicians (who are in-house) in the diagnosis and treatment of cerebrovascular disease, or have neurologists and neurosurgeons in the community on call in a rotation with the understanding that they will immediately come to the hospital to evaluate any patients with acute stroke. Having personnel in-house, however, is certainly preferable.

Emergency Brain Resuscitation: Triage, Diagnosis, Treatment

We propose that resuscitation be a two-phase process: prehospital triage followed by in-hospital management. Ideally, the prehospital phase will begin with a call to 911 (or its equivalent outside the United States) when a patient with acute stroke is identified. Use of the 911 system has been shown to be the fastest way for patients with acute stroke to enter the health care system [37]. New triage protocols should be implemented to speed patient flow in the emergency department. The team should be notified immediately that a patient is en route to the hospital; for hospitalized patients who are suspected of having a stroke, the team should be notified when the patient is first seen.

When the patient arrives in the emergency department, the team leader should assume primary responsibility for managing the patient. Airway, breathing, and circulatory functions must be stabilized. An intravenous line should be established, and blood should be sent for a complete blood count, coagulation studies, chemistries, and additional studies as determined by the clinical situation. The patient's vital signs and neurologic status must be monitored continually throughout this period. A neurologic screening and a general examination should be done to determine the probable territory and type of stroke and to assess for other systemic diseases, such as atrial fibrillation and severe hypertension.

The next step is an emergent computed tomographic scan of the head. This will probably occur before a complete history has been taken and before most laboratory tests are completed. The initial scan should be read from the video monitor to avoid delays in filming. While these initial assessments are under way, a member of the team should approach the patient and the family, gather additional medical history, and discuss any appropriate experimental interventions that require informed consent.

The expertise of the team will be beneficial in several areas: blood pressure management, respiratory care, fluid management, cardiac status, management of intracranial pressure, use of anticoagulation, and glucose management. Although controversy exists about some of these areas [46], the expertise of a team would help to establish rational treatment protocols and to test new treatments.

Several areas of investigation that may lead to rapidly treating and reversing an acute stroke are shown in Table 2. The two major approaches to the treatment of ischemic stroke are arterial recanalization (reperfusion) and cytoprotection. Both require that treatment begin as soon as possible. Pilot studies of thrombolysis for ischemic stroke have been completed in the United States, Japan, and Europe, and several large, randomized trials are nearing completion. Most studies require that treatment begin within 90 to 360 minutes (6 hours) of the onset of symptoms [42, 43, 47, 48].

Agents that protect ischemic neurons from excitatory neurotransmitters, calcium influx, and free radicals have shown great promise in laboratory stroke models [14, 49]. Preliminary results of tests using one compound, CGS 19755, have shown it to be beneficial for patients with stroke [50, 51]. Another group of drugs, the 21-amino steroids, has been shown to reduce brain damage after experimental stroke, perhaps by inactivating oxygen free radicals [52]. One of these compounds, tirilazad, is well tolerated when given to patients with subarachnoid hemorrhage [53]. A trial of tirilazad in patients with subarachnoid hemorrhage showed a significant reduction in mortality for some patients treated with doses of 6 mg/d (Kassell N. Unpublished data).

In addition to medical therapies, interventional and surgical options are available for the treatment of stroke, including angioplasty, embolectomy, and acute carotid endarterectomy [54-58]. The efficacy of most of these approaches has not yet been proven.

Implementation of an Emergency Brain Resuscitation Program

In this section, we outline the steps necessary to begin forming teams at selected hospitals. This organizational approach may not be appropriate for all settings, and particular steps may require modifications. A summary of these steps is given in Table 3.

1. Designate one or more team or project directors. One or two persons (ideally, neurologists or neurosurgeons) with expertise in clinical stroke should organize and lead the team.

2. Create a steering committee (optional). This committee would set long- and short-term goals for the team, review key policy decisions, and provide support should problems arise.

3. Establish funding resources. The funding level should be sufficient to support staffing, communications, publicity, data collection and entry, and analysis. Seeking funds from various agencies is possible for some pilot programs. The American Heart Association, the National Stroke Association, the National Institute of Neurological Diseases and Stroke, and pharmaceutical companies may be receptive to requests for funding.

4. Develop specific short- and long-term goals. Both qualitative and quantitative goals should be set. End points such as response time, rates of common complications, mortality, length of stay, location after discharge, neurologic function, and costs will be important for assessing efficacy and providing data for subsequent protocols.

5. Develop a data collection form. Data forms should be designed to provide information on the demographics of the patients treated (including age, sex, and referring hospital) and time data. They should include scales for determining clinical outcomes and data on enrollment in research protocols.

6. Educate professionals and the public. The success of this program will partially depend on the education of health care providers and the public. Local or regional efforts, directed by medical personnel who have an intimate knowledge of the population and referral patterns, may be effective [37, 38].

7. Do pilot studies at select centers that have the staff and expertise to do emergency brain resuscitation. Simple, objective, and meaningful goals should be established for this phase of the program. In one small pilot study, stroke code teams shortened in-hospital delays in treating patients in the emergency department [59]. Patients seen by this team had an average delay of only 4.8 minutes between team notification and initiation of a bedside evaluation.

8. Test new therapies. Once a network of successful programs is formed, the centers in this network should lead the testing of new therapies for stroke. The inclusion of community as well as academic hospitals may be necessary to achieve sufficient patient enrollment.

Costs and Limitations

It could be argued that this approach would be successful only after an acute treatment for stroke is identified. As discussed above, time is probably the most important factor in determining the survivability of ischemic neurons and the success of any interventions for acute stroke. Large numbers of patients with acute stroke will have to be treated soon after stroke onset to validate some new therapies [60]. Unless a system is developed to rapidly identify and treat patients with stroke, the study and validation of new therapies may be stunted.

The costs of forming and implementing teams are small when compared with the operating budgets of most hospitals. Assuming a modest on-call compensation for nurses and for physicians, the annual costs for nursing and physician coverage would be $10 000 to $20 000. If fringe benefits, educational efforts, and additional beepers are included, we estimate a cost of approximately $225 000 per year per facility. If two or three patients with stroke per hospital per year can return to work (as opposed to being permanently disabled) because of emergency brain resuscitation, or if total hospital costs are reduced for patients with stroke by an average of 10%, then, in our opinion, the expense of the program would be warranted. Less intensive efforts have yielded more impressive savings and improvements in patient outcomes [61, 62].

Conclusion

Top Conclusion Author & Article Info References

The approach to treating patients with acute stroke with emergency brain resuscitation has the potential to significantly reduce disability and costs and to change attitudes about the emergent nature of stroke. If successful, this program should be implemented at all hospitals. As this approach gains acceptance, stroke therapy will move into an era of action rather than one of reaction.

Appendix

Members of A Working Group on Emergency Brain Resuscitation are Mark J. Alberts, MD, P.O. Box 3392, Duke University Medical Center, Durham, NC 27710; Patrick D. Lyden, MD, and Justin A. Zivin, MD, PhD, Department of Neurosciences, University of California, San Diego, 3350 La Jolla Village Drive, San Diego, CA 92161; Thomas J. Brott, MD, University of Cincinnati College of Medicine, 231 Bethesda Avenue, Cincinnati, OH 45267-0525; and Lawrence M. Brass, Yale Cerebrovascular Center, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510.