The 5 Ps of acute ischemic stroke treatment: parenchyma, pipes, perfusion, penumbra, and prevention of complications. (Featured CME Topic: Stroke).

Abstract: Stroke is a treatable disease. Despite the therapeutic nihilism of the past, the advent of thrombolysis has changed the way stroke is approached. Acute ischemic stroke is a challenging and heterogeneous disease. Treatment needs to be based on an understanding of the underlying pathophysiology of ischemia. Interventions are designed to improve neuronal salvage and outcome. The underlying tenets of stroke therapy focus on the brain parenchyrna, arterial flow (pipes), perfusion, the ischemic milieu or penumbra, and prevention of complications. This article focuses on the practical issues of ischemic stroke care, with a brief review of supporting literature.

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Stroke therapy and care are advancing at a welcome pace. However, despite Food and Drug Administration-approved therapies and national educational efforts, 97% of acute stroke victims nationwide are not being offered thrombolysis. In addition, many unproved and potentially harmful therapies remain in common usage. The lack of standardization in stroke care may be because of the complicated and heterogeneous nature of ischemic stroke. Rowley (1) put forth the "four Ps" concept of acute ischemic stroke imaging. We borrow from this simple concept to clarify our approach to acute stroke treatment. We hope to assist treating clinicians in understanding the underlying evidence and pathophysiology of basic stroke care.

Parenchyma 

Stroke is caused by ischemia to the neuronal structures. Although nearly 85% of strokes are ischemic in nature, there are multiple different subtypes of ischemic strokes. These individual subtypes have differing presentations, causes, prognoses, and treatments. The remaining 15% of strokes are hemorrhagic in nature. Aneurysmal rupture and subarachnoid hemorrhage constitute 5 to 6% of all strokes, and intracerebral hemorrhage makes up the remaining 10%. The damage from intracerebral hemorrhage seems to occur in the first moments after stroke, and treatment is mainly supportive. (2) The emphasis of this article is on ischemic stroke.

Ischemic stroke, in general, presents with a sudden and painless loss of neuronal function. This process typically occurs because of thrombotic occlusion of a supplying artery. When neuronal tissue, which normally receives 60 to 70 ml of perfusion per 100 g of brain tissue per minute, has a reduction of flow to 25 ml/100 g/min, aerobic metabolism cannot be maintained and loss of function occurs. Prolonged ischemia results in a stereotypical series of biochemical events leading to eventual cell death, the so-called ischemic cascade. (3)

The first task in stroke treatment is differentiating ischemic from hemorrhagic stroke. Importantly, hemorrhagic stroke cannot be excluded on the basis of clinical examination and history. Before any intervention, a computed tomographic (CT) image of the brain is mandated. The differentiation of ischemic from hemorrhagic stroke is primarily the role of CT scanning, although magnetic resonance imaging is being investigated for this purpose. (4)

The importance of early CT findings of acute ischemic stroke is controversial, mainly because of the lack of intraobserver agreement. When presented with definite clinical scenarios and direct questions on the size and nature of a CT scan abnormality, general neurologists and radiologists are not perfect, (5) and even experts have fair agreement at best. (6) Treating clinicians should have an appreciation of neuroimaging, and a close relationship with radiology is a requirement.

Stroke Syndromes

There are three general ischemic stroke syndromes (Table 1). The first of these syndromes are the lacunar strokes. These are caused by ischemia within the deep arterioles supplying white matter structures and the thalamus. Caused by a process of intimal reduplication or lipohyalinosis, these strokes typically have the best prognosis. Because they are caused by compromise of small vessels, angiographic studies are often normal. However, despite the lack of visualized thrombus, these strokes do respond to systemic thrombolysis.

The second typical stroke syndrome is caused by thrombotic occlusion of the major intracranial vessels. This produces large, wedge-shaped cortical infarction and presents with loss of the eloquent functions such as language. This stroke subtype is the most well studied and often has a poor prognosis, as with the so-called malignant middle cerebral artery (MCA) syndrome. (7) The cause is nearly always embolic, either from unstable plaque (atheroemboli), cardiac sources (cardioembolism), or spontaneous thrombosis resulting from hypercoagulable states. A thrombus can be visualized 80% of the time during angiography.

The final stroke subtype is brainstem stroke. Although brainstem stroke may be caused by either small-vessel (pontine perforating) or large-vessel (basilar artery) compromise, clinical presentation can be confusing. Brainstem ischemia can present with variable cranial neuropathy, hemiparesis, and levels of consciousness. It is also important to remember that posterior circulation terminates in posterior cerebral arteries, and occipital infarcts with resultant visual field deficits are common. Reference to a textbook on neurologic localization is recommended for further information.

Clinically, it is not always possible to differentiate lacunar, large-vessel, and brainstem infarction. Localization and stroke subtype point toward a causative entity and the location of arterial obstruction. This information can assist with intervention and secondary prevention.

After ensuring that there is no evidence of hemorrhage on CT imaging, the treating clinician should develop a general diagnosis for location, stroke subtype, and possible causes. These first steps help to determine therapy and potential intervention.

Pipes

Ischemic stroke is caused by compromise of flow through either large or small arteries supplying the brain parenchyma. Dissolution of this thrombus and restoration of flow is the goal of thrombolysis. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study (8) established the utility of intravenous thrombolysis in 1995. This trial was the first, and is thus far only one, to show a benefit for neurologic function with treatment for stroke in a double-blinded, controlled, clinical study that led to Food and Drug Administration approval of an acute stroke therapy. Attempts to extend the narrow window of 3 hours from the onset of symptoms have not been successful. (9) Intravenous thrombolysis continues to be the most widely accepted standard of care for patients who meet the stringent criteria.

Some centers use intra-arterial thrombolysis for patients who do not meet the strict criteria for intravenous therapy. This work is supported by the results reported in the Prolyse in Acute Cerebral Thromboembolism trial, (10) which showed a significant benefit for intra-arterial therapy with prourokinase within a 6-hour window from the onset of symptoms. Many centers are using t-PA instead of prourokinase, (11) although it has not been tested in the same rigorous fashion as urokinase for this indication. The indications for intra-arterial therapy and interventional neurology are expanding rapidly, but are limited by the need for a skilled team that must be immediately available, specialized interventional physicians, and costly equipment.

Most neurointerventional therapy is centered on occlusion of the MCA or basilar artery. Much like coronary procedures, intervention may be immediate, delayed, or performed as a rescue if other therapies fail. For select patients, the results are often excellent. (12) In one uncontrolled series, angioplasty of proximal MCA occlusion led to a greater immediate reduction in the National Institutes of Health Stroke Scale, although the scores were not different the day after the intervention or a month later. (12)

Angiography itself is not risk free, and a diagnostic angiogram may cause an embolic event. In a variety of studies, the risk of stroke during diagnostic (ie, nonemergent) angiography is approximately 1%, (13,14) with permanent deficits in about half that. The risk is substantially higher in patients with recent cerebral ischemia or stroke in progress, when there is already unstable plaque.

Intracarotid techniques have changed over time as well, allowing for the learning curve of the technique (eg, how to size the balloon, how fast to inflate, how long to maintain inflation) and the advent of new equipment. One center has found that slightly undersizing the balloon and using slow inflation has minimized complications over a period of years. (15) Rapid improvements in technique are likely to continue. (16) Selection of patients remains very important. A reasonable group is patients who continue to have events on "maximal" medical therapy (however it may be individually defined), and in small series excellent results have been obtained. (17)

Medical Therapies

Fibrinolytic snake venoms show promise. The best studied is ancrod, which is derived from the Malaysian pit viper. The mechanism of action is the degradation of fibrin without platelet activation. One trial of 500 patients reached statistical significance for improved outcome when ancrod was started within 3 hours of symptom onset, and larger trials in Europe and China are planned. (18) For now, ancrod is not licensed for use in the United States. It is uncertain how ancrod will compare with the use of intravenous t-PA, and patient selection for the competing therapies remains to be seen.

Aspirin

Aspirin is the most commonly used antiplatelet medication. It exerts an antiplatelet effect by irreversibly acetylating and deactivating cyclooxygenase, halting production of thromboxane [A.sub.2]. A single 100-mg dose is adequate to irreversibly inhibit this mechanism of platelet activation, and the effect persists for the life of the platelets. However, it does not inhibit platelet aggregation directly. The large Chinese Acute Stroke Trial (19) assessed low-dose aspirin versus placebo in acute ischemic stroke. This trial only tested aspirin versus placebo, and found a similar benefit to the International Stroke Trial (see below). When the results of the International Stroke Trial and the Chinese Acute Stroke Trial are taken together, low-dose aspirin improved the outcomes in approximately 13 per 1,000 patients treated.

Heparin

Heparin is purified from beef lung, and consists of a variety of sugar moieties with anticoagulant properties. Probably the most important mechanism of action is its potentiation of antithrombin, which decreases the activity of factors IX, X, XI, XII, and II (thrombin). It also has some modest antiplatelet effect from its inhibition of thrombin-mediated platelet aggregation. Although its anticoagulant effects occur immediately on administration, after discontinuing an infusion, the half-life is approximately 1.5 hours. The other major risk of heparin is heparin-induced thrombocytopenia (HIT). HIT occurs approximately 4 to 7 days after an infusion has started and is defined by a decrease in the platelet count of 50% or greater; the only treatment is stopping the heparin. After an episode of HIT, both unfractionated and low-molecular-weight heparin have a low risk of causing HIT again; in heparin-naive patients, low-molecular-weight heparin does not lead to HIT.

The efficacy of heparin is standardized per unit, but individual patient responses vary widely, requiring intensive monitoring for patients receiving the full intravenous dose. The activated partial thromboplastin time is the standard on hospital inpatient wards and intensive care units. Although it is inexpensive and the technique is standard at higher intensities of anticoagulation, it is less accurate. The activated coagulation time (ACT) retains a linear relationship to heparin-mediated anticoagulation, and automated ACT machines may be kept in the catheterization laboratory for monitoring during procedures. Low ACT increases the risk of stent thrombosis, (20) but heparin need not be continued more than 24 hours after stent placement.

Although use of intravenous full-dose unfractionated heparin has become uncommon and generally discouraged, the use of low-dose subcutaneous (SC) heparin has acquired strong evidence to support it. The International Stroke Trial randomized 20,000 patients in a 2 X 2 factorial design (ie, patients were independently randomized to receive neither, one, or both of two treatments) to low-dose aspirin and/or low-dose heparin. Although, as a whole, heparin in a dose of 5,000 U SC every 12 hours or 12,500 U SC every 12 hours did not change outcome overall, 5,000 U SC every 12 hours led to significant (if modest) benefit. The group that received 5,000 U SC every 12 hours and aspirin 3,325 mg every day did best.

It is important to keep in mind that patient selection is very important for any stroke therapy. The relative risks and benefits of any stroke therapy must be tailored to the individual patient profile when there are not a priori defined guidelines. General considerations are outlined in Table 2.

Perfusion

Along with restoration, attempts to salvage the brain at risk from ischemia have often focused on increasing collateral flow. Positron emission tomographic and single-photon emission computed tomographic imaging of stroke has demonstrated that ischemic brain parenchyma will extract the maximum oxygen, much like a "miser" hoards maximum resources available. (21) The outlying border zones of the region of ischemia are supplied by means of alternate routes through the leptomeningeal collaterals from adjacent vascular territories. By increasing the quantity and quality of collateral flow to these ischemic regions, there is a potential for salvage from increased nutritive perfusion.

There is strong evidence that decreased collateral flow is harmful. Because of a loss of autoregulation, brain perfusion is strongly affected by changes in systemic blood pressure. Hypotension and dehydration should be avoided. Hypertension, in the form of the Gushing response, is a normal response to cerebral ischemia. Blood pressure should not be lowered in acute stroke, except in the setting of thrombolysis or end-organ damage. (22) Gravity also can have an effect on perfusion. Patients have been seen to experience increased deficit on standing. Alternatively, many patients show clinical and physiologic improvement when the head of the bed is positioned at less than a 30-degree angle. (23)

Despite some initial promise, large trials have not shown conclusive effectiveness of increasing collateral flow. Pentastarch, a synthetic albumin analogue, showed no benefit in the Hemodilution in Stroke Study. (24) However, post hoc analysis suggested that patients who had an increase in cardiac output of >10% have improved outcome compared with placebo and patients who had a <10% increase in cardiac output. In addition, patients with congestive heart failure and low cardiac output tend to have worse stroke outcomes in general, suggesting a role for perfusion.

Small trials of induced hypertension through pharmacologic techniques have shown benefits. (25) No large trial has yet confirmed this benefit, but induced hypertension is often used in clinical practice, with good anecdotal results. Experimental techniques to deliver blood through transvenous routes have shown benefit in animal studies. Despite early encouraging results, logistical issues have hindered further trials. Summaries of intervention to maximize perfusion are shown in Table 3.

Penumbra

Within minutes after an ischemic insult, there is a region of irreversibly damaged tissue. This is named the "necrotic core." Surrounding this necrotic core is a region of tissue that is receiving inadequate nutritive flow. The tissue will undergo a series of preprogrammed biologic steps called the ischemic cascade that will eventually lead to death of the cells within the "ischemic penumbra." (3) Specific actions can be taken to minimize damage to the penumbra.

Normoglycemia 

Maintenance of normoglycemia is important beyond the increased risk of stroke in general in patients with diabetes. The mechanism is believed to be related to anaerobic metabolism and increased lactic acid production; the acidosis is toxic and promotes neuronal cell death. (26) Hyperglycemia it self may be caused by the stress response of the event, (27) but this has not been completely elucidated. The type of stroke seems to matter for the effects of the glucose level on the outcome. In the Trial of ORG 10172 in Acute Stroke Treatment, (28) hyperglycemia predicted worse outcome in all strokes in general and especially in nonlacunar stroke. Among patients treated with t-PA, absence of diabetes and admission normoglycemia predict good outcome as well. (29)

Fever

A link between neuronal damage and fever has been known for some time, but only recently has interest quickened in using hypothermia as a treatment. Fever has been reliably shown to be associated with worse outcome, (30,31) and lowering body temperature may lead to neuronal salvage by a variety of mechanisms. (32) Treatment of fever with antipyretic medications is standard and probably helpful. Induced hypothermia is labor intensive and costly. Cooling patients below 34[degrees] to 35[degrees]C requires intubation, sedation, and intravenous infusion of ice-cold saline. A recent trial failed to show lower body temperatures with cooling blankets as opposed to acetaminophen alone, in part because some patients could not tolerate the blanket. (33)

Pharmacologic Neuroprotectants

A number of neuroprotectants have been tested in human trials after promising studies in animals, typically murine models of stroke. Despite reasonable preclinical models, doseescalation studies and excellent clinical and statistical oversight, none of these have shown improvements in neurologic outcome. Trials of tirilazad (an inhibitor of lipid peroxidation), (34) clomethiazole (a [gamma]-aminobutyric acid activator), (35) and lubeluzole (which inhibits an increase in extracellular glutamate), (36) among other agents, have shown no benefit.

Hyperbaric Therapy

Hyperbaric oxygen seems a logical and attractive option, but it has been difficult to show benefit despite some case reports showing benefit. One pilot trial of hyperbaric oxygen therapy in acute stroke was stopped because there were difficulties in nearly all aspects: it was difficult to organize smoothly, a substantial number of patients requested the treatments stopped, and there were worrisome trends toward harm in the oxygen group. (37) This therapy is limited by the availability of the hyperbaric chamber.

Preventing Complications

Most stroke complications can be avoided. Through the use of standardized stroke pathways, nursing education, and the designation of a stroke unit, these common causes of increased morbidity can be addressed. The importance of treating hyperthermia, glycemic derangements, and hypoxia are discussed above.

Hospital-acquired infections are frequent complications. Aspiration pneumonia is usually caused by inability to protect the airway in combination with atelectasis from immobility. Before feeding, patients should be screened for swallowing risks and a speech pathologist should be consulted. Careful attention to silent aspiration and respiratory rate is paramount because tachypnea of >22 breaths/min often precedes clinically evident pneumonia. Early mobilization starting within 24 hours is also important in preventing many complications.

Urinary tract infections are usually caused by indwelling catheters. These catheters are often unnecessary and should be removed as soon as possible. A rapid urinary catheter protocol can be useful in this regard. Constipation leading to gastrointestinal distress is also a frequent occurrence. Patients should be placed on a bowel regimen from admission with the goal of a bowel movement every other day. Mobilization will also help in this regard.

Stroke units seem to be an idea whose time has come, much like the development of the coronary care unit in the past. The idea is that a core multidisciplinary team of professionals who primarily treat stroke patients will produce better outcomes and further research more effectively than a general neurology or medical ward team. In the United States and Europe, (38) these units have taken a leading role in care and research. Evidence has accumulated that they produce improved outcomes by meticulous attention to details that occur frequently in stroke patients. (39,40) The minimum requirements for such a team are a streamlined Emergency Medical System that delivers patients to the emergency department as soon as possible, accurate triage by the emergency department, 24-hour availability of a treating stroke physician (typically a neurologist) and nursing staff, a neurosurgeon, and 24-hour availability of neuroimaging with at least CT scanning (Table 4).

Conclusion

Acute ischemic stroke is a treatable condition. Recovery is time dependent, with intervention required within minutes. In general, the earlier the treatment, the better the outcome. Attention to the five Ps of acute stroke care will allow the treating clinician to logically and systematically approach treatment with an appreciation of underlying disease and pathophysiology. Use of a multidisciplinary stroke team appears essential in coordinating care and improving outcome.

Table 1

Anterior and posterior vascular syndromes (a)

Syndrome                                 Localization

Anterior (carotid) artery syndromes
 Middle cerebral artery
  Expressive aphasia                     Dominant posterior frontal lobe
  Receptive aphasia                      Dominant superior temporal lobe
  Weakness of arm and/or leg             Contralateral (to weakness)
                                          parietal lobe
  Loss of lateral visual fields          Contralateral parietal lobe
 Anterial cerebral artery
  Weakness of leg                        Medial (parafalcine)
Posterior (vertebrobasilar) artery        parietal lobe
  syndromes Vertigo, nystagmus that      Cerebellum
   changes with the direction of
  gaze, cranial nerve palsies,           Brainstem
  retropulsion Hemiparesis, hemisensory
  loss, of one-half of the body,
  swallowing difficulty
Lacunar syndromes (These do not
 have the "cortical signs" of,
 e.g., aphasia, visual loss.)
 Pure motor stroke                       Corona radiata, internal
                                          capsule, basis pons
 Pure sensory stroke                     Thalamus
 Ataxic hemiparesis                      Pons
  Clumsy hand-dysarthria
 Mixed motor-sensory stroke              Junction of thalamus and
                                          internal capsule

(a) The dominant hemisphere is the side that controls language function.

Table 2

Patient selection for thrombolysis (a)

Characteristic               Desirable/required

Intravenous thrombolysis     Start of therapy within 3
                             h of symptom onset Disabling deficit






Intra-arterial thrombolysis  Presence of catheterization team and
                             equipment Start of therapy within 6 h
                             of symptom onset Lack of
                             improvement with IV therapy

Characteristic               Contraindicated

Intravenous thrombolysis     Platelet count < 100
                             BP > 185/110 mm Hg despite labetalol
                             20 mg IV Hemorrhage on CT scan
                             Seizure at symptom onset
                             Recent stroke, surgery, arterial puncture
                             at noncompressible site
                             History of intracranial hemorrhage

Intra-arterial thrombolysis  Inability to obtain informed consent
                             Technical considerations



(a) BP, blood pressure; IV, intravenous; CT, computed tomographic.

Table 3

Maximization of prefusion

Intervention                Benefit

Induced hypertension        Increase in cerebral perfusion
                             pressure
Colloid solutions           Increase in intravascular volume
 (heststarch, pentastarch)   and tissue perfusion
Crystalloid solutions       Increase in intravascular volume
Bed positioning             Increase in perfusion
Bed rest

Table 4

Prevention of complications (a)

Intervention                     Comments

Neuroprotectants                 Theoretical benefits thus far
                                   depend on agent; negative
                                   clinical trials
Control of fever                 Fever is known to be harmful in
                                   stroke; difficult to achieve
                                   hypothermia
Glycemic control                 Hyperglycemia is known to be
                                   harmful
DVT prevention                   Stroke patients at particularly
                                   high risk (eg, paretic limbs)
Aspiration precautions           Standardized speech pathology
                                   examinations
Avoidance of indwelling urinary  Daily review of need for catheters
  catheters
Bowel regimen                    Goal of one bowel movement every
                                   other day
Early mobilization               Critical to prevention of
                                   complications; start mobilizing
                                   patient to chair early in stroke
                                   course

(a) DVT, deep vein thrombosis.

Accepted November 7, 2002.

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From the Department of Neurology, Ochsner Foundation Clinic and Hospital, and the Department of Neurology, Tulane University School of Medicine, New Orleans, LA. Dr. Naidech is now with the Department of Critical Care Neurology, Columbia Presbyterian Medical Center, New York, NY.

Reprint requests to Robert A. Felberg, MD, Department of Neurology, Ochsner Foundation Clinic and Hospital, 1514 Jefferson Highway, New Orleans, LA 70121. Email: [e-mail]

Copyright [c] 2003 by The Southern Medical Association 0038-4348/03/9604-0336