Guidelines for acute ischemic stroke treatment: part II: stroke treatment

Diretrizes para o tratamento do acidente vascular cerebral isquêmico: parte II: tratamento do acidente vascular

GUIDELINES

Guidelines for acute ischemic stroke treatment – Part II: Stroke treatment

Diretrizes para o tratamento do acidente vascular cerebral isquêmico – Parte II: tratamento do acidente vascular

Sheila Cristina Ouriques Martins; Gabriel Rodriguez de Freitas; Octávio Marques Pontes-Neto; Alexandre Pieri; Carla Heloísa Cabral Moro; Pedro Antônio Pereira de Jesus; Alexandre Longo; Eli Faria Evaristo; João José Freitas de Carvalho; Jefferson Gomes Fernandes; Rubens José Gagliardi; Jamary Oliveira-Filho and Executive Committee from the Brazilian Stroke Society and the Scientific Department in Cerebrovascular Diseases of the Brazilian Academy of Neurology^*

^{Correspondence}

ABSTRACT

The second part of these Guidelines covers the topics of antiplatelet, anticoagulant, and statin therapy in acute ischemic stroke, reperfusion therapy, and classification of Stroke Centers. Information on the classes and levels of evidence used in this guideline is provided in Part I. A translated version of the Guidelines is available from the Brazilian Stroke Society website (www.sbdcv.com.br).

Key words: stroke, thrombolysis, stroke centers.

RESUMO

A segunda parte das Diretrizes aborda os tópicos de antiagregantes plaquetários, anticoagulantes e terapia de reperfusão para acidente vascular cerebral (AVC) isquêmico. Os critérios para nível de evidência e graus de recomendação estão contidos na primeira parte do documento. Uma versão traduzida destas Diretrizes encontra-se publicada no portal da Sociedade Brasileira de Doenças Cerebrovasculares (www.sbdcv.org.br).

Palavras-Chave: acidente vascular cerebral, trombólise, centros de AVC.

ANTICOAGULANTS, ANTIPLATELET AGENTS, AND STATINS IN ACUTE ISCHEMIC STROKE

Anticoagulation in acute ischemic stroke

In 2004, the Cochrane Collaboration published a systematic review of 22 trials involving 23,547 patients^1,2 who were started on standard unfractionated heparin, low-molecular-weight heparins, heparinoids, oral anticoagulants, or thrombin inhibitors 2 weeks after the occurrence of a stroke. Although anticoagulant therapy was associated with approximately 9 fewer recurrent ischemic strokes per 1000 patients treated (OR=0.76; 95%CI 0.65–0.88), this benefit was nullified by the occurrence of approximately 9 more symptomatic intracranial hemorrhages per 1000 patients treated (OR=2.52; 95%CI 1.92–3.30).

Early administration (within 48 hours of symptom onset) of heparin in patients with cardioembolic stroke was evaluated in a recent meta-analysis³ which failed to show any significant reduction in recurrence of ischemic stroke or any change in mortality and disability rates. A study of heparin administration in the hyperacute phase (within 3 hours of symptom onset) of acute nonlacunar hemispheric infarction showed that more patients on anticoagulation therapy reached the endpoint of functional independence (38.9 versus 28.6%; p=0.025), but had a higher rate of symptomatic cerebral hemorrhage (6.2 versus 1.4%; p=0.008), with no increase in mortality⁴. Early discontinuation of the RAPID (Rapid Anticoagulation Prevents Ischemic Damage) trial, after the enrollment of only 67 patients, precluded comparison of unfractionated heparin versus aspirin in the prevention of early recurrence⁵. A comparative analysis of the efficacy of low-molecular-weight heparin versus aspirin, conducted with Asian patients with intracranial stenosis and acute stroke, did not find heparin to be superior⁶.

Recommendations

1) Routine anticoagulation with unfractionated or low-molecular-weight heparin is not recommended in acute ischemic stroke (Level of Evidence 1, Class A Recommendation).

2) Particularly, anticoagulation in the acute phase of ischemic stroke is not recommended for patients with moderate to extensive cerebral infarction due to increased risk of severe intracranial hemorrhagic complications (Level of Evidence 1, Class A Recommendation).

Antiplatelet agents in acute ischemic stroke

Two clinical trials showed a significant benefit of aspirin as to the reduction of morbidity and mortality rates when initiated within 48 hours of symptom onset at daily doses of 160 mg and 300 mg respectively. The primary effect of aspirin appears to be prevention of early stroke recurrence^7,8. Definitive long-term antithrombotic treatment should be initiated 2 weeks after the episode of stroke⁹.

Use of ticlopidine, clopidogrel, dipyridamole, or other antiplatelet agents during ischemic stroke, whether alone or in combination, has yet to be assessed properly^10,11. The FASTER study evaluated administration of clopidogrel and aspirin to patients with transient ischemic attack or minor stroke within 24 hours of symptom onset as one arm of a factorial design. However, as this trial was interrupted early due to failure to recruit patients at the prespecified minimum enrolment rate, no conclusions could be drawn as to the potential benefit of this combination¹². In patients who were allergic, non-responsive, or intolerant to aspirin, other antiplatelet agents may be therapeutic alternatives.

Although phase II studies suggest an adequate safety profile, a phase III trial of platelet glycoprotein IIb/IIIa inhibitor (abciximab) in acute stroke was halted due to high rates of bleeding¹³.

Recommendations

1) Initiation of oral aspirin at a daily dose of 160 to 300 mg within 48 hours after of the occurrence of ischemic stroke is recommended (Level of Evidence 1, Class A Recommendation).

2) To date, there is no evidence to support routine administration of any other antiplatelet agents alone or in combination with other substances (Level of Evidence 2, Class B Recommendation).

3) Administration of platelet glycoprotein IIb/IIIa inhibitors (abciximab) is not recommended in the acute phase of ischemic stroke (Level of Evidence 1, Class A Recommendation).

Statins in acute ischemic stroke

Administration of atorvastatin to acute ischemic stroke patients 1 to 6 months after the event has been shown to reduce recurrence, which suggests that early use of statins reduces vascular risk¹⁴. Simvastatin was shown to reduce vascular events in patients with history of stroke and to reduce the risk of stroke in patients with other vascular diseases¹⁵. Withdrawal of statin therapy in the acute phase of stroke may be associated with an increased risk of death or dependency¹⁶.

Recommendations

1) Patients who are already on statins at the time of stroke onset should continue taking them (Level of Evidence 1, Class B Recommendation).

2) Administration of statins after 48 hours of the occurrence of stroke is safe (Level of Evidence 1, Class B Recommendation).

INTRAVENOUS THROMBOLYSIS PROTOCOL

When administered in 4 hours and 30 minutes after the stroke, intravenous recombinant tissue plasminogen activator (rt-PA) has been shown to decrease functional disability as compared to placebo, and has thus become one of the leading specific treatments recommended for acute management of ischemic stroke (Level of Evidence 1A)^17-20. Diabetic patients with history of prior stroke were excluded from the ECASS III trial, but phase IV studies and meta-analysis suggest benefit in this population as well (Level of Evidence 1B). Streptokinase was assessed in a variety of studies, but its use is no longer recommended due to high rates mortality associated with hemorrhage (Level of Evidence 1A)^21-23.

For greater safety, rt-PA administration should comply with the following criteria^10,11,17,20:

Inclusion criteria

a) Ischemic stroke in any cerebrovascular territory;

b) Possibility of initiating rt-PA infusion in 4 hours and 30 minutes after symptom onset (which requires precise determination of the symptom onset timing. If symptoms are noted on waking, the last time at which the patient was observed to be normal should be used instead);

c) No evidence on intracranial hemorrhage on head computed tomography (CT) scan or magnetic resonance imaging (MRI);

d) Age >18 years.

Exclusion criteria

a) Use of oral anticoagulants and prothrombin time (PT) >15 s (INR>1.7);

b) Use of heparin in the last 48 hours and prolonged aPTT;

c) History of ischemic stroke or severe head trauma in the last 3 months;

d) History of intracranial hemorrhage or cerebrovascular malformation;

e) Hypodensity of more than one-third of the middle cerebral artery territory on head CT;

f) Systolic blood pressure (SBP) >185 mmHg or diastolic blood pressure (DBP) >110 mmHg (on 3 separate measurements obtained after with 10 minutes of interval) refractory to antihypertensive agents;

g) Rapid and complete resolution of signs and symptoms before thrombolytic agent administration;

h) Mild neurological deficit (with no significant functional deterioration);

i) History of major surgery or invasive procedure in the last 2 weeks;

j) History of genitourinary or gastrointestinal bleeding in the last 3 weeks, or history of esophageal varices;

k) Arterial puncture at a noncompressible site within the last 7 days;

l) Coagulopathy (prolonged PT [INR >1.7], prolonged aPTT, or platelet count <100,000/mm³);

m) Blood glucose <50 mg/dL with resolution of symptoms after hypoglycemia was treated;

n) Evidence of endocarditis, septic embolus, or pregnancy;

o) Recent myocardial infarction (occurred in the last 3 months);

p) Clinical suspicion of subarachnoid hemorrhage or acute aortic dissection.

Some centers use multimodal neuroimaging (MRI with diffusion and perfusion imaging or perfusion CT scan) to select candidates for thrombolytic therapy, particularly in patients outside the therapeutic range or when the exact time of symptom onset cannot be determined.

In patients with no recent history of oral anticoagulant or heparin use, rt-PA infusion may be initiated before the results of a coagulation panel are available, but should be discontinued if these results reveal an INR>1.7, a prolonged aPTT as defined by local reference ranges, or a platelet count <100,000/mm³.

The following factors are not considered absolute exclusion criteria if the treating neurologist is convinced they are unrelated to the patient's acute neurological deficits: blood glucose level >400 mg/dL, epileptic seizure at the onset of neurological deficit, and diagnosis of cerebral aneurysm (Level of Evidence 4C).

Certain factors alter the risk/benefit ratio of thrombolytic therapy, but does not constitute a contraindication to its use^17,24:

- NIHSS >22

- Age >80 years

- Hyperglycemia

Informed consent form

The risk/benefit ratio of treatment must be discussed with the patient's relatives or legal caregivers, and consent should be reported in writing in the patient record.

Management of arterial hypertension

Use of rt-PA in the treatment of acute ischemic stroke entails a need for strict blood pressure control, as the risk of cerebral hemorrhage correlates with BP levels²⁴. Special attention should be given to the risk of iatrogenic hypotension during treatment. In candidates for thrombolytic therapy, adherence to the NINDS rt-PA Stroke Study Group^17,24 is recommended, which accepts the following blood pressure levels in up to 24 hours after the stroke: DBP <105 mmHg and SBP <180 mmHg (Tables 1 and 2).

GENERAL CARE

1) Rigorous control is required, with assessment of neurological status every 15 minutes during thrombolytic infusion and every 30 minutes during the first 6 hours after the stroke. In the first 24 hours thereafter, neurological status is recommended to be assessed every hour. Increase in 4 points of more in NIHSS score is related to potential intracranial hemorrhage and an indication for control CT scan. Other signs include severe headache, decreased level of consciousness, a sudden increase in blood pressure, nausea, and vomiting.

2) Blood pressure should be strictly monitored as recommended in Table 2.

3) Antithrombotic agents (antiplatelets, heparin, or oral anticoagulants) should not be administered in the first 24 hours after the administration of a thrombolytic.

4) Central venous catheter placement and arterial puncture should not be performed in the first 24 hours after rt-PA infusion.

5) Urinary catheterization should be performed no sooner than 30 minutes after completion of rt-PA infusion.

6) Nasoenteric tube placement should not be performed within 24 hours of rt-PA infusion.

7) Neuroimaging (cranial CT scan or MRI) is recommended in the first 24 hours of thrombolytic therapy.

Protocol for rt-PA infusion

Two peripheral intravenous catheters should be placed. The rt-PA is to be administered at 0.9 mg/kg to a maximum of 90 mg. Ten percent of the dose should be given as an IV bolus in one minute, and the rest, over the course of 60 minutes by infusion pump. The patient must be monitored for at least 24 hours as to changes in neurologic condition, vital signs, and evidence of bleeding complications^17,24. Monitoring may be carried out in a special bed for hyperacute stroke management in the Emergency department or, preferably, in a Stroke-specialized Unit. Management should preferably be led by a neurologist with exp erience in the treatment of acute stroke. When a neurologist is not available on site, management may be led by another trained health care provider under the guidance of a neurologist via telemedicine²⁵.

Hemorrhagic complications

The hemorrhagic complications of thrombolysis occur most commonly in 24 hours after starting therapy. Contraindications include deterioration of neurological status, nausea, vomiting, headache, decreased level of consciousness, and abrupt elevation of blood pressure. Should these symptoms arise, the recommended management is as follows:

a. discontinue infusion at the first sign of neurological deterioration or evidence of significant bleeding;

b. ensure that fluid resuscitation is given, with infusion of crystalloid via two peripheral intravenous lines;

c. perform cranial CT scan to confirm bleeding;

d. request the following laboratory tests: hematocrit, prothrombin time, aPTT, platelet count, fibrinogen;

e. give six to eight units of cryoprecipitate if available or two to three units of fresh frozen plasma otherwise. If clinical status continues to deteriorate after four to six hours, give blood products as required according to coagulation panel results. Repeat cryoprecipitate if fibrinogen is low; give fresh plasma if PT or aPTT are abnormal. Infuse six to eight units of platelets if the count is low;

f. give packed red blood cells as required to keep hematocrit within normal range;

g. use fluid resuscitation and/or vasoactive agents to treat hypotension. Avoid hypotonic fluids;

h. in case of bleeding of the central nervous system, consider neurosurgery and hematology consult;

i. consider restarting thrombolytic infusion if CT shows no evidence if intracranial hemorrhage.

Orolingual angioedema

According to the CASES study, this complication may arise in approximately 5% of patients given intravenous thrombolytics (particularly those with insular and frontal cortical infarctions) while on angiotensin-converting enzyme (ACE) inhibitors. The clinical course is usually favorable²⁶.

Clinicians should be aware of the potential for orolingual angioedema aiming at prompt management, particularly in patients who are prone to this complication (Level of Evidence 4, Class C Recommendation)²⁶.

Recommendations

1) Intravenous rt-PA therapy is recommended in the forst 4 hours and 30 minutes of after the occurrence of ischemic stroke (Level of Evidence 1, Class A Recommendation).

2) Streptokinase is not recommended for the treatment of stroke (Level of Evidence 1, Class A Recommendation).

3) The inclusion and exclusion criteria for thrombolytic therapy should be followed strictly (Level of Evidence 3, Class C Recommendation).

4) Multimodal neuroimaging may be useful to select candidates for thrombolytic therapy when the exact time of symptom onset cannot be determined or if 4 hours and 30 minutes have passed since the onset of symptoms (Level of Evidence 3, Class C Recommendation).

5) Where no neurologist is available, thrombolytics may be administered under telemedicine guidance (Level of Evidence 3, Class B Recommendation).

6) Thrombolysis should be performed in a monitored bed in the emergency room or, preferably, in a dedicated Stroke Unit (Level of Evidence 4, Class C Recommendation).

PROTOCOL FOR INTRA-ARTERIAL THROMBOLYSIS

The intra-arterial approach to reperfusion therapy in acute stroke is an alternative to intravenous thrombolysis that may provide some advantages, such as increased concentration of the thrombolytic agent at the site of occlusion, a higher recanalization rate, and the potential for use in patients with contraindications to intravenous chemical thrombolysis²⁷. On the other hand, clinical benefits may be offset by the greater time required to begin the intra-arterial procedure. Currently, patients selected for intra-arterial therapy are those meeting some exclusion criteria for intravenous thrombolysis. Examples include cases in which 4 hours and 30 minutes and 6 hours have passed since the onset of symptoms, or patients with severe neurologic deficits, recent history of major surgery, or evidence of large extra- or intracranial artery occlusive disease on imaging tests. The CT criteria for exclusion of intravenous thrombolysis and those for exclusion of intra-arterial therapy are identical. However, the amount of data to support the use of intra-arterial therapy in these settings is limited. In the PROACT II phase III trial, patients who received intra-arterial treatment of proximal MCA occlusion with prourokinase 6 hours after symptom onset had a significantly higher recanalization rate and a improved prognosis significantly when compared to controls²⁸. In this study, symptomatic bleeding occurred in 10% of treated patients and 2% of controls (p<0.06). Prourokinase is not FDA-approved and is not available as reperfusion therapy. Further small randomized clinical trials of prourokinase (PROACT I)²⁹ and urokinase (MELT)³⁰ and a meta-analysis of the PROACT I, PROACT II, and MELT trials suggest that intra-arterial thrombolysis can be beneficial in patients with proximal MCA occlusion. Although intra-arterial thrombolysis with rt-PA is not supported by randomized clinical trials, data from observational and nonrandomized comparative studies suggest it can be beneficial^31,32. A nonrandomized trial compared patients with and without hyperdensity of the MCA territory at baseline CT who were then given intravenous or intra-arterial rt-PA. Intravenous rt-PA therapy was associated with less favorable outcomes in patients with hyperdense MCA sign as compared to patients without it³³. Although observational studies of urokinase and rt-PA for intra-arterial treatment of basilar artery occlusion have shown encouraging results, there are no randomized clinical trials with adequate statistical power^34-36. A systematic review found no significant differences between intravenous or intra-arterial thrombolysis for basilar artery occlusion³⁷.

Recommendations

1) Intra-arterial thrombolytic therapy is a valid option to selecting patients with ischemic stroke due to MCA, carotid, or basilar artery occlusion if given in 6 hours after the stroke (Level of Evidence 2, Class B Recommendation) and, by extrapolation of the results of intravenous thrombolysis studies, rt-PA is used as the thrombolytic agent (Level of Evidence 4, Class C Recommendation).

2) Intra-arterial thrombolytic therapy should only be performed in centers staffed by interventional radiologists experienced in cerebrovascular techniques and with rapid access to a catheterization laboratory (Level of Evidence 2, Class C Recommendation).

3) Intra-arterial thrombolytic therapy may be considered for patients with contraindications to intravenous thrombolysis (Level of Evidence 4, Class C Recommendation).

4) In eligible patients, intravenous thrombolysis should not be deferred in favor of intra-arterial therapy (Level of Evidence 3, Class C Recommendation).

5) Intra-arterial thrombolytic therapy is recommended for the treatment of acute basilar artery occlusion in selected patients (Level of Evidence 4, Class C Recommendation).

PROTOCOL FOR COMBINED (INTRAVENOUS AND INTRA-ARTERIAL) THROMBOLYSIS

The best for combined thrombolysis is a synergy between the advantages of each method, combining the ease of administration and speed of intravenous thrombolytic therapy and the higher recanalization rates and potentially superior outcomes of its intra-arterial counterpart^38,39. The Interventional Management of Stroke Study (IMS) I compared a group of patients who underwent IV thrombolysis with low-dose rt-PA (0.6 mg/Kg) followed by arteriography and IA thrombolysis in case of persistent occlusion⁴⁰. As there was no control group, patients in the experimental group were compared to patients in the NINDS study. Combined thrombolysis was associated with functional outcomes similar to those of IV thrombolysis and superior to those of placebo. The rate of bleeding was similar to that reported in the NINDS study (6.6%). These results were confirmed by the IMS II trial⁴¹. More recently, another group of investigators used a protocol consisting of full-dose IV rt-PA plus IA thrombolysis in case of recanalization failure⁴¹. Transcranial Doppler has been recommended as a search method for patients in this setting^42,43. The IMS III trial, comparing IV thrombolysis and combined thrombolysis in 3 hours after the occurrence of stroke, is currently underway.

Recommendations

1) There is insufficient high-level evidence to recommend combined thrombolysis as first-line therapy (Level of Evidence 4, Class C Recommendation).

2) Combined thrombolysis should preferably be performed in a controlled clinical trial setting (Level of Evidence 5).

3) Combined thrombolysis may be considered on a named-patient basis, pending informed consent, when there is persistent arterial occlusion and high risk of permanent sequelae (Level of Evidence 4, Class C Recommendation).

PROTOCOL FOR MECHANICAL THROMBOLYSIS

There are countless endovascular interventions under study as potential treatment options for extracranial and intracranial large vessel occlusion^44-48. These interventions include emergency angioplasty with stent placement, mechanical clot fragmentation, clot removal with up-to-date devices, suction thrombectomy and stent retriever thrombectomy.

Mechanical procedures are sometimes combined with intravenous or intra-arterial thrombolytic therapy.

A meta-analysis comparing the natural evolution of ischemic stroke (no treatment) with different forms of reperfusion therapy showed that recanalization was the most important independent factor for good outcome, with a strong association with functional independence and lower mortality⁴⁹.

Angioplasty and stenting

Data on angioplasty and stent placement in the acute phase of ischemic stroke are limited^50-52. Angioplasty and stenting have been used to treat acute stroke secondary to carotid artery dissection⁵³. In a case series, emergency carotid angioplasty with stent implantation in addition to intra-arterial thrombolysis was performed in patients with stroke due to arterial embolism. This study reported favorable outcomes in the endovascular treatment group as compared with controls⁵⁴. Combined angioplasty and thrombolysis, with or without stent placement, has also been used in patients with basilar artery occlusion^55,56.

Mechanical clot fragmentation

In one study, 16 patients with MCA occlusion and 16 with internal carotid artery occlusion were treated with mechanical thrombectomy with or without local administration of a thrombolytic agent⁵⁷. A Swiss study reported higher recanalization rates with mechanical clot fragmentation in patients who had received intra-arterial thrombolytic therapy⁵⁸.

Clot removal

Several devices have been used for mechanical removal of clots from occluded arteries^59,60. In the MERCI study, arterial recanalization was achieved with the use of a device that physically removed the thrombus from the lumen of the occluded vessel⁶¹. In 48% of patients managed with the device, recanalization was achieved in up to eight hours after symptom onset. No randomized clinical trials with prognostic data are available for any intra-arterial recanalization device. Although the FDA has approved the MERCI device for recanalization of intracranial arteries, its clinical effectiveness has yet to be established. MERCI is not available in Brazil.

Suction thrombectomy

The Penumbra stroke system uses an aspiration device to extract the thrombus in acute ischemic stroke⁶². All prospective (single arm) and retrospective studies reported rates of recanalization of 83 to 100% in patients treated in the first eight hours of symptom onset^48,62. Intracranial hemorrhage and vessel perforation or dissection occurred in 0 to 5% of patients⁴⁸. Despite high recanalization rates, only 25 to 30% of patients achieved functional independence⁶², probably because of late recanalization in many cases.

The FDA has approved the Penumbra system for recanalization of intracranial arteries in the US, as well as the Brazilian National Health Surveillance Agency (Anvisa) in Brazil.

Stent retriever thrombectomy

Stent retrieval devices are a combination of removable cerebral stents and clot retrievers to be used in the first eight hours of symptom onset⁶². Examples include the Solitaire and Trevo devices. In a recent meta-analysis of 30 observational studies⁶³ with 262 acute stroke patients treated with the Solitaire device, successful recanalization was achieved in 90% of cases (range, 67–100%). The rates of symptomatic hemorrhagic complications and mortality were 7 and 11%, respectively, and functional independence (mRS 0 to 2) was achieved by 47% of patients. The Solitaire device was approved for treatment of stroke in Brazil in 2012.

Recommendations

1) Although the use of the MERCI device is an acceptable intervention for removal of intra-arterial thrombus in patients carefully selected, its effectiveness in improving prognosis after stroke is still uncertain (Level of Evidence 2, Class B Recommendation). Further clinical trials of this device are required before its role in the emergency management of stroke can be defined.

Other devices available in Brazil could be useful for thrombectomy in an attempt to achieve reperfusion in acute stroke patients with large vessel occlusion admitted to care within 8 hours of symptoms onset, being ineligible for intravenous thrombolysis or in whom endovenous treatment has failed (Level of Evidence 2, Class B Recommendation).

DESIGNATION OF REFERRAL CENTERS FOR DIAGNOSIS AND TREATMENT OF STROKE

In its National Opinion Statement on Stroke⁶⁴, the Brazilian Stroke Society proposed a classification of referral centers for the diagnosis and treatment of acute stroke. This classification was updated in 2009 to include centers with telemedicine capabilities and backup hospitals (Table 3).

Received 21 May 2012

Accepted 4 July 2012

Conflict of interest: There is no conflict of interest to declare.

*Executive committee (in order of last name):

Charles André, Aroldo Luiz Bacellar, Daniel da Cruz Bezerra, Roberto Campos, João José Freitas de Carvalho, Gabriel Rodrigues de Freitas, Roberto de Magalhães Carneiro de Oliveira, Sebastião Eurico Melo de Souza, Soraia Ramos Cabette Fábio, Eli Faria Evaristo, Jefferson Gomes Fernandes, Maurício Friedrich, Marcia Maiumi Fukujima, Rubens José Gagliardi, Sérgio Roberto Haussen, Maria Clinete Sampaio Lacativa, Bernardo Liberato, Alexandre L. Longo, Sheila Cristina Ouriques Martins, Ayrton Roberto Massaro, Cesar Minelli, Carla Heloísa Cabral Moro, Jorge El-Kadum Noujaim, Edison Matos Nóvak, Jamary Oliveira-Filho, Octávio Marques Pontes-Neto, César Noronha Raffin, Bruno Castelo Branco Rodrigues, José Ibiapina Siqueira-Neto, Elza Dias Tosta, Raul Valiente, Leonardo Vedolin, Marcelo Gabriel Veja, Fábio Iuji Yamamoto, Viviane Flumignan Zétola

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Publication Dates

• Publication in this collection
  14 Nov 2012
• Date of issue
  Nov 2012

History

• Received
  21 May 2012
• Accepted
  04 July 2012