The first two trials with endarterectomy for asymptomatic carotid stenosis yielded inconclusive results. The CASANOVA¹³ (Carotid Surgery Versus Medical Therapy in Asymptomatic Carotid Stenosis) study found no differences in outcome between immediate surgery and non-surgery patients. However, a seriously flawed protocol design resulted in nearly half of the patients in the non-surgical group undergoing endarterectomy. In the Veterans Affairs Cooperative Studies Program Asymptomatic Stenosis Trial¹⁴, the combined incidence of ipsilateral neurological events, were significantly reduced in patients undergoing endarterectomy. When endpoints of ipsilateral stroke and perioperative death were analyzed, there was a suggestive benefit for surgical group which was not statistically significant (P=0.056), probably secondary to inadequate sample size. However, recently the Asymptomatic Carotid Atherosclerosis Study ¹⁵ (ACAS) demonstrated that among 1662 patients with a high grade stenosis (greater than 60% diameter reduction by ultrasound and/or angiography) who were randomized to medical or surgical groups, there was a projected overall 53% relative-risk reduction in ipsilateral stroke rates over 5 years (mean follow-up 2.7 years) in patients receiving carotid endarterectomy (5.1%) compared with patients not receiving surgery (11.0%). The benefit of surgery was apparent by 10 months and was statistically significant for three years.

Risk of carotid endarterectomy surgery. Carotid endarterectomy is not without its own morbidity and mortality. Data from NASCET¹¹ in symptomatic patients from 50 clinical centers performing carotid endarterectomy revealed a 5.8% incidence of perioperative stroke, an 0.9% incidence of acute myocardial infarction, a 7.6% incidence of cranial nerve injury, a 5.5% incidence of wound hematoma, and a 3.4% incidence of would infection. Restricting the analysis to the most serious events resulted in a rate of 2.1% for major stroke plus death and a fatality rate of 0.6%. In ACAS¹⁵ where surgery was performed in lower risk asymptomatic patients, the 30-day peri-operative risk of stroke or death was 2.3% in the carotid endarterectomy cohort.

Results of supra-aortic cerebrovascular angioplasty. Considering the efficacy of carotid endarterectomy for stroke prevention and the acknowledged peri-operative risks, alternatives to surgical revascularization have been sought. Percutaneous transluminal angioplasty has been used extensively as an alternative to surgical revascularization, both in peripheral and coronary atherosclerotic vascular disease. There is significant but less extensive experience with PTA of the supra-aortic arteries including the carotid and vertebral arteries. In a review of over 700 supra-aortic artery PTA's ¹⁶, the success rate was 95% and major complications were 0.5% with no deaths; 338 of these procedures were in the carotid, vertebral or innominate artery and the remaining 436 involved the suvbclavian artery. In a series of 29 angioplasties involving the common carotid and internal carotid arteries, there were no major complications and follow-up ranging from 3 months to 4 years did not reveal any recurrence of symptoms.¹⁷ These authors further extended the series to 41 patients and there were still no major complications, but follow-up data were not presented¹⁸. Higashida reported a series of 42 angioplasties in vertebral and basilar artery stenosis of greater than 70%; 34 lesions involved the proximal vertebral artery, 5 lesions involved the distal vertebral artery, and 3 involved the basilar artery¹⁹. Complications were confined to the distal vertebral artery and basilar artery procedures with 2 strokes and 1 death occurring in these groups. The follow-up period was 12 months and there was a 7% restenosis rate. Kachel¹⁶ published a series of 112 supra-aortic PTA's in 105 symptomatic patients. There were 35 stenoses of the internal carotid artery and 15 stenoses of the vertebral artery with the remaining lesions involving the external carotid, common carotid, innominate or suvbclavian arteries. The success rate was 95.2%; there were no major complications and 4 minor complications. After a mean follow-up period of 58 months, there were 2 (1.8%) cases of restenosis, both in the subclavian arteries.

From the limited amount of data available on long term follow-up after supra-aortic PTA's, the resenosis rate appears to be low, consistent with the results of angioplasty in other similar size vessels. Large vessels, such as the iliacs and proximal femoral arteries, have restenosis rates of 20-25% at 3 years while smaller vessels such as popliteals and coronaries have restenosis rates of 35-45%^20,21. Therefore, one would expect the carotid arteries, which typically range in size from 4 to 10mm, to have relatively low restenosis rates, certainly much lower than in the coronary circulation.

Despite the apparently good results obtained after supra-aortic PTA procedures, there remain several real and/or perceived risks which must be addressed. First, the clinical trial experiences thus far have been poorly controlled with little attention to standardized patient inclusion criteria, angioplasty techniques, pre-specified endpoint evaluations, and clinical event reporting. Although distal embolization from the treatment site appears to be well tolerated by the cerebral circulation without significant transient or permanent neurologic sequellae, this still may pose problems in ulcerated or thrombus-containing lesions in patients with unstable plaque morphology. Dissection and abrupt vessel closure are ubiquitous after mechanical balloon barotrauma techniques and late vessel closure after carotid PTA would undoubtedly lead to major strokes and possible mortality. Finally, the expected late restenosis rate of 20-25% in carotid arteries after PTA is as yet unconfirmed and may well be considerably higher than comparably treated patients after surgical carotid endarterectomy.

Endovascular stents for obstructive vascular disease. For almost a decade endovascular permanent prosthetic devices, or stents, have been utilized to improve results and minimize complications associated with balloon angioplasty procedures. Stents may be superior to conventional angioplasty techniques for the following reasons: (1) stents increase acute procedural minimal lumen diameters, (2) stents prevent or "seal" flaps/dissections decreasing the incidence of early and late abrupt closure, (3) stents entrap friable material, thus reducing the likelihood of distal embolization, and (4) stents decrease the frequency of late restenosis. In two randomized clinical trials, STRESS²² and BENESTENT²³, comparing the long-term efficacy of coronary stents versus balloon angioplasty in patients with focal de nova lesions in native coronaries, there was a 30% reduction in both angiographic restenosis and the need for subsequent revascularization procedures. Similarly, data from a randomized trial comparing stents and balloon angioplasty in the treatment of iliac stenoses/occlusions revealed that only 2% of the stent patients versus 28% of the PTA patients required repeat target lesion interventional procedures during the three-year follow-up period^24. Importantly, refinements in operator techniques including the use of intravascular ultrasound guidance and post-stent high pressure balloon inflations to optimize stent implantation appear to have reduced the frequency of subacute stent thrombosis while further lowering restenosis frequency

CSSA (Carotid Stent Supported Angioplasty). Since the results of stent procedures indicate significant incremental benefits over conventional balloon angioplasty under most clinical circumstances, the present study is designed to evaluate the effects of primary elective stent implantation as the optimal catheter-based interventional treatment strategy for occlusive carotid artery disease. CSSA has several potential advantages over surgical carotid endarterectomy: the use of local anesthesia allows continuous monitoring of the neurological status, treatment of lesions inaccessible to surgery (e.g. supra-aortic common carotid lesions and intracranial internal carotid stenoses extending into siphon), reduced patient discomfort, potential for shorter hospital stay, potentially reduced costs, and possibly a significant lower morbidity and mortality. It would be particularly well-suited for the 35% of patients with symptomatic carotid disease who have severe coronary artery disease and have a high mortality and morbidity associated with carotid endarterectomy²⁵.

Thusfar, there are few published data describing the technique, safety, and efficacy of CSSA procedures. Mathias and coworkers²⁶ reported an observational study utilizing the self-expanding Wallstent for internal carotid artery stenoses with technical success in 46 of the 47 patients and residual stenosis <20% in all patients at the completion of the procedure. Complications included transient ischemic attacks in 2 patients and no strokes of deaths. Follow-up clinical assessments and anatomic evaluations (either angiography or ultrasound) were available in 44 of the 47 patients. There were no late or recurrent neurologic events and although minimal neointima formation at the stent site was frequent, there was no clinically significant recurrent stenosis and no patient required repeat revascularization procedures.

In the United States, there have been multiple single center observational studies of CSSA represented by the following principal investigators (and locations): Gerald Dorros, M.D. (Milwaukee, Wisconsin), Edward B. Diethrich, M.D. (Phoenix, Arizona), Robert G. Ferguson, M.D. (Memphis, Tennesse), Mark Wholey, M.D. (Pittsburgh, Pennsylvania), Martin Leon, M.D. (Washington , D.C.), Christopher Cates, M.D. (Atlanta, GA), and Gary S. Roubin, M.D. (Birmingham, Alabama). These study sites encompass the full range of interventional expertise including interventional cardiologist, interventional radiologist, vascular surgeons, and interventional neuroradiologist.

25 patients with extra-cranial carotid artery disease treated during CSSA procedures were treated at the Washington Hospital Center. Patient demographics were predominantly male (82%), mean age 64 years old, 70% coexistent coronary artery disease, and 52% had antecedent lesion-related neurologic symptoms. Technical success was 96% (inability to access a single right internal carotid artery due to excessive aortic root tortuosity) and angiographic success was achieved in all treated lesion sites. Only JJIS stents were used, including 42 biliary (medium size: P104, P154, and P204) and 3 coronary stents. Including all procedure-related and 30-day outcomes, there have been no deaths, no major strokes, and two (4%) minor neurologic events (one resolving in less than 24 hours and the other resolving in less than 7 days).

The largest ongoing CSSA study is being conducted by a multidisciplinary group of investigators at the University of Alabama (Birmingham, Alabama), led by Gary S. Roubin, M.D.²⁷ Thusfar, >250 vessels (predominantly internal carotid arteries) in ~230 patients have been treated utilizing FDA-approved stents to properly cover all lesion sites. Initially, combinations of Johnson & Johnson Interventional Systems (JJIS, Warren, New Jersey) and Cook (Bloomington, Indiana) stent were used to treat specific lesion morphologies. More recently, the self-expanding Schneider Wallstent (Minneapolis, MN) has been preferentially used due to its ability to resist deformity from external compressive forces. The study protocol requires careful on-line quantitative angiography to assess lesion sites and to accurately determine stent size, as well as careful endpoint analyses including pre-, post-, and follow-up independent neurologic evaluations, ultrasound imaging, and angiography. Preliminary results indicate successful stent deployment and angiographic success (<50% residual stenosis) in all patients with one episode of subacute stent thrombosis. In-hospital, there has been one death, two major strokes (one in the same patient who died), and no myocardial infarctions. Other in-hospital complications have included 10 minor neurologic events (transient ischemic attacks or minor strokes). During the first 30-day follow-up period, additional complications have been 1 major stroke (contralateral hemispheric cerebral embolism in a patient with atrial fibrillation) and 1 minor stroke. Follow-up angiography has been performed in over 70 patients and angiographic restenosis has been observed in <5% of treatment sites. In patients treated with the JJIS stents there has been evidence of asymptomatic external stent compression of sufficient severity to warrant repeat balloon dilatation in 3 patients. Importantly, these data reflect early learning curve experiences in consecutive patients with both favorable and unfavorable lesion morphologies and frequent comorbid disease states, rendering many patients at higher risk for carotid endarterectomy treatment. There have apparently been no major strokes or death in the last 150 consecutive cases, possibly reflecting improved technique after the initial learning curve. These early data which suggest a low 30-day event rate (~1-2%) for death and major strokes (the "traditional" combined primary endpoint) even in unfavorable patient subsets, are most encouraging and justify the further exploration of CSSA as an alternative treatment modality for symptomatic and asymptomatic patients with carotid artery disease.

Summary of clinical data. Based upon the analysis of previous clinical trials and observations from published or ongoing observational studies the following conclusions are justifiable: (1) the presence of symptomatic and asymptomatic carotid artery disease indicated by a measurable internal carotid artery diameter stenosis (>60-70%) is associated with known significant risks for subsequent morbid and mortal neurologic events; (2) aspirin alone or in combination with other anti-platelet agents, and ticlopidine (alone or combined with aspirin) represent "reasonable" medical therapy with an expected 20% relative-risk reduction of recurrent neurologic events; (3) surgical carotid endarterectomy for symptomatic patients (e.g. NASCET) and in asymptomatic patients (e.g. ACAS) results in an additional 25-65% reduction of major events (death of major stroke) compared with medical therapy; (4) carotid PTA appears to be a safe and effective catheter-based alternative to carotid endarterectomy, although direct comparisons have not been made and critical independent analyses of large patient cohorts with late follow-up results are not available; (5) CSSA may be a safer and more effective (i.e. predictable) alternative to carotid PTA based upon large experiences in other vascular distributions (both coronary and extra-cardiac) and therefore should be the preferred or optimal interventional carotid procedure, especially given the unforgiving nature of cerebrovascular complications and the good results already achieved by carotid endarterectomy procedures.

CSSA pilot study. This single center (Borgess Medical Center), consecutive patient, observational pilot study will examine the safety and acute (in-hospital and 30-day) efficacy of CSSA in patients with symptomatic and asymptomatic carotid artery stenoses. Specific anatomic and clinical inclusion/exclusion criteria will be established and patients will be subanalyzed according to pre-specified risk profile. A total of 15-30 patients will be entered into the study over a 6-12 month period. Multidisciplinary investigators from interventional cardiology, neurology, and vascular surgery will approve patient enrollment and participate in study design and data collection/analysis. Standardized interventional techniques will be applied utilizing FDA approved devices for vascular and/or extra-vascular treatments. Pre-, post-, and follow-up evaluations including neurologic assessments, and ultrasound imaging will be performed to determine the event rate for primary and secondary endpoints. Finally, to ensure patient safety, detailed reports will be filed with the Borgess Medical Center Institutional Review Board after the first 15-patient are treated and at the conclusion of the 30-patient study.

Secondary objectives. The secondary objectives of this study include the following: (1) technical success of stent deployment in variable morphology carotid stenoses; (2) acute angiographic results of CSSA; (3) procedural, in-hospital, and 30-day major and minor complications; (4) efficacy and safety of CSSA as determined by independent neurologic assessments post-procedure, @ 30-days, @ 6 months, and @one year; (5) efficacy of CSSA as determined by carotid ultrasound imaging post-procedure, @30 days, @ 6 months, and @ one year; (6) late clinical efficacy of CSSA. as determined by the need for repeat revascularization procedures (surgery or interventional therapy) @ 6 months and @ one year; (7) assessment and standardization of optimal operator techniques to be utilized for future randomized clinical trials comparing CSSA with surgical endarterectomy procedures.

Patient Selection - Criteria for eligibility. Candidates for this study must meet ALL of the following criteria:

The patient must be over 18 years of age.

The patient must have a >70% diameter stenosis of the extracranial internal carotid artery (using the NASCET quantitative stenosis measurement methodology) with or without antecedent neurologic symptoms. The lesion site diameter stenosis measurements will be made using on-line operator independent quantitative artery stenosis analysis software programs.

Female patients with child bearing potential must have a negative pregnancy test.

The patient and the patient's physician must agree to have the patient return for a 30-day, 6-month, and one-year clinical and imaging follow-up evaluations as indicated in the protocol.

The patient must provide written informed consent using a form that is reviewed and approved by the Institutionsal Review Board of the Borgess Medical Center.

Patient Selection - Criteria for exclusion. Candidates will be excluded from the study if ANY of the following conditions apply.

The patient has an intracranial tumor or cerebral arterio-venous malfor-mations(s).

The patient has had a previous disabling stroke or dementia.

The patient has had within four weeks of the treatment procedure an intracranial hemorrhage, hemorrhagic stroke, major stroke, or any stroke with mass effect demonstrated on MRI.

The patient has isolated intracranial internal carotid artery stenosis. The only exceptions would be if there is intracranial internal carotid disease in association with extracranial bifurcation carotid disease OR if a distal dissection occurs during the procedure requiring treatment of the previously normal intracranial internal carotid artery.

The patient has inaccessible intracranial arterial stenosis greater in severity than the extracranial internal carotid artery lesion.

The patient has isolated common carotid disease more than 10 mm proximal to the carotid bifurcation.

The patient has a known allergy to heparin.

The patient has a known allergy to anti-platelet agents (aspirin or ticlopidine).

The patient has a history of bleeding diathesis or coagulopathy.

There is angiographic evidence of significant intra-luminal thrombus burden with presumed increased risk of plaque fragmentation and consequent distal embolization. For the purposes of this submission, "significant" intra-luminal thrombus will be defined as an intra-luminal filling defect which extend for more than 5mm in axial length and occupies more than 50% of the reference vessel diameter.

There is total occlusion of the carotid artery treatment site with TIMI O flow characteristics.

The reference segment diameter (internal carotid artery segment cephalad to the lesion) is less than 3 millimeters by quantitative analysis.

The patient has peripheral vascular, supra-aortic or internal carotid artery tortuosity precluding use of catheter-based techniques required for successful CSSA.

The patient is absolutely contraindicated for surgical carotid endarterectomy, has no history of neurologic symptoms and has <70% diameter stenosis of the target carotid artery lesion. Patients considered absolutely contraindicated for carotid endarterectomy must be refused for surgical consideration by a least two board certified vascular surgeons due to prohibitive co-morbidity OR there is "local" anatomy co-morbidity such as radical neck dissection, burns, or radiation fibrosis after therapy for head and neck cancer.

The patient has one or several carotid lesions involving the internal and/or common carotid arteries, wherein the total lesion length (from the beginning of the most proximal lesion to the end of the most distal lesion) is greater than 5 cm.

The patient has unstable angina, evolving myocardial infarction, or recent (within 5 days) myocardial infarction.

The patient is currently participating in another study protocol which may influence either procedure results or follow-up evaluations.

Study design. A single center prospective observational pilot registry of 15-30 consecutive patients fulfilling protocol entry criteria.

Primary analysis population. The primary clinical endpoint and all secondary safety and efficacy endpoints will be analyzed on an intent-to-treat basis, i.e., after fulfilling patient entry criteria and obtaining informed consent, each outcome will be attributed to the CSSA procedure regardless of the actual sequence and results of specific devices utilized.

Deregistration is provided for analytical purposes to deal with the problem of determining study endpoints in patients who dropout before treatment is initiated. In this consecutive case registry series, the only situations where deregistration may be appropriate are (1) clinical factors developing or first recognized after obtaining informed consent and before initiating treatment, and (2) anatomic factors at the time of the procedure which are sufficiently changed to constitute clear deviation from protocol entry criteria (e.g. new significant intra-luminal thrombus or significantly improved stenosis severity). Under no circumstances, will deregistration be allowed after the CSSA treatment has begun. All deregistered patients will be subjected to clinical follow-up for the first year after initial entry into the CSSA study.

Withdrawal. Following the CSSA procedure, all patients are subject to complete clinical follow-up.

Secondary analysis population. The secondary analysis patient subset includes the per protocol treatment sample. Patients in this category have had a successful CSSA procedure defined as successful stent deployment with <50% residual diameter stenosis at all treatment sites and no significant procedure-related complications (death, MI, or major neurologic event). The per protocol treatment sample will provide valuable insights concerning the clinical and angiographic outcomes of only those patients who have had successful CSSA procedures.

High risk subset population. After entering the study, patients will be stratified into high and low (i.e. usual) risk populations for the purpose of retrospective subset analysis and comparison with appropriate patient cohorts from previous or ongoing clinical trials. Eligible patients will be considered low (or usual) risk unless they fulfill any of the following high risk patient characteristics:

1) The femoral artery and vein (right or left) will be cannulated and sheaths will be placed in standard fashion.

2) A 5 or 6 French temporary venous pacemaker or a 7 French pacing Swan-Ganz catheter may be placed, and/or atropine may be given before or during the procedure as needed.

3) The target vessel carotid artery (right or left) will be selectively cannulated in standard fashion using an angiographic catheter.

4) Selective angiography of the carotid vessel would be performed in multiple oblique views to best isolate and define the carotid lesion.

5) Quantitative carotid angiography will be analyzed to determine the baseline stenosis severity and to measure precise reference vessel size at appropriate locations (distal and possible proximal to the stenosis) to best select correct size balloon and stents. As previously stated, NASCET quantitative measuring criteria will be applied in defining the distal reference vessel location and the calculation of percent diameter stenosis.

6) Utilizing a standard guidewire exchange technique, the angiographic catheter will be exchanged for a 9 French guiding catheter (usually a multipurpose shape) whose distal tip should lie just proximal to the internal and external carotid artery bifurcation. The guiding catheter will permit continuous arterial pressure measurement and selective contrast injection to visualize the lesion site.

7) A steerable guidewire (0.014" or 0.018" diameter), under fluoroscopic control and with the visual assistance of contrast injections, will traverse the lesion. If a sufficiently stiff guidewire cannot be safely used initially to cross the lesion, an exchange procedure may be necessary utilizing a transport catheter for insertion of a stiffer guidewire to facilitate balloon predilatation and stent placement.

8) In most cases, predilatation with a conventional (typically coronary) balloon catheter would be necessary or advisable to ensure subsequent safe stent deployment. In some cases with non-critical stenoses (70% diameter narrowing), especially in straight segments within larger vessels (>6 mm), or with ulcerated friable-appearing lesions, predilatations with a balloon catheter may not be performed. Generally, the predilatation balloon should be "undersized" for the true reference vessel diameter, as the purpose of predilatation is t merely create a channel of sufficient size to accommodate subsequent stent introduction and deployment. After choosing an appropriate balloon catheter size and length, the catheter will be advanced over the guidewire and across the lesion site, with contrast injection to confirm balloon position. One or more brief inflations (30-60) seconds) will be performed at below or at nominal balloon pressures. Subsequent angiography will confirm the predilatation balloon angioplasty results, and if a sufficient vessel lumen caliber is achieved, the balloon catheter will removed.

9) Stent deployment will be accomplished using the correct size (length and diameter) device based upon previous quantitative carotid angiographic and analysis. It is anticipated that the FDA-approved Schneider Wallstent will be the stent used primarily in this pilot study. The Wallstent is a self-expanding stainless steel mesh-stent that is delivered via a delivery catheter with a smooth outer sheath. It comes in a variety of lengths and diameters. This stent is self-deployed as the outer sheath is pulled back. It is possible that in some cases it will be deemed appropriate to use the (tubular slotted) Johnson and Johnson Palmaz stent. This stent type comes in 3 types (P104, P154, and P 204) without articulations and can be expanded to a diameter range from 4 to 10 mm. The Palmaz stents will be hand crimped and mounted on the dedicated Opta 5 balloon catheter (Cordis, Miami Lakes, Fl) which has been subjected to rigorous qualifying engineering tests. Occasionally, it may be necessary to use the JJIS coronary stent (PS1530, PS1535, and PS1540) which is available as part of a sheath-based delivery system in diameters of 3.0, 3.5, and 4.0mm and 15mm in length. These stents would only be used in the treatment of intra-cranial internal carotid artery disease, where the vessel size mandates use of a smaller stent and/or vessel tortuosity would preferably favor the articulated version. Importantly, placement would only be in portions of the internal carotid artery wherein bending motions of the neck and/or external compression could not deform the more delicate articulated coronary stent. Based upon others’ experiences, we predict that the coronary articulated stent would be used in <5% of treatment sites.

The chosen stent-balloon catheter assembly should be advanced across the lesion site, under fluoroscopic control and with the visual assistance of contrast injections. After confirming the ideal trans-lesion stent position, the stent should be deployed by balloon expansion for 15-30 seconds at 6-8 atmospheres pressure. The deflated balloon catheter is than removed and carotid angiography is performed to assess stent implantation results.

10) Our intention would be to cover (or span) the entire lesion length utilizing the one Wallstent whenever possible. If multiple stents are required, the procedure outlined above must be repeated. Generally, in multiple stent cases, the distal stent(s) are placed first and there is slight overlap of the stent ends.

11) Post-stent high pressure balloon inflations are usually required to achieve optimal stent implantation characteristics (i.e. flush apposition and full expansion). Utilizing commercially available non-compliant balloons of appropriate sixes (based on quantitative carotid angiography), one or more brief inflations (~15 seconds) will be performed @ 12 to 20 atmospheres within the stent margins. Repetitive carotid angiography will be required to determine if optimal stent expansion is achieved and the need for further post-stent balloon expansion using either higher pressures or with larger balloon catheters.

12) Final post-CSSA quantitative carotid angiography will be obtained utilizing the same pre-treatment designated views to assess angioraphic results and complications. Optimal stent expansion is defined based upon the on-line quantitative angiography and requires that there be less than 20% residual lumen diameter stenosis at all sites within the stented segment after initial deployment and subsequent post-stent high-pressure balloon dilatations.

13) After the technical portions of the CSSA procedure are completed, final intracerebral angiography is obtained in the frontal and lateral projections to be certain that significant distal embolization has not occurred and to re-assess antegrade and collateral flow patterns after restoration of normal carotid artery perfusion.

14) At the completion of the CSSA procedure, patients will return to a monitored bed in an intensive care unit setting for careful neurologic and hemodynamic valuations by a trained staff for 12 to 24 hours. Uniform post-CSSA orders for patient care will be followed. Arterial and venous sheaths will be removed as quickly as possible (when the ACT is below 150 seconds) and gradual ambulation will commence the following day.