Day-Case Angioplasty in Diabetic Patients With Critical Leg Ischemia

By Zayed, H A Fassiadis, N; Jones, K G; Edmondson, R D; Edmonds, M E; Evans, D R; Wilkins, C J; Sidhu, P S; Rashid, H I

Aim. Recent studies have shown that percutaneous transluminal angioplasty (PTA) can be safely performed as a day-case procedure. Many centers consider diabetes mellitus as a contraindication to day- case PTA. In this study, the safety and efficacy of 95 day-case PTA in 66 diabetic patients with critical leg ischemia (CLI) were evaluated. Methods. Diabetic patients with CLI were assessed in a onestop multidisciplinary outpatient clinic. Sixty-six outpatients with CLI deemed suitable for radiological intervention by non- invasive imaging (ultrasound angiology or magnetic resonance angiography) were scheduled for daycase PTA. Results. PTA was initially successful in 63 out of 66 patients (95%). In 3 patients (5%), PTA was not possible because the lesion could not be balloon dilated or crossed with a guide wire. Clinically suspected first, second and third re-stenosis confirmed by non-invasive studies occurred in 20 out of 63 (31%), 7 out of 20 (35%) and 2 out of 7 (28%) patients, respectively. Following PTA, debridement was performed in 11 patients (17%), minor amputation in 8 (13%) and major amputation in 3 (5%). Relief of the primary symptom of rest pain or healing of ulcers was achieved in 23 out of 32 (72%) and 25 out of 27 (92.5%) patients, respectively. No peri-interventional morbidity or mortality was encountered.

Conclusion, PTA is feasible and safe as a day-case procedure in diabetic patients with CLL Re-stenosis can be managed by repeat day- case PTA.

[Int Angiol 2008;27:232-8]

Key words: Angioplasty – Diabetes mellitus – Leg – Ischemia.

Peripheral vascular disease (PVD) is a recognized complication of diabetes mellitus (DM). Recently, PVD prevalence in patients with diabetes over 50 years of age has been estimated as high as 30%.1 Endovascular treatment has an increasing role in the treatment of diabetic patients with critical leg ischemia (CLI) and ischemic foot ulcer 2, 3 and has also been demonstrated to be of value in “limb salvage”.4 Therefore, percutaneous transluminal angioplasty (PTA) is considered as one of the revascularization options in diabetic patients with PVD3 as it provides similar outcomes to the nondiabetics with CLI.5

PTA has previously been shown to be performed safely as a day- case procedure.6 However, no similar studies have been performed in diabetic patients with CLI as some centers consider DM a contraindication to day-case PTA due to difficulty to achieve satisfactory periprocedural blood sugar levels and to control associated morbidities, such as renal impairment.7

The aim of this study was to evaluate the safety and efficacy of performing endovascular interventional procedures in patients with DM and CLI as day-cases in a dedicated Vascular Interventional Radiology Unit.

Materials and methods

Hospital Ethical Board approval to report this study was obtained. The study was conducted over a 23-month period (December 2003 to October 2005). All diabetic mellitus patients with CLI were assessed in a one-stop multidisciplinary outpatient clinic. PVD was determined by history taking, clinical examination, ankle-brachial pressure index, arterial waveforms and transcutaneous oxygen tension. Further non-invasive imaging assessment was performed as needed with initially a color and spectral Doppler ultrasound examination with documentation of velocity parameters and if inconclusive a contrast-enhanced magnetic resonance angiogram. Based on the results of the non-invasive imaging, all suitable patients (based on TASC classification of arterial lesions) were offered endovascular intervention on a “daycase” basis. The endovascular interventional procedure was performed in a purpose-built unit with 10 beds adjacent to the angiography suite, staffed by 8 full-time radiology specialist nurses (RSN) and equipped with the S600 series portable patient monitoring systems (Siemens, Bracknell, UK).

This study was performed on a selected group of patients who accepted this concept and were further assessed for the suitability to have an endovascular day-case procedure based on predetermined criteria outlined in Table I. Patients who had a medical or social contraindication to have day-case PTA were offered the procedure as an inpatient intervention. All patients had an initial telephone conversation with the RSN to ascertain suitability for attendance at the pre-assessment clinic. The assessment clinic was held in the surgical outpatients, a short distance from the radiology department. In the assessment clinic, the RSN and a surgical pre- registration house officer (PRHO) reviewed patients and both completed a pre-formatted Care Document (Appendix I). The PRHO obtained a clinical history and examined the patient whilst the RSN established whether there were any other pre-determined contraindications to day-case PTA not apparent at initial telephone screening. In addition, the RSN gave an explanation of the procedure and its potential complications and answered patient questions. If, on physical examination, there was a contraindication to day-case PTA, (e.g. the femoral pulses were not palpable), this was discussed with the radiologist-in-charge and a decision was made regarding the suitability for day-case PTA. The patient was then accompanied on a tour of the angiography suite and the radiological day case unit (RDCU); a Patient Information Sheet was provided (Appendix II) and an admission date made to attend for the procedure. At the same preassessment clinic visit, the patient underwent screening investigations, consisting of a full blood count, including platelets and blood clotting parameters, renal and liver function tests. If indicated, screening for sickle cell disease, a chest radiograph and an electrocardiogram were also performed.

On the day of the procedure, patients arrived in the RDCU, 30 min prior to their procedure. The patients had been instructed to continue with routine medication and ingest clear fluids only. If they were taking metformin, they had been instructed to stop it on the day of the procedure and restart it 48 h after the procedure. A brief pre-procedure assessment was made by the RSN to exclude recent illness, re-confirm adequate social support, check the screening results and obtain baseline observations (pulse rate, blood pressure, and oxygen saturation). If the clinical status of the patient had altered, the decision to cancel the procedure was discussed with the radiologist-in-charge and the patient before either a new date for a day-case PTA was given or altered to an inpatient investigation. The radiologist obtained full informed consent and selected a suitable arterial puncture. No pre- medication in the form of a sedative or systemic pain relief was administered. All patients with impaired renal function were given intravenous fluids and N-acetyl cysteine for kidney protection prior to the procedure.8 Those with moderate to severe renal dysfunction were discussed with the renal physicians.

Angiographic procedure

All procedures were performed by experienced consultant radiologists or specialist registrars under consultant supervision. Procedures were conducted in an angiography suit with digital subtraction units (Multistar TOP, Siemens Germany or Axiom Artis, Siemens, Germany). Standard departmental angiographic practice was adhered to. The standard approach to femoral puncture was employed using the Seldinger technique, in either a retrograde or antegrade fashion as needed. Lignocaine 1% (10 mL) local anaesthetic was used at the puncture site. A variety of angiographic catheters and sheaths were used, with the majority between 4 and 6 Fr in size. The balloon sizes varied according to the site of the balloon dilatation; iliac arteries (7-10 mm), superficial femoral artery (SFA) (5-7 mm) and for below knee procedures (2-4 mm) balloon catheters were used. Stents were only used in the iliac arteries, when a suboptimal angioplasty result was encountered, and were sized appropriately. Occlusions were crossed with a guide wire using the sub-intimal technique as necessary. When a balloon dilatation or arterial stent insertion was performed, intra-arterial heparin (5 000 IU), and in most cases isosorbride dinitrate (Isoket 0.1%, 1 mg) were administered. Patients were routinely given non-ionic iodinated contrast material (either Omnipaque 350 mgI/mL or Visipaque 320 mgI/ mL) (GE Healthcare, Oslo, Norway).

Following the endovascular procedure, patients were transferred from the angiography room to the adjoining RDCU. Catheters were removed by the radiologist and satisfactory hemostasis was ensured. If all observations were satisfactory and hemostasis was achieved by manual compression, the patient was allowed to sit up in bed after 1 h, sit out of bed after 2 h, commence gentle mobilization after 3 h and discharged after 4 h. If a hemostatic device was used, the patient was allowed to sit up in bed after 30 min, sit out of bed after 60 min, commence gentle mobilization after 90 min and discharged after 2 h. The radiologist reviewed all patients prior to discharge. Patients were given 24-h contact telephone numbers; a future followup in the multidisciplinary clinic was arranged. Patients were discharged accompanied by a responsible adult. All patients were kept on a single antiplatelet agent for life, if not contraindicated. Arrangements for 24-h follow-up were made were general patient well being, puncture site status and kidney functions were checked. Any complications were noted and appropriate action taken. Results

Sixty-six suitable diabetic patients with CLI were prospectively included in this study (median age: 67 years; age range: 43-90 year; 39 males and 27 females). Risk factors are listed in Table II. Thirtytwo patients had rest pain, 27 had ulcers and 16 had gangrene. Nine patients had rest pain as well as tissue loss (gangrene: n=3; and ulcer: n=6).

Successful balloon dilatation of both stenotic and occlusive lesions was achieved in 63 out of 66 patients (95.7%) and performed in 17 common iliac artery (CIA), 4 external iliac artery, three common femoral artery, 26 SFA, 12 popliteal artery (PopA), 4 anterior tibial artery, two tibio-peroneal trunk (TPT), two posterior tibial artery (PTA) and two peroneal artery lesions. Intravascular stents were inserted in 5 CIA lesions. Angioplasty was not feasible in 3 out of 66 (4.3%) patients either because the lesion was “undilatable” (one TPT and one SFA lesions) or “uncrossable” (one PTA lesion). During the period of the study, hemostatic devices (Angioseal, St. Jude Medical, Belgium; Perclose and Starclose, Abbott Vascular, Galway, Ireland) were used in 11 out of 66 patients (16.7%).

Clinically suspected first, second and third restenosis confirmed by non-invasive studies occurred in 20 out of 63 (31.7%), 7 out of 63 (11.1%) and 2 out of 63 (3.2%) patients. These 20 patients required a second balloon dilatation following a period ranging between 2-98 weeks with a mean of 31.5 weeks. On repeat angiography, three intravascular stents were inserted for lesions in CIA (n=2) and PopA (n=1); the remainder had balloon dilatation performed. Seven out of 20 patients required a third PTA. One stent was inserted in an SFA lesion, while the remainder underwent balloon dilatation. The duration between the second and third PTA ranged between 2 -82 weeks with a mean of 21 weeks. Two out of 7 patients required a fourth PTA with a duration ranging from 2-11 weeks with a mean of 6.5 weeks. All repeat endovascular interventional procedures were performed within the RDCU. The sites of redo-PTA are shown in Table III.

Following the endovascular procedure, in the group of patients with rest pain, 23 had complete pain resolution, 8 had partial resolution, while 3 had no improvement. In the 27 patients with ischemic ulcers, complete healing was achieved in 14, partial healing in 11 and non-healing in 2. Debridement was required in 11, minor amputations in 8 while major amputations were performed in 3 patients (4.5%).

No peri-interventional morbidity or mortality was encountered and no patient required in-hospital admission. Over the study period, PTA was performed on an “in-patient” basis in 180 patients with underlying DM. These patients required hospital admission either to optimize their diabetic control, treat co-morbidities or surgically drain associated infection.

Discussion

The role of PTA in the management of patients with PVD is increasing with some studies describing a five-fold increase in the use of PTA in patients with CLI in the last decade.8-11 Also, PTA has been proven to be feasible in the majority of diabetic patients with PVD and foot ulcers.12 The aim of the procedure is to obtain a ‘straight-line flow to the foot’ by treating all significant stenoses and short occlusions that impair distal vascularization.2 PTA is usually successful initially to relieve any ischemic pain and prompt ulcer healing, but often the arterial disease recurs.3 The current study demonstrates that a PTA can be performed as a “day- case” procedure to manage this group of patients successfully and safely.

In this study, PTA was successful in 63 out of 66 patients (95%). This is comparable to the success rates in other studies,13-15 showing that performing PTA as a day-case procedure did not compromise its success rate. Clinical re-stenosis is a well- recognized consequence of angioplasty and PTA can be successfully repeated in most cases.3 In the current study, re-stenosis occurred in 20 out of 63 patients (30%), of which two affected the crural vessels. Seven out of 20 patients required a third PTA of which 3 were for crural vessels re-stenoses. Two out of 7 patients required a fourth PTA for crural vessel lesions. Repeat PTA were predominantly for crural vessels; stenosis at this level has a higher tendency to recur after PTA. We have demonstrated that when stenosis recurs the endovascular treatment can be safely repeated again as a “day-case” procedure.3, 16

In the current study, none of the patients suffered any peri- interventional morbidity or mortality. With respect to the clinical outcome, ulcer healing rate and resolution of rest pain among the study group were comparable to previously reported rates in other studies performed in patients with DM when the PTA was performed as an inpatient procedure.17 The amputation rate in this study was 4.5%, which compares favorably to the recently published results of the BASIL trial.18 This confirms that PTA performed as a day-case procedure in selected patients had a high limb salvage rate comparable to in-patient procedures.

From the economical point of view, previous studies concluded that cost savings are significant using the day-case PTA policy.16 In one study of a nurse-led orthopedic pre-assessment clinic, patient screening and cancellation of non-attendees by nurses reduced costs (by Pounds 36 000/year), saved doctors’ time, reduced patient anxiety and was valued by the majority of patients.19 In a general surgical setting, patients pre-assessed in a nurse-led clinic were more satisfied with the amount of information received and, once admitted, were much less likely to have their operations cancelled, compared to those who had not undergone a form of pre- assessment prior to admission.17 In the current study, 95 procedures were performed, thus saving 95 bed-days over a period of 23 months. This has also reduced the waiting list for PTA in times where in- patient cancellation has significantly increased due to limited bed availability. Accordingly, without the reliance on the availability of an inpatient bed, the radiological intervention list can be optimally planned and utilized, thus effectively reducing the waiting list for intervention.

However, in order to establish a successful daycase PTA policy, certain measures need to be enforced. These include a well-designed protocol that can ensure proper patient selection through the pre- assessment visit, which can be efficiently nurse-led as was the case in this series. In this study, 6 patients in chronic renal failure underwent day-case PTA successfully without complications. This was achieved through appropriate communication with the renal physicians. Close postprocedure observation is of paramount importance to detect early complications. Although previous studies showed that day-case PTA can be safely done using the hemostatic devices,16, 20 in this series hemostatic devices were used in 16.7% procedures only without puncture site complications. However, the use of these devices has now increased, with experience, and is used in the majority of day-case PTA in our institute to allow early mobilization.

It is important to point to the fact that during the same period of time PTA was done as an inpatient procedure on 180 patients. This means that only 26% of patients requiring PTA were suitable for a day-case procedure. Thus, the majority of diabetic patients with CLI will require admission due to concomitant pathology such as managing infections and extensive tissue loss. Routine duplex scanning was not offered to all patients after PTA. However, patients with persisting clinical signs or deteriorating symptoms were rescanned for re-stenosis and PTA was repeated as a day-case procedure when indicated.

Conclusions

We have found that PTA is feasible and safe as a day-case procedure in selected patients with DM and CLI, allowing for cost- savings. Re-stenosis is common but can be again managed by repeat daycase PTA, up to four times in our series where the crural vessels were often subject to re-stenosis. Adherence to a strict protocol allowed patient selection and periprocedural management to be successfully performed by trained radiological nurse. A majority of patients with DM and CLI will continue to require in-patient management because of co-morbidity. For those suitable patients, a day-case procedure is an attractive option, and is of comparable safety to an in-patient procedure.

Received on July 4, 2007; acknowledged on August 24, 2007; sent for revision on September 19, 2007; resubmitted on October 18, 2007; accepted for publication on January 10, 2008.

References

1. Muhs BE, Gagne P, Sheehan P. Peripheral arterial disease: clinical assessment and indications for revascularization in the patient with diabetes. Curr Diab Rep 2005;5:24-9.

2. Beyssen B, Pagny JY, Piquois A, Raynaud A, Sapoval M. [Critical limb ischaemia: endovascular treatment in diabetic patients?]. Arch Mal Coeur Vaiss 2004;97 Spec No 3:33-9.

3. Faglia E, Maniero M, Caminiti M, Caravaggi C, De Giglio R, Pritelli C et al Extensive use of peripheral angioplasty, particularly infrapopliteal, in the treatment of ischaemic diabetic foot ulcers: clinical results of a multicentric study of 221 consecutive diabetic subjects. J Intern Med 2002;252:225-32.

4. Hanna GP, Fujise K, Kjellgren O, Feld S, Fife C, Schroth G et al. InfrapopUteal transcatheter interventions for limb salvage in diabetic patients: importance of aggressive interventional approach and role of transcutaneous oximetry. J Am Coll Cardiol 1997;30:664- 9.

5. Jacqueminet S, Hartemann-Heurtier A, Izzillo R, Cluzel P, Golmard JL, Ha Van G et al Percutaneous transluminal angioplasty in severe diabetic foot ischemia: outcomes and prognostic factors. Diabetes Metab 2005;31(4 Pt l):370-5. 6. Butterfield JS, Fitzgerald JB, Razzaq R, Willard CJ, Ashleigh RJ, England RE et al Early mobilization following angioplasty. Clin Radiol 2000;55:874-7.

7. Clements SD Jr, Gatlin S. Outpatient cardiac catheterization: a report of 3,000 cases. Clin Cardiol 1991;14:477-80.

8. Henry M. Peripheral transluminal angioplasty. What is new? Int Angiol 2003;22:219.

9. Pell JP, Whyman MR, Fowkes FG, Gillespie I, Ruckley CV. Trends in vascular surgery since the introduction of percutaneous transluminal angioplasty. Br J Surg 1994;81:832-5.

10. Skotnicki SH. The vascular surgeon and transluminal angioplasty. Eur J Vasc Surg 1988;2:143-4.

11. Motarjeme A. PTA and thrombolysis in leg salvage. J Endovasc Surg 1994;1:81-7.

12. Faglia E, Favales F1 Quarantiello A, Calia P, Brambilla G, Rampoldi A et al. Feasibility and effectiveness of peripheral percutaneous transluminal balloon angioplasty in diabetic subjects with foot ulcers. Diabetes Care 1996;19:1261-4

13. Sigala F, Menenakos C, Sigalas P, Baunach C, Langer S, Papalambros E et al Transluminal angioplasty of isolated crural arterial lesions in diabetics with critical limb ischemia. Vasa 2005;34:186-91.

14. Faglia E, Dalla Paola L, Clerici G, Clerissi J, Graziarli L, Fusaro Metal Peripheral angioplasty as the first-choice revascularization procedure in diabetic patients with critical limb ischemia: prospective study of 993 consecutive patients hospitalized and followed between 1999 and 2003. Eur J Vase Endovasc Surg 2005;29:620-7.

15. London NJ, Varty K, Sayers RD, Thompson MM, Bell PR, Bolia A. Percutaneous transluminal angioplasty for lowerlimb critical ischaemia. Br J Surg 1995;82:1232-5.

16. Wilentz JR, Mishkel G, McDermott D, Ravi K, Fox JT, Reimers CD. Outpatient coronary stenting using the femoral approach with vascular sealing. J Invasive Cardiol 1999;11:709-17.

17. Reed M, Wright S, Armitage F. Nurse-led general surgical pre- operative assessment clinic. J Coll Surg (Edinb) 1997;42:310-3.

18. Adam DJ, Beard JD, Cleveland T, Bell J, Bradbury AW, Forbes JF et al.; BASIL trial participants. Bypass versus angioplasty in severe ischaemia of the leg (BASIL.): multicentre, randomised controlled trial. Lancet 2005;366: 1925-34.

19. Newton V. Care in pre-admission clinics. Nursing Times 1996;92:27-8.

20. Yee KM, Lazzam C, Richards J, Ross J, Seidelin PH. Sameday discharge after coronary stenting: a feasibility study using a haemostatic femoral puncture closure device. J Interv Cardiol 2004;17:315-20.

H. A. ZAYED1, N. FASSIADIS1, K. G. JONES1, R. D. EDMONDSON1 M. E. EDMONDS2, D. R. EVANS3, C. J. WILKINS3, P. S. SIDHU3, H. I. RASHlD1

1 Department of Vascular Surgery, King’s College Hospital, London, UK

2 Department of Medicine, King’s College Hospital, London, UK

3 Department of Radiology, King’s College Hospital, London, UK

Address reprint requests to: Mr. H. A. Zayed, Department of Vascular Surgery, King’s College Hospital, Denmark Hill, London SE 5 9RS, United Kingdom. E-mail: zayedha@yahoo.com

Appendix I. Care Document

Care Document: Part I.

PATIENT ASSESSMENT

Performed in Radiology Day Case Unit (RDCU) and completed by Radiology Specialist Nurse (RSN):

* Have you had this type of examination before?

* Are you taking any medicines (tablets, patches, inhalers, injections)?

* Have you any allergies (previous contrast reactions, drugs, plasters)?

* Have you had any serious illnesses in the past?

* Do you have high blood pressure?

* Do you have asthma?

* Do you have anemia or any other blood disorder?

* Do you have kidney disease?

* Do you have diabetes mellitus (Ask if on metformin)?

* Are you or could you be pregnant (female patients)?

PHYSICIAN CLERKING

From clinical notes and transcribed to RDCU notes by RSN:

* History of claudication and risk factors.

* Past medical history.

* Drug and allergy history.

* Social history.

* Examination of respiratory and cardiovascular systems (including peripheral pulses).

* Screening investigations (full blood count, clotting, renal and liver function, sickle cell test, CXR, ECG; as required).

* Vascular laboratory assessment (results).

PATIENT CHECK LIST

Patient made aware of socio-domestic requirements:

* 24 hour accompaniment by responsible adult.

* Transport by car or taxi.

* Availability of GP/nursing back up.

* Reasonable access to a telephone.

Patient made aware of medico-legal requirement:

* Understanding and acceptance by the patient of his/her obligations to the RDCU concerning his/her procedure welfare.

* Patient demonstrates an understanding of the procedure.

* Patient pre-angiography information sheet given (see Appendix 2).

* Clear fluids from midnight.

DATE FOR DAY CASE ANGIOGRAM

* Given to patient.

* Entered in the day case angiogram (DCA) diary.

* Referral doctor informed.

* Surgical admissions informed.

RESULTS

Pre-angiographic screening investigations documented in day case notes.

Care Document: Part II

Completed by the RSN and/or Radiologist

PRE-PROCEDURE ASSESSMENT

* New health problems.

* Ill today?

* Eaten in the last 4 hours?

* Last menstrual period (female patient).

* Responsible adult for journey home.

* Responsible adult for 24 hours after DCA (if negative response to any of the above, new date made for DCA).

* Blood pressure, pulse, temperature, weight, oxygen saturation.

* Arterial puncture site preparation.

* Femoral and distal pulses recorded.

* Consent obtained by Radiologist.

PROCEDURE DETAILS

* Procedure technique.

* Drugs administered, including contrast volume.

* Procedure result.

* Any further action.

* Procedure complications.

* Instructions.

POSTPROCEDURE ASSESSMENT

* Time catheter removed.

* Time to hemostasis

* Hematoma

* Blood pressure, pulse, oxygen saturation

* Puncture site inspection

* Any complications recorded

DISCHARGE CHECKLIST

* Mobile.

* Passed urine.

* Any discharge medication prescribed.

* Appropriate discharge letters.

* Surgical follow-up arranged.

* Patient aware of puncture site wound care.

* Patient aware of action in case of complications.

* Patient agreed to telephone RSN at RDCU by 11 a.m. the next day.

FOLLOW-UP AT 24 HOURS

* General well being.

* Puncture site.

Appendix II.

Patient Information Sheet, Pre-angiography.

Name:

Angiography appointment date:_____Time:

An appointment has been made for you for vascular angiography, to be carried out as a ‘day case’ in the Radiology Day Case Unit under local anaesthetic.

Please come straight to the Radiology Department on the date given above. You will be met by the Radiology Nurse and admitted to the Day Case Unit.

The angiogram will take place during the morning. You will need to rest in the Radiology Day Case Unit for about 4-5 hours after the procedure before going home.

On the day of the appointment it is very important that you remember:

* Not to have anything to eat from midnight prior to your morning appointment. You may however drink clear fluids like water, tea or coffee but without milk.

You are advised to bring your diabetes tablets to the hospital on the day and you will be able to have them and something to eat immediately after the procedure.

* To arrange for a responsible person to collect you by car from the Unit and for someone to look after you for 24 hours after the angiogram.

* Not to drive for 24 hours after the examination.

* To ask the adult escorting you to contact the Radiology Day Case Unit at about 11 a.m. on the day of your angiography to find out the time you are likely to be ready to go home.

* To bring a dressing gown and a pair of slippers.

* To bring something to read while you are resting after the angiogram.

* To bring all your prescribed medication/ tablets that you take regularly.

* To telephone the Radiology Day Case Unit on the day before your appointment (on Friday for a Monday), to confirm that you are definitely attending for the examination. Failure to do this may result in your appointment being cancelled.

Please do not hesitate to contact us at any time between 9 a.m. and 5 p.m., Monday to Friday if you have any queries.

Radiology Nurse Manager, Radiology Day Case Unit Telephone_____

Copyright Edizioni Minerva Medica Jun 2008

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