Aquamid PPT

1. Patients with adverse reactions to subcutaneous injection of Aquamid (polyacrylamide hydrogel) Lise Christensen, MD, dr.med. Senior pathologist Rigshospitalet, Copenhagen, Denmark

2. Polyacryl amide hydrogel (PAAG) A gel consisting of a backbone of approximately 2.5 % cross- linked polyacrylamide and 97.5 % water soft contact lenses, opthalmic surgery, packaging agent in food, clarification agent for sugar juices , in water purification Has been used in plastic and aesthetic surgery in the former Soviet Union for more than 15 years and in Europe for 7 years Excellent plasticity, widely atoxic and non-immunogenic

3. Normal host response to foreign material 1. 24 hours: neutrophils and small round cells predominate 2. 48 hours: monocytes predominate – no neutrophils from now on 3. 7 days: early formation of foreign-body giant cells occur 4. 2 weeks: the cellular response remains mild 5. 4 weeks: monocytes diff. into epitheloid cells, fibroblasts appear 6. 6 weeks: foreign-body giant cells common, increase of coll. deposition 7. 8 weeks: chronic inflammatory cells and a heavy collagen deposition 8. 6 months: stable giant cell and low-grade cellular response along with a reduced amount of more dense collagen and the conversion of fibroblasts into fibrocytes

4. Heavy foreign body response in cheek tissue after 2 months No granulocytes No clinical symptoms

5. PAAG (Aquamid) in front tissue (glabella) after 7½ months.

6. After 2 years. Hardly any cellular reaction

7. HUMAN TISSUE AFTER 2 YEARS

8. Adverse reactions

9. It is common to see some swelling about 10 days after Aquamid injection. This swelling is probably due to a tissue response to the gel in order to reach a steady-state. This swelling disappears spontaneously after 12-13 days Classical signs of infection are not present (warmth, pulsation, pain and redness)

10. Generalised adverse reactions 1. Allergic/hypersensitivity reactions (rash, Quinckes oedema, anaphylactic chok) 2. Autoimmune reactions (collagenoses- LED, rheum arthr. lung fibrosis, PBC, Mb Graves, atherosclerosis etc) Local or regional adverse reactions 1. Short-term reactions: pain, oedema, pruritus, ecchymosis, pigmentation changes, excessive elevation and embolism, if gel is accident.injected into the vascular system appear within 2 days of the injection and disappear spontaneously within 1-2 weeks. Pruritus subside within weeks or months 2. Long-term reactions: inflammatory nodule (clinically a granuloma) appear after weeks, months or years and present as a tender nodule and/or Swelling and redness at the point of injection. Later this may lead to fistulation, ulceration, discharge of pus and/or filler material and tissue destruction.

11. Inflammatory nodule Characterised by polymorphnuclear granulocytes and microorganisms (bacteria) – which may be difficult to detect – As well as the foreign-body reaction which is seen in all tissues injected with a foreign material.

12. Adverse reaction, 6 weeks Granulomatous inflamm.

13. Injection technique • Sterility precautions should be as in open surgery: • Gloves, mask, hut • Skin disinfection of injection site • Retraction of injection needle as prescribed • Tell patient to refrain from activities increasing • risk of contamination with micro-organisms • for 8 hours after the injection

14. Incidence of Microorganisms in Human tissue Cultures taken from breast tissue far away from the papilla and not previously operated upon have shown a 53% positivity for coagulase-negative staphylococci. Propionibacterium acne was the most frequently found anaerobic bacterium (Thornton, 88). Cultures from 389 periprosthetic breast tissues with no clinical signs of infection have shown 23.5 % microorganisms including aerobic and anaerobic bacteria as well as fungi and other organisms (Netscher, 95),

15. We all harbour bacteria within out tissues. Our immune system take care of them. Patients with long-term antibiotic treatment for different diseases (colitis ulcerosa, Mb. Crohn, DM) may grow antibiotic-resistant bacterial strains Patients on long-term steroid or NSAID treatment (collagenoses) have a reduced immune system.

16. 1. Aquamid should be treated like any other implant (heart valves, artificial blood vessels, breast silicone prostheses and hip replacement prostheses). The local immune defence is reduced 2. In case of sepsis (e.g. tooth extraction, pneumonia, abdominal surgery) antibiotic treatment should be given

17. A negative tissue cultureis no proof that microorganisms are not present A negative GRAM or PAS stainon microscopy of a cell smear or tissue section is no proof that microorganisms are not present Antibiotic therapyprior to a culture swap or biopsy may immobilize or reduce the number of microorganisms hindering their detection

18. Report on 56 cases of adverse events out of 40.000 patients injected with Aquamid (1.4 ‰) Information from treating physicists and patients on filled-in pre-printed forms distributed by and sent to the manufacturer Number of patients: 56 Patient age (75%):23-60 years - mean 44, median 45

19. Study period: May 21. 2001 to September 15. 2003 Contributing countries: Australia (9 pt.s), Austria (4 pt.s), Belgium (1 pt.), Brazil (5 pt.s), Equador (1 pt.), France (7 pt.s), Germany (7 pt.s), Holland (3 pt.s), Israel (1 pt), Italy (7 pt.s), New Zealand (1 pt), Spain (6 pt.s), Sweden (1 pt), Switzerland (2 pt.s), USA (1 pt.)

20. Injection sites: Lip 32 Naso-labial folds 24 Glabella 5 Cheekbone 4 Cheek 2 Chin 2 Forearm, allergy test 2 Nosetip 1

21. Type of physician: Plastic surgeon 23 Dermatologist 12 Aesthetic/cosmetic doctor 20 Unknown 1 Symptoms: Swelling, redness, pain, fistulation, pus discharge Symptom delay (Time from last injection to first symptom of adverse reaction: median 12 days.

22. Established causes of adverse reactions (found in 18 (32%) of patients) Herpes labialis 5 cases Bacteria 1. Positive culture Streptococci viridans: 3 cases Atypical mycobacteriae: 1 case 2. DNA cloning Shigella 1 case Streptococci viridans 1 case 3. Microscopy (gram stain) Gram positive cocci 2 cases Gram positive rods 1 case . Total: 9 cases Too superficially injected 2 cases Palsy1 case Breast cancer subsequently 1 case

23. Known contraindications: Several previous injections at the same site: 9 patients Mb. Crohn and Colitis Ulcerosa: 2 patients Pemphigus: 1 patient Insulin dependent Diabetes Mellitus: 1 patient Dentistry at the injection site: 1 patient Face-lift just prior to injection: 1 patient Oral sex right after injection: 1 patient Make-up during injection: 1 patient

24. First line Treatment: None: 6 patients Antibiotic alone: 10 patients Antibiotic+steroid: 13 patients Antibiotic+steroid+NSAID: 7 patients Steroid: 6 patients NSAID: 6 patients Anti-histamine: 4 patients Drainage only: 4 patients Total 56 patients

25. Second line treatment: 32 patients Antibiotic: 29 patients Steroid: 3 patients Third line treatment 8 patients Antibiotic: 8 patients ___________________________________________________ Primary treatment . Steroid + weak antibiotic: 2 patients Steroid alone: 2 patients Steroid + NSAID and/or antihistamine 3 patients Antihistamine 1 patient They all received antibiotics the third time with improvement or complete recovery.

26. Fastest recovery was obtained for those patients treated with antibiotics from the start - in spite of negative findings on culture and/or microscopy. • A prolonged course resulted if primary (antibiotic) treatment was delayed/weak or if it included steroids or NSAIDs. • Anti-histamines or anti-viral drugs did not hinder recovery.

27. Cause of adverse reactions Bacteria, sometimes preceded by herpes Treatment of adverse reactions Antibiotics in high dosage i.m. or i.v.– steroids or NSAIDs are stongly contraindicated

28. Treatment of adverse inflammatory reactions: • Immediate administration of a broad-spectered antibiotic in high dosage, e.g.: • Fluoroquinolon (Ciproxin) 500 mg x 2 for up to 7 • days • 2. Vancomycin/Teicomycin, i.m. 1 g x 2 , or • Lincomycin 300 mg x 2 for 2 days followed by ½ • dosis for the next 10-20 days. • *Tell patient to go to injecting doctor for treatment and show patience