adverse reactions - aquamid

Patients with adverse reactions to subcutaneous injection of Aquamid (polyacrylamide hydrogel)

Lise Christensen, MD, dr.med.

Senior pathologist

Rigshospitalet, Copenhagen, Denmark

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 waterpurification

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

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

Heavy foreign body

response in cheek

tissue after 2 months

No granulocytes

No clinical symptoms

PAAG (Aquamid) in

front tissue (glabella)

after 7½ months.

After 2 years. Hardly any cellular reaction

HUMAN TISSUE AFTER 2 YEARS

Adverse reactions

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)

Generalised adverse reactions1. 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.

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.

Adverse reaction, 6 weeks

Granulomatous inflamm.

Injection technique

Sterility precautions should be as in open surgery:

1. Gloves, mask, hut

2. Skin disinfection of injection site

3. Retraction of injection needle as prescribed

4. Tell patient to refrain from activities increasing

risk of contamination with micro-organisms

for 8 hours after the injection

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),

Incidence of Microorganisms in Human tissue

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.

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

A negative tissue culture is no proof that microorganisms are not present

A negative GRAM or PAS stain on microscopy of a cell smear or tissue section is no proof that microorganisms are not present

Antibiotic therapy prior to a culture swap or biopsy may immobilize or reduce the number of microorganisms hindering their detection

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-inpre-printed forms distributed by and sent to the manufacturer

Number of patients: 56

Patient age (75%): 23-60 years - mean 44, median 45

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.)

Injection sites:

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

Type of physician: Plastic surgeon 23Dermatologist 12Aesthetic/cosmetic doctor 20Unknown 1

Symptom delay (Time from last injection to first symptom of adverse reaction: median 12 days.

Symptoms: Swelling, redness, pain, fistulation, pus discharge

Bacteria1. Positive cultureStreptococci viridans: 3

casesAtypical mycobacteriae: 1 case2. DNA cloningShigella 1 caseStreptococci viridans 1 case3. Microscopy (gram stain)Gram positive cocci 2 casesGram positive rods 1 case .Total: 9 cases

Herpes labialis 5 cases

Established causes of adverse reactions (found in 18 (32%) of patients)

Too superficially injected 2 cases

Palsy 1 case

Breast cancer subsequently 1 case

Known contraindications:

Several previous injections at the same site: 9 patientsMb. Crohn and Colitis Ulcerosa: 2 patientsPemphigus: 1 patientInsulin dependent Diabetes Mellitus: 1 patientDentistry at the injection site: 1 patientFace-lift just prior to injection: 1 patientOral sex right after injection: 1 patientMake-up during injection: 1 patient

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

Second line treatment: 32 patients

Antibiotic: 29 patients

Steroid: 3 patients

Third line treatment 8 patientsAntibiotic: 8 patients___________________________________________________Primary treatment .Steroid + weak antibiotic: 2 patientsSteroid alone: 2 patients Steroid + NSAID and/or antihistamine 3 patientsAntihistamine 1 patient

They all received antibiotics the third time with improvement or complete recovery.

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.

Cause of adverse reactions

Bacteria, sometimes preceded by herpes

Treatment of adverse reactionsAntibiotics in high dosage i.m. or i.v.– steroids or NSAIDs are stongly contraindicated

Treatment of adverse inflammatory reactions:

Immediate administration of a broad-spectered antibiotic in high dosage, e.g.:

1. Fluoroquinolon (Ciproxin) 500 mg x 2 for up to 7 days2. 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