Extravasation: new strategies

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• Extravasation new strategies
• Robert Terkola
• Sozialmedizinisches Zentrum Süd
• Kaiser-Franz-Josef-Spital, Vienna
• Pharmacy Department

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In the beginning ...

• Extravasation is a case of emergency

• Emergencies call for clear instructions

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... there is often a question!
Do we have these instructions?
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Instrumentarium versus ...

• Potential of damage of cytotoxic agents
• Predisposition und risk factors
• Prevention
• Early detection integrating the patient
• Start unspecific and specific measures like
  application of antidota
• Surgical intervention
• Aftercare
• Transfer of knowledge documentation, training

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... clinical routine!

• Potential of damage of cytotoxic agents
• Predisposition und risk factors
• Prevention
• Early detection integrating the patient
• Start unspecific and specific measures like
  application of antidota
• Surgical intervention
• Aftercare
• Transfer of knowledge documentation, training

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Type of damage

• non vesicant

• irritant local pain, burning, phlebitis, but
  without necrosis

• vesicant besides irritation ulceration and
  necrosis

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Risk factors
Associated with drugs

• 1. Vesicant potential of effective drugs and/or
  excipient(s)
• 2. Concentration of effective drugs and/or
  excipient(s)
• 3. Osmolarity
• 4. pH
• 5. Duration of exposure

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Risk factors
Associated with patients

• 1. Difficult veins
• 2. Impaired lymph flow and venous circulation
• 3. Age
• 4. Recall phenomena
• 5. Other factors restlessness, neuropathie as a
  result of, for example, previous treatment with
  vinca alkaloids ...

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Risk factors
Iatrogenic

• Insufficient training and experience
• 2. Insufficient patient information
• 3. Organisational difficulties
• 4. Poor venipuncture and application technique

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General measures I

• 1. Stop injection/infusion immediately
• 2. Get extravasation kit
• 3. Put on (sterile) gloves
• 4. Replace infusion lead with 5 ml disposable
  syringe and aspirate slowly as much as possible
  Cave! Do not exert pressure
• 5. Remote i.v. access while aspirating
• 6. If blisters occur aspirate with 1 ml syringe
  and s.c canulla

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General measures II

• 7. Elevate limb and immobilise
• 8. Start substance specific measures
• 9. Complete extravasation documentation sheet
• 10. Inform and instruct the patient and relatives
• 11. Regular control (aftercare)
• 12. Always consult a (plastic) surgeon within 72
  hours

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Specific measures

• Topical cooling
• Dry heat

• Antidota
• Dimethylsulfoxide (DMSO)
• Hyaluronidase
• Sodium bicarbonate
• Sodium thiosulfate
• Corticosteroids

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Topical cooling

• Discussed mechanism of action
• Vasokonstriction
• Local demarcation of the extravasation area
• Reduction of cellular absorption and cytotoxic
  effect of doxorubicin (synergistic to DMSO)

Cave! Moisture combined with cold can cause
macerations ? alcohol compresses should not be
used
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Application

• 1. Apply cold, dry pack immediately for at least
  1 hour
• 2. Continue several times daily for 15 minutes
  each time

Topical cooling alone Liposomal
anthracyclines In combination mit
DMSO Amsacrine, Cisplatin, Dactinomycin,
anthracyclines, Mitomycin C, Mitoxantrone
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Heat

• Discussed mechanism of action
• Vasodilatation
• Increased local blood flow ? improved
  distribution and absorption

Cave! The remaining activity of some cytotoxic
agents may be increased (Doxorubicin, Cisplatin,
Bleomycin, ...)
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Application

• Application of dry heat in a subjectively
  agreeable manner
• 4 x daily over 20 minutes

• In combination with Hyaluronidase
• Vinblastine
• Vincristine
• Vindesine
• Vinorelbine

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DMSO

• Discussed mechanism of action
• Vasodilatation
• Increased permeability of skin
• Fast penetration of tissue
• Anti-inflammatory effect
• Radical scavenger
• Reduced cytotoxicity of Cisplatin in vitro

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Application

• 1. Apply DMSO (99) every 8 hours without
  pressure
• 2. Allow to air dry
• Cave! Do not cover
• 3. Continue for a minimum of 7 days

In combination with topical cooling Amsacrine,
Cisplatin, Dactinomycin, anthracyclines,
Mitomycin C, Mitoxantrone
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Hyaluronidase

• Discussed mechanism of action
• Enzymatic degradation of hyaluronic acid and thus
  increased absorption of extravasated drug from
  the affected tissue
• Synergism with heat has been postulated but
  proved neither clinically nor by animal experiment

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Application

• Inject up to 1500 IU hyaluronidase s,c, around
  the affected area depending on size of
  extravasation

Disadvantage invasive measure
Hyaluronidase alone Paclitaxel In combination
with heat Vinca-Alkaloids
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Sodium bicarbonate

• Discussed mechanism of action
• Increase of local pH value reduces the binding of
  anthracyclins to DNA
• Chemical degredation of carmustine under alkaline
  conditions

Cave! The use is being discussed very
controversially because of its potential to cause
necrosis ? its use is not recommended
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Questionable use ...

• Sodium thiosulfate
• The local effectiveness is not sufficiently
  proved At least the same result can be achieved
  with the application of DMSO

Corticosteroids Extravasations are only rarely
accompanied by inflammatory processes ?
pharmacologically not indicated
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... et al.

• Heparin
• N-acetylcysteine
• Chondroitin sulfatase
• DHM3 (3,5-Dimethyl-5-hydroxymethyl-2-oxomorpholin
  e-3-yl)
• Tetrachlorodecaoxide (TCDO)
• Retinol (vitamin A)
• b-Carotene
• Pyridoxine (vitamin B6)
• Ascorbic acid (vitamin C)
• a-Tocopherol (vitamin E)

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Surgical intervention
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Surgical intervention
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Surgical intervention
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Surgical intervention
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Surgical intervention
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Surgical intervention
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Surgical intervention
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Surgical intervention
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Evidence Based ?

• Contradictory statements in the literature
• Animal experiments mostly on mice
• Case studies dominate
• Prospective trials with extremely limited design
  (small number of cases, no randomisation, no
  standardised documentation, ...)
• The extent of an extravasation can only be
  roughly estimated Dose-adverse effect?

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Conclusion

• Although many data are still lacking, for some
  groups of substances well defined instructions
  can be set up. (anthracyclines, vinca alkaloids)

• Even a Consensus in the literatur does not
  necessarily have to support any evidence

• Promising concepts (DHM3 e.g.) have not been
  transfered to clinical practice

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Conclusion

• Besides prevention, future efforts should focus
  on experimental and clinical investigations about
  antidota, where still a lot of development has to
  be done

• The future role of patients, pharmacists, nursing
  staff should be a more active one

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Acknowledgement Beata Laszloffy Catherina
Pietrzak Maria Schmidmair Stefanie
Chromy Brigitte Spicker Pietro Giovanoli and
EBEWE Pharma www.extravasation.at