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Optimising adrenaline administration

Speaker: Anthony J Frew

29 September 2012

Strategies for Optimising Adrenaline Administration in the Treatment of Anaphylaxis Prof. AJ Frew Department of Respiratory Medicine Royal Sussex County Hospital Brighton United Kingdom

Disclosure • In relation to this presentation, I declare the following, real or perceived conflicts of interest: ALK Advisory Board 2008-2011


1. It must deliver adrenaline to the correct tissue compartment 2. It must deliver adrenaline within the correct timeframe

3. It must deliver the correct dose of adrenaline 4. It must be robust and reliable enough to withstand real life use 5. It must be easy, convenient and safe for patients or carers to use

Cartridge adrenaline auto-injector • e.g., EpiPen, Jext • Relatively easy to activate – only the safety cap needs to be removed • Adrenaline is only released after needle is fully deployed • Requires adequate activation force, which must be maintained during injection

Syringe adrenaline auto-injector • e.g. Anapen • Needle shield and safety cap must be removed before activation • An extra operational step is required • Delivery may begin before the needle is inserted into the target muscle

Exposed needle lengths A B


15.36 mm

15.02 mm 7.49 mm

Exposed needle lengths (mm) of Jext (A; note that the black needle guard is manually retracted to show the needle, EpiPen (B) and Anapen (C) Jext had the longest exposed needle length, followed by EpiPen and Anapen Note: effective penetration depth is dependent on: needle length & bore, activation force, and tissue characteristics

Ballistic gelatine methodology

1. Preparation of ballistic gelatine cubes and validation of sample tissues

2. Preparation of Auto-Injectors with standard ink solution (similar viscosity)

3. Test on force testing machine and filmed with high speed camera

Ballistic gel: volume over time Area [% of reference area]


90 80 70 60 50

40 Anapen Epipen Jext

30 20 10 0












Time [seconds] Graph showing the estimated area (volume) of the dispensed solution from the AAIs into gelatine over time (seconds), based on pixel area (digital image processing) from a series of photographs taken during activation Almost 50% of the reference area was reached by Jext and EpiPen within 0.5 seconds, compared with 5% for Anapen

Ballistic gel: total injection depth






Anape n

Photographs showing the total injection depth into gelatine 10 seconds after activation, measured as the vertical distance from the surface of the gelatine to the lowest part of the ink area using digital image processing The injection depth was significantly shallower for Anapen than for EpiPen and Jext (p<0.001 for both comparisons)

Ballistic gel: activation method


1 sec.

2.5 sec.

5 sec.

10 sec.

Place & Press





Swing & Jab





Exposed needle length, injection depth and volume over time are comparable so Jext can be activated using either activation method

Muraro A. Adrenaline auto-injectors are not all the same: important differences. European Academy of Allergy and Clinical Immunology 31st Annual Meeting, Geneva, 2012: Abstract 1691

Pork shoulder methodology Skin Fat Muscle

Anapen 300, 500; EpiPen 300; Jext 300

Pork shoulder sample

CT scanner

• Preparation: contrast agent (Jopamiro 300) • Test procedure: injection into cut and warmed up (30°C) pieces of pork shoulder (fresh from slaughter) • Analysis: 1) injection depth and injected volume with a CT scanner (about 1000 single pictures / scan); 2) 3D- rendering and measuring of fat layer thickness (skin to muscle distance), max. injection depth and volume (voxel calculation)

Anapen 500

Anapen 300

EpiPen 300

Jext 300

Exposed Needle Length (mm)

Anapen 500

Anapen 300

Jext 300

Epipen 300

9.70 8.90 9.20

9.30 9.80 9.90 9.70

15.00 14.90 15.10 15.10

14.50 15.20 15.20

Skin-to-Muscle Distance (mm); italics = lean samples

Anapen 500

Anapen 300

Jext 300

EpiPen 300

4.10 13.60 3.90

7.45 4.90 18.15 16.70

4.15 13.30 8.90 19.40

5.50 10.40 19.10

Maximum Injection Depth (mm)

Anapen 500

Anapen 300

Jext 300

Epipen 300

10.00 11.70 13.25

14.80 14.25 12.80 12.15

35.05 25.65 24.60 28.40

22.45 30.05 22.75

The maximum injection depth for Anapen failed to reach the muscle each time the skin-to-muscle distance was greater than the exposed needle length.

Robustness methodology: drop test


â&#x20AC;˘ Each AAI is dropped three times from a height of 1500mm/4.92 feet onto a hard, rigid concrete plate. Once horizontally and twice vertically. The injector is rotated 180° between the two vertical drops.

PC: add visual

Robustness methodology: static load â&#x20AC;˘ Each auto-injector is subjected to a vertical load of 400N (40 kg) for 10 sec.


10 sec.

Robustness tests: activation force

Box plots showing the force required (N) to activate each AAI at base conditions, after free-fall and after static load pre-conditioning. Median (line inside box), mean (diamonds) and outlying values (circles) demonstrate that the static load significantly increased the force needed to activate EpiPen and Anapen. The force needed to activate one Anapen was above the upper limit for the testing equipment. The free-fall conditions (drop test) resulted in a broken carpoule of another Anapen.

Robustness tests: implications

Images of an EpiPen following 1.5m free-fall test. Bent needle tips, accordingly reduced needle lengths (p<0.001), and pierced rubber sealings (red arrow), were evident on all EpiPens. Image of a broken Anapen carpoule.

Special Precautions for Storage EpiPen



Do not store above 25째C Do not store above 25 째C Adrenaline is sensitive to light. Keep the autoinjector in the outer carton

To protect from light, store in the original package

Do not refrigerate or freeze

Do not freeze

EpiPen 300, Anapen 300, Jext 300 SmPCs

Do not freeze

Maximum Shelf-life from date of manufacture EpiPen



18 months

21-24 months

24 months

â&#x20AC;˘ Number of unused auto-injectors to replace may be lower with Jext and Anapen than EpiPen which is more convenient for patients â&#x20AC;˘ Longer maximum shelf-life from date of manufacture may also reduce the likelihood of a patient carrying an out-of-date auto-injector

EpiPen 300, Anapen 150, 300, 500 , Jext 300 SmPCs

1. It must deliver adrenaline to the correct tissue compartment 2. It must deliver adrenaline within the correct timeframe

3. It must deliver the correct dose of adrenaline 4. It must be robust and reliable enough to withstand real life use 5. It must be easy, convenient and safe for patients or carers to use

Anthony J Frew  
Anthony J Frew