The purpose of this guideline is to provide guidance about intravenous and subcutaneous immunoglobulin infusions at Great Ormond Street Hospital (GOSH).
Immunoglobulin is a blood product used in the treatment of children with primary antibody deficiency and other complex immune deficiency disorders, to prevent life-threatening infections (Wood et al, 2007) (Rationale 1).
In addition, it can be used as supportive therapy for secondary immunodeficiency where extrinisic factors such as chemotherapy cause damage to the immune system, eg following stem cell transplantation where immunoglobulin levels remain low (Department of Health, 2011).
Immunoglobulin has also been shown to be effective in a wide range of diseases where 'modulation' of the immune system is required, although the mechanism of action is not well understood.
Licensed indications other than in primary immune deficiency include Kawasaki disease, idiopathic thrombocytopaeniac purpura, Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy. It may also be used selectively in intensive care (Department of Health, 2011).
There is some anecdotal evidence for the use of immunoglobulin in autoimmune disease, and some other conditions, although these are unlicensed at present.
Guidance on appropriate use of immunoglobulin can be found in the National Clinical Guidelines for use of Immunoglobulin on the Department of Health website.
Route of administration
There has been an increase in the range of therapeutic options for patients with antibody-deficiency who need immunoglobulin replacement (Ponsford et al, 2015). Immunoglobulin can be given by the intravenous route (IVIg); subcutaneous (SCIg) route; manual rapid push, and recently licensed for paediatrics, facilitated SCIg (fSCIg) using recombinant human hyaluronidase. There are advantages and disadvantages of all routes. What is important is that patients have a choice and use the route best suited to them (Jolles et al, 2015).
For the purpose of these guidelines and current practice in our hospital we will talk about IVIg and SCIG Different preparations are used for the two routes. Both routes provide good protection against infection (Chapel et al, 2000).
The choice of route will depend on a number of factors, including the clinical indication, venous access and patient choice. For children or young people requiring regular long-term infusions (min six months) careful consideration of these factors and others, on an individual basis, is vital in ensuring success and compliance. The children/young people have the option of home treatment, and parents or older children/young people can be taught how to give their own infusions, usually via the subcutaneous route, although home IVIg can also be established in selected cases.
Advantages of SCIg over IVIg include ease of administration, fewer side effects and reduced administration time, although the frequency of infusions is greater. SCIg also results in steady plasma IgG levels, whereas IVIg is associated with peaks and troughs.
Immunoglobulin is a blood product, made from pooled collections of human plasma. Plasma collected from thousands of screened donors is used to generate a single batch of an Ig product, providing a wide variety of antibodies to protect against pathogens. As for all blood products, there is a small, but unquantifiable, risk of transmitting infections such as hepatitis. Plasma is purified using rigorous multi-step manufacturing processes designed to inactivate / or remove bacterial and viral pathogens. British plasma has not been used in the manufacture of immunoglobulin since 1998, due to the theoretic risk of transmitting variant Creutzfeldt Jacob disease (vCJD), for which there is no screening process at present.
The supply of immunoglobulin is limited and demand continues to rise. National Clinical Guidelines for Immunoglobulin Use have been produced by the Department of Health in order to ensure that an appropriate supply and demand balance can be maintained (Department of Health, 2011).
All immunoglobulin products contain primarily IgG, with only trace amounts of IgA and IgM, IgA concentrations vary between products. Stabilizing agents also vary between manufacturers. When choosing a product for an individual patient factors to consider include administration route and time, concentration, IgA levels, stabilizing agents, sugar and sodium content.
For children/young people requiring regular immunoglobulin replacement, it is considered best practice not to change products once commenced on a particular brand. Different commercial products are not identical and children/young people who tolerate one product may not necessarily tolerate another (Department of Health, 2008).
In addition, switching products exposes the recipient to another large donor plasma pool and increases the risk of exposure to acquired infection such as hepatitis C virus (Chapel et al, 2000).
(i) Information and consent
A risk assessment should be carried out to ensure the family understand the need for treatment and how it is administered (Power, 1997) (Rationale 2). The benefits of treatment should always outweigh the potential risk of infections from Ig (Wood et al, 2007).
It can be given by one of two routes:
Intravenous - for use in immunomodulation and for giving higher doses of IgG and for some children/young people on long-term replacement. Usually best option for patients with a central line in situ.
Subcutaneous - suitable for IgG replacement and ideal in younger children with poor venous access. Use with caution if patient has low platelets, but it is not contraindicated (Rationale 3). The risk of adverse reactions is also reduced compared with IVIg (Abrahamsen et al, 1996).
Select the most appropriate route in consultation with the family. Explain the procedure to the child/young person and family and gain consent (Department of Health, 2001). Explanation of the procedure must include (Rationale 2):
the reason for treatment
the risks and benefits
the plan and options for ongoing treatment (Rationale 4)
Supply the child/young person and their parents with the appropriate information (Rationale 5) (ie PIDUK young person's guide to immunoglobulin / PIDUK guide to immunoglobulin leaflet). Immunology CNS team have access to DVDs and training packs for SCIg.
When prescribing immunoglobulin for the first time, an immunoglobulin request form must be completed online, printed and signed by the prescriber. This must go to pharmacy with the pink blood product prescription.
For indications that are not included in the 'Red' or 'Blue' categories in the National Guidelines, approval will need to be sought from the GOSH Immunoglobulin Advisory Panel.
Immunoglobulin is a human blood product and must not be administered unless it is prescribed on the child / young person's electronic prescription chart as per hospital policy (Power, 1997) (Rationale 6).
Calculate the dose (Rationale 7):
replacement therapy: 400–600mg/kg/3 weeks (divide dose by 3 for weekly SCIg dose)
modulation: 1–2g/kg in as a single or divided dose
Prescribe premedication if required. Premedication is usually only given if there has been a recent adverse reaction (Rationale 11).
Clean the preparation area (Rationale 12). Gather the appropriate equipment:
- Local anaesthetic cream or cryogesic spray may be applied to the venous access site (Rationales 13 and 14).
- Immunoglobulin product for intravenous use (Appendix 1).
- IV infusion pump (Rationale 15).
- IV infusion set.
- Saline flush.
- Cannula (22g/24g), extension set with female luer adaptor, alcohol wipes, such as chlorhexidine gluconate 0.5%, in 70% alcohol (peripheral infusion).
- Adhesive tape and/or clear dressing (to secure the cannula).
Local anaesthetic cream (LAC) may be applied to the infusion sites for a time prior to infusion (follow manufacturers guidelines) (Rationales 13 and 16). In the medium term it may be worth trying the patient with one site using LAC and one without so they can decide if required. In our experience the distress of having LAC and removing the adhesive can cause more distress than inserting the needle itself.
- Immunoglobulin product for subcutaneous use (Appendix 1).
- two portable infusion pumps (eg Micrel ml/hr+ Cane Crono PID 20 or 50) (Groves, 2003; McNeilly et al, 2004) one Freedom 60infusion pump.
- two luer lock syringes (10ml / 20ml / 50ml, NB crono pump MUST have cane crono syringes. Freedom 60 require 1 x 60ml luer lock syringe) (Rationale 24).
- two b.braun mini spike transfer devices (for drawing up the immunoglobulin).
- two infusion needles 27g butterfly needles (60cm / 80cm extensions), 27g (6mm / 8mm / 10mm / 12mm length) neria© (Ross et al, 2002; Torre, 2002) (Rationales 23 and 24). (if using 1x50ml crono for dose 40ml–50ml, bi-furcated 27g neria infusion sets will be required).
- Alcohol swab (one to clean top of each vial and one for each injection site).
- Tape and / or clear dressing (to secure the infusions. Use as little adhesive as possible whilst ensuring needle secure. NB. Neria needle has own adhesive).
Prepare the child/young person for cannulation or subcutaneous needle insertions, using appropriate topical anaesthetics and distraction therapy (Broome, 1990).
Complete pre-treatment blood tests and investigations (Wood et al, 2007):
- Immunoglobulin trough levels (IgGAM. Serum, 1ml) (Rationale 21).
- Serum and plasma for long term storage (Store Ig. Serum, 1ml and Clotted sample, 1ml) (Rationale 22).
- Liver function tests (Lithium Heparin, 0.5ml) (Rationale 22).
- Hepatitis C screen/PCR (serum 5ml) (Rationale 22).
- Full blood count (EDTA, 0.5ml).
- Other investigations as indicated.
Check the product, dose, batch number and expiry date (Rationale 22).
Check the product integrity (intact seals) and quality (clarity and colour of product according to Summary of Product Characteristics (SPC) for individual product)
Record the product, dose, batch numbers and expiry date on the blood product administration chart (Rationale 24).
Ensure the immunoglobulin is a room temperature (Rationale 25).
Check the child/young person's identity band and prescription according to the hospital policy before starting the infusion (NMC, 2008) (Rationales 23 and 26).
Infuse the immunoglobulin at the prescribed rate, starting slowly, and increasing to the maximum prescribed rate as directed (Rationale 29). Measure vital signs before each rate increase.
Do not leave the child/young person unattended during the infusion. This may be negotiated with any family members in attendance and they should be advised to call the nurse if they have any concerns about their child/young person during the infusion (Rationale 28).
Check the peripheral infusion site half hourly for inflammation (tenderness, swelling, redness) and leakage (Rationale 30). STOP the infusion if there are any signs of inflammation.
Check the infusion line is intact and record the infusion rate, pressures, volume infused, hourly (Rationale 31).
On completion of the infusion, flush the administration set with 0.9% sodium chloride solution if the total amount of immunoglobulin infused was less than 100mls (Rationale 32).
Thighs are preferred in children under two. The thighs become more muscular as the child gets older (Rationale 34, Rationale 35).
The abdomen is preferred in older children/young people as the skin is more pliable and allows larger volumes to be infused (Rationale 34, Rationale 35).
Trial and error may be required until best site and infusion time is identified for a particular patient. Choice of site may change with weight gain/loss and dose adjustment.
Remove the local anaesthetic cream (if used) five minutes before the needles are inserted (Rationale 36).
Draw up the immunoglobulin into the syringe and prime the administration line using a non-touch technique (Rationale 12). Ig dose should be split between two syringes.
Ensure that the needle is dry primed so that no Ig is in the needle. Stop priming the line about an inch before the needle (Ig can continue to travel in line once priming stopped then leak out making dressing sticky. Ig also irritates the dermis contriubting to local site reactions.
Clean site of insertion with alcohol wipe, allow to dry. Lift a skin fold and insert the needle into the subcutaneous tissue (Fleming, 1999) (Rationale 37). The angle of insertion will depend on the needle type, length and amount of subcutaneous tissue. For a Neria needle insert quickly and confidently at 90° to reduce the risk of breakage and bending.
The whole needle must lie within the numbed area of skin where local anaesthetic is used (Rationale 14).
Secure the needle with tape or occlusive dressing as appropriate (Rationale 38). Loop the line to give additional security in case line is pulled.
Assess the child's subcutaneous tissue to decide on the infusion rate. The rate can be increased as the child grows as long as tolerated / no leakage (Rationale 14, Rationale 35), for example:
- 5–10ml can be infused in babies one to six months over one hour.
- 10ml can be infused in 40–60 minutes in children over six months.
- 10-50ml can be infused in 40–90 minutes in older children/young people.
- >50ml may need to be divided into more than two sites.
Set the appropriate rate for the syringe size (Rationale 14). For first infusions administer over 90 minutes to ensure tolerance of infusion.
Observe the child/young person and monitor the infusion rate (Rationale 31).
Record details of the infusion, site, rate and syringe size.
Please note: Swelling and redness at the site of the infusion is normal and will disappear around 24 hours after the infusion has finished. Redness likely to decrease with subsequent infusions. It is common to have some local itching/stinging for first five to 10 minutes of infusion. Use distraction therapy and re-assure parent and child/young person.
Do not leave the child unattended during the infusion as there is always a risk of adverse reactions (Rationale 28).
(vi) Adverse reaction management - see appendix 2
Adverse reactions to immunoglobulin are uncommon if infusions are given according to guidelines.
There may be acute reactions, occurring during an infusion, shortly after a subcutaneous infusion, or delayed (occurring 24–48 hours after the infusion) (Wood et al, 2007).
Most reactions are minor and respond to slowing down the infusion, but severe reactions may occur, requiring prompt intervention.
Serious adverse reactions are extremely unlikely if instructions are followed. It is vital however, that those responsible for giving the infusions know how to recognise a serious reaction and what action to take should one occur.
The most common cause of reactions is administration of immunoglobulin when there is active untreated bacterial infection.
The risk of adverse reactions can be minimised by adhering to the following guidelines:
- Do not give an infusion if the child/young person is unwell or has a fever.
- Give the infusion at the prescribed rate.
- First infusions should be given more slowly (over 90 minutes for SCIg).
See Appendix 1 for management of adverse reactions to IVIg and SCIg.
(vii) Completing the infusions
Remove the needles or cannula using universal precautions and dispose of in a sharps bin in accordance with Trust Waste policy (Rationale 6, Rationale 12).
Document in the child/young person's's medical and medical health care records the following (Rationale 6, Rationale 24):
- Immunoglobulin dose and batch numbers (Rationale 22).
- Date and time for starting and completing the infusion (Rationale 24).
- Sign that you are responsible for the administration of the infusion (Rationale 6).
Document how long infusion took and what rate increases/decreases were made, any problems patient experienced during infusion (and response to these), and any pre-medication given. For SCIg infusions, document teaching interventions and parent / patient competencies achieved (Younger et al, 2012).
Document any specific routines required for child/young person and family to reduce psychological and physical implications of regular infusions. (Younger et al, 2012).
(viii) Home treatment
For many children / young people with primary immune deficiencies, life-long immunoglobulin treatment is required.
Treatment needs to be acceptable and convenient so that the family can incorporate it into their family routine (Cochrane, 1997). At GOSH, training for home infusions can be organised through the immunology clinical nurse specialists (ext. 5024). Almost all children/young people receiving long-term SCIg have their treamtment at home. Home IVIg can be established in specific circumstances.
Training should include:
- Risk assement of the home environment.
- Practical aspects of preparation and administration of treatment, including non-touch technique.
- Management of potential adverse events and importance of not infusing if child/young person has pyrexia.
- Recording of the infusion details.
- Signing of agreement between person being trained and trainer.
- Observations are not required for home therapy patients – only pre-first SCIg infusion administered in hospital setting. Parents can take a temperature if they think child/young person may be unwell.
- Parent/carer is advised to supervise child/young person at all times during infusion in case of adverse event.
Organisation of home treatment must include regular provision of the treatment, equipment and all disposable supplies, as well as an appropriate means for the safe disposal of sharps and contaminated equipment.
The home therapy training centre is responsible for all aspects of homecare:
- obtaining funding for homecare if relevant
- prescribing treatment
- monitoring treatment
- look-back in the event of any transmissible infections.
The child/young person must be reviewed at least every six months by the prescribing team. During these reviews, an annual follow-up form must be completed as per the Department of Health's Demand Management Programme (Department of Health, 2011):
- For non-primary immunodeficiency patients at GOSH, this should be returned to Pharmacy.
- For primary immunodeficiency patients at GOSH, these should be completed by the Immunology team and returned to the data manager within the Immunology department.
In addition to routine monitoring, an annual store of Ig (save serum and plasma) and Hepatitis C screen should be obtained (Rationale 22).
Rationale 1: Immunoglobulin provides passive immunity by replacing a wide variety of antibodies, which have been purified from a large pool of human plasma donors.
Rationale 2: To prepare the family for treatment and obtain consent.
Rationale 3: To reduce the risk of severe bleeding and bruising.
Rationale 4: To plan ahead and liaise with local services.
Rationale 5: To address any information needs and answer any questions or concerns.
Rationale 6: To maintain hospital policy.
Rationale 7: To give appropriate treatment.
Rationale 8: To prevent wastage.
Rationale 9: To avoid product switching
Rationale 10: The rate is product specific and must be calculated in mls/hr. It will be dependent on the child / young person’s weight.
Rationale 11: Premedication is usually only given if there has been a recent adverse reaction
Rationale 12: To minimise the risk of infection
Rationale 13: Local anaesthetic cream promotes vasodilation and may aid cannulation. Local anaesthetic cream is used as licensed according to the SPC for each product.
Rationale 14: To minimise the discomfort of the procedure. Local anaesthetic cream is used as licensed according to the SPC for each product.
Rationale 15: To enable the infusion to be given safely
Rationale 16: Some local anaesthetic creams may be left in situ for up to five hours - longer contact times may increase the effectiveness. Local anaesthetic cream is used as licensed according to the spcSPC for each product.
Rationale 17: To establish what is normal and rule out pre-existing disease processes if an infusion reaction is suspected.
Rationale 18: Alterations in vital signs could indicate an infusion reaction.
Rationale 19: If pyrexia is present and / or other signs of an acute infection, the infusion may need to be postponed until antibiotic treatment is started and / or pyrexia settles. Infusing when patient has acute infection can lead to adverse events.
Rationale 20: To calculate the appropriate dose. Any significant change may indicate a need for dose increase or (less likely) reduction.
Rationale 21: To monitor the effectiveness of treatment
Rationale 22: To enable look-back in the event of an outbreak of infection.
Rationale 23: To avoid medication errors.
Rationale 24: To enable accurate recording of the infusion details.
Rationale 25: To avoid chilling the patient and increase their comfort.
Rationale 26: To ensure the treatment is given to the right child / young person.
Rationale 27: To prevent air embolism.
Rationale 28: To reduce the risk of adverse reactions
Rationale 29: To enable prompt detection and treatment of any adverse events.
Rationale 30: To detect for signs of extravasation.
Rationale 31: To ensure the correct amount is being given and the infusion pump is working correctly.
Rationale 32: To ensure the whole amount is given (the infusion set may retain up to 20mls of the infusion).
Rationale 33: To promote steady absorption
Rationale 34: To reduce swelling.
Rationale 35: To maximise mobility.
Rationale 36: To allow the skin to dry and to maximise its effect.
Rationale 37: To prevent the needle penetrating the underlying muscle, which would increase the discomfort, and increase the risk of adverse reactions.
Rationale 38: To prevent the infusions being dislodged.
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Appendix 1: Immunoglobulin products available in the UK
|Brand name||Strength||Vial sizes||Manufacturer|
|Gammunex||10% solution||1g, 5, 10g, 20g||Grifols UK|
||10% solution||5g, 10g, 20g
|| Grifols UK
|| 5% solution
||0.5g, 2.5g, 5g, 10g, 20g
|| Grifols UK
|| 5% solution
||1g, 2.5g, 5g, 10g,
||10% solution||1g, 2.5g, 5g, 10g, 20g, 30g
||Baxter Healthcare Ltd|
|| 10% solution
|| 2g, 5g, 6g, 10g, 20g
|| Octapharma Ltd
|Octagam||5% solution||2g, 5g, 10g, 25g||Octapharma Ltd|
|| 10% solution
||2.5g, 5g, 10g, 20g|| CSL Behring UK Ltd
2.5g, 5g, 10g, 20g
Bio Product Laboratories
Baxter Healthcare Ltd
|Bio Product Laboratories|
|CSL Behring UK Ltd|
*Products usually available in GOSH Pharmacy.
However, should patients need a different product for a particular reason, pharmacy needs to be notified as early as possible so that the specific products can be ordered in for the patient.
Appendix 2: How to manage adverse reactions during or after giving immunoglobulin infusion
Headache, light headedness
Stop or slow the infusion
Severe headache, dizziness
Stop the infusion
Severe anaphylactic reaction:
Tightness or swelling around the throat
Appendix 3: How to manage adverse reactions for SCIG infusions - as above but specifically
|Itching at site||
Distract (common to have itching the first 5-10 minutes, improve with subsequent infusions). Can apply cold compress. If persists after 15 minutes and unable to tolerate administer antihistamine.
|Redness||Likely to improve for subsequent infusions.
If no improvement consider sensitivity to anaesthetic cream / dressing / adhesive
|Pain/Discomfort||Stop infusion. Check site. Ensure needle secure and inserted fully. May be too long and intramuscular. May be too short and in dermis.
Re-start infusion. Slow rate.
Re-assure patient pain should go within 10 mins
If intolerable consider removing needle and replacing different size or alternative site.
Ensure alcohol evaporated before inserting needle.
Swelling at site
Always present for SCIg patients. More so in leaner patients / those with larger dose.