Premixed Insulin

Humalog Mix^® 25 [insulin lispro], Humalog Mix^® 50 [insulin lispro], Humulin^® M3 [human insulin], Hypurin Porcine^® 30/70 mix [porcine animal insulin], Insuman Comb^® 15 [human insulin], Insuman Comb^® 25 [human insulin], Insuman Comb^® 50 [human insulin], NovoMix^® 30 [insulin aspart]

[SANOFI have announced discontinuation of Insuman Comb^® 15 and Insuman Comb® 25 with an expected end of supply date of June 2020.  At the current time, this preparation remains in the British National Formulary and has been included in this monograph] 

  Issues for Surgery

Hypoglycaemia if continued during nil by mouth period / during liver reduction diet (LRD) in patients undergoing Bariatric Surgery.

Increased risk of post-operative infection and delayed wound healing due to poor glycaemic control if discontinued.

  Advice in the Perioperative period

Insulin products are classified according to their duration of action and it is important to understand the type of insulin the patient is on in relation to the advice to be given perioperatively.  Confirm with the patient the exact name, strength, dose, frequency and preparation of insulin(s) that they are using (see Further Information).

Elective Surgery 

Continue, but at a reduced dose - see figure 1 below for details of dose reduction.
When reducing insulin doses round to the nearest unit.

EXCEPT: -

• Patients undergoing Bariatric Surgery – see below
  
  

_{*e.g. Humulin® M3 contains isophane insulin 70units per 1ml and soluble insulin 30units per 1ml therefore give 70% of usual dose as Humulin® I (isophane insulin).  For the insulin analogues the basal component is not available separately as a commercially available product therefore for Novomix® 30 use 70% of usual dose as Insulatard® (isophane insulin) and for Humalog® 25 use 75% of usual dose as Humulin I® (isophane insulin).}

Figure 1 – Management of PREMIXED insulin in the Perioperative Period¹

Patients undergoing Bariatric Surgery
Patients with type 1 diabetes mellitus need an individualised management plan formulated with the Diabetes Specialist Team. 

Patients with type 2 diabetes mellitus commencing on liver reduction diet (LRD): Give 50% of usual dose when the LRD commences, with close monitoring of CBG² (see Further Information). When reducing insulin doses round to the nearest unit. 

Patients with type 2 diabetes mellitus not following a LRD: Follow the advice in figure 1 above for Elective Surgery. 

Emergency Surgery
Monitor CBG, ketones, renal profile and lactate on admission to exclude diabetic ketoacidosis (DKA) or hyperosmolar hyperglycaemic state (HHS)¹. The advice given above can be applied to patients presenting for emergency surgery; however, it must be remembered that these patients are high risk and are likely to require intravenous insulin infusion; either variable rate intravenous insulin infusion (VRIII), or in the case of DKA or HHS a fixed rate intravenous insulin infusion – see Further Information¹. Continue to monitor ketones if CBG>13mmol/mol¹.

Perioperative Considerations
Commence variable rate intravenous insulin infusion (VRIII) perioperatively where indicated, omit patient’s usual PREMIXED insulin, and commence a long-acting insulin at a dose of 0.2 units per kilogram¹ (see figure 1 above and Further Information).

Ensure emergency treatment of hypoglycaemia is prescribed i.e. Glucogel^® and 20% dextrose. Rapid acting insulin should also be prescribed^{1, 3}.

Post-operative Advice
Encourage an early return to normal eating and drinking (as deemed appropriate by the Surgical Team), facilitating return to the patient’s usual diabetic regimen¹.  The insulin dose(s) may need adjusting, as insulin requirements can change due to post-operative stress, infection or altered food intake – monitor CBG levels and seek advice from specialist diabetes team if necessary^{1, 3}.

Patients undergoing Bariatric Surgery
Improved glycaemic control is expected because of reduced calorie intake, early satiety and weight loss following bariatric surgery.

Patients with type 1 diabetes mellitus should be reviewed by the Specialist Diabetes Team post-operatively.

Patients with type 2 diabetes should hold their premixed insulin post-operatively. Blood glucose should be monitored until eating habits and food intake stabilises². Patients should have their need for ongoing pharmacological management of their diabetes reviewed by their General Practitioner / Bariatric Surgical Team.

  Interaction(s) with Common Anaesthetic Agents

Reduction of Blood-Glucose Lowering Effect
Substances that may reduce the blood-glucose-lowering effect include sympathomimetics (e.g. epinephrine / adrenaline)^{4, 5, 6, 7, 8}.

  Interaction(s) with other Common Medicines used in the Perioperative Period

Enhancement of Blood-Glucose Lowering Effect
Substances that may enhance the blood-glucose lowering effect of insulin and increase susceptibility to hypoglycaemia include sulphonamide antibiotics (e.g. co-trimoxazole)^{4, 5, 7, 8, 9}.

Reduction of Blood-Glucose Lowering Effect
Corticosteroids can reduce the blood-glucose-lowering effect of insulin^{4, 5, 6, 7, 8, 9, 10}. Clinically important hyperglycaemia has been seen⁹.  Monitor CBG closely when corticosteroids are given to patients with diabetes¹⁰.

Somatostatin analogues (octreotide and possibly lanreotide) may either increase or decrease the insulin requirements^{4, 5, 6, 7, 8, 9, 10} but most patients with type 1 diabetes are likely to require a reduction in insulin dose, with some studies suggesting a potential reduction of 50% in patients taking concomitant octreotide^{9, 10}.  Monitor CBG when somatostatin analogues are given to patients with diabetes¹⁰.

  Further Information

Safe Prescribing and Administration of Insulin
Insulin should be prescribed according to National Patient Safety Agency (NPSA) recommendations for safe use of insulin, with the brand name and units written in full^{1, 3}.

Patients and nursing staff should be reminded of the importance of rotating injection sites within the same body region to reduce or prevent the risk of cutaneous amyloidosis and other skin reactions; injecting into an affected ‘lumpy’ area may reduce the effectiveness of insulin³.

VRIII
Patients with a planned short starvation period (no more than one missed meal in total) should be managed by modification of their usual diabetes medication, avoiding VRIII wherever possible (although VRIII may be necessary in patients with type 1 diabetes who have not received their long-acting insulin, in patients with type 1 diabetes who are expected to miss more than one meal, if emergency surgery or in people with poorly controlled diabetes (HbA1c >69mmol/mol))¹.  Patients with type 2 diabetes who are expected to miss more than one meal should have VRIII if they develop hyperglycaemia (CBG >12mmol/L)¹.

Commence a long-acting insulin at 0.2 units per kilogram during treatment with VRIII to prevent hyperglycaemia and ketosis on cessation of VRIII¹.  In patients with type 1 diabetes do not discontinue VRIII unless patient has received alternative subcutaneous insulin within the last 30 minutes¹.

Liver Reduction Diet (LRD)
Most people needing bariatric surgery have a large, fatty liver which can cause difficulty for laparoscopic surgery, as the stomach cannot be easily accessed. The LRD typically start 10 – 15 days prior to bariatric surgery and is based on low calories, in particular low carbohydrate, and fat. This forces stored glycogen to be released from the liver (plus some water), making it softer, more flexible and easier to move. Due to the reduced calorie and carbohydrate intake, CBG levels will most likely be reduced. Patients are at increased risk of hypoglycaemia when their usual dose of premixed insulin is continued during this period.

  References

1. Centre for Perioperative Care. Guideline for Perioperative Care for People with Diabetes Mellitus Undergoing Elective and Emergency Surgery (March 2021). Available at: https://cpoc.org.uk/guidelines-resources/guidelines [Accessed on 8^th March 2021]
2. Busetto L, Dicker D, Azran C et al. Practical Recommendations of the Obesity Management Task Force of the European Association for the Study of Obesity for the Post-Bariatric Surgery Medical Management. Obesity Facts 2017;10:597 – 632. DOI: 10.1159/000481825
3. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 1^st March 2021]
4. Summary of Product Characteristics – Humulin^® M3 (human insulin) KwikPen (Mixture 3) 100 IU/ml suspension for injection. Eli Lilly and Company Limited. Accessed via www.medicines.org.uk 01/03/2021 [date of revision of the text October 2020]
5. Summary of Product Characteristics – Insuman Comb^® 25 (human insulin) SoloStar 100 IU/ml suspension for injection in a pre filled pen. SANOFI. Accessed via www.medicines.org.uk 01/03/2021 [date of revision of the text September 2020]
6. Summary of Product Characteristics – Hypurin Porcine 30/70 Mix (porcine insulin) Cartridges – PL 29831/0119. Wockhardt UK Ltd. Accessed via www.medicines.org.uk 01/03/2021 [date of revision of the text September 2020]
7. Summary of Product Characteristics – Humalog Mix^® 50 (insulin lispro) 100 units/ml KwikPen, suspension for injection in pre-filled pen. Eli Lilly and Company Limited. Accessed via www.medicines.org.uk 01/03/2021 [date of revision of the text September 2020]
8. Summary of Product Characteristics – NovoMix^® 30 (insulin aspart) FlexPen 100 units/ml. Novo Nordisk Limited. Accessed via www.medicines.org.uk 01/03/2021 [date of revision of the text October 2020]
9. Insulin. In: Brayfield A (Ed), Martindale: The Complete Drug Reference. London: The Royal Pharmaceutical Society of Great Britain. http://www.medicinescomplete.com [Accessed 1^st March 2021]
10. Baxter K, Preston CL (eds), Stockley’s Drug Interactions (online) London: Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 1^st March 2021]