Diabetes Mellitus - What Do I Do When the Insulin Doesn't Seem to Be Working?
Vice Principal (Learning and Student Experience), Professor of Small Animal Studies, The Royal Veterinary College, University of London, London, UK
What to Do with Those Diabetics That Don't Stabilise as the Textbook Suggests
Even when best practice has been implemented, a proportion of diabetics will be "difficult to control". These difficulties generally fall into three categories: firstly, patients which appear to become increasingly sensitive to insulin; secondly, patients with a variably inadequate response to insulin; and thirdly, patients with the clinical syndrome known as diabetic ketoacidosis.
Patients with an increasing sensitivity to insulin are generally animals who have the potential for reversible insulin deficiency. Reversible insulin deficiency is seen most commonly in feline diabetes mellitus and is brought about by exogenous insulin administration "unloading" the demand on the islets for ongoing excessive insulin secretion. In both dogs and cats, hyperglycemia caused by pancreatitis-induced acute insulin deficiency is also commonly reversible; however, in these cases, the clinical signs may be more referable to the active pancreatic inflammation, and diabetes mellitus is not being considered as the likely explanation for these clinical signs.
Patients with a variably inadequate response to insulin are likely to have concurrent diseases that result in insulin resistance. The author believes it can be helpful to think about these concurrent diseases in two broad categories - "non-endocrine concurrent disease" and "endocrine concurrent disease".
Often, although not always, the "non-endocrine concurrent disease" will produce clinical signs that are not consistent with those associated with diabetes mellitus. This might be as subtle as inappetence in a non-ketotic patient or as obvious as clinical signs indicating significant gastrointestinal or intrathoracic pathology. However, perhaps the most difficult diabetics with "non-endocrine concurrent disease" to detect are those patients with insulin resistance secondary to urinary tract disease - particularly upper urinary tract infections.
Diabetic patients are prone to developing urinary tract infections, and it is important to remember that an animal may well have a clinically significant urinary tract infection and have no other clinical signs to alert you to the presence of urinary tract inflammation. The ultrasonographic appearance of the urinary tract can certainly be within normal limits and, most importantly, there might be no abnormalities detected on routine urinalysis - including no evidence of hematuria, proteinuria, pyuria or even a mildly increased number of white blood cells in the urine. Indeed the only abnormality present may be a positive urine culture. Interestingly, it is becoming increasingly apparent that many diabetics with a significant urinary tract infection resulting in insulin resistance will have no abnormalities pertaining to this urinary tract infection present on chemical or microscopic examination of their urine.
The endocrine disorders that are likely to produce significant insulin resistance are hyperadrenocorticism and acromegaly. Both diseases are dealt with in other sections; however, it is worth remembering that both can have substantial effects on diabetic control well before they produce any clinical signs. Additionally, many of the clinical signs attributable to both of these disorders are indistinguishable from those produced by poorly controlled diabetes mellitus.
In this situation, testing for these disorders needs as sensitive a test as possible. Consequently, a marked elevation in basal IGF1 is required for a diagnosis of acromegaly, and an abnormal low-dose dexamethasone suppression test rather than an abnormal ACTH stimulation test is required for a diagnosis of hyperadrenocorticism because of the latter's poor sensitivity.
Diabetic ketoacidosis should be thought of as a clinical syndrome. Many diabetics will have sufficient elevations in serum ketone bodies to produce ketonuria as well as ketonemia and indeed may have a marked metabolic acidosis. However, as long as these animals are eating and drinking with no vomiting, they can be managed similarly to a standard non-ketotic diabetic.
However, if the ketoacidosis is sufficiently severe to produce clinical signs referable to the toxemia caused by the marked ketonemia (inappetence, vomiting, dehydration), then the patient needs to be managed with parenteral fluid therapy and more aggressive insulin therapy. Because all diabetic ketoacidotic patients will have a marked depletion of total body potassium, it is important that any fluids administered should be supplemented with additional potassium.
The management of those diabetics with diminishing insulin requirements centres around more intensive monitoring and insulin dose adjustment while, wherever possible, the management of diabetics with concurrent disease focuses on the correction of the concurrent disorder or disorders.
However, if the concurrent disorder has resulted in inappetence and/or vomiting such that the animal is potentially in negative fluid balance, then management of the patient's diabetes requires a different approach until the clinical syndrome has been resolved.
Managing the Inappetent Unwell Diabetic or the Diabetic with Clinically Significant Ketoacidosis
Usually a diabetic patient that is unwell, either because of intercurrent disease or due to the endogenous toxaemia that results from marked ketosis, will be inappetent, making standard subcutaneous insulin therapy difficult. In these cases, continuous intravenous insulin can be a very effective means of short-term management. Furthermore, as long as there is a volumetric pump available, a continuous intravenous insulin infusion is the simplest and least labour-intensive means for treatment of these patients.
Parenteral Fluid Therapy
Inappetent diabetics usually require total parenteral hydration and, by virtue of their poorly controlled diabetes, have relatively high fluid maintenance requirements. Consequently, flowing intravenous fluids at around 150 ml/kg/24 h generally will provide some replacement and adequate maintenance. The optimum fluid composition is 0.45% NaCl with 30–40 mmol/l of KCl added. While one aim is to rehydrate the patient, the other must be to provide some measure of diabetic control, or at least inhibit ongoing peripheral lipolysis and hence to start reducing the potential for ketoacidosis.
It is important to remember in a substantial number of cases, particularly in cats, parenteral fluid therapy alone will substantially lower blood glucose levels. Consequently in any diabetic ketoacidotic cat, providing adequate parenteral fluid therapy with appropriate potassium supplementation for at least 6 to 12 h before considering starting insulin supplementation is a well worthwhile activity.
When insulin therapy is being considered to treat clinically significant ketoacidosis, the choice is continuous intravenous insulin therapy or repetitive intramuscular insulin injections. In both situations, the insulin should be in a soluble and hence relatively rapidly acting form. Although an intravenous insulin infusion sounds daunting, it is certainly the simplest and least labour-intensive means of treating diabetic patients with GIT signs sufficiently severe to warrant a "nil per os" recommendation. In this situation, we are trying to maintain adequate glucose homeostasis in a patient where parenteral drug and nutrient delivery is the only available route for administration.
One easy method for setting up the intravenous insulin fluid line is to add 25 units of soluble insulin to a 500-ml bag of fluids, producing an insulin concentration of 50 mU/ml. Since the standard insulin infusion rate is 40–60 mU/kg/h, a convenient compromise is to flow 1 ml/kg/h of this solution. Obviously a flow rate of approximately 1 ml/kg/h is inadequate for maintenance. Consequently intravenous insulin has to be administered through a second infusion line, usually attached to the "Y" piece of the maintenance fluid line.
The insulin is infused at a rate of 1 ml/kg/h until plasma glucose concentrations fall to 10–12 mmol/l. At this time, the flow rate should be halved (0.5 ml/kg/h) and a concurrent dextrose infusion introduced through the maintenance fluid line. One simple and effective means of achieving a balance between the insulin and glucose infused is to change the maintenance fluids from 0.45% NaCl and 30 mmol/l KCl to 0.45% NaCl and 2.5% dextrose with 30 mmol/l KCl while continuing to run this combination at 150 ml/kg/24 h. This will introduce a glucose infusion rate of around 150 mg/kg/h which should balance the insulin being infused at 0.5 ml/kg/h.
During this time the patient's blood glucose and plasma potassium are checked regularly. Over a period of 48–72 h, the blood glucose should remain relatively steady; ketonaemia, when present, should disappear; and generally the patients return to a normal water and nutrient intake. Once this level of normality is established, it is likely that, at least in the short term, the patient will be able to be stabilised on a regular feeding regimen and a regular insulin dose regimen.
For a variety of reasons, it will not always be possible to administer an intravenous insulin infusion to an anorectic diabetic patient who requires relatively urgent insulin therapy. On some occasions, the clinician may try and use lower doses of a subcutaneously administered lente preparation twice daily. Although this practise may be effective and relatively safe if the dose is kept at around 0.25 IU/kg/12 h, there is always the possibility of giving a little too much. Any overdose in this situation is likely to last at least 12 h.
Consequently, in the absence of a reliable infusion pump, a more attractive alternative to a continuous intravenous insulin infusion is repeated intramuscular injections of soluble insulin.
Dogs and cats should receive soluble insulin at a loading dose of 0.2 IU/kg followed by 0.1 IU/kg hourly thereafter. All injections should be administered intramuscularly. Blood glucose levels are monitored regularly (every 2–3 h) until they have fallen to 12–15 mmol/l. At this point, it is usually satisfactory to change to subcutaneous soluble insulin every 6 h (0.2–0.4 IU/kg). Because of the likely persistence of ketonaemia and hence inappetence, it is important to maintain adequate blood glucose concentrations by introducing dextrose into the intravenous fluids. Generally a 2.5% dextrose solution run at twice normal maintenance rates is satisfactory, although blood glucose levels should be checked every 4 to 6 h.
Once the patient has been satisfactorily controlled, more traditional methods of management can be employed.