Pathophysiology
As discussed in Chapter 1, the primary cause of ketoacidosis is an absolute or relative insulin deficiency. Briefly, the effects of insulin deficiency and thus an increase in glucagon insulin ratio in the portal circulation together with increases in levels of counter-regulatory hormones catecholamines, cortisol and growth hormone are summarised in Figure 2.1. Elevated levels of ketone bodies result from mobilisation of fatty acids from adipose tissues and their preferential b-oxidation within...
Prognosis 1
Lactic acidosis associated with metformin therapy is typically associated with a mortality rate of around 50 per cent, similar to that reported with phenformin. However, since lactic acidosis in critically ill patients also carries a poor prognosis, it is important to clarify whether poor outcome is due to metformin alone, to the associated disorders, or both. To clarify this issue, the outcome of lactic acidosis in metformin treated patients in whom plasma metformin concentrations were...
Airway and breathing
The first priority in the treatment of diabetic ketoacidosis, as in the treatment of any life-threatening illness, is to protect and maintain the airway. If the childs level of consciousness is impaired, a nasogastric tube should be inserted immediately, aspirated and left on free drainage. An oral airway may also be necessary. If respiration is depressed, or there is accompanying respiratory pathology, intubation and ventilation may be required if in doubt, this is the safest option. Tissue...
Are metformin accumulation and associated disorders underlying factors
Metformin accumulation may be either a precipitating factor, as in metformin overdose or acute renal failure when there has been no discontinuation of metformin therapy an underlying factor, as in chronic renal failure. Similarly, system failures may be either precipitating factors, as in sepsis or in haemorrhage, or underlying conditions, as in chronic organ failure. Taking such factors into consideration should help in estimating the prognosis.
Subsequent management
Check plasma urea and electrolytes 2 h after resuscitation has begun and then at least 4 hourly during treatment. Check fluid balance and the clinical state of the child at least 4 hourly, to ensure that positive fluid balance is maintained. If a massive diuresis continues fluid input may need to be increased measurement of urinary electrolytes may be helpful to determine the type of fluid replacement required. If large volumes of gastric contents are aspirated, these should be replaced with...
Diagnosis
Delays in initiating therapy may have disastrous consequences. Diabetic ketoacidosis should be considered in any unconscious or hyperventilating patient. If there is any doubt about the severity of the metabolic disturbance in a diabetic patient with ketosis, the arterial pH should be measured. A brief clinical examination focuses on Bedside blood and urine tests should rapidly confirm the diagnosis. Treatment should then be commenced without delay. The initial clinical and biochemical...
Thromboembolic complications
Despite the high frequency of thrombo-embolic complications in patients with the hyperosmolar syndrome, the role of prophylactic anticoagulation is unclear. Anti-coagulation in an acutely sick patient carries risks of gastrointestinal haemorrhage - an occasional cause of death. The alternative approach is to treat clinically overt thrombo-embolic events as they arise this approach will lead to occasional failure to recognise the insidious development of serious thrombosis. The risk-benefit...
Differential diagnosis
The diagnosis is rarely difficult except in younger children, where the acidotic breathing pattern may easily be confused with an Table 2.1 Differential diagnosis of diabetic ketoacidosis in children predominant Physical stress, e.g. intercurrent Alcoholic ketoacidosis infection with transient hyperglycaemia MODY Severe sepsis Renal tubular defects Certain inborn errors of precipitate metabolic decompensation Hyperosmolar non-ketotic coma Type 2 diabetes MODY maturity onset diabetes of the...
Mortality
Diabetic ketoacidosis continues to be an important cause of death among patients with type 1 diabetes. The average mortality rate for ketoacidosis today is quoted as between 5 and 10 per cent although rates vary widely. Experienced centres would expect to report a mortality rate of less than five per cent. Some deaths are inevitable consequences of associated medical conditions such as overwhelming infection. Clearly, the mortality associated with diabetic ketoacidosis has not been abolished,...
Phosphate
Diabetic ketoacidosis is associated with severe phosphate depletion due to excessive urinary losses, and once insulin treatment is started levels will fall, because phosphate, like potassium, is taken up by the cells. Although plasma concentrations may fall in adults to levels known to have been associated with impaired cardiac function, respiratory failure and reduced red cell 2,3-diphosphogly-cerate concentrations, these complications are rarely seen, and have not been reported in children....
Clinical features
The cardinal symptoms of ketoacidosis include rapidly increasing polyuria and polydipsia rapid weight loss - dehydration nausea and vomiting - hyperketonaemia is emetic generalised muscular weakness These are followed by serious signs of cerebral dysfunction progressive drowsiness and obtundation While a decrease in the level of consciousness is common, coma is encountered in only about 10 per cent of patients. The mechanism by which ketoacidosis induces coma remains uncertain impairment of...
Symptoms of hypoglycaemia
Patients with insulin-treated diabetes rely on the physiological responses to hypoglycaemia to alert them to a falling glucose that Irritability and bad temper Sweating Lack of concentration Diminished conscious level Coma prompts them to take action by taking refined carbohydrate Table 4.2 . Symptoms are generated through a combination of 1. sympathoadrenal activation often termed autonomic symptoms and 2. cerebral dysfunction caused by a failing glucose supply to the brain termed...
Pathophysiology of hypoglycaemia in diabetes
Recovery from insulin-induced hypoglycaemia would take many hours if dissipation of insulin were the sole mechanism Figure 4.1 . Additional physiological mechanisms help to resist the glucose lowering effect of insulin and restore blood glucose after an episode of hypoglycaemia. Secretion of counter-regulatory hormones promotes glucose release from the liver opposes glucose uptake in peripheral tissues such as fat and muscle. The most important of these hormones, in terms of recovery from...
A high plasma metformin concentration would have been expected with the
Table 6.2 Pharmacokinetic characteristics of metformin Plasma half-life from 1.5 to 4.9 h Metabolism not detectable - excreted unchanged Elimination rapid renal elimination involving glomerular filtration and tubular secretion with a clearance of four to five times that of creatinine Approximately 90 of the ingested dose is eliminated in 12 h dosage and time of last metformin administration. It is also possible to measure metformin concentration in red blood cells, where the elimination is far...
Myocardial infarction
Coronary artery disease is the most common cause of death in patients with type 2 diabetes and is an important cause in premature mortality in type 1 diabetes. Diabetic patients tend to have more severe and widespread atherosclerosis than age matched non-diabetic controls. Acute myocardial infarction has a higher immediate and delayed mortality than in non-diabetic individuals, cardiac failure and re-infarction being the main causes of death. The excess mortality among patients with diabetes...
Ketogenesis
Insulin deficiency and catabolic hormone excess, especially of catecholamines, promote lipolysis within adipocytes, wherein triglycerides are converted to three fatty acids and one molecule of glycerol. These effects are mediated via the activity of hormonesensitive lipase triacylglycerol lipase , an enzyme normally regarded as being exquisitely sensitive to inhibition by insulin. Concurrently, re-esterification, i.e. the formation of new triglycerides, within adipocytes is impaired. This...
Diabetes and myocardial infarction
Diabetes is associated with a two- to fourfold increase in risk of cardiovascular disease relative to the general population. Cardiovascular mortality is doubled in diabetic men and the relative risk is even higher in women with diabetes. Data from Finland have suggested that mortality rates are comparable to those of non-diabetic people who have previously suffered a myocardial infarction. Acute myocardial infarction accounts for 30 per cent of all deaths in the whole diabetic population. More...
Laboratory assessment
Hyperglycaemia can be confirmed quickly by a high capillary blood glucose measurement, but it is important to ensure that reagent strips are fresh, that reflectance meters are well maintained and that staff are trained in their use. Ketone measurements are also possible on capillary blood, or urine if available. Treatment can then be started while the results of further tests, such as plasma electrolytes, are awaited. Suggested laboratory investigations are listed in Table 2.3. Arterial or...
Fluid replacement
Severe dehydration is the leading element in the development of hyperosmolar non-ketotic hyperglycaemia and is a major determinant plasma Na lt 130 mmol L plasma Na gt 130 mmol L decreased 10 15 , continue normotensive, plasma 0.5 1.0 L h Na gt 130 mmol L Reduce insulin when plasma glucose 15 mmol L Change to 5 dextrose 0.5 1.0 L h when plasma glucose 15 mmol L 6 11 mmol L Adjust insulin infusion to maintain plasma glucose If plasma K lt 3.3 mmol L add 40 mmol L to initial saline infusion and...
Fluid and electrolyte depletion
Dehydration and electrolyte losses are prominent features of diabetic ketoacidosis. Water. When the renal threshold for glucose re-absorption in the proximal convoluted tubule is exceeded, the resulting osmotic diuresis leads to dehydration and secondary losses of electrolytes Table 1.1 . Ketonuria compounds the loss of both water and electrolytes. Sodium. Insulin deficiency and glucagon excess exacerbate sodium depletion via effects on renal sodium reabsorption. Hyperventilation, fever and...
Severe recurrent or prolonged hypoglycaemia may cause permanent brain damage
Cerebral damage secondary to hypoglycaemia seems to be a relatively rare cause of death in diabetic patients treated with insulin however, insulin-induced death may result from other mechanisms. In a seminal paper, Tattersall and Gill 1991 investigated all unexpected sudden deaths in patients with type 1 diabetes in the UK under the age of 40 during a single year. They identified only two deaths that could be attributed to hypogly-caemic brain damage with certainty. This study highlighted the...
The pharmacokinetics of sulphonylureas is an important determinant of the risk
Table 5.2 Risk factors for hypoglycaemia with sulphonylureas Renal insufficiency Hepatic insufficiency Prolonged fasting, e.g. peri-operatively Acute or chronic intercurrent illness Long acting sulphonylureas chlorpropramide, glibenclamide Drugs that interfere with the metabolism of sulphonylureas and prolong their bioactivity see Table 5.3 Short duration of use Elderly patients Polypharmacy Alcohol consumption Other factors include the following. Advanced age. This appears to be an additional...
Role of dialysis
Haemodialysis is classically considered to be the most efficient method, providing both symptomatic and aetiological treatment by eliminating lactate and metformin. This is actually a misconception. Lactate elimination cannot participate in recovery of acid-base balance since lactate per se is not an acid generating substance. Instead, the excess protons from hydrolysis of ATP during anaerobic glycolysis tend to be removed by endogenous buffers, which are regenerated through lactate metabolism....
Discharge planning
It is important to emphasise the need to continue some insulin to avoid relapses of hyperglycaemia and or hyperosmolarity. Subcutaneous insulin treatment should not be initiated too early insulin may be absorbed poorly and erratically from subcutaneous tissue before effective perfusion is re-established. By 12-24 h, once the patient is able to eat and drink, subcutaneous insulin can be commenced, either as a multiple-daily basal-bolus regimen or as twice-daily injections of biphasic insulin....
Labour
Diabetic women have a higher incidence of spontaneous premature delivery than non-diabetic women. Labour and delivery are potentially hazardous events for both mother and infant. Insulin resistance increases during the second and third trimesters, necessitating an increase in insulin doses. All women with tablet treated type 2 diabetes should be treated with insulin during pregnancy. Blood glucose must be monitored carefully during labour. An intravenous infusion of soluble insulin should be...
Pathophysiology 1
All of the sulphonylureas are associated with a risk of hypoglycaemia. The mechanism of hypoglycaemia is related to the mechanism of action and the pharmacodynamic properties of the drugs. As shown in Figure 5.1, sulphonylureas work by increasing insulin availability through a multi-step process. They initially bind to the sulphonylurea receptor located on the plasma membrane of the islet p-cell. Upon binding to the receptor, an adenosine-phosphate-dependent potassium channel is inhibited. This...