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Practical Diabetes Care, 3rd Ed., Excerpt #1: Diabetes in the Emergency Department

David Levy, MD, FRCP



Every day many patients with established or newly diagnosed diabetes pass through emergency departments. Few require admission, but all need careful evaluation and management: emergencies in diabetes can develop rapidly, and they carry a risk of mortality. Deciding who needs admission requires clinical skill and experience. Type 1 patients are often young and may look superficially well even though metabolically decompensated, and type 2 patients with, for example, apparently minor foot infections may be severely septic with relatively few symptoms or signs. Those presenting without a primary diabetes problem may be much sicker as a result of poorly controlled diabetes and underlying long-term complications (especially renal and cardiac) that are not always apparent….


Differentiating between DKA and hyperglycemic hyperosmolar state (HHS, previously hyperosmolar nonketotic state or HONK) is not difficult, but is important (Table 2.1). HHS has a different pathogenesis, occurs in a different group of patients (older, type 2, often with significant comorbidities) and carries a worse prognosis, with quoted mortality rates of about 15%. Fortunately, despite increasing numbers of cases, deaths from DKA are now uncommon and in developed countries mortality is around 2%, lower than the 4–10% quoted in the literature, although mortality increases with age, reaching 15% in those aged over 70. In the USA, mortality due to all hyperglycemic emergencies fell consistently between 1985 and 2002. Nevertheless, even in a cohort of European youngsters diagnosed since 1989, there is a twofold increased standardized mortality rate, and up to one-third of deaths in this relatively early phase of diabetes, before the onset of late complications, may be related to DKA [1]. In the UK, one-quarter of all DKA cases occur in those under 18.

All true hyperglycemic emergencies require clinical and biochemical vigilance. They are not ‘set-piece’ emergencies, especially HHS. Some studies quote up to 30% of DKA patients having a simultaneous hyperosmolar state, though clinically it seems to be much less frequent. Finally, despite hyperglycemic emergencies being so common, the evidence base for their management is surprisingly slim.

Diabetic ketoacidosis

It is important to distinguish between DKA and hyperglycemic states that require different, less urgent and less intensive treatment. Writing ‘DKA’ is easy, because it is a simple acronym, but all three elements must be present to make the diagnosis.

  • Hyperglycemia, though it is not always very marked.
  • Ketosis, signifying insulin deficiency.
  • Acidosis: other causes of metabolic acidosis that are clinically rare, for example alcohol intoxication or salicylate overdose, can present as ketoacidosis (alcohol intoxication is a frequent precipitant of DKA, but very rarely through its metabolic consequences).


Therefore it is important to distinguish DKA from severe hyperglycemia and ketosis.

  • Severe hyperglycemia: many type 1 patients have occasional blood glucose levels above 20 mmol/L (360 mg/dL), and those in chronically very poor control, e.g. HbA1c above 10% (86 mmol/mol) may occasionally have values in excess of 30 mmol/L (540 mg/dL) without being unwell or ketotic.
  • Ketosis: high blood glucose levels with ketonuria (?:1+) but no acidosis in an otherwise well patient. Significant ketonuria is quite uncommon these days in ambulatory practice; always try to find a reason for it, and ensure the patient has a supply of urine test strips (e.g. Ketostix, Bayer; Ketur Test, Roche Diagnostics) to monitor ketonuria two or three times daily, and report back if there are symptoms, or ketonuria does not remit within 24 hours.

The primary problem in DKA is therefore insulin deficiency, not hyperglycemia. Appreciating this permits efficient and safe management; however, the insulin deficiency is often ignored in preference to treating blood glucose levels, which do not correlate with clinical severity.


Even when there is significant ketonuria (?:2+) and hyperglycemia, e.g. up to 20 mmol/L (360 mg/dL), an otherwise well younger patient does not routinely require admission, but they need immediate attention, where available, by the hospital diabetes team and a clear plan for close follow-up. Emergency outpatient insulin is straightforward, especially with modern disposable insulin pens, and many patients can learn to inject insulin very quickly. However, for this to be safe, the following are mandatory:

  • telephone access to diabetes specialist nurse;
  • good home circumstances and support;
  • no physical or other disabilities that could impede insulin administration;
  • follow-up within 24 hours of discharge, preferably in person.

In general, patients with known type 1 disease and marked hyperglycemia and ketonuria without acidosis should be admitted at least briefly as there may be compliance problems that make immediate discharge more hazardous. Intravenous rehydration is not routinely required if patients are drinking; where available, measure capillary ketones (see below), and if elevated a brief admission for intravenous fluids and insulin should rapidly resolve the situation.

Diabetic ketoacidosis
Immediate precipitating causes include the following.

    1. Newly presenting type 1 or type 2 diabetes (10–20%).
    2. Infection, most commonly chest, urinary tract or gastrointestinal (30–40%).
    3. Other intercurrent medical illness, e.g. myocardial infarction, stroke, occasionally surgical illness (especially acute pancreatitis).
    4. Omission of insulin (15–30%):

(a) Most commonly through failure to implement the sick-day rule not to stop insulin treatment if not  eating (‘no food, no insulin’).
(b) Accidental, e.g. failure of insulin pump (very rare) or insulin pen, more commonly simply running out of insulin supplies.

  • There are several reports from the USA of recreational drugs, especially cocaine, being associated with DKA (especially if recurrent). Screening has been suggested but poses ethical problems; nevertheless, remember the association and ask [2].
  • Other causes: ‘brittle diabetes’; young women with disordered eating and associated insulin omission (see Chapter 13); patients with advanced neuropathy and gastroparesis, leading to recurrent vomiting; and antipsychotic drugs, especially olanzapine and clozapine, are associated with DKA, probably by directly inhibiting insulin secretion.


A common clinical scenario is the young person who drinks too much alcohol, vomits, and fails to take their bedtime insulin and mealtime insulin the following morning and lunchtime because they do not wake up. In up to 40% of cases there is no identifiable precipitating factor.

Hyperglycemic hyperosmolar state
HHS is much more commonly a presentation of previously undiagnosed type 2 diabetes than is DKA a presentation of type 1 diabetes, though the quoted figure of 30% is 20 years old and it is probably much lower now. Infection, renal impairment, cardiac events and the slow, relentless and sometimes undetected progression of hyperglycemia that is the hallmark of type 2 diabetes are probably the most important factors, together with the thirst impairment associated with old age.

Accelerated lipolysis caused by excess catecholamines and insulin defi- ciency are the major factors generating elevated ketone levels in DKA. The normal plasma ratio of the major ketone bodies, acetoacetate and 13-hydroxybutyrate, is 1:1 (total concentration about 0.5–1.0 mmol/L), but in DKA may rise to 6:1 or more, with 13-hydroxybutyrate concen- trations up to 12 mmol/L (1.2 mg/dL). To adequately suppress ketogen- esis, the key to managing DKA is intravenous insulin at approximately 0.1 unit/kg per hour (see below). Acetone, the minor ketone body, is not dissociated and does not contribute to acidosis, but together with aceto- acetate is detected on routine urinalysis for ketones. Many people cannot smell acetone on the breath of DKA patients; others can detect apparently low concentrations.


Insulin deficiency in untreated DKA results in excess acetyl-CoA, which condenses to acetoacetate and is reduced to 13-hydroxybutyrate; the reverse oxidation occurs once insulin is given, resulting in decreased plasma 13-hydroxybutyrate, but increased urinary acetoacetate and acetone [3]. Resolution of ketosis is therefore not reliably detected by the use of urinary ketones, which may remain positive long after 13-hydroxybutyrate has dis- appeared from the plasma.

Simple quantitative capillary 13-hydroxybutyrate measurements are now available using a standard blood glucose meter with specific strips (Abbott Optium Xceed Meter with Optium 13-Ketone Test Strips). The assay range is 0–8 mmol/L; less than 0.6 mmol/L is normal, and significant ketosis is present with values above 1.0–1.5 mmol/L; patients in DKA may have levels in excess of 6 mmol/L. Where meters and strips are available, in DKA blood ketones should be measured frequently, for example every 4 hours, to monitor resolution of ketosis. Because of the delayed resolution of ketonuria compared with blood ketone levels, the measurement is also useful in patients who have positive urinary ketones despite being clinically well. Blood ketones should be normal (<0.6 mmol/L) before discharge. The use of capillary ketone measurements in DKA has been shown to reduce length of hospital stay.

Local policy varies – in some countries all DKA patients are admitted to the intensive care unit (ICU) – but all patients with impaired consciousness should be promptly assessed by the ICU team, as level of consciousness is related to the degree of metabolic derangement. They are at risk of (or may already have) cerebral edema, particularly common in children and adolescents (up to 5% of cases) and which carries a mortality of up to 25%. The youth and lack of comorbidity of a DKA patient should not influence decision-making: a young person in pre-coma is a high-risk patient. Other groups who should be considered for ICU include those in shock and those with a surgical illness or severe coexisting medical illness, for example sepsis, pneumonia or rhabdomyolysis.

Most patients can be managed well in emergency medical centres/units, where intensified medical, nursing and biochemical supervision can easily be given, especially in the critical first 12–24 hours.

Abdominal pain in hyperglycemic emergencies
Abdominal pain is common in DKA, its severity related to the degree of acidosis but not to the degree of hyperglycemia or dehydration; it is particularly likely to be present when serum bicarbonate is less than 5 mmol/L, and with alcohol or cocaine use. Acute pancreatitis secondary to severe hypertriglyceridemia is more likely to occur in HHS than DKA, but serum amylase measurements correlate also with pH and serum osmolality; even a threefold increase in serum amylase is not a reliable indication of acute pancreatitis, and amlyase cannot be measured in severely lipaemic serum, common in all hyperglycemic emergencies. Investigate abdominal pain if pH is near-normal or if pain persists after resolution of DKA [4]

Do not waste time ordering unnecessary emergency investigations. A biochemical flow chart is invaluable.


  • Urinalysis for ketones (and where available capillary 13-hydroxybutyrate); write results prominently and clearly in the notes. Urinalysis results should be recorded using the familiar semi-quantitative grades (negative, trace, 1+, 2+, 3+) and not as pseudo-quantitative measurements which may be misinterpreted.
  • Plasma glucose, urea, creatinine and electrolytes (blood gas [K+] measurements can be clinically misleading).
  • Blood pH and bicarbonate: in clinically stable patients who are not hypoxic, venous blood is satisfactory and allows frequent sampling.
  • Full blood count and C-reactive protein (CRP): ketosis itself causes neutrophilia, but there is no agreement on what constitutes non-specific elevation. Assess for presence of infection clinically and with CRP.
  • Place a large intravenous line.

According to circumstances

  • ECG in patients over 40 years old (then maintain on cardiac monitor, especially if there is hyperkalemia or hypokalemia).
  • Chest radiography.
  • Cultures: blood, urine, throat, cerebrospinal fluid, septic site (always quickly check the feet for painless infected ulcers). Symptoms of infection can be blunted by acidosis and neuropathy.
  • Creatine kinase (CK): rhabdomyolysis can occur in both DKA and HHS. Consider when there is high glucose and osmolality, low phosphate, otherwise unexplained renal impairment (though this is very common in HHS) or clinically dark urine. Measure CK in all patients found collapsed in pre-coma or coma.
  • Phosphate and magnesium in severe metabolic disturbance (see below).

The hazards of DKA and HHS include the following.

  • Circulatory collapse (hypovolaemia, acidosis, electrolyte disturbance).
  • Cerebral edema, associated with massive fluid over-replacement and rapid changes in osmolality.
  • Pulmonary edema in older people, again associated with fluid over-replacement.
  • Hypokalemia, especially if serum [K+] is normal or low to begin with.
  • Rapid changes in serum [Na+] (see below): central pontine myelinolysis has been reported in a small number of cases of HHS with very high glucose levels at presentation where treatment caused rapid changes in osmolality.

Fluid replacement
When surveyed, physicians say they aim to replace the fluid deficit of 5–8L in only 8 hours, although the general view is that this replacement should be over 24 hours, especially in HHS. The traditional approach of giving one or more ‘stat’ litres of 0.9% NaCl in the accident and emergency department is potentially hazardous, especially in HHS. Severe prerenal failure is often present in both DKA and HHS, and occult ischaemic heart disease should be assumed in older HHS patients. Hypotension should be treated on its own merits. Insulin is less effective in the hyperosmolar state, so starting fluids before the insulin infusion may have advantages.

Fluid replacement: correcting serum [Na+] for prevailing glucose levels
Sodium chloride 0.9% is recommended. However, hypernatremia (serum [Na+] >150 mmol/L) is common in both DKA and HHS. This occurs because severe hyperglycemia causes initial hyponatremia due to osmotic effects from water moving out of cells: an increase in glucose of 3.4 mmol/L (60 mg/dL) reduces serum [Na+] by 1 mmol/L (use the approximation of 4 mmol/L for 1 mmol/L).

Therefore, a glucose level of about 40 mmol/L (700 mg/dL) depresses [Na+] by about 12 mmol/L, and at presentation HHS glucose values of 80–100 mmol/L (1440–1800 mg/dL) are not uncommon, accounting for serum [Na+] levels being depressed by 24–30 mmol/L. Many patients presenting with severe hyperglycemia and low or normal serum [Na+] are therefore at risk of hypernatremia once the glucose is corrected. Always correct laboratory [Na+] for prevailing glucose levels. Consider using 0.45% (‘half normal’) NaCl after the first litre or two of isotonic NaCl in patients with high corrected [Na+]. The clinical impression is that serum [Na+] continues to climb for several hours after appropriate fluid is given, so anticipate this problem. Triglycerides are not osmotically active, and the often severe hypertriglyceridemia of uncontrolled diabetes, caused by insulin deficiency (and resulting in ‘strawberry yoghurt’ venous blood), does not cause hyponatraemia with modern laboratory methods for measuring electrolytes.

In the UK, there is a move away from NaCl for routine fluid replacement towards Hartmann’s solution (sodium lactate), which has a lower sodium concentration (131 vs. 154 mmol/L) and lower chloride concentration (111 mmol/L). However, patients in DKA may already have elevated lactate levels, and the additional lactate in Hartmann’s solution could generate higher glucose levels. More practically, Hartmann’s solution contains a fixed low potassium concentration (5 mmol/L); restrictions on adding KCl to intravenous infusions could limit flexible and adequate potassium replacement. The advice is that NaCl remains standard intravenous fluid for initial treatment of hyperglycemic emergencies [5].

Intravenous insulin regimen and blood glucose monitoring

Diabetic ketoacidosis
In severe hyperglycemia, most glucose disposal is through non-insulin-dependent pathways (e.g. renal). Insulin is used primarily to suppress ketogenesis and glucagon levels, and not to reduce hyperglycemia (see above). Rehydration and correction of acidosis will cause blood glucose levels to fall independent of the rate of insulin infusion. Current UK guidelines recommend continuing subcutaneous long-acting analogue insulin in the usual dose and at the usual time.

In the UK, insulin is usually given by continuous intravenous infusion through an infusion pump (soluble insulin: 50 units Humulin S or Actrapid in 50 mL 0.9% NaCl), although intermittent intramuscular insulin regimens are effective and still widely used. Ketosis is suppressed with insulin at the usual starting rate of 6 units/hour, but this rate often causes a precipitous fall in blood glucose, especially in HHS. Usual practice is to change from 0.9% NaCl to 5% glucose infusion when capillary blood glucose falls below 14 mmol/L (250 mg/dL), but at this level most so-called ‘sliding scale’ (variable rate) intravenous insulin infusions specify rates of 1–2 units/hour, too low to suppress ketogenesis but still sufficient to cause hypoglycemia, especially when given with 5% glucose. Finally, since this point may be reached only a few hours after presentation, substantial rehydration with NaCl is still required. Where possible, therefore, after initial resuscitation and once capillary blood glucose levels are below 14 mmol/L, use a triple infusion regimen (Fig. 2.2):

  • 10% glucose at 100 mL/hour (or 500 mL over 4 hours);
  • maintain rehydration (and potassium replacement) with 0.9% NaCl (in the UK 10% glucose does not come with pre-added KCl);
  • soluble insulin infusion at a constant 6 units/hour with careful capillary blood glucose monitoring.

Perform frequent (4-hourly) capillary ketone measurements (where available) and venous bicarbonate measurements until the acidosis has resolved, in addition to hourly capillary blood glucose measurements. Remember that most near-patient glucose meters read up to a maximum of 33mmol/L (600mg/dL), some (those manufactured by Abbott) up to 27.8mmol/L (500mg/dL); use laboratory measurements until values are below this level.

Hyperglycemic Hyperosmolar State
HHS patients have residual 13-cell function and are not ketotic, so high insulin doses should not be required; clinically, HHS patients are often sensitive to insulin. The risk of rapid osmotic shifts and severe hyper-natremia can be reduced by using low-dose insulin infusions (e.g. 1–2 units/hour), which can be increased if blood glucose levels do not fall, together with gentle intravenous 0.9% NaCl (e.g. 1 L every 6–8 hours).

Although the metabolic disturbance may not be as evident as in DKA, the high level of comorbidity, especially renal impairment (which may be severe), means that HHS patients, especially the elderly, require careful clinical assessment and management. Very rapid rehydration may be fatal.


  • Measure creatinine and electrolytes at 4 and 8 hours, thereafter according to the clinical and biochemical state.
  • Hypokalemia, rather than hyperkalaemia, is often a problem, because insulin and rising pH both drive extracellular potassium into cells.
  • Bicarbonate: do not give unless pH is below 7.0 and patient is gravely ill. There is no indication for bicarbonate in an otherwise well DKA patient even with severe acidosis. Give 700 mL of 1.2% sodium bicarbonate solution over 45 min, together with 20 mmol KCl, and repeat until pH exceeds 7.0. DKA requiring bicarbonate should be managed on the ICU or under intensivist supervision.
  • Magnesium and phosphate can both be low in DKA (low phosphate occurs in about 15%), but they are of little clinical importance except in the most severe metabolic disturbances. DKA associated with acute alcoholic intoxication or rhabdomyolysis can cause hypophosphatemia, so measure serum phosphate in these circumstances. Severe hypophosphatemia is associated with respiratory failure, arrhythmias and generalized weakness. Consider intravenous phosphate replacement in critically ill patients in ICU [6].
  • Hyperchloremic acidosis, a transient non-anion gap acidosis, may occur as ketones are replaced by chloride, especially when large quantities of NaCl have been given. This may account for slow resolution of acidosis in some cases of DKA. Move to a high-glucose (10%) and high-insulin infusion regimen with frequent biochemistry and pH monitoring.

Other interventions

  • Patients with impaired consciousness should have a urinary catheter and nasogastric tube placed, but these patients should be managed in ICU. There is no need for either in an otherwise clinically well patient; unnecessary use, especially of urinary catheters, may delay discharge and predispose to infection that was not there in the first place.
  • Urinary tract and chest infections are frequent precipitants or associations of DKA and HHS. Neutrophilia is a non-specific finding in DKA, neuropathy may blunt pleuritic or ischaemic chest pain and dysuria, and ketosis can suppress fever. After taking appropriate cultures, antibiotics (e.g. co-amoxiclav) should be used freely in these patients.
  • Anticoagulation: use prophylactic anticoagulation in HHS patients, and immobile or unconscious DKA patients.
  • Keep meticulous fluid balance charts; most hospitals have their own monitoring and prescription charts for hyperglycemic emergencies.


The first 12–24 hours of a hyperglycemic emergency are usually managed with few problems, but the transition to discharge can be less smooth. Always involve the inpatient diabetes team as soon as possible after admission: they are likely to know many of the DKA patients.

Establish the cause of the emergency. This can be explored in more detail by the diabetes team. There must be an educational review: DKA should be seen as a failure of integrated diabetes care in the community. Many DKA patients are poor clinic attenders with premature complications, poor long-term glycemic control and high rates of associated psychiatric problems. A definitive follow-up plan must be formulated and agreed with the patient; organize a further diabetes review (telephone or in-person) within a few days of discharge. Try to remember to request an HbA1c measurement, particularly in poor clinic attenders, as this will help medium-term management planning.

Duration of intravenous insulin infusion. In moderate or severe DKA, most patients will require 24 hours of intravenous insulin, often longer in the sicker HHS patients. As soon as ketosis has resolved, preferably judged by capillary ketone measurement, transfer patients to subcutaneous insulin. If ketonuria persists while the patient is well and eating, confirm the absence of true ketosis by measuring capillary ketones.

Where possible, discontinue intravenous insulin early in the day. Discontinued intravenous insulin after a subcutaneous dose has been given, just before a meal.

Hyperosmolar patients with persistently negative ketones
Hyperosmolar patients with persistently negative ketonuria can usually be transferred to oral hypoglycemic agents before discharge.

  • Do not use metformin alone: it acts too slowly under these circumstances and impaired renal function may contraindicate its use.
  • Start newly diagnosed patients on a low dose of sulphonylurea (e.g. gliclazide 40–80 mg b.d.), together with a low dose of metformin if no contraindications. Unless the patient is thin, regard the sulphonylurea as a temporary glucose-reducing measure that should be discontinued as soon as possible. Ensure the patient has clear straightforward advice on the symptoms of hypoglycemia, on how to contact the diabetes team if it occurs, and how to reduce or stop the medication.
  • Even in ketone-negative patients, err on the side of caution, and discharge patients on insulin if there has been preceding weight loss or if the patient is thin or of normal weight.
  • Where possible, observe for 24 hours after starting oral hypoglycemic agents to ensure reasonable blood glucose levels (e.g. 8–12 mmol/ L, 145–220 mg/dL).
  • Ask for a dietitian consultation: at this stage of type 2 diabetes, resolve will be at its greatest and a substantial proportion will be well controlled on diet with or without metformin in due course.
  • Involve the inpatient diabetes team or diabetes specialist nurses: education is critical, especially about hypoglycemia, which is perceived by most to be a problem that only occurs in insulin-treated diabetes.
  • Ensure that there is good communication with the patient’s primary care team, and arrange follow-up within a week with either team.

Known type 1 patients
Re-establish the previous insulin regimen, unless there is good reason to believe that it was itself responsible for the emergency, which would be unusual compared with the much more frequent problem of failing to take the previously agreed insulin dose. Making changes while an inpatient often delays discharge, is often pointless and is potentially hazardous. Changes are much better made in the ambulatory setting shortly after discharge, with inpatient time being used to discuss the reasons for the episode.

Newly diagnosed type 1 patients
Most patients at some stage will be established on a multiple-dose insulin (MDI) regimen. In some countries, newly diagnosed patients remain in hospital for an intensive period of education. In Norway, for example, many start insulin pump treatment immediately after diagnosis. Elsewhere, the major considerations are safety – avoiding hypoglycemia and suppressing ketogenesis – and this can be achieved with relatively low doses of insulin. There is no agreement about whether patients do better in the early stages with a twice-daily fixed mixture regimen or MDI. Twice-daily biphasic mixtures (e.g. NovoMix 30 or Humalog Mix 25 given with breakfast and the evening meal, or Humulin M3 or Insuman Comb 25 given 30 min before these meals) are easy to teach and use, especially with insulin pens (see Chapter 4). Where there are the educational resources, low-dose MDI is secure and will avoid the need to change insulin preparations.

Newly presenting ketotic patients with initially indeterminate diabetes
The practical rule is simple: newly presenting ketotic patients (i.e. those with initial insulin deficiency), with or without acidosis, should be discharged on insulin treatment. Classical type 1 patients will be clinically apparent, but the heterogeneity of ketosis-prone diabetes (see Chapter 1) means that during an initial hospital admission there can be diagnostic uncertainty, and results of supportive laboratory tests (e.g. GADA) are usually not immediately available. The only safe approach is to discharge on insulin, and review frequently until the clinical course becomes clear.

Initial insulin doses
The widely used rule of adding up the previous 24-hour intravenous insulin requirements and dividing into two or four doses according to the planned number of daily injections may be hazardous: DKA is an insulin-resistant state, and using this rule may result in high insulin doses causing hypoglycemia. Patients treated with high-dose insulin and 10% glucose will inevitably need large doses. Finally, patients are likely to be moving into ‘honeymoon’, with partial temporary recovery of 13-cell function, and will also be much more active once they return home. Calculate an initial total daily dosage at about 0.5 units/kg body weight, the lower end of the usual range of stable insulin requirements for type 1 patients (i.e. 30–40 units/day).

However, there is no room for complacency over glycemic control in the period following diagnosis of type 1 diabetes. In the DCCT, about one-third of patients with disease duration of less than 5 years had some residual insulin secretion, and intensive treatment (i.e. HbA1c <7.0%, 53 mmol/mol) can help sustain endogenous insulin secretion for perhaps another 5 or 6 years, with lower risks of severe hypoglycemia and of microvascular complications [7]. This is particularly important (and challenging) for adolescents where, because of worse overall glycemic control than adults, the beneficial long-term ‘legacy’ effects on retinopathy are much less pronounced (see Chapter 9).

Every person presenting to an emergency department with impaired consciousness must have a reliable capillary glucose measurement recorded in the notes.

  • Hypoglycemia is the commonest complication of type 1 diabetes.
  • Hypoglycemia is frequent in insulin- and sulphonylurea-treated type 2 patients.
  • Hypoglycemia carries a substantial mortality, either directly through brain damage or indirectly through injuries sustained while hypoglycemic.
  • Hypoglycemia is frightening and disruptive to family, social and work life, undermines confidence, sometimes in the long term, may have neuropsychiatric consequences (e.g. scholastic achievement), especially in the young, and remains the major barrier to implementing intensive glycemic control in type 1 patients.

Always try to find a reason for the episode. Where possible, trace a recent HbA1c measurement to assess prior over-tight control (e.g. HbA1c < 6.0%, 42mmol/mol). Reduce oral hypoglycemic agents or insulin dosages before discharge (with clear written suggestions, especially for the elderly, the forgetful and those who were admitted with severe hypoglycemia), emphasize increased frequency of home blood glucose monitoring, and arrange early follow-up with the primary or secondary care diabetes team.

Singly or in combination, the following factors account for most episodes of hypoglycemia:

  • dietary (missing or delaying a meal);
  • too much insulin (inadvertent administration);
  • unaccustomed exercise;
  • alcohol and other drugs.

However, consider the more uncommon causes listed below.

  • Overdose of insulin or sulphonylurea: factitious sulphonylurea overdosing in patients with documented severe hypoglycemia is surprisingly common. A wide range of sulphonylureas can be measured in plasma. Factitious insulin overdosing can be diagnosed by detecting high insulin and low C-peptide levels in hypoglycemic patients. Metformin, glitazones, glucagon-like peptide (GLP)-1 analogues and DPP-4 inhibitors do not cause hypoglycemia individually or in combination, although mild hypoglycemia can occur in normoglycemic people treated with metformin, for example patients with polycystic ovarian syndrome.
  • Newly developing endocrine disorders, especially Addison’s disease (increased risk in type 1 diabetes) and hypopituitarism. The onset may be insidious: consider Addison’s in type 1 patients where insulin dose falls by more than about 20% in response to frequent hypoglycemia, even if the classical biochemical picture (↑ [K+], ↓ [Na+]) is absent.
  • Impaired absorption: gastroenteritis, coeliac disease (check tissue transglutaminase).
  • Impaired gastric emptying: gastroparesis.
  • Failure to decrease insulin dose postpartum; breast-feeding.
  • Early pregnancy: decreased insulin requirements plus nausea/ hyperemesis.

In the appropriate setting, remember the non-diabetic causes of hypoglycemia: insulinoma (not in type 1 patients), hypothermia, alcohol and drugs.

  • Severe hypoglycemia has been reported in patients taking glibenclamide who are prescribed fluoroquinolone antibiotics (fluoroquinolones inhibit the cytochrome P450 CYP3A4 hepatic system that metabolizes gliben-clamide) [8]. There is an isolated case report of severe hypoglycemia in a type 1 patient taking the anti-smoking drug varenicline.
  • Non-steroidal anti-inflammatory drugs (including aspirin) can also potentiate the actions of sulphonylureas.
  • Combinations of drugs may contribute to hypoglycemia in patients already in good control (e.g. beta-blockers, ACE inhibitors), though this is rarely seen in practice.
  • Reports surface intermittently of herbal remedies and internet and street drugs being spiked with sulphonylureas. Always take a full drug history.

Operational classification of hypoglycemia

Counter-regulation in the non-diabetic person (increased glucagon, reduced endogenous insulin) begins when blood glucose levels fall below 3.8 mmol/L (70 mg/dL) (Fig. 2.3). This value is the basis for the wide-spread recommendation to avoid blood glucose levels lower than 4 mmol/ L (72 mg/dL) – ‘four’s the floor’ is a useful mnemonic, though somewhat less snappy when expressed in traditional units. Educating patients that hypoglycemia is not necessarily an impairment of consciousness, but is frequently a ‘numerical’ and almost asymptomatic problem that may nevertheless have serious consequences, is important. Cognitive function becomes impaired at blood glucose levels below 3 mmol/L (54 mg/dL), and this level is used by the European drug licensing authority (EMEA) in assessments of adverse effects of diabetes therapies.

Patients should take or be offered prophylactic glucose when asymptomatic blood glucose levels below 4.0 mmol/L are detected. It should go without saying that appropriate dose reductions in insulin or oral hypoglycemic agents should be made if biochemical hypoglycemia is frequent, with arrangements for monitoring and follow-up, but unfortunately it still needs saying.

Mild (self-treated) symptomatic hypoglycemia
Most well-controlled type 1 patients have about two mildly symptomatic hypoglycemic episodes each week [9]. Symptoms are variable, but in individuals they are often stereotyped in nature and sequence.

  • Autonomic: sweating, hunger, trembling, anxiety, pounding heart.
  • Neuroglycopenic: confusion, odd behaviour, difficulty concentrating. The earliest signs of neuroglycopenia are often very subtle, for example an almost imperceptible slowing or hesitation of speech, and only those who know the patient well (family members, friends, co-workers and sometimes members of the diabetes team) may be able to detect them.
  • Motor: incoordination, difficulty walking.
  • Sensory: visual disturbance, perioral tingling.
  • Others: headache, nausea, difficulty speaking.

Take about 20 g carbohydrate, for example:

  • two slices of bread;
  • two snack-sized chocolate bars;
  • 100 mL Lucozade or equivalent glucose sports drink;
  • 200 mL non-diet cola drink;
  • three cubes of sugar (sucrose);
  • in the UK, Glucogel (40% dextrose gel, formerly HypoStop) is available in 25-g tubes (containing 10 g carbohydrate) or 80-g bottles (containing 32 g carbohydrate).

Absorption characteristics for solid and liquid glucose are similar, although liquid is usually recommended. glycemic response occurs within 10–15 min, though symptoms improve more rapidly. There is no point in repeating capillary blood glucose measurements after a shorter interval. Do not use nutritional supplements, for example Fortisip (Nutricia), to treat hypoglycemia in hospitalized patients. These consist mainly of complex carbohydrates (maltodextrins) with only small amounts of free sugars, and are probably not absorbed as quickly as glucose.

Severe hypoglycemia
An event where blood glucose falls below 2.8 mmol/L (50 mg/dL) and the patient requires the assistance of another person.

  • About 10% of type 1 patients have an episode of severe hypoglycemia every year, rising to about 30% in intensively treated patients. The DARTS/MEMO collaboration in Scotland found that insulin-treated type 2 patients have the same frequency of severe hypoglycemia as type 1 patients.
  • About 3% of type 1 patients have recurrent severe hypoglycemia but despite concern that this could cause long-term cognitive decline, an 18-year EDIC (Epidemiology of Diabetes Interventions and Complications) follow-up of the DCCT cohort found no evidence for it [10]. The corresponding rate in patients treated with oral hypoglycemic agents is much lower, about 0.5% per year.
  • About 6% of deaths during the DCCT were hypoglycemia related, similar to the 2–4% rate reported elsewhere. Since DCCT reported in 1993, the rate of severe hypoglycemia has not decreased, and may have increased; motivation, education and intensive monitoring, as in the DCCT, therefore remain critical in reducing severe hypoglycemia.
  • ACCORD (see Chapter 5) confirmed the link between severe hypoglycemia and death in type 2 patients, regardless of the intensity of glycemic treatment (actually the hypoglycemia rate was higher in the conventional rather than the intensive treatment group) [11].

Most patients are aware of autonomic symptoms at glucose levels of 2–3 mmol/L (36–54 mg/dL), but patients with habitual low blood glucose levels often have a degree of hypoglycemia unawareness, probably due to a combination of impaired sympathetic autonomic and catecholamine responses, and may apparently be fully alert and responsive at levels of 1–2 mmol/L (18–36 mg/dL). However, demonstrable impairment of cognitive function is invariable at levels below 3 mmol/L. The term ‘hypoglycemia-associated autonomic failure’ describes the vicious cycle of hypoglycemia perpetuating hypoglycemia by reducing humoral and neurological responses to antecedent hypoglycemia. Strict avoidance of hypoglycemia for as little as 2–3 weeks can restore hypoglycemia awareness. Achieving this is a challenge [12].

Risk factors for severe hypoglycemia

    1. Intensive insulin therapy (multiple dose insulin or insulin pump treatment).
    2. Type 1 diabetes: low HbA, often in the non-diabetic range (4–6%, 20–42 mmol/mol). Anecdotally, patients tend to be young or middle-aged males without microvascular complications despite long duration of type 1 diabetes. Intensive monitoring of HbA1c levels with frequent specialist follow-up can be helpful: whether it is beneficial to demonstrate hypoglycemia objectively with CGM is not yet known.
    3. Type 2 diabetes: ACCORD (see Chapter 5) identified the following risk factors:

(a) female
(b) African-Americans compared with non-Hispanic whites
(c) lower levels of education
(d) the elderly
(e) insulin-treated patients.

  • In striking contrast with type 1 patients, there was a consistent decrease in hypoglycemia, less marked for intensively treated patients, with lower HbA1c levels. This may account for, though not easily explain, the frequent hypoglycemia often encountered in insulin-treated type 2 patients with apparently poor HbA1c levels [13].
  • The elderly, often treated with sulphonylureas, and who may not have been sufficiently educated about hypoglycemia.
  • Alcohol: the conventional view is that moderate alcohol taken alone has little effect acutely on blood glucose but can cause hypoglycemia the next day. This is not consistent, either clinically or in research studies, but always caution about the possibility of late hypoglycemia after alcohol, even when taken with food. Moderate hypoglycemia (e.g. 2.3 mmol/L, 40 mg/dL) combined with low levels of blood alcohol (below the current UK driving limit) severely impair cognitive function; if they are driving, type 1 patients should not drink any alcohol.
  • Exercise: a factor that consistently leads to late hypoglycemia, characteristically 17–30 hours after moderate exercise. Adolescents have impaired counterregulation caused by sleep itself, leading to a possible increased risk of hypoglycemia during the night after exercise [14].
  • Hypoglycemia unawareness: risk factors include increasing duration of insulin treatment, extremes of age, and previous hypoglycemia.
  • Established autonomic neuropathy is not consistently a factor, although autonomic neuropathy is associated with long-duration diabetes.
  • Pancreatic diabetes, due to absent glucagon secretion, through destruction of a. cells.
  • Social isolation.
  • Remember the unusual presentations of hypoglycemia:
    • seizure;
    • hemiparesis;
    • aggressive (possibly criminal) behaviour;
    • ‘He’s been drinking, doctor’;
    • acute back pain (opisthotonos or rarely crush fracture of thoracic vertebra caused by fits).


Intravenous glucose. Give 20–30 mL of 50% glucose (10–15 g) by bolus intravenous injection into a large peripheral vein. Potential problems include the following.

  • Viscous solution: may be difficult to inject, especially in a restless patient.
  • Phlebitis (with both intravascular and extravascular placement): superficial extravasation, sometimes caused by attempts to give glucose via a small cannula inserted on the dorsum of the hand, can cause severe skin necrosis (Fig. 2.4).
  •  Gaining venous access in patients who have had repeated previous infusions: avoid using peripheral leg veins, and veins in the antecubital fossa in pre-dialysis patients.

Where available 20% glucose, 50–75 mL is safer.

Glucagon. A major insulin antagonist hormone, useful in management by paramedics out of hospital, by partners of type 1 patients at risk of hypoglycemia, especially nocturnal, and as initial treatment in the unconscious or restless patient where there is a delay in gaining venous access. The standard presentation contains 1 mg glucagon in powder form for reconstitution with water for injection in a prefilled syringe (GlucaGen Hypokit, NovoNordisk). Glucagon acts by directly stimulating hepatic glycogenolysis and is therefore:

  • relatively ineffective in the patient with poor hepatic glycogen stores (thin, malnourished, starving, anorectic or alcoholic);
  • relatively effective in patients with pancreatic diabetes, who are gluca- gon deficient;
  • usually clinically effective within 20 min;
  • usually transiently effective (∼90 min) and needs supplementing with oral glucose as soon as the patient is capable of taking it.

Glucagon can be given by intravenous, intramuscular or subcutaneous injection, but intramuscular administration is preferable; subcutaneous administration may be ineffective in vasoconstricted patients and intravenous injection can cause nausea.

Sulphonylurea-induced hypoglycemia
Admit all patients with sulphonylurea-induced hypoglycemia because of the risk of late relapse after treatment, especially with long-acting sulphonylureas such as glibenclamide and glimepiride. Both 50% glucose and glucagon stimulate residual insulin secretion and may exacerbate hypoglycemia. Use continuous intravenous 10% or 20% glucose, with hourly blood glucose monitoring. The somatostatin analogue octreotide inhibits insulin and glucagon secretion (as well as many other hormones) and is of value in severe sulphonylurea-induced hypoglycemia (50 µg s.c. 12-hourly).

Follow-up of patients with severe hypoglycemia

  • After initial treatment in the emergency department, replenish hepatic glycogen stores with a substantial carbohydrate-containing snack after recovery (three to six biscuits, bread, or sandwiches) to prevent recurrent hypoglycemia.
  • Check blood glucose level after 20 min.
  • If the patient has recovered, is fully conscious and has a blood glucose above 7 mmol/L (126 mg/dL) within an hour, admission is not required, but make firm arrangements for prompt follow-up by the diabetes team, especially if there is no obvious reason for the episode. In the meantime suggest at least 10% reduction in relevant insulin dose(s), and stop or halve the dose of sulphonylureas. A few days of moderate hyperglycemia is much preferable to another possibly even more severe episode of hypoglycemia.

When to admit

  • Patients with residual neurological deficits or prolonged coma after treatment: consider postictal state, cerebral edema, head injury, intracranial infection, bleed or infarction, and coexisting poisoning with alcohol or drugs. Obtain an urgent brain CT scan.
  • Patients living on their own with no facilities for close supervision over the next 24 hours. In type 1 diabetes, episodes of severe hypoglycemia seem to cluster, presumably through impairment of hypoglycemia awareness following the first episode, though other factors are likely to be involved.
  • Recurrent hypoglycemia, despite adequate initial treatment, suggesting liver disease, insulin or sulphonylurea overdose, intentional or otherwise.

Detailed investigation and management of the patient with diabetic foot ulceration is covered in Chapters 7 and 10. However, lower-limb infections, with or without ulceration, commonly present to emergency departments, and the default should be admission unless:

  • the infection is truly minor and
  • there is a firm immediate management plan in place and
  • the patient has low-risk, adequate accommodation and social support if sent home.

The reasons for caution include the following.

  • Symptoms and signs of infection are likely to be less obvious (impaired inflammatory responses, sensory impairment from neuropathy): patients with known severe neuropathy who describe any symptoms of discomfort in the foot may be harbouring a severe occult infection.
  • Seemingly trivial infections can spread very rapidly: diabetes is a risk factor for necrotizing fasciitis.
  • Underlying lesions (osteomyelitis, deep abscesses, Charcot neuroarthropathy) may not be clinically or radiologically apparent, and may be difficult to differentiate on plain radiography.
  • Antibiotic therapy alone is insufficient; it must be combined with good wound care and bed rest for optimum outcomes.

Many classification systems for diabetic foot ulceration have been devised, but a recent one has been supported by prospective correlation. Admit any patient with a moderate infection associated with ulceration, i.e. more than one of the following:

  • >2 cm cellulitis around ulcer;
  • lymphangitis;
  • spread beneath fascia;
  • abscess or gangrene.

Patients with systemic toxicity (fever, hypotension, leucocytosis, impaired renal function) must be admitted [15].

More difficult clinically are patients with cellulitis but without foot ulceration. Again, always err on the side of caution and admit, especially with additional risk factors, for example:

  • chronic leg edema, lymphedema;
  • skin blistering;
  • immobility;
  • recurrent cellulitis;
  • known methicillin-resistant Staphylococcus aureus (MRSA) infection;
  • presentation on Friday/public holiday.

All that is needed initially is recognition of the need for admission, basic blood tests, a plain foot radiograph and referral to the admitting medical or diabetes team. Many patients will be known to the diabetes and specialist podiatry team.
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David Levy, MD, FRCP, Consultant Physician, Gillian Hanson Centre, Whipps Cross University Hospital; Honorary Senior Lecturer
Queen Mary University of London London, UK

This edition first published 2011, © 2011 by David Levy. 1st edition 1998 (Greenwich Medical Media/Cambridge University Press) 2nd edition 2006 (Altman Publications)