INTRODUCTION
Hyperglycemia crisis and hypoglycemia are both life-threatening medical emergencies but are usually readily treatable if recognized early. Hyperglycemic crises comprise diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS). While some elements of their clinical presentation and pathophysiology are distinct, the general principles of treatment are similar. They will be discussed together. Hypoglycemia is a problem commonly seen in patients with diabetes mellitus (DM) and requires prompt treatment. The common causes and treatment regimens will be outlined here.
HYPERGLYCEMIC CRISIS
KEY POINTS
Hyperglycemic crisis has a high mortality, particularly in the elderly.
Mortality rates are falling due to improved recognition and medical care.
Fluid volume restoration, insulin, and electrolyte management are key.
Regular electrolyte and glycemic assessment is needed.
DKA is more commonly seen in younger patients with type 1 DM.
Patients presenting with HHS are often older with type 2 DM.
Precipitating causes should be sought.
Serum glucose is a continuum and there is a spectrum of hyperglycemia. DKA and HHS represent the extremes of hyperglycemia and are regarded as medical emergencies. Hyperglycemia is caused by a relative insulin insufficiency. This may be caused by any combination of
a) Decreased insulin production
b) Increased insulin requirements
c) Increased counterregulatory hormones
d) Decreased peripheral glucose utilization
In type 1 diabetes mellitus (DM), autoimmune-mediated β-cell death leads to a dramatic fall, and eventually a complete cessation, of insulin production. This can lead to hyperglycemia over a very short period of time. In type 2 DM, there is lowered insulin sensitivity, increased hepatic gluconeogenesis, and a more gradual reduction in insulin secretion over years. Traditionally DKA was seen almost exclusively in patients with type 1 DM, while HHS was a rare complication of elderly patients with type 2 DM. HHS has supplanted the older terms hyperglycemic hyperosmolar nonketotic coma and hyperglycemic hyperosmolar nonketotic state. This change reflects that patients with HHS may have detectable ketonemia and need not have an altered sensorium or present with coma.
Profound insulin deficiency leads to conversion of excess fatty acid to acetyl coenzyme A (ACA) via β-oxidation. Ordinarily ACA would be further oxidized via the TCA cycle. In the absence of insulin, excess amounts of ACA form ketone bodies (acetone, acetoacetate, and B-hydroxybutyrate) via acetoacyl-CoA and β-hydroxy-β-methylglutaryl-CoA. Ketone bodies are produced in small physiologically acceptable amounts (<0.5 mM) in the fasting state when carbohydrate is unavailable or inaccessible for short periods of time. However, hyperketonemia (>1 mM, usually >3.0 mM in ketoacidosis) can result in a raised anion gap metabolic acidosis, ketonuria, dehydration, and electrolyte imbalance.1
Ketonemia and ketoacidosis are classically seen in patients with type 1 DM leading to DKA. However, DKA can be seen in any form of DM with significant insulin deficiency, usually during times of physiological stress (eg, sepsis, cardiovascular event, or trauma). Increasingly, DKA is being described as the presenting illness of African American patients with type 2 DM.2 Initially these patients may require high doses of insulin but often remain off insulin therapy for many years after their original presentation.3,4 Glucotoxicity and lipotoxicity are postulated causes for this transient β-cell dysfunction but the etiology is uncertain.5 These patients are typically negative for both anti-islet antibodies and mutations in genes known to be associated with maturity onset diabetes of youth (MODY).6
In response to significant hyperglycemia, a cascade of counterregulatory hormones is released. Glucagon, catecholamines, cortisol, and growth hormone all stimulate gluconeogenesis and lipolysis, have anti-insulin effects, and reduce glucose utilization in the peripheral tissues. In patients with type 2 DM, high insulin resistance coupled with this increase in anti-insulin hormones can lead to a relative insulin deficiency. This combination can result in profound hyperglycemia without ketosis as there is sufficient circulating insulin to prevent significant ketonemia.7
Once the renal threshold for reabsorption of glucose is breached (∼10.0 mmol/L or 180 mg/dL), glycosuria occurs.8 The resultant osmotic diuresis gives rise to many of the symptoms and signs associated with hyperglycemia. Hyperglycemia itself is a β-cell toxic state and insulin secretion is reduced.9 This cycle of hyperglycemia, falling insulin secretion, and dehydration through glucose-mediated osmotic diuresis can result in HHS, particularly if unmatched by increased oral increased free water intake. Peripheral insulin sensitivity, peripheral glucose utilization, and endogenous insulin production, all increase after HHS is treated. When euglycemia is restored, endogenous insulin production may be sufficient to prevent recurrence of uncontrolled hyperglycemia if combined with dietary changes and oral hypoglycemic agents.
Initially, rising serum glucose draws free water into the intravascular space. While transiently maintaining intravascular volume, this process can lead to a dilutional hyponatremia. Over time, intravascular volume contraction occurs if water loss through hyperglycemia associated osmotic diuresis is not met by an increase in oral free water intake. Serum sodium, urea, and glucose rise gradually and thus serum osmolality climbs. Hypertriglyceridemia, secondary to hyperglycemia, can also result in lowering of serum sodium concentration.10
There is huge variation in the presentation patterns of patients with hyperglycemia emergencies. The typical signs, symptoms, and biochemical profiles are represented in Tables 101-1 and 101-2. DKA develops over a short period of time, often less than 24 hours, while HHS tends to be a more insidious process. Patients with hyperglycemia can range from being relatively asymptomatic to unresponsive and obtunded. Patient factors including age, access to water, ability to communicate thirst, and pre-existing medical conditions affect the mode of presentation. Biochemical factors such as degree of acidosis and hyperglycemia also influence both the severity of the illness and the mode of presentation.
Signs and Symptoms of Hyperglycemic Crisis
| Symptoms | Signs |
|---|---|
|
Elderly patients with reduced mobility and an inability to access sufficient fluids to counter the hyperglycemic diuresis are particularly vulnerable. Equally infants may have quite nonspecific signs and become profoundly dehydrated prior to contact with medical services. Significant neurological compromise is rare in the absence of hyperosmolarity or acidosis.11 DKA can be graded based on the severity of acidosis (see below).12 However, other coexisting conditions at presentation, which also affect the acid-base balance, may result in DKA being graded incorrectly. Therefore, it is important to identify other factors affecting the acid-base balance in patients at initial assessment and not rely solely on pH and serum bicarbonate for risk stratification.13
The classical triad seen in DKA is hyperglycemia, ketosis, and a raised anion gap metabolic acidosis. The key features of HHS are hyperglycemia, dehydration, and hyperosmolarity without significant ketosis. Most patients can be readily separated into DKA or HHS, but there can be overlap with clinical presentation.14 In HHS, plasma glucose can reach >60 mmol/L or 1080 mg/dL while it is unusual to have readings >30 mmol/L or 541 mg/dL in DKA. Treatment regimens (see below) are similar but should be adjusted to suit individual patients.
The reported incidence of DKA in the Unites States has increased by approximately 50% over the last 20 years. DKA was the primary reason for admission for 81,000 hospital discharges in 1989. That figure has risen steadily to 140,000 in 2009.15 Over the same period, hospital lengths of stay have fallen from 5.8 days to 3.4 days.16 In children with diabetes mellitus (aged <18 years) admitted to hospital, DKA represents the primary reason for admission in 47% of discharges.17,18
Any cause of raised anion gap acidosis should be considered as an alternative or a coexisting diagnosis in patients presenting with DKA. Ingestion of salicylates, ethylene glycol, sulfates, propylene glycol, and methanol can result in a raised anion gap acidosis. Usually these can be readily distinguished from DKA, as ketonemia is not present. Polyuria, polydipsia, dehydration, and hyperosmolarity are all features of diabetes insipidus but the absence of significant hyperglycemia at presentation distinguishes it from HHS.
Lactic acidosis and uremia can result in a similar biochemical profile to DKA but they can also complicate severe DKA/HHS.19 Their initial presence may worsen prognosis but rarely affects treatment regimen/algorithm. Alcoholic and starvation ketosis rarely present with hyperglycemia. Ketonemia and acidosis can be marked in alcoholic ketosis but starvation ketosis rarely presents with significant acidosis.20
Death: Despite the exponential rise in incidence of new cases of diabetes,21,22 there has been a fall in overall mortality for hyperglycemic crisis over the last 30 years.23,24 Mortality remains high in elderly patients presenting with hyperglycemic crisis despite the significant improvements in survival rates.14,24 Patients with HHS continue to have a significantly higher mortality (10%-15%) than those with DKA (<3%).25,26 This may be due to an older population with more comorbidities.27 However, DKA is still the leading cause of death in children and young people (aged <24) with type 1 DM.28,29
Tackling these figures involves a combination of improving emergency care and preventative measures to reduce the frequency of delayed presentation. Medical staff confronted with hyperglycemic emergencies should have local guidelines available to them and access to experienced ICU and diabetes services. Recognition of gravely ill patients is vital as a low-dose insulin regimen in an ICU setting has been shown to significantly reduce DKA mortality.30
Delays in presentation to medical services and diagnosis have been recognized as contributing to mortality.26 Public education campaigns and frequent consultation with diabetes services have been shown to reduce DKA rates in the pediatric population.31,32
Cerebral Edema: The pathophysiology of cerebral edema is uncertain. It is an infrequent (0.3%-1%) complication in adult cases of DKA but a major cause of mortality and morbidity in children.29,33
With rising intracranial pressure and eventual brainstem herniation, cerebral edema usual presents with headache and a gradual deterioration in level of consciousness. Loss of sphincter tone, pupillary changes, papilledema, and bradycardia may be followed by hypertension, seizures, and respiratory arrest.
The clinical picture should guide the diagnosis of cerebral edema. Radiographic evidence of cerebral edema is relatively common in asymptomatic children with mild acidosis but can also be falsely reassuring as approximately 40% of children who develop cerebral edema have no abnormality on initial imaging.34,35 Neurological signs on presentation, low partial pressure of arterial CO2, use of sodium bicarbonate therapy, slowed rise in serum sodium during treatment, and higher concentrations of serum urea are all associated with cerebral edema in children.36,37
Dramatic fluxes in serum glucose, bicarbonate, sodium, and potassium are seen in DKA during treatment. Rapid fluid resuscitation, correction of glucose and electrolytes have all been postulated as precipitating or causative factors.38 Cerebral hypoperfusion and reperfusion injuries may play a role. The resultant cerebral ischemia and hypoxia may generate inflammatory mediators.39 Other authors have pointed to abnormalities in aquaporin channels and multiple metabolic derangements.40-42
The standard treatment regimen for those with cerebral edema is a combination of intravenous manitol,43,44 reduced IV fluid volume, consideration given to using hypertonic saline,45 and avoiding hypocapnea in the intubated patient.33 Early recognition of those at risk and regular neurological surveillance are key.
Gastroparesis: Acute hyperglycemia can result in gastroparesis.46 Typically this resolves once patients become euglycemic but chronic hyperglycemia can result in persistent gastric dysmotility.47 Enteric feeding may need to be suspended in the acute setting of a hyperglycemic crisis. The presence of a succussion splash, persistent nausea, or vomiting should prompt suspicion.
DVT and Intra-Arterial Disease: Raised serum osmolality and viscosity in hyperglycemic states can predispose to disseminated intravascular coagulation, intra-arterial and intravenous thrombus formation.48,49 In vitro dysfunctional platelet and protein aggregation in patients with DM has been demonstrated in patients with poor glycemic control.50-52 In the absence of contraindications, thromboprophylaxis therapy should be commenced for patients with HHS.53,54 Therapeutic doses of heparin should be reserved for those with a clinical evidence of an acute thrombus.
Mucormycosis: Mucormycosis (previously known as zygomycosis) is a fungal infection that can occur in immunocompromised patients and is an infrequent complication of hyperglycemic crisis. It can present with any combination of sinusitis, pyrexia, nasal discharge, headache, facial/orbital edema, ophthalmoplegia, decreased visual acuity, or nasal ulceration. It carries a high mortality even when treated with appropriate antifungal agents (amphotericin B).55 This opportunistic pathogen is presumably carried in the nasal sinuses. Hyphae may invade the vasculature and structure surrounding the sinuses. Palatal necrosis, cerebral involvement, and disseminated disease, all carry huge mortality risks. Early recognition and treatment are key.56
Hypokalemia: Serum potassium often falls quickly during treatment. The combination of intravenous insulin, saline without potassium supplementation, and bicarbonate use contributes to dramatic changes in serum potassium. Frequent monitoring (initially 2 hourly) is required to gauge the appropriate rate of replacement.
Dysglycemia: Iatrogenic hypoglycemia is a common occurrence during the course of treatment of hyperglycemia. Frequent blood glucose monitoring and using low-dose insulin therapy lessen the risk of this complication. Rebound hyperglycemia and ketosis may arise from either inappropriate overlap of intravenous with subcutaneous insulin or failure to continue insulin therapy long enough. Twenty-four to 48 hours of IV therapy may be needed to completely “turn off” ketone-generating enzymes in the liver.
Other Complications: Rhabdomyolysis is a rare but potentially fatal finding in hyperglycemic crisis.26 Serum creatine kinase measurement should be performed on all patients presenting with HHS. Acute lung injury is also an established complication. Changes in alveolar capillary permeability coupled with overzealous fluid resuscitation may result in noncardiogenic pulmonary edema.57
HHS and DKA are medical emergencies and should be managed in a unit with
Experienced nursing and medical staff, trained in the management of hyperglycemic emergencies
Regularly updated guidelines for DKA and HHS treatment
Access to frequent and timely biochemical investigations
Goals of Therapy
Restoration of circulatory volume and improved tissue perfusion
Steady reduction of serum glucose and osmolality/ketonemia
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