Diabetic Ketoacidosis

DKA is a syndrome of hyperglycemia (blood glucose >13.8 mmol/L), metabolic acidosis (pH <7.30, serum bicarbonate <18 mmol/L, anion gap >10), ketosis, and severe volume depletion. DKA occurs mainly in insulin-dependent diabetics, and severe insulin deficiency is the hallmark of this syndrome. Raised serum levels of stress hormones (glucagon, catecholamines, cortisol, and growth hormone) are also a feature. The hyperglycemia results in a glucose load in the glomerular filtrate that overwhelms the reabsorptive capacity of the renal tubules, resulting in an osmotic diuresis with fluid and electrolyte depletion. Ketone bodies contribute to this osmotic diuretic effect. The lack of insulin causes unfettered lipolysis and formation of ketoacids.

DKA has an incidence of approximately 8.6% in diabetics² and occurs in a younger age group (mean age, 33 years) compared with DKA-HNHS (44 years) or HNHS (69 years).¹ Precipitating factors associated with the development of DKA include^3–5:

Although there are many “stressors” in the intensive care unit (ICU) environment that could potentially cause or predispose to DKA (e.g., sepsis, altered caloric intake, use of total parenteral nutrition, catecholamine use), new development of DKA in the ICU is not common, presumably because of the high level of vigilance in this environment. Presenting clinical features of DKA reflect the underlying metabolic derangements of dehydration, ketosis, and metabolic acidosis and include:

Laboratory tests supporting the diagnosis of DKA commonly reveal the following:

Hyperosmolar Nonketotic Hyperglycemia Syndrome

The defining features of HNHS include hyperglycemia (blood glucose level >33.3 mmol/L), acidemia (pH <7.3, bicarbonate >15), dehydration, and hyperosmolality (serum osmolality >320) without ketoacidosis. The main differentiation from DKA appears to be the presence of at least some insulin (i.e., relative rather than absolute lack of insulin), more variable levels of stress hormones or counter-regulatory hormones, and the fact that renal dysfunction is commonly present. Renal dysfunction and impaired tubular function result in less capacity to deal with high solute and osmotic loads. This, together with impaired water intake, may result in severe dehydration.

As mentioned earlier, HNHS is less common than DKA, occurs in an older age group, and has a higher mortality rate. Mortality may be associated with missed diagnosis (especially if the patient’s mental state is impaired), comorbidity, or delayed or inappropriate therapy.

For HNHS, particularly in elderly patients, the precipitating factors (in addition to those listed for DKA above) commonly feature:

Laboratory test results are similar to those listed for DKA but differ somewhat in degree, in that:

Metabolic Derangements in Hyperglycemic Syndromes

The main metabolic derangements that result in morbidity and must be urgently addressed in the management of both DKA and HNHS are severe dehydration, insulin deficit, electrolyte depletion, and metabolic acidosis. These are discussed in detail in Chapters 12 and 18.

Severe dehydration is estimated to be a water deficit in the range of 100 to 200 mL/kg.⁴ Although there is no consensus on the ideal approach to fluid management in these patients, prompt restoration of the circulation with isotonic fluid (e.g., normal saline or preferably compound sodium lactate solution), followed by more moderate replacement of the water deficit using hypotonic fluid, are the underlying principles.

The insulin deficit should be treated initially with intravenous soluble insulin to produce normal blood glucose levels within 12 to 24 hours. More rapid correction may predispose to cerebral edema.

Electrolyte depletion is treated by appropriate replacement of sodium, potassium, magnesium, calcium, and chloride, as indicated by frequent laboratory testing during the early phase after presentation.

Metabolic acidosis rarely requires specific therapy and corrects with volume expansion and insulin therapy. Bicarbonate therapy is controversial but currently is not advocated, regardless of the presenting pH, because of the possibilities of exacerbation of hypokalemia, intracellular acidosis, reduced myocardial contractility, and reduced tissue oxygenation.

Figure 163-1 shows serial measurements taken from a typical patient with DKA on presentation and during his treatment in the ICU.

Figure 163-1 Trends in metabolic parameters monitored during treatment of diabetic ketoacidosis. ABG, arterial blood gases.

Therapy may be complicated if there is severe comorbidity such as acute or acute-on-chronic renal failure or severe congestive heart failure, and in the patient who requires complex postsurgical care. In all cases, treatment of hyperglycemic syndromes should occur in an appropriate ICU environment with adequate monitoring and meticulous attention to detail to avoid the neurologic sequelae associated with these syndromes.

Altered Mental State

Patients who present with DKA or HNHS commonly have an altered mental state, which may range from delirium to coma. Often the patient is very unwell and as a consequence is stuporous and uncommunicative, requiring continual prompting to elicit responses to questioning. This condition rapidly improves after rehydration, correction of the hyperglycemia, and correction of acidemia if present, provided there is no underlying neurologic disease. Occasionally, a patient is completely unresponsive, even to painful stimuli, and requires management appropriate to the unconscious patient during treatment of the hyperglycemic syndrome (see later discussion). Clinically, there is no good correlation between blood glucose level, osmolality or pH, and the presenting mental state, which appears to be more a function of the patient’s general health, comorbidities, precipitating cause, and duration of the hyperglycemic syndrome before presentation.

Clinical features of the comatose patient include all the features of the hyperglycemic syndrome and in addition, reduced level of consciousness as determined by the Glasgow Coma Scale (GCS), reactive pupils, variable reflex responses (due to the possibility of diabetic peripheral nerve disease), and occasional lateralizing motor signs. The presence of lateralizing signs and lack of improvement in level of consciousness with correction of the metabolic derangement mandate further investigations such as urgent computed tomographic (CT) scanning of the brain or toxicology screening for sedative or illicit drugs.

Less commonly, the main feature of altered mental state is delirium. Delirium is marked by features of disorientation and psychomotor agitation. Delusions and hallucinations may also be manifested, particularly if drug intoxication has been a precipitant of the hyperglycemic episode. These patients can be very difficult to manage, presenting a danger to themselves and to their caregivers (e.g., pulling out venous or monitoring lines, refusing to cooperate with treatment regimens). Adequate sedation with either minor or major tranquilizers may be necessary to allow treatment to proceed smoothly.

Cerebral Edema

Rapid correction of hyperglycemia and hyperosmolality is associated with the development of cerebral edema in patients with hyperglycemic syndromes. The mechanism of how the cerebral edema arises is unclear.^6–8 The edema might be due to an effect of pH on the Na⁺/K⁺ exchange pump causing entry of sodium and water into brain cells, osmotic or inflammatory disruption of the blood-brain barrier, or accumulation of osmotically active solutes (“pseudo-osmoles”) such as amino acids, polyols, and trimethylamines as an adaptation to the hyperosmolar environment. Other theories of the mechanism of cerebral edema include paradoxical central nervous system acidosis or a left shift in the oxygen-hemoglobin dissociation curve that reduces tissue oxygenation.

The use of isotonic rather than hypotonic solutions for rehydration and avoidance of a too-rapid correction of hyperglycemia appear to offer some protection against the development of cerebral edema. Cerebral edema is more common after treatment of DKA than after treatment of HNHS. Cerebral edema is also more common in newly diagnosed diabetics and in young patients.

Cerebral edema after treatment for a hyperglycemic syndrome usually manifests as prolongation of the altered mental state seen on presentation or new development of an altered mental state with features as described previously. In adults, the signs and symptoms may be very subtle and abate over the course of a few days. Usually no specific therapy is required besides good supportive care. Rarely, cerebral edema can produce focal and permanent neurologic damage.⁹ Cerebral edema associated with DKA in children is a much more serious condition with a considerable mortality.^6,8 Urgent treatment of severe cerebral edema relies on intravenous osmotherapy (e.g., mannitol) in the first instance, followed by steroids and loop diuretics as second-line therapy.

Focal Neurologic Deficits Associated With Hyperglycemic Syndromes

There are isolated reports in the literature describing focal neurologic damage in patients with hyperglycemic syndromes. Most commonly, cerebrovascular accidents (CVA), particularly hemorrhagic and thrombotic types, have been associated with HNHS. This is not surprising, because CVA may be the precipitating factor for the development of HNHS in diabetic patients, and the hyperosmolar state in both DKA and HNHS may predispose to thrombotic CVA. Intracerebral venous thrombosis has also been reported¹⁰ and has a poor outlook.

CVA may result in neurologic deficit evident on presentation, but often the final clinical picture is obscured by the altered mental state and only becomes clear after treatment of the hyperglycemic syndrome. The high incidence of neurologic signs and symptoms in diabetics may make the detection of new neurodeficits difficult. Many of the focal neurologic signs seen in these patients, particularly those with HNHS, disappear after treatment of the hyperglycemic syndrome. This may represent unmasking of focal areas of cerebrovascular insufficiency by the dehydration.⁵

Focal neurologic damage may also occur as a result of fluid and electrolyte shifts produced during treatment of the hyperglycemic syndromes (e.g., putaminal hemorrhage,⁹ lateral pontine and extrapontine myelinolysis¹¹). In patients who are treated for prolonged periods in the ICU for complications related to their episode of hyperglycemic syndrome, critical illness polyneuropathy is also a possibility.

Adequate investigation of a residual or new focal neurologic deficit is mandated. This may include CT scanning, magnetic resonance imaging (MRI), and nerve conduction studies.

Cognitive Impairment after Hyperglycemic Syndromes

Cognitive impairment may occur after hyperglycemic syndrome. This impairment may be gross and clinically apparent (more common in elderly patients) or very subtle (e.g., poor concentration, loss of memory). It may be associated with focal or global neurologic deficit, as described previously, or it may be apparent in the presence of a structurally normal brain. Most cognitive impairment that is not caused by structural brain damage improves with time. Sensory evoked potentials have shown promise as a sensitive test to detect subclinical brain dysfunction in patients with severe DKA.¹²

Seizures Associated With Hyperglycemic Syndromes

Focal and generalized seizures are common in patients with hyperglycemic syndromes and may be resistant to treatment with the usual anticonvulsant agents.⁵ Epilepsia partialis continua, an unusual form of seizure typified by abnormal MRI signal intensity in the precentral gyrus, can occur in DKA or HNHS.¹³

Pain Associated With Hyperglycemic Syndromes

Pain may be a prominent clinical feature of patients with hyperglycemic syndromes. Pain, often neuropathic in origin, may be so severe as to mimic the acute surgical abdomen. Pleuritic chest pain and headache are also common. Proper evaluation of pain is very difficult in the patient with emergent hyperglycemic syndrome. Frequent clinical evaluation, while addressing the main pillars of therapy (fluid and electrolyte replacement and insulin therapy) is important to detect early the true surgical cause of pain. Pain caused by the hyperglycemic syndrome itself usually diminishes with time and appropriate treatment, whereas other pathologic causes of pain may not. To complicate matters, chronic pain syndromes are also common in diabetics. A careful history is essential to differentiate the known (“old”) pain from the new pain.

Hyperglycemia and Poor Neurologic Outcome after Head Injuries and Cerebrovascular Accidents

Hyperglycemic syndromes are possible in diabetics who have suffered head injury or CVA. In these patients, it is vital to regain control of metabolic function and provide adequate resuscitation to prevent secondary neurologic damage. Both hypovolemia and hyperglycemia have been shown to contribute to poorer neurologic outcomes.

Diagnosis

Metabolic derangement is a differential diagnosis for all obtunded patients, even those who present with a much more graphic confounding diagnosis such as traumatic brain injury, because such injuries may be the result of an altered mental state associated with a hyperglycemic syndrome, or they may be the precipitating cause of a hyperglycemic syndrome. The usual clinical pathway of careful history, clinical examination, and appropriate laboratory testing will reveal the underlying hyperglycemic syndrome. Once the hyperglycemic syndrome is detected, the precipitating cause for DKA or HNHS should also be carefully sought. In particular, blood, sputum, and urine cultures should be taken early, and a chest radiograph may reveal pneumonia. If the initial tests do not reveal a source of sepsis, a more extensive series of tests for sepsis (e.g., cerebrospinal fluid examination) may be deferred until the metabolic state has been improved. Similarly, extensive neuroradiologic testing (CT or MRI) can usually wait until the patient has been appropriately resuscitated and treated. Because many of the neurologic signs resolve with the acute treatment, unnecessary testing is thereby avoided.

Specific diagnostic tests that are useful in the diagnosis and management of DKA or HNHS in the obtunded patient include:

Management Principles

Treatment must be provided in a safe environment, preferably in an ICU, with adequate monitoring of the cardiovascular system (blood pressure, heart rate, electrocardiographic parameters) and the respiratory system (pulse oximetry and serial blood gas measurements). More invasive monitoring techniques such as central venous or pulmonary arterial catheterization should be reserved for patients with severe comorbidities (e.g., renal or cardiac failure). Catheterization of the urinary bladder provides a sample for culture as well as a monitor of urine flow. Treatment for DKA or HNHS (as described earlier and in detail elsewhere) must be promptly initiated:

Complications of Treatment

Complications of the treatment itself must also be dealt with and may include:

Ongoing Care

Once the patient is stable and has been adequately resuscitated and metabolic control has been reestablished, arrangements should be made for the smooth transition of care to an endocrinologist familiar with the chronic care of diabetic patients. This may be facilitated by the institution of enteral feeding and conversion from short-acting intravenous insulin to longer-acting subcutaneous insulin before handover. Ongoing care of the patient must address preventable precipitating factors (e.g., prompt treatment of septic foci, compliance with diabetic treatment regimens).³

Key Points