Epinephrine (adrenalin) is released from the medulla of the adrenal glands. Epinephrine increases cerebral blood flow and cerebral oxygen consumption and may be the trigger for recruitment of the hypothalamic-pituitary axis.6

The pituitary gland has two parts (anterior and posterior) that function under control of the hypothalamus, as described in Figure 23-1 in Chapter 23. As a response to stress, the posterior pituitary gland releases antidiuretic hormone (ADH), also known as vasopressin (pitressin). This hormone is an antidiuretic with a powerful vasoconstrictive effect on blood vessels.⁶ The combination of epinephrine and vasopressin raises blood pressure quickly; it also decreases gastric motility.⁶ Epinephrine increases heart rate, causes ventricular dysrhythmias in susceptible patients, and provides some analgesia or lack of pain awareness during acute physical stress.⁶

The anterior pituitary gland is under the control of the hypothalamus (see Figure 23-1 in Chapter 23). In acute physiological stress, “pulses” of growth hormone (GH) are released from the anterior pituitary gland to boost serum GH levels.¹⁰ In critical illness, the anterior pituitary actively secretes GH hormone, but the quantity may be insufficient for extreme physiological needs. A different problem is that peripheral tissues may be resistant and unable to use the anabolic GH.¹¹ The anterior pituitary gland also produces corticotropin (also called ACTH), which stimulates release of cortisol from the adrenal cortex.¹² Cortisol release is an important protective response, and serum levels increase sixfold with normal adrenal function.¹²

The liver releases the hormone glucagon to stimulate the liver to pour additional glucose into the bloodstream. This greatly raises blood glucose levels.3 Paradoxically, the pancreas does not produce more insulin, and serum insulin levels remain normal, even with the increased metabolic demand associated with critical illness or sepsis. Peripheral tissues become insulin resistant.³ In other words, the tissues are unable to use the available insulin to transport glucose inside the cells for normal metabolism. This raises blood glucose levels, causing persistent hyperglycemia. There is an alternative glucose transport system that enables insulin to enter the cell by means of specialized glucose transporters, usually abbreviated as GLUT. Although insulin-independent glucose transporters (GLUT-1, GLUT-2, and GLUT-3) are active during physiological stress, they cannot keep up with the massive increase in glucose production by the liver.¹³

Within 2 hours after trauma or surgery, serum levels of triiodothyronine (T₃) decrease.10 The greater the decrease of T₃ in the first 24 hours, the more severe the critical illness.⁸ Thyroid-stimulating hormone (TSH) and thyroxine (T₄) briefly increase and then return to normal levels. In the acute phase of critical illness, a low serum T₃ is associated with a poor prognosis.¹⁰

Systemic illnesses that do not directly involve the thyroid gland but alter thyroid gland metabolism are referred to as nonthyroidal illness syndromes or sick euthyroid syndromes.¹⁴ The significance of altered thyroid function in critical illness is unknown.^14,15

Adrenal dysfunction is a frequent finding if critical illness lasts longer than 7 to 10 days. A 20-fold increase in adrenal failure has been reported in critically ill patients older than 50 years who spend more than 14 days in a critical care unit.10 If the critical illness is prolonged and the patient remains hypotensive, vasopressor-dependent, and mechanically ventilated, adequacy of adrenal function must be evaluated. Older patients are particularly susceptible to adrenal failure.¹⁶

Hyperglycemia is often persistent. Gluconeogenesis (the metabolism of glucose from fat or protein) and proteolysis (protein breakdown) continue throughout the catabolic phase of critical illness.11 Critically ill patients can lose up to 10% of their lean body mass per week.¹¹ The addition of adequate supplemental nutrition is recommended, in addition to an intravenous insulin infusion, to reduce hyperglycemia and provide additional substrate other than the patient’s own body tissues.^1,2 Insulin is an anabolic hormone and can improve protein synthesis and reduce protein breakdown.¹¹ While the critical illness is ongoing, nutrition and insulin seem to limit rather than stop the loss of lean body mass.

The thyroid gland appears to follow a pattern similar to that of the pituitary gland when critical illness is prolonged. The serum levels of T₃, T₄, and TSH are greatly reduced, and the normal pulses of TSH are flattened.10

Clinical assessment of adrenal dysfunction is difficult in the critically ill, and a specialized laboratory assay is necessary for an accurate diagnosis. First, a baseline serum cortisol level is obtained. Adrenal failure is likely if the cortisol level is less than 10 mcg/dL.7

Further confirmation of adrenal dysfunction may be obtained by performance of a corticotropin stimulation test (cosyntropin test). Cosyntropin is a medication made from the first 24 amino acids of corticotropin.12 In the test, 250 mcg cosyntropin is administered by the intravenous route, and serum blood levels are measured 30 minutes later. A serum cortisol rise from baseline of less than 9 mcg/dL after 30 minutes denotes inability of the adrenal gland to respond to a stress stimulus (nonresponder).^7,12 If the cortisol rise is greater than 9 mcg/dL in response to corticotropin stimulation, the adrenal glands are functioning normally (responder).⁷ Corticosteroids are given only to nonresponders. The combination of a low baseline cortisol value (<10 mcg/dL) with minimal or no rise (<9 mcg/dL) after cosyntropin stimulation is evidence of corticosteroid deficiency.⁷

Clinical practice guidelines7 recommend short-term provision of low-dose hydrocortisone for patients who have a diagnosis of septic shock with refractory vasopressor-dependent hypotension. Hydrocortisone is the recommended replacement because it is the pharmacological steroid that most resembles endogenous cortisol.

The guidelines recommend use of the cosyntropin stimulation test as described previously. However, the test is not recommended as a stand-alone method to identify patients who might receive low-dose steroids. This apparent contradiction is explained by the fact that several clinical trials of low-dose steroid replacement in sepsis have demonstrated a faster resolution of the shock symptoms but no difference in overall mortality compared with placebo.⁷ The controversy continues. The most recently published randomized control trial of low-dose steroids versus placebo in 499 patients with septic shock did not show any mortality benefit, even among responders to the cosyntropin stimulation test. Nor was there any difference in survival between those who responded to the 250 mcg cosyntropin and received steroids and those who responded and received a placebo.²⁰

High-dose steroid replacement is never recommended in the management of sepsis. Corticosteroids are never discontinued abruptly and must be tapered gradually over several days.⁷

As a result of the studies just described, the American Association of Clinical Endocrinologists (AACE) and the American Diabetes Association (ADA) developed clinical practice guidelines that recommend the use of continuous insulin infusions to maintain blood glucose in critical care patients between 140 to 180 mg/dL, with frequent monitoring of blood glucose.5 The 140 to 180 mg/dL level was selected to minimize the risk of hypoglycemia.

Other glucose-control guidelines relevant to critical illness have also been published. The Society of Critical Care Medicine (SCCM) Surviving Sepsis guidelines recommend maintaining blood glucose concentration lower than 150 mg/dL in critically ill septic patients after initial stabilization.⁴ The American Heart Association recommends a target range of 90 to 140 mg/dL while avoiding hypoglycemia.²⁶ The American College of Physicians (ACP) recommends a target blood glucose range of 140 to 200 mg/dL for ICU patients whether diabetic or nondiabetic.²⁷ More liberal blood glucose ranges for critically ill patients are now recommended in clinical guidelines.^4,5,26,27

Many patients who are admitted to the hospital with acute complications of atherosclerotic disease are diabetic. Risk of coronary artery disease is two to three times higher in diabetics compared with nondiabetics.28 Hyperglycemia is present in 25% to 50% of patients with acute coronary syndrome (ACS) who are admitted to the hospital, and the higher the blood glucose level, the greater the risk of death.²⁶ Diabetic patients who were admitted to the hospital for an acute myocardial infarction and had an admission blood glucose level greater than 180 mg/dL had a 70% relative increase in the risk of in-hospital death compared with similar patients who had a normal glucose value on admission.²⁶ Retrospective analyses of blood glucose levels of cardiac surgery patients show a higher in-hospital mortality rate for patients with elevated blood glucose concentrations.^29,30 Patients who were unaware of their diabetes before hospital admission and nondiabetic patients who were hyperglycemic during their critical illness also had higher mortality rates.^31,32

The brain does not store glucose and is dependent on a continuous supply of glucose from the peripheral bloodstream. It is essential to avoid hypoglycemia in any brain-injured patient. However, there are no published guidelines as what the correct target glucose range should be for this population. Experts favor a less restrictive target, because blood glucose concentrations lower than 135 mg/dL (6 mmol/L) have been shown to increase brain metabolic distress.33

Monitoring blood glucose with a point-of-care glucometer is the basis of targeted glucose control. As part of the comprehensive initial assessment, the blood sugar is measured by a standard laboratory sample or by a finger-stick capillary blood sample. In many institutions, if the blood sugar is greater than 180 mg/dL (an initial value that may vary among hospitals), the patient is started on a continuous intravenous insulin infusion. In critically ill catabolic patients, the initial blood glucose level can be well above 200 mg/dL. While the glucose is elevated, blood sample measurements are usually obtained hourly, to allow titration of the insulin drip to lower blood glucose. After the patient is stable, blood glucose measurements can be spaced approximately every 2 hours, based on individual hospital protocols.21

Several different blood-sampling methods are available. A capillary finger-stick is perhaps the easiest initial option, although the fingers can become noticeably marked if there are numerous sticks over several days. Trauma to the fingers is also exacerbated if peripheral perfusion is diminished. If a central venous catheter (CVC) or an arterial line with a blood conservation system attached is in place, this can be a highly efficient system for sampling, because there is no blood wastage. If a blood conservation setup is not attached, use of the venous or arterial catheter for access is unacceptable because of the amount of waste blood that would be discarded.

Many hospitals use insulin infusion protocols that are implemented by the critical care nurse for management of stress-induced hyperglycemia.5 Effective glucose protocols gauge the insulin infusion rate based on two parameters: (1) the immediate blood glucose result and (2) the rate of change in the blood glucose level since the last hourly measurement. The following three examples illustrate this concept:

The important point to emphasize is that the rate of change of the blood glucose is as important as the most recent blood glucose measurement. Each of the patients described in the examples may have the same insulin infusion rate, depending on their catabolic state, but individualization among patients with different diagnoses can be safely achieved as long as the rate of change is also considered.

A person’s insulin requirement often fluctuates over the course of an illness. This occurs in response to changes in the clinical condition, such as development of an infection, caloric alterations caused by stopping or starting enteral nutrition or TPN, administration of therapeutic steroids, or because the person is less catabolic.³⁴ A method to allow for corrective incremental changes (up or down) to adapt to the reality of clinical developments and maintain the glucose within the target range is essential.³⁴ Some protocols alter only the infusion rate, whereas others incorporate bolus insulin doses if the glucose concentration is greater than a preestablished threshold (e.g., 180 mg/dL). Typically, after the blood glucose has remained within the target range for a number of hours (4 to 12 hours, depending on the hospital protocol), the time interval between measurements for blood glucose monitoring is extended to every 2 hours.

The transition from a continuous insulin infusion to intermittent insulin coverage must be handled with care to avoid large fluctuations in blood glucose levels. Before the conversion, the regular insulin infusion should be at a stable and preferably low rate, and the patient’s blood glucose level should be maintained consistently within the target range. The transition from intravenous to subcutaneous administration depends on numerous factors, especially whether the patient is able to eat a normal diet.34

Clinicians use various methods to calculate the quantity of insulin to prescribe during the transition from intravenous to subcutaneous insulin to maintain stable blood glucose levels. Figure 24-1 depicts hypothetical examples of how a combination of basal and bolus insulin regimens (prandial insulin) can work in clinical practice.^21,35 The following paragraphs describe the application of one calculation method for a 67-year-old patient, Alice Smith, who is recovering from critical illness and has recently been extubated.

After the transition to subcutaneous insulin, the dosage is adjusted to the individual patient’s needs. In a stable insulin-sensitive patient, 1 unit of short-acting insulin will lower the blood glucose by 50 to 100 mg/dL.²¹ In a critical care patient, more insulin is typically required to reduce blood glucose levels, because of the physiological stress of the critical illness.³⁶

Table 24-2 describes the various types of insulin available for use. These include ultra-short-acting, short-acting, intermediate-acting, long-acting, and combination insulin replacement options. Even after the transition to subcutaneous insulin is completed, blood glucose is monitored frequently to maintain blood glucose within the target range and detect hyperglycemia or hypoglycemia.

A patient may be prescribed supplemental “correctional” doses of insulin in addition to the basal/prandial insulin combination. The use of the trio of basal, prandial, and correctional insulin is designed to eliminate the use of the traditional sliding scale.35 A frequent criticism of sliding-scale therapy is that the dosages are rarely reevaluated or adjusted once established.³⁴ A second criticism is that the scales treat hyperglycemia only after it has occurred; they are not proactive in the manner of continuous insulin infusions.³⁴

It is important to have a protocol for the management of hypoglycemia. The major drawback to use of intensive insulin protocols, as described earlier, is the potential for hypoglycemia. Whenever hypoglycemia is detected, it is important to stop any continuous infusion of insulin. An example of one protocol to reverse hypoglycemia follows:

In all cases of hypoglycemia, the blood glucose concentration is monitored every 15 to 20 minutes until the blood sugar has risen into a safe range. The ADA recommends incorporation of level of consciousness plus the blood glucose result as a guide to glucose replacement to treat hypoglycemia.³⁷ Administer 15 to 20 g of glucose to the conscious hypoglycemic patient. A different protocol suggests the following response to a blood glucose concentration of less than 60 mg/dL:³⁶

Two vasopressors frequently used as continuous infusions to counteract hypotension in the critically ill also raise blood glucose. Epinephrine and, to a lesser extent, norepinephrine stimulate an increase in gluconeogenesis (creation of new glucose), an increase of skeletal muscle and hepatic glycogenolysis (increased glucose production), an increase in lipolysis (increased fat breakdown), direct suppression of insulin secretion, and an increase in peripheral insulin resistance.13 All of these actions serve to raise the serum glucose level in the bloodstream.

The critical care nurse is responsible for the hourly monitoring of blood glucose and titration of the insulin infusion according to the hospital’s established protocol while the patient is hyperglycemic. The use of standardized protocols makes possible a systematic approach to the control of blood glucose. This results in improved glycemic control and lower rates of hypoglycemia. It is essential and recommended that nurses receive effective and ongoing education about the anabolic impact of insulin therapy in critical illness.5 Hospital protocols to minimize development of hypoglycemia, such as using the 140 to 180 mg/dL target range,⁵ and rapid reversal of any occurrence of severe hypoglycemia (below 40 mg/dL) by provision of intravenous dextrose (D₅₀W) are mandatory.

Whenever an insulin infusion is started to lower blood glucose, nutritional support (enteral or TPN) should be considered. In the absence of nutrition, a 10% dextrose solution may temporarily be infused. The 10% dextrose offers the advantage of carbohydrate calories for metabolism, limits fluctuations in the blood sugar, and reduces the risk of hypoglycemia. After the patient’s metabolic condition is stable, introduction of non-glucose nutrition (protein and fat) is recommended.38

Type 1 diabetes mellitus accounts for only about 5% to 10% of the diabetic population.37 Older names for this condition included insulin-dependent diabetes (IDDM) and juvenile diabetes. Type 1 diabetes is a cellular-mediated autoimmune disease that causes progressive destruction of the beta cells of the islets of Langerhans in the pancreas. Autoantibodies falsely identify the patient’s own pancreas as “foreign” and destroy the native pancreatic tissue. Many responsible autoantibodies contribute to pancreatic destruction, including autoantibodies to the islet cell, to insulin, to glutamic acid decarboxylase (GAD65), and to the tyrosine phosphatases IA-2 and IA-2β.³⁷ One or more of these autoantibodies are present in 85% to 90% of individuals with type 1 diabetes when fasting hyperglycemia is initially detected.³⁷ Over time, the autoantibodies render the pancreatic beta cells incapable of secreting insulin and regulating intracellular glucose. In type 1 diabetes, the rate of beta-cell destruction is highly variable. It occurs rapidly in some individuals (mainly children) and slowly in others (mainly adults). Some patients, particularly children and adolescents, may have ketoacidosis as the first manifestation of their disease.

Genetic predisposition and unknown environmental factors are also believed to play an important role.³⁷ Patients with type 1 diabetes are prone to development of other autoimmune disorders such as Graves’ disease (hyperthyroidism), Hashimoto’s thyroiditis, Addison’s disease, autoimmune hepatitis, myasthenia gravis, and pernicious anemia.³⁷ Lack of insulin impairs carbohydrate, protein, and fat metabolism.

An estimated 8.7% of the population in the United States has diabetes; almost all of them have type 2.44 Most individuals are older and obese and have a condition known as cardiometabolic syndrome.⁴⁵ However, the number of adolescents and young adults with type 2 diabetes is also rising.⁴¹ Up to one third of people with diabetes remain undiagnosed. Patients at high risk for type 2 diabetes include those who meet the following criteria:^44–46

In type 2 diabetes, pancreatic beta cells are present and functioning; however, the amount of insulin they produce varies greatly among patients:

Insulin resistance describes a complex metabolic situation in which organ and tissue cells deny entry to insulin and glucose. This creates the clinical paradox in which elevated serum insulin levels and hyperglycemia are present at the same time. Obesity increases insulin resistance.⁴¹ Insulin resistance has a strong association with type 2 diabetes.^45,47

Insulin is the metabolic key to the transfer of glucose from the bloodstream into the cell, where it can be used immediately for energy or stored for use at a later time. Without insulin, glucose remains in the bloodstream, and cells are deprived of their energy source. A complex pathophysiological chain of events follows (Figure 24-2).⁵⁴ The release of glucagon from the liver is stimulated when insulin is ineffective in providing the cells with sufficient glucose for energy. Glucagon increases the amount of glucose in the bloodstream by breaking down stored glucose, a process known as glycogenolysis. Noncarbohydrates (fat and protein) are converted into glucose, by a process known as gluconeogenesis. The breakdown of protein is termed proteolysis. The breakdown of fat (lipid) is known as lipolysis.

Blood glucose levels for the patient in DKA typically range from 300 to 800 mg/dL of blood. The reason the plasma glucose concentration is not higher is because of the short time period during which DKA develops in a patient with established type 1 diabetes. Elevated serum glucose levels alone do not define DKA; the major determining factor is an elevation in the total blood concentration of ketones⁵⁴ and often the presence of ketoacidosis.

Dehydration stimulates catecholamine production in an effort to provide emergency support. Catecholamine output stimulates further lipolysis, glycogenolysis, and gluconeogenesis, pouring glucose into the bloodstream (see Figure 24-2). Counterregulatory hormones, such as glucagon and epinephrine, govern this physiological process. These hormones are normally released with hypoglycemia. In DKA, although the plasma glucose is elevated, the interior of the cells are starved of glucose, and the lack of intracellular glucose initiates the physiological processes described in Figure 24-2. DKA presentation is described as mild, moderate, or severe, depending on the plasma blood glucose (Table 24-3). As the blood glucose rises, acidosis develops and the level of consciousness decreases.

Polyuria (excessive urination) and glycosuria (sugar in the urine) occur as a result of the osmotic particle load that occurs with DKA. The excess glucose, filtered at the glomeruli, cannot be resorbed at the renal tubule and spills into the urine. The unresorbed solute exerts its own osmotic pull in the renal tubules, and less water is returned to circulation through the collecting ducts. As a result, large volumes of water, along with sodium, potassium, and phosphorus, are excreted in the urine, causing a fluid volume deficit. The serum sodium concentration may be decreased because of the movement of water from the intracellular to the extracellular (vascular) space.54

In the healthy individual, the presence of insulin in the bloodstream suppresses the manufacture of ketones. In insulin deficiency states, fat is rapidly converted into glucose (gluconeogenesis). Ketoacidosis occurs when free fatty acids are metabolized into ketones: acetoacetate, β-hydroxybutyrate, and acetone are the three ketone bodies that are produced.56 During normal metabolism, the ratio of β-hydroxybutyrate to acetoacetate is 1 : 1, with acetone present in only small amounts. In insulin deficiency, the quantities of all three ketone bodies increase substantially, and the ratio of β-hydroxybutyrate to acetoacetate increases to as much as 10 : 1.⁵⁶ β-Hydroxybutyrate and acetoacetate are the ketones responsible for acidosis in DKA. Acetone does not cause acidosis and is safely excreted in the lungs, causing the characteristic fruity odor.

Ketones are measurable in the bloodstream (ketonemia). Blood tests that measure the quantity of β-hydroxybutyric acid, the predominant ketone body in the blood, are the most useful.⁵⁴ Because ketones are excreted by the kidney, they are also measurable in the urine (ketonuria). Ketone blood tests are preferred over urine tests for diagnosis and monitoring of DKA in critical care. When the blood and urine become clear of ketones, the DKA is resolved.

The acid-base balance varies depending on the severity of the DKA. The patient with mild DKA typically has a pH between 7.25 and 7.30. In moderate to severe DKA, the pH can drop below 7.00.54 Acid ketones dissociate and yield hydrogen ions (H⁺), which accumulate and precipitate a fall in serum pH. The level of serum bicarbonate also decreases, consistent with a diagnosis of metabolic acidosis. Breathing becomes deep and rapid—a respiratory pattern known as Kussmaul respirations—to release carbonic acid in the form of carbon dioxide. Acetone is exhaled, giving the breath its characteristic fruity odor.

DKA has a predictable clinical presentation. It is usually preceded by patient complaints of malaise, headache, polyuria (excessive urination), polydipsia (excessive thirst), and polyphagia (excessive hunger). Nausea, vomiting, extreme fatigue, dehydration, and weight loss follow. Central nervous system depression, with changes in the level of consciousness, can lead quickly to coma.41,54

The patient with DKA may be stuporous or unresponsive, depending on the degree of fluid-balance disturbance. The physical examination reveals evidence of dehydration, including flushed dry skin, dry buccal membranes, and skin turgor that takes longer than 3 seconds to return to its original position after the skin has been lifted. Often “sunken eyeballs,” resulting from lack of fluid in the interstitium of the eyeball, are observed. Tachycardia and hypotension may signal profound fluid losses. Kussmaul respirations are present, and the fruity odor of acetone may be detected.

Considering the complexity and potential seriousness of DKA, the laboratory diagnosis is straightforward. With a known diabetic patient, the presence of urine ketones and hyperglycemia on bedside finger-stick samples provides rapid diagnostic confirmation of DKA. If a blood gas sample is obtained, it can confirm the acid-base imbalance. Other clues may be gleaned from the venous blood chemistry panel. CO₂, if measured, is low in the presence of uncompensated metabolic acidosis, and the anion gap is elevated. Serum sodium may be low because water moves from the intracellular space into the extracellular (vascular) space.54 The serum potassium level may be elevated, as potassium moves from inside the cell to the extracellular space.⁵⁴

The patient with DKA is dehydrated and may have lost 5% to 10% of body weight in fluids. A fluid deficit of up to 6 L can exist in severe dehydration. Aggressive fluid replacement is provided to rehydrate the intracellular and extracellular compartments and prevent circulatory collapse (Figure 24-3).⁵⁴ Assessment of hydration is an important first step in the treatment of DKA.

Intravenous isotonic normal saline (0.9% NaCl) is infused to replenish the vascular deficit and to reverse hypotension. For the severely dehydrated patient, 1 L of normal saline is infused immediately. Laboratory assessment of serum osmolality and the serum sodium concentration can help guide the subsequent interventions.

After the serum glucose level decreases to 200 mg/dL, the infusing solution is changed to a 50/50 mix of hypotonic saline (0.45% NaCl) and 5% dextrose, infused at 150 to 250 mL/hour.⁵⁴ Dextrose is added to replenish depleted cellular glucose as the circulating serum glucose level falls. Dextrose infusion also prevents unexpected hypoglycemia when the insulin infusion is continued but the patient cannot take in sufficient carbohydrate from an oral diet.

In moderate to severe DKA, an initial intravenous (IV) bolus of regular insulin at 0.1 unit for each kilogram of body weight is administered.54 Subsequently, a continuous infusion of regular insulin at 0.1 unit/kg/hr is infused simultaneously with intravenous fluids (see Figure 24-3).⁵⁴ The plasma glucose concentration is expected to fall by 50 to 75 mg/dL per hour with this regimen. The glucose measurement should be rechecked and the hydration status of the patient re-evaluated. Figure 24-3 is a diagrammatic representation of intravenous and subcutaneous insulin administration options in DKA.

Frequent assessment of the patient’s blood glucose concentration is mandatory in moderate to severe DKA. Initially, blood glucose tests are performed hourly. The frequency then decreases to every 2 to 4 hours as the patient’s blood glucose level stabilizes and approaches normal. After the level has decreased to 200 mg/dL, the acidosis has been corrected, and rehydration has been achieved, the insulin IV infusion rate may be decreased to 0.02–0.05 unit/kg/hr.⁵⁴ It is important to verify that the serum potassium concentration is not lower than 3.3 mEq/L and to replace potassium if necessary, before administering the initial insulin bolus.⁵⁴

Adequate hydration and insulin replacement usually correct the acidosis, and this treatment is sufficient for many patients with DKA. As shown in Figure 24-3, replacement of bicarbonate is no longer routine except for the severely acidotic patient with a serum pH value lower than 7.0.⁵⁴ An indwelling arterial line provides access for hourly sampling of arterial blood gases (ABGs) to evaluate pH, bicarbonate, and other laboratory values in the patient with severe DKA. If an arterial line is not available, the venous pH can be used.⁵⁴

Hyperglycemia usually resolves before the ketoacidemia does. In one clinical report, patients with previously diagnosed type 1 diabetes in DKA took an average of 21 hours after being started on an intravenous insulin protocol to clear ketones from the urine; the infusion was continued for 36 hours until the patients could tolerate an oral diet; and the patients received a total of 9.5 L of normal saline for rehydration.⁵⁵ Patients who are newly diagnosed with type 1 diabetes take longer to clear urine ketones and require more insulin to achieve normal glycemic control, compared with long-term diabetics.⁵⁵

The serum phosphate level is sometimes low (hypophosphatemia) in DKA. Insulin treatment may make this more obvious as phosphate is returned to the interior of the cell. If the serum phosphate level is less than 1 mg/dL, phosphate replacement is recommended.54 See Figure 24-3 for further information about potassium replacement options.

Rapid intravenous fluid replacement requires the use of a volumetric pump. Insulin is administered intravenously to patients who are severely dehydrated or have poor peripheral perfusion, to ensure effective absorption. Patients with DKA are kept on NPO status (nothing by mouth) until the hyperglycemia is under control. Throughout the insulin therapy, the patient’s response and the laboratory data are assessed for changes relating to blood glucose levels. The critical care nurse is responsible for monitoring the rate of plasma glucose decline in response to insulin. The goal is to achieve a fall in glucose levels of approximately 50 to 75 mg/dL each hour.54 The coordination involved in monitoring blood glucose, potassium, and often blood gases on an hourly basis is considerable.

When the blood glucose level falls to 200 mg/dL, a 5% dextrose solution (D₅W) with 0.45% NaCl solution is infused to prevent hypoglycemia.⁵⁴ At this time, it is likely that the insulin dose per hour will also be decreased. The regular insulin drip is not discontinued until the ketoacidosis subsides, as identified by absence of ketones and a normal pH by arterial or venous blood gas analysis.⁵⁴

Insulin is given subcutaneously after glucose levels, dehydration, hypotension, and acid-base balance are normalized and the patient is in stable condition and taking an oral diet.

Accurate intake and output (I&O) measurements must be maintained to monitor reversal of dehydration. Hourly urine output is an indicator of kidney function and provides information to prevent overhydration or underhydration. Vital signs, especially heart rate (HR), hemodynamic values, and blood pressure (BP), are continuously monitored to assess response to the fluid replacement. Evidence that fluid replacement is effective includes normal central venous pressure (CVP), decreased HR, and normal BP. Box 24-1 lists the standard features to be included in an assessment of hydration status. More invasive hemodynamic monitoring, such as a pulmonary artery catheter, is rarely needed. Further evidence of hydration improvement includes a change from a previously weak pulse to a pulse that is strong and full, and a change from hypotension to a gradual elevation of systolic BP. Respirations are assessed frequently for changes in rate, depth, and presence of the fruity acetone odor.

Blood glucose is measured each hour in the initial period. Sometimes, potassium is measured just as frequently. The serum osmolality and serum sodium concentration are evaluated, and blood urea nitrogen (BUN) and creatinine levels are assessed for possible kidney impairment related to decreased renal perfusion. The purpose of these frequent assessments is to determine that the patient’s clinical status is improving. After the patient has stable laboratory indicators and is awake and alert, the transition to subcutaneous insulin and an oral diet can be made. Hypoglycemia is a risk during the transition period. For example, in anticipation of discontinuing the insulin and intravenous dextrose infusion, a patient receives a subcutaneous dose of insulin and is expected to eat a meal. However, if the patient is then unable to eat an adequate amount, hypoglycemia results from the administration of subcutaneous insulin without adequate glucose.⁵⁵

The markers for resolution of DKA include a blood glucose level lower than 200 mg/dL, absence of ketones in the blood, a serum bicarbonate level greater than 18 mEq/L, and a venous pH level greater than 7.3.⁵⁴

It is important to be aware of the knowledge level and compliance history of patients with previously diagnosed diabetes to formulate an appropriate teaching plan. Learning objectives include a discussion of target glucose levels, definition of hyperglycemia and its causes, harmful effects, symptoms, and how to manage insulin and diet when one is unwell and unable to eat.55 Additional objectives include a definition of DKA and its causes, symptoms, and harmful consequences. The patient and family are also expected to learn the principles of diabetes management. Universal precautions must be emphasized for all family caregivers.³⁴ The patient and family must also learn the warning signs to report to the attention of a health care practitioner. Education of the patient, family, or other support persons is crucial to achieve knowledge-based, independent self-management of blood glucose level and avoidance of diabetes-related complications, which are the ultimate goals of the teaching process.

Clinically, HHS is distinguished from DKA by the presence of extremely elevated serum glucose, more profound dehydration, and minimal or absent ketosis (see Table 24-3). Another major difference is that protein and fats are not used to create new supplies of glucose in HHS as they are in DKA; as a result, the ketotic cycle is never started or does not occur until the glucose level is extremely elevated. Patients with type 1 diabetes do not develop HHS, whereas some patients with type 2 diabetes do develop DKA.^54,55

HHS has a slow, subtle onset and develops over several days. Initially, the symptoms may be nonspecific and may be ignored or attributed to the patient’s concurrent disease processes. History reveals malaise, blurred vision, polyuria, polydipsia (depending on the patient’s thirst sensation), weight loss, and advancing weakness.56 Medical attention may not be obtained for these nonspecific, nonacute symptoms until the patient is unable to take sufficient fluids to offset the fluid losses. Progressive dehydration follows and leads to mental confusion, convulsions, and eventually coma, especially in older patients.

The physical examination may reveal a profound fluid deficit. Signs of severe dehydration include longitudinal wrinkles in the tongue, decreased salivation, and decreased CVP, with increases in HR and rapid respirations (Kussmaul air hunger does not occur). In older patients, assessment of clinical signs of dehydration is challenging. Neurological status is affected as the serum glucose climbs, especially at levels greater than 1500 mg/dL. Without intervention, obtundation and coma occur.

Laboratory findings are used to establish the definitive diagnosis of HHS. Plasma glucose levels are strikingly elevated (>600 mg/dL). Serum osmolality is greater than 320 mOsm/kg. Acidosis is absent (arterial pH >7.3), and the serum bicarbonate concentration is greater than 18 mEq/L. Ketonuria is absent or mild.54 The patient may have an elevated hematocrit and depleted potassium and phosphorus levels.

Point-of-care finger-stick or arterial-line testing of glucose at the bedside is the usual method for frequent monitoring of the serum blood glucose. Insulin replacement is then prescribed according to the blood glucose result. Some electrolytes also can be tested at the bedside (potassium, sodium, ionized calcium), but usually an arterial line is required for frequent blood access. If point-of-care testing is not available, traditional serial laboratory tests keep the clinician apprised of the fluctuating serum electrolyte levels and provide the basis for electrolyte replacement. Intracellular potassium and phosphate levels usually are depleted as a result of dehydration.

The total body deficit of sodium and potassium may be as high as 500 to 700 mEq. Physiological saline solution (0.9%) is infused at 1 L/hr, especially for the patient in hypovolemic shock. Between 6 and 10 L of fluid replacement in the first 10 hours may be required to achieve a BP and CVP within normal range. This may necessitate an initial infusion rate of 250 to 500 mL/hour with infusion volumes adjusted according to the patient’s hydration state and sodium level (see Figure 24-3).⁵⁴

The serum sodium concentration is the parameter that is monitored to determine whether to change from isotonic (0.9%) to hypotonic (0.45%) saline. For example, patients with sodium levels equal to or less than 140 mEq/L may be given 0.9% normal saline solution, whereas those with levels greater than 140 mEq/L are given 0.45% saline solution (see Figure 24-3). In reality, it is difficult to assess the serum sodium level in the presence of hemoconcentration. Another recommendation is to calculate a corrected sodium value. This involves adding 1.6 mEq to the sodium laboratory value for each 100 mg/dL plasma glucose above normal.⁵⁴ Sodium input should not exceed the amount required to replace the losses. Careful monitoring of the serum sodium level is recommended to avoid a sodium-water imbalance and hemolysis as hemoconcentration is reduced.

To prevent hypoglycemia, when the serum glucose decreases to 300 mg/dL, change the hydrating solution to D₅W with 0.45% NaCl to infuse at 150 to 250 mL/hr.⁵⁴

Volume resuscitation lowers the serum glucose level and improves symptoms even without insulin administration.56 However, insulin replacement is recommended in the treatment of HHS because of clinical reports that acidosis can develop if insulin is withheld.⁵⁶ Insulin is given to facilitate the cellular use of glucose.

Methods to lower the blood glucose level vary. One method is to administer an intravenous bolus of regular insulin (0.1 unit/kg of body weight) initially, followed by a continuous insulin drip. Regular insulin, infusing at an initial rate calculated as 0.1 unit/kg hourly (e.g., 7 units/hr for a person weighing 70 kg) should lower the plasma glucose concentration by 50 to 75 mg/dL per hour. If the measured glucose level does not decrease by at least 10%, 0.14 insulin unit/hour may be given as a bolus.⁵⁴ The goal is to reduce the blood glucose by 50 to 75 mg/dL per hour.⁵⁴

Increasing the circulating levels of insulin with therapeutic doses of intravenous insulin promotes the rapid return of potassium and phosphorus into the cell. Serial laboratory tests keep the clinician apprised of the serum electrolyte levels and provide the basis for electrolyte replacement. Potassium typically is added to the intravenous infusion (see Figure 24-3). If the serum potassium concentration is lower than 3.3 mEq/L, it is essential to replenish the serum potassium before giving insulin.⁵⁴ Many hospitals have potassium replacement algorithms that are used to treat hypokalemia. Serum phosphate levels are carefully monitored, and phosphate replaced if the level is lower than 1.0 mg/dL.⁵⁴

Rigorous fluid replacement and continuous intravenous insulin replacement must be controlled with an electronic volumetric pump. Accurate I&O measurements are maintained to monitor fluid balance. I&O measurements include the total of all fluids administered minus hourly losses, typically urine output and sometimes emesis. Hemodynamic monitoring may include use of an arterial line and measurements of CVP if the patient manifests signs of hypovolemic shock. Arterial line access is very helpful in monitoring serial blood glucose and electrolyte values. The use of a blood conservation system on the arterial line is essential to avoid iatrogenic exsanguination of the patient. Most critical care units have developed protocols or guidelines to ensure that patients in hyperglycemic crisis are managed safely (see Figure 24-3). The major responsibility for delivery of insulin, hourly monitoring of blood glucose, and infusion of appropriate crystalloid solutions lies with the critical care nurse. Many hospitals mandate a double-check procedure for medications such as insulin that have the potential to cause harm if wrongly administered.

The serum glucose level should decrease by 50 to 75 mg/dL per hour with insulin administration.54 This decrease is monitored by hourly blood glucose determinations. Based on the glucose result, the critical care nurse can alter the infusion of insulin according to hospital protocol (see Figure 24-3).

In central DI, there is an inability to secrete an adequate amount of arginine vasopressin in response to an osmotic or nonosmotic stimuli, resulting in inappropriately dilute urine.59,60 The synthesis of ADH is incomplete in the hypothalamus, or the release of ADH from the pituitary is interrupted. Central DI can be congenital or idiopathic. In critical care, the most likely acute cause of central DI is neurosurgery, traumatic head injury, tumors, increased intracranial pressure, brain death, and infections such as encephalitis or meningitis. Among patients undergoing surgery on the pituitary gland, DI occurs in approximately 12% and is permanent in 3%.⁶¹ The degree of hormone replacement required after surgery depends on the quantity of pituitary tissue removed.⁶¹ One prospective study reported the incidence of central DI to be 15% among patients with traumatic brain injury.⁶²

Nephrogenic DI is a rare congenital or acquired disorder that occurs when the V₂ receptors on the kidney tubule become nonresponsive to the action of ADH. Some drugs cause nephrogenic DI by decreasing the responsiveness of the kidney tubules to ADH. Long-term use of lithium carbonate, prescribed for bipolar disorder, was a frequent culprit in the past.63

The core diagnostic tests used to establish the presence of DI and that evaluate the body’s ability to balance fluid and electrolytes are not specific to the endocrine system. The most common laboratory tests are serum sodium concentration, serum osmolality, and urine osmolality (Table 24-4). The combination of an obvious clinical picture with high volumes of hypotonic urine, in the presence of the following laboratory criteria, is sufficient to diagnose central DI:⁶⁰

Central DI requires immediate pharmacological management. Table 24-5 presents the medications most frequently prescribed to treat central DI and replace ADH.

The clinical manifestations of SIADH relate to the excess fluids in the extracellular compartment and the proportionate dilution of the circulating sodium. Edema usually is not present, although slight weight gain may occur from the expanded extracellular fluid volume. Early clinical manifestations of dilutional hyponatremia include lethargy, anorexia, nausea, and vomiting. Severe neurological symptoms usually do not develop until the serum sodium concentration drops to less than 120 mEq/L.70 Progressively deteriorating neurological signs of hyponatremia then predominate, and the patient is admitted to the critical care unit. Symptoms of severe hyponatremia include inability to concentrate, mental confusion, apprehension, seizures, decreased level of consciousness, coma, and death.

Patients with SIADH present with very concentrated urine output and very dilute serum. Laboratory values confirm this clinical picture. In SIADH, the serum is hypoosmolar (<275 mOsm/kg H₂O), with low serum sodium concentration and a urine osmolality greater than would be expected with such hypotonic blood (>100 mOsm/kg has been suggested).67 A serum sodium concentration of less than 125 mEq/L (<120 mEq/L according to some experts) is associated with increasing severity of neurological symptoms.^64,70 An elevated urine sodium concentration, greater than 30 to 40 mEq/L, is congruent with the concentrated urine output of SIADH.^64,67,70 Use of diuretics negates the reliability of the urine sodium and urine osmolality levels.⁷⁰ Table 24-5 compares the typical laboratory values associated with SIADH with those of DI.

The medical therapy that is the most effective (along with treatment of the primary disease) is simple reduction of fluid intake.64 This is achieved most successfully in the patient with a moderate increase in body fluid volume and hyponatremia. Although fluid restrictions are calculated on the basis of individual needs and losses, a general criterion is to restrict fluids to 500 mL less than average daily output.⁵⁷

Patients with severe hyponatremia (<125 mEq/L serum sodium) experience severe neurological symptoms, even seizures. How rapidly the sodium should be corrected and which sodium concentration to use remain controversial.71 One recommended regimen is an intravenous rate that provides sufficient sodium to raise serum sodium levels by up to 12 mEq/day for the first 24 hours (no more than 0.5 mEq each hour), with a total rise of 18 mEq/L in the initial 48 hours.⁶⁴ Another option is to add furosemide (Lasix) to increase the diuresis of free water.

If hyponatremia is severe (<120 mEq/L), an infusion of 3% hypertonic saline solution may be used to replenish the serum sodium without adding extra volume. It is imperative to be aware that hypertonic saline solution is dangerous if administered too quickly, and calculation of the quantity of sodium that will be administered is advised. An example of one sodium replacement regimen is an infusion of 3% saline infusion at 35 mL/hr in a 70-kg patient, which will increase the serum sodium level by approximately 0.5 mEq/L per hour (12 mEq/day).⁶⁴ Suggested end points at which to stop the acute sodium repletion include the following: (1) the patient’s symptoms are abolished; (2) a safe serum sodium level is achieved (usually >120 mEq/L); (3) a total correction of 20 mEq/L is achieved.⁶⁴

Too-rapid serum sodium correction must be avoided to reduce the risk of osmotic demyelination, previously known as central pontine myelinolysis. The demyelination occurs in the pons and in other areas of the brain’s white matter.⁵⁷ The lesions may be detected on imaging studies (computed tomography and magnetic resonance imaging), and severe neurological damage or death can result.⁵⁷ Patients with a baseline serum sodium level lower than 120 mEq/L are most at risk.⁵⁷ Serum sodium levels must be evaluated at least every 4 hours during the acute phase of sodium replacement.⁶⁴