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