Location	Enzymes	Target substance
Oral cavity	Salivary amylase (ptyalin)	Starch and glycogen
	Bromelain	Protein
Stomach	Pepsin	Proteins
	Gelatinase	Proteoglycans in meat (gelatine and collagen)
	Gastric amylase	Starch
	Gastric lipase	Triglyceride
	Chymosin	Milk
Pancreas	Trypsin, chymotrypsin, carboxypeptidase, elasatases	Proteins
	Pancreatic lipase	Triglycerides
	Pancreatic amylase	Carbohydrates
Small intestine	Sucrase	Sucrose
	Lactase	Lactose
	Maltase	Maltose (into 2 molecules of glucose)
	Isomaltase	Maltose into isomaltose
	Intestinal lipase	Fatty acid

The secretion of enzymes and absorption of these small molecules produced during digestion is an energy-consuming process that can be negatively influenced by gastrointestinal hypoperfusion and the failure of the gastrointestinal tract to receive sufficient oxygen and nutritients required for cellular function.

The gastrointestinal tract also plays a role in immunity. It has a variety of mechanisms in place that prevent the movement of substances (other than nutrients, water and electrolytes) into the systemic circulation (see Table 19.2). In the setting of critical illness, where gastrointestinal hypoperfusion may be present, these protective functions may be diminished, so it is essential to understand the alterations in normal gastrointestinal physiology that occur during critical illness.

TABLE 19.2 Protective mechanisms of the gastrointestinal system and impact of critical illness ^1,³^–¹²

Mechanism	Action
Motility	Propels bacteria through the GI tract. In critical illness, motility may be altered because of enteric nerve impairment and altered smooth muscle function, inflammation (mediated by cytokines and nitric oxide), gut injury, hypoperfusion, medications (opioids, dopamine), electrolyte disturbances, hyperglycaemia, sepsis and increased intracranial pressure.³
Hydrochloric acid secretion	Reduces gastric acidity and destroys bacteria. Parietal cells in the stomach produce hydrochloric acid and keep the intragastric environment relatively acidic (pH approx 4.0). An acidic pH has bactericidal and bacteriostatic properties,⁴ thus limiting overgrowth in the stomach.
Bicarbonate	Bicarbonate ions bind with hydrogen ions to form water and carbon dioxide, preventing the hydrogen ions (acid) from damaging the duodenal wall.⁵
Bile salts	Bile salts provide protection against bacteria by breaking down the liposaccharide portion of endotoxins,⁶ thereby detoxifying gram-negative bacteria in the gastrointestinal tract. The deconjugation of bile salts into secondary bile acids inhibits the proliferation of pathogens and may destroy their cell walls.⁷
Mucin production	Prevents the adhesion of bacteria to the wall of the GI tract. Mucous cells secrete large quantities of very thick, alkaline mucus (approximately 1 mm thick in the stomach). Glycoproteins present in the mucus prevent bacteria from adhering to and colonising the mucosal wall.⁸
Epithelial cell shedding	Limits bacterial adhesion. The mucosal lining of the entire gastrointestinal tract is composed of epithelial cells that create a physical barrier to bacterial invasion. These cells are replaced approximately every 3–5 days⁹ limiting bacterial colonisation.
Zonea occludulns (tight junctions surrounding each cell in the epithelial sheet)	The junctions between epithelial cells provide a barrier to microorganisms. Intermediate junctions (zonula adherens) function primarily in cell–cell adhesion, while the tight junctions (zonula occludens) limit the movement of bacteria and toxins across the gut wall.¹⁰
Gut-associated lymphoid tissue	Protection against bacterial invasion is provided by gut-associated lymphoid tissue,¹¹ capable of cell-mediated and humoral-mediated immune responses.¹²
Kupffer cells	Kupffer cells in the liver and spleen provide a back-up defence against pathogens that cross the barrier of the gastrointestinal wall and enter the systemic circulation.¹

Alterations to Normal Gastrointestinal Physiology in Critical Illness

During critical illness, the digestion and absorption of nutrients may be altered. Gastric acid production is commonly thought to increase in critical illness, although evidence suggests that many critically ill patients do not hypersecrete gastric acid ¹³ with increased gastric pH being observed in some critically ill patients, even in the absence of pharmacological inhibition of gastric acid secretion.^14,¹⁵ The ability of the small intestine to absorb nutrients can be impaired during critical illness,¹⁶ although most critically ill patients appear to be able to tolerate enteral nutrition, making the clinical significance of impaired absorption unclear.

Some alterations to normal gastrointestinal physiology in critical illness relate to hypoperfusion and decreased oxygenation in this area and have high metabolic demands. Historically, gastrointestinal dysfunction in critical illness was described in relation to symptoms, such as gastrointestinal bleeding, mechanical obstruction, and pancreatitis ¹⁷ resulting from ischaemia.¹⁸ However, the presence of covert ischaemia has resulted in a heightened interest in the prevention and early detection of gastrointestinal ischaemia in the critically ill, in an attempt to minimise ischaemia-related dysfunction.

Gastrointestinal Mucosal Hypoperfusion

The gastrointestinal system is particularly susceptible to alterations in regional blood flow and oxygen delivery because it has a higher critical oxygen delivery (DO₂) than the rest of the body. Splanchnic vasoconstriction is also proportionally greater than other vascular beds and the countercurrent O₂ exchange between vessels within the villi further contribute to decreased regional oxygen delivery.⁵

During shock states, decreased blood flow from vasoconstriction occurs in this region first. It is the last place to be restored following successful resuscitation.¹⁹ In shock states, the gastrointestinal system attempts to maintain adequate cellular oxygenation by increasing the amount of oxygen extracted from the blood. This increase in oxygen extraction may prevent serious compromise of tissue oxygenation even in the presence of reduced oxygen delivery.²⁰

Practice tip

Remember, assessment of arterial blood pressure, heart rate and urine output provides information about the haemodynamic and oxygenation status of the whole body. A reduction in regional perfusion and oxygenation may occur despite conventional clinical assessment findings being normal.

During periods of ischaemia and hypoxia, oxygen free-radicals are generated as byproducts of anaerobic metabolism. With successful resuscitation of the gastrointestinal tract, blood flow and oxygen delivery are restored but the oxygen free-radicals are liberated, contributing to the microvascular and mucosal changes characteristic of ischaemia and reperfusion of the gut mucosa.²¹

Consequences of Gastrointestinal Hypoperfusion

The consequences of gastrointestinal hypoperfusion are significant, and include disruption of the physical barrier to pathogens; disruption of chemical control of bacterial overgrowth; decreased peristalsis; and reduced immunological activities of gastrointestinal-associated lymphoid tissue. In health, all of these mechanisms work efficiently to contain bacteria within the gastrointestinal tract. During critical illness, however, reduced oxygenation contributes to decreased cellular function and failure of the protective mechanisms described in Table 19.2. Consequently, bacterial proliferation and translocation from the gastrointestinal tract to the systemic circulation may occur.²²

Changes in gastrointestinal perfusion also has the capacity to affect hepatic perfusion, oxygenation and function. In approximately 50% of critically ill patients, ischaemic hepatitis or ‘shock liver’ occurs, which is evidenced by jaundice, elevation of liver function tests or overt hepatic dysfunction.²³ Ischaemic hepatitis can vary from a mild elevation of serum aminotransferase and bilirubin levels in septic patients, to an acute elevation following haemodynamic shock. Ischaemic hepatic injury influences morbidity and mortality but remains underdiagnosed, probably because the clinical signs become apparent long after hypoperfusion has occurred. Physiological changes contributing to ischaemic hepatitis include changes to the portal and arterial blood supply as well as hepatic microcirculation. The degree to which the liver is damaged is directly related to the severity and duration of hypoperfusion, and both anoxic and reperfusion injury can damage hepatocytes and the vascular endothelium.²³

Alterations to Normal Metabolism in Critical Illness

There is little information describing the changes to the exocrine function in the gastrointestinal system during critical illness, and it is uncertain how critical illness influences the metabolism of nutrients. While there is data to demonstrate that the secretion of hydrochloric acid by the parietal cells in the stomach is decreased, it is not certain whether the exocrine failure also extends to a decreased pepsin secretion. It is also possible that secretion of digestive enzymes might also be influenced by critical illness-induced pancreatitis, although clear data demonstrating this level of dysfunction are unavailable.¹⁶

Nutrition

Optimal nutritional support in the critically ill aims to prevent, detect and correct malnutrition, optimise the patient’s metabolic state, reduce morbidity and improve recovery.²⁴ The metabolic response of stress or injury is hypermetabolism. There is an increased release of cytokines (e.g. interleukin-1, interleukin-6, tumor necrosis factor-α) and production of counter-regulatory hormones (e.g. catecholamines, cortisol, glucagon and growth hormone) that induce catabolism and oppose the anabolic effects of insulin.²⁵ Hypercatabolism occurs with the imbalance between anabolism (i.e. the chemical process by which complex molecules, such as peptides, proteins, polysaccharides, lipids and nucleic acids, are synthesised from simpler molecules) and catabolism (i.e. the convergent process, in which many different types of molecules are broken down into relatively few types of end products). To compensate for the altered metabolic regulation, neuroendocrine stimulation increases the mobilisation and consumption of nutrients, such as glycogen and protein, from existing body stores. As the metabolic rate rises, nutritional requirements in critical illness are increased, characterised by a rise in resting energy expenditure and oxygen consumption, which in some critically ill patients can be increased by over 50%.²⁶ Depletion of body energy stores result from alterations in protein, carbohydrate and fat metabolism.²⁷ In addition to the rise in metabolic demands, patients who are critically ill often experience a concomitant fall in nutritional intake. The metabolic and nutrition alterations vary with the stress level, severity of illness, type of injury, organ dysfunction and nutrition status.²⁵

To maintain normal cellular function, body cells require adequate amounts of the six basic nutrients: carbohydrates, fats and proteins to provide energy, vitamins, minerals and water to catalyse metabolic processes. Unlike normal metabolism, which preferentially uses carbohydrates and fats for energy, the hypermetabolic state associated with critical illness consumes proportionally more fats and proteins than carbohydrates to generate energy.²⁸ As a consequence of the gluconeogenesis and the synthesis of acute-phase proteins, there is a decrease in lean body mass and negative nitrogen balance.

Consequences of Malnutrition

When adequate and timely nutrition support is not provided, body energy and protein depletion can occur with negative consequences on patient outcome.²⁹ Critically ill patients require adequate nutrition to limit muscle wasting, respiratory and gastrointestinal dysfunction and alterations in immunity, all of which are associated with malnutrition.³⁰ Respiratory support is often necessary during critical illness, and changes in respiratory muscle function and ventilatory drive may contribute to an increase in the number of ventilator days. Furthermore, infection rates may be increased in malnourished critically ill patients. The decrease in lean body mass and negative nitrogen balance is associated with delayed wound healing and a higher risk of infection.²⁸

These complications contribute to increased length of stay, cost, morbidity and mortality.³¹ The degree of critical illness and hypercatabolism varies between patients and is often difficult to accurately determine. For this reason it is necessary to assess, as accurately as possible, the nutritional requirements of each individual patient.

Nutritional Assessment

The majority of studies report cumulative energy deficit or caloric debt is associated with worse clinical outcomes.³²^–³⁵ Krishnan and colleagues,³⁶ however, describe better clinical outcomes for patients fed fewer than the target nutrition goals when compared to those who received near target goals. Nutritional assessment includes patient history, physical examination and assessment of nutritional indices (see Table 19.3), but is often unreliable in the critically ill patient.^37,³⁸ Clinical judgement remains the most common way of assessing a patient’s nutritional status, and is shown to be as reliable as biochemical tests.³⁹^–⁴¹ Clinical judgement takes into consideration recent weight loss, reduced dietary intake, anorexia, vomiting, diarrhoea, muscle wasting and signs of nutritional deficiency.⁴² Appreciation of the importance of nutritional assessment and the impact of malnutrition in the critically ill informs management and is likely to improve outcomes.³⁰

TABLE 19.3 Nutritional indices

Assessment	Limitations in critical illness
Subjective global assessment	Not validated in the critically ill^40,⁴³
Biochemical markers:
• albumin • transferrin • prealbumin	Decreased sensitivity because of 20-day half-life; influenced by fluid balance/shifts ⁴² Half-life of 8 days but lacks the sensitivity and specificity for determining nitrogen balance;⁴³ influenced by fluid balance/shifts Most sensitive with a half-life of 2 days,⁴⁴ but changes may result from the metabolic response to illness rather than change in nutritional status; influenced by fluid balance/shifts
Delayed hypersensitivity	Used to assess the patient’s immune status, but alterations can be related to underlying disease rather than nutritional status⁴²
Skeletal muscle function	Mechanical characteristics of skeletal muscle influenced by energy stores rather than loss of muscle mass⁴²

Determining Nutritional Requirements

Determining caloric requirements is largely dependent on energy expenditure, influenced by patient activity, stage of illness, type of injury and previous nutritional status.⁴² Indirect calorimetry is the ‘gold standard’ and most precise way of determining the nutritional requirements in critical illness.⁴⁵ Energy expenditure is measured using the oxygen consumption obtained from carbon dioxide levels (PaCO₂), or using a metabolic monitor. It is infrequently used in critical care settings, possibly because of the high equipment costs and unreliability in the critically ill.⁴⁶

Calculating basal energy expenditure using the Harris-Benedict equation is a common, but less precise, method of determining nutritional requirements.^42,^47,⁴⁸ The Harris-Benedict equation, and others, takes into account the age, height, weight and gender of the patient, with adjustments made for treatment, disease process and metabolic state. Importantly, these equations fail to find any significant benefits in outcomes, most likely because they do not measure energy requirement.⁴⁹

The Prognostic Inflammatory Nutrition Index (PINI) uses the elevations in acute phase proteins (alpha-1-acid glycoprotein and C-reactive protein [CRP]) that occur with simultaneous reductions in transport proteins (albumin and pre-albumin) in a simple formula to stratify critically ill patients by risk of complications or death.⁵⁰

Nutrition Support

For patients in ICU who are unable to take oral nutrition, enteral nutrition (EN), parenteral nutrition (PN) or combined EN and PN is available. The best method of providing nutrition to the critically ill who cannot have oral feeding is controversial. Infectious complications have been associated with PN when used alone,⁵¹ but no differences in infectious complications were seen with concurrent use of EN and PN.⁵² In a meta-analysis, PN was associated with reduced mortality when comparing PN with delayed EN despite the increased risk for infectious complications associated with PN.⁵¹ Meta-analyses are limited by the quality of the studies included in the analyses.^53,⁵⁴ Recent guidelines advocate early enteral nutrition^53,⁵⁵^–⁵⁹ but better evidence is needed.⁶⁰

Enteral Nutrition

EN has benefits beyond the supply of nutrients to the body,⁶¹ including:

• gut-derived mucosal immunity ⁶² and decrease in septic complications⁶³^–⁶⁵

• preservation of gastrointestinal mucosal integrity ^66,⁶⁷

• improved gastrointestinal mucosal cell growth and replacement ⁶⁸

• increased gastric mucosal blood flow.⁶⁹

Absence of enteral nutrients (despite the provision of PN) has been linked to atrophy of the intestinal villi, a reduction in the number of epithelial cells produced, reduced gastrointestinal mucosal thickness, and ineffective functioning of the intestinal brush border enzymes of the gastrointestinal mucosa.^59,⁷⁰^–⁷³ Stimulating and improving gastrointestinal immune function is an important goal of early EN.⁵⁹ Early enteral feeding (within 48 hours) is recommended.^55,⁵⁶

Hypocaloric Intake in the Critically Ill

A significant number of hospitalised patients receiving EN do not have their nutritional needs met.^70,⁷¹ Hypocaloric feeding in the first few days of critical illness may be beneficial,^36,⁷⁴^–⁷⁷ but results are conflicting.^34,⁷⁸^–⁸⁰ The belief that early enteral feeding prevents gut dysfunction independently of calorie intake⁸¹ perpetuates the acceptance of administration of EN below the nutrition target.^33,^70,^82,⁸³ In most cases, hypocaloric feeding is unnecessary and avoidable.^84,⁸⁵ Severe underfeeding over a short time particularly during the initial week of ICU stay is associated with the formation of an energy debt that leads to increased infections, complications and longer ICU stays.³⁴ Factors that contribute to unintentional hypocaloric feeding include staffing shortages, unavailability of feeds/equipment, low priorities for feeding, fasting for clinical investigations, blockages in feeding tubes and variations in feed prescriptions.⁸⁶ Delivery issues, such as elective interruption for investigative procedures or operations, contributed to hypocaloric feeding with only 76% of prescribed feeds delivered to critically ill patients.⁸⁷ Similar results were observed in mechanically-ventilated patients,⁸⁸ where more than 36% of patients received less than 90% of their caloric requirements.

Enteral Feeding Protocols

Enteral feeding protocols improve the delivery of enteral feeds ^87,^89,⁹⁰ and have been shown to improve clinical outcomes.^83,^91,⁹² But protocols vary widely between units and institutions,^24,^58,⁹³^–⁹⁵ primarily as a consequence of the shortage of reliable and valid research into the effective delivery of enteral nutrition. In the absence of strong research evidence, rituals are embraced and rarely challenged.⁸⁶ Furthermore, the implementation and sustainability of guidelines is influenced by multiple factors, e.g. clinicians, patients, context and contents of guidelines.⁹⁶

Management of Enteral Feeding

Routes of enteral feeding

The insertion of enteral feeding tubes into the correct place in the critically ill can be difficult because of reduced cough reflex, altered sensorium and use of sedative and narcotic medications.⁹⁷ Wide-bore nasogastric tubes (sump tubes) are most commonly used in the critically ill in the early stages of enteral feeding. Because long-term use of wide-bore tubes can contribute to sinusitis, a fine-bore feeding tube is often introduced if enteral feeding is expected to continue beyond a few days. Should prolonged enteral feeding be anticipated (longer than 1 month), gastrostomy, duodenostomy or jejunostomy tubes may also be used.⁹⁸ Postpyloric feeding has not been shown to be beneficial over gastric feeding,^99,¹⁰⁰ but is useful for later enteral feeding in patients if gastric atony is present and the patient has persistent high gastric residual volumes.¹⁰¹

For some critically ill patients, gastric secretions may increase when small bowel feeding is initiated.¹⁰² A double-lumen tube is available, one lumen for gastric aspiration and decompression and the second for simultaneous jejunal feeding, but these tubes are not widely used in the clinical setting.¹⁰³

Assessment of enteral feeding tube placement

Correct placement of enteral feeding tubes in the critically ill can be difficult.^104,¹⁰⁵ Misplacement of the feeding tube into the tracheobronchial tree are important complications of tube insertion.¹⁰⁶ Additional complications such as infusion of tube feedings, pneumothorax, pneumonitis, hydropneumothorax, bronchopleural fistula, empyema and pulmonary hemorrhage have been reported.¹⁰⁷^–¹¹² While confirmation of tube placement is routinely done with radiography, this approach does not prevent incorrect placement occurring during insertion; less reliable methods of confirming tube placement include the use of auscultation and aspiration, and other novel methods such as capnography.^105,¹¹³

Assessment of feeding tube placement by auscultation of air insufflated into the stomach remains a common clinical practice. Auscultation should not be used as the sole method to determine placement of the gastric tube because it is unreliable. Other important points are:

• Aspirate from critically ill patients who receive continuous feedings may have the appearance of unchanged formula, regardless of the site of the feeding tube, therefore this method should not be used.¹¹⁴

• Analysis of the pH of gastric secretions is not reliable. A pH of 0–5 may be used to indicate gastric placement of enteral feeding tubes, although this technique may be problematic for patients receiving histamine-2-receptor antagonists or proton pump inhibitors. If the aspirated fluid has a low pH, it may be assumed that the fluid originated in the stomach but the pH of fluid from an infected pleural space can also be acidic,¹¹⁵ therefore pH testing as a sole method to determine tube placement is not recommended.¹¹⁶

• End-tidal CO₂ (ETCO₂) detectors: capnometry and capnography. Capnometry and capnography use ETCO₂ CO₂ detectors to evaluate enteral tube placement but they are not used in routine clinical practice.^107,¹¹⁷^–¹²² Differentiating between oesophageal, stomach or intestinal placement is not possible.¹¹⁶

• Pepsin/trypsin. Measuring the concentrations of pepsin and trypsin in feeding tube aspirates can be used as a method of predicting tube placement however methods to measure pepsin and trypsin at the bedside are currently unavailable.¹²³

Ongoing assessment of feeding tube placement is essential, as feeding tubes may migrate after initial placement. Marking the feeding tube at the point where it exits the nose and measurement of tube length protruding from the anterior nares will facilitate detection of migration of the enteral tube. Radio-opaque tubes have markers to enable accurate measurement and documentation of tube position. It should be used with the methods previously described for ongoing assessment.

In the absence of X-ray, several approaches should be used in combination to verify tube position. Metheny and colleagues ¹¹⁴ found measuring: (a) length of tubing extending from the insertion site, (b) volume of aspirate from the feeding tube, (c) appearance of the aspirate, and (d) pH of the aspirate were able to correctly differentiate between gastric and bowel tube placement during continuous feedings in 81% of the predictions. Ongoing assessment of feeding tube placement is also essential, as feeding tubes may migrate after initial placement.

Feeding regimens

Once the enteral feeding tube is successfully placed, administration of the feeding solution can begin using a variety of methods, including bolus, intermittent and continuous enteral feeding (see Table 19.4). Bolus enteral feeding is rarely used in the critically ill, but it is less clear whether intermittent or continuous feeding is more beneficial.¹²⁴^–¹²⁶ Because of inconclusive evidence regarding feeding regimens, decisions are best based on individual patient assessment and the clinician’s clinical judgement.

TABLE 19.4 Methods of feed delivery

Method	Description
Bolus	• Delivery of a large volume of tube feed into the stomach over a short period of time (>100 mL) • Associated with complications, such as aspiration and vomiting ^127,¹²⁸
Intermittent	• A several-hour infusion a few times a day (e.g. 150 mL/h for 3 hours, three times per day), or delivered over a longer period (12–16 hours) with an 8–12-hour rest period ¹²⁷ • Allows gastric acidity and therefore limits bacterial overgrowth • Requires a higher hourly rate to meet caloric requirements
Continuous	• The delivery of small amounts of formula per hour over a 24-hour period ¹²⁹ • May make caloric requirements more achievable • Continuous dilution of gastric acid may contribute to bacterial overgrowth

Commencing enteral feeding

The starting rate for enteral feeding is controversial, with suggestions in the range of 10–100 mL/h,⁸⁶ and the commonest starting rate being 30 mL/h, despite there being no empirical data on which to base this recommendation. Increasing the rate of enteral feeding is equally variable, but strategies to progress patients towards meeting their daily caloric requirements should be employed. When a patient has experienced a prolonged period of starvation or total parenteral nutrition, the approach to enteral feeding is somewhat more reserved, as the risk of refeeding syndrome is increased.¹³⁰^–¹³² Although not common, this syndrome is associated with severe derangement in fluid and electrolyte levels (particularly hypophosphataemia, hypomagnesaemia and hypokalaemia), and may result in significant morbidity and mortality.

Managing complications of enteral feeding

Once enteral feeding is established, it is important to assess for such complications as:

• feeding intolerance

• gastric distension

• vomiting

• diarrhoea

• pulmonary aspiration

• hyperglycaemia

• hypercarbia

• electrolyte imbalances

• feed contamination.

This intolerance to enteral feeding can result in gastric distension, diarrhoea and increased GRV.^87,^133,¹³⁴

Practice tip

When evaluating gastric residual volume in relation to the rate of enteral feeding, remember to take into account the production of gastric secretion, which can be as much as 2500 mL/day.

Critically ill patients exhibit elevated gastric residual volume for a variety of reasons including feeding intolerance ¹³⁵^–¹³⁹ and reduced gastric motility.^135,^136,¹⁴⁰ Monitoring tolerance to enteral feeding through the measurement of gastric residual volume has always been viewed as an important aspect of nursing management, although consensus on what constitutes a high gastric residual and any recommendations for interventions remain controversial. Ceasing feeds in response to gastric residual volume is questionable,¹⁴¹ particularly as a balanced enteral diet in itself has a prokinetic effect.¹⁴²

Practice tip

In determining feeding intolerance, a single high gastric residual volume in the absence of physical examination or radiographic findings should not result in the cessation of enteral feeding. Persisting with enteral feeding has demonstrated benefits. It is thought that a balanced enteral diet, in itself, has a prokinetic effect.¹⁴³

Development of diarrhoea is another complication for enterally fed patients, and is a common reason why enteral feeding is often reduced or ceased. Diarrhoea may contribute to fluid and electrolyte disorders, patient (and nursing) distress, and a higher cost of patient care.¹⁴⁴ Unfortunately, defining diarrhoea is problematic, as it is a subjective assessment that relies on nursing interpretation rather than on quantifiable assessment of stool weight.¹⁴⁵ There are various aetiologies for diarrhoea in the enterally fed, critically ill patient, including:

• antibiotic use ¹⁴⁶

• hypoalbuminaemia ¹⁴⁴

• use of histamine-2 receptor antagonists ¹⁴⁷

• contamination of enteral feeding solution.¹⁴⁸

Probiotic administration may limit the development of diarrhoea,¹⁴⁹ although its efficacy is yet to be established.^150,¹⁵¹

Enteral feeding solutions present an excellent medium for the growth of microorganisms,¹⁵² and bacterial contamination of enteral feeds is common.¹⁵³^–¹⁵⁵ Strategies to limit bacterial contamination of enteral feeding solutions include:

Despite hesitancy by nurses to persist with enteral feeding in the presence of diarrhoea, there is no evidence to support the withholding of enteral feeding in critically ill patients unless there are significant disturbances in fluid and/or electrolyte balance.

Prevention of pulmonary aspiration

An important complication of enteral feeding is the development of pulmonary aspiration and nosocomial pneumonia. Determining whether aspiration has occurred is difficult, even for experienced clinicians. High gastric residual volumes have been linked to the potential for pulmonary aspiration, although this has not been shown in research.¹⁴¹ Oropharyngeal secretions can contribute to nosocomial pneumonia and subglottic aspiration has improved outcomes.¹⁶⁹ Nursing strategies to improve gastric emptying includes elevation of the head of the bed 30–45 degrees (unless otherwise contraindicated),¹⁷⁰ reducing the likelihood of gastro-oesophageal reflux, which is present in up to 30% of patients in the supine position.

Prokinetic agents can improve gastric emptying and feeding tolerance, and avoid gastro-oesophageal reflux and pulmonary aspiration. Cisapride, erythromycin and metoclopramide have all been used clinically to improve gastrointestinal motility. A systematic review noted that, as a class of drugs, promotility agents have a beneficial effect on gastrointestinal motility in the critically ill patient.¹⁷¹ These prokinetic agents do, however, have undesirable effects. Use of erythromycin is associated with the development of bacterial resistance, and metoclopramide is associated with numerous systemic side effects. Erythromycin is more effective than metoclopramide in treating gastric intolerance among patients receiving enteral nutrition.¹⁷² However, combination therapy with erythromycin and metoclopramide is more effective than erythromycin alone in improving the delivery of enteral nutrition.¹⁷³

Assessment of pulmonary aspiration

Despite preventive strategies, pulmonary aspiration may still occur in some patients, and accurate assessment is essential. Common methods that can be performed easily at the bedside to determine whether a patient has experienced aspiration of gastric contents and/or enteral feeding formula follow:

• The dye method involves the addition of blue food colouring to the enteral feeding formula, theoretically making it possible to visualise gastric contents if they have been inhaled into the tracheobronchial tree. However, the use of blue dye is poorly standardised and has a low sensitivity in detecting microaspiration.¹⁷⁴ The use of methylene blue is not recommended because of associated side effects and high costs.¹⁷⁵ There have been case reports of blue dye absorption describing discolouration of the skin, urine, serum and organs,¹⁷⁶ and refractory hypotension and severe acidosis, suggesting poisoning by a mitochondrial toxin.^177,¹⁷⁸ These safety concerns, coupled with minimal benefits, have resulted in the recommendation that the practice of using blue food colouring in enteral feeding solutions be abandoned.¹⁷⁹

• Measurement of glucose in tracheobronchial secretions is another method to detect pulmonary aspiration.¹⁸⁰ As these secretions normally contain <5 mg/dL glucose, higher amounts of glucose may indicate the aspiration of glucose-rich enteral feeding formula.⁶⁸However, differences in enteral feeding solutions affect the sensitivity of this method, with low glucose solutions being more difficult to detect. Also, patients not receiving enteral feeding can have detectable glucose in aspirates.¹⁸¹ This is further confounded by the presence of blood, which is closely associated with glucose values >20 mg/dL; consequently, any blood in the respiratory tract could contribute to a false-positive result.¹⁸¹ These findings led to the consensus that glucose monitoring in respiratory secretions should also be abandoned.¹⁷⁹

• Measurement of pepsin in tracheobronchial secretions has been used in an animal study suggested that the detection of pepsin, a component of gastric secretions, may be useful in determining pulmonary aspiration.¹⁸² however, further investigation in acutely ill patients receiving enteral feeding is necessary.

Parenteral Nutrition

The appropriate use of PN in the context of critical illness continues to be debated.¹⁸³^–¹⁸⁵ EN is the preferred method of nutritional support because it is less expensive and is associated with fewer infectious and metabolic complications than PN. However, it is not uncommon for critically ill patients to have difficulty in meeting daily caloric intake^34,⁷¹ and this may necessitate supplementation of enteral nutrition with PN or the sole provision of nutritional support through parenteral means (as TPN). For patients who are unable to be fed by the enteral route and who were healthy prior to ICU admission, with no evidence of protein-calorie malnutrition, then it is recommended that PN be initiated after 3–7 days¹⁸⁶ of hospitalisation.¹⁸⁷ The lack of agreement on the efficacy of PN means that the use of this therapy varies both within and between countries.^58,^186,¹⁸⁷

PN solutions contain carbohydrates, lipids, proteins, electrolytes, vitamins and trace elements. PN, whether supplementary or complete, provides daily allowances of nutrients and minerals. The components of PN are listed in Table 19.5. The addition of vitamins and trace elements to PN solutions is necessary, particularly as water-soluble vitamins and trace elements are rapidly depleted (see Table 19.6). Glucose is the primary energy source in PN solutions. Concentrations of 10–70% glucose may be used in PN solutions although the final concentration of the solution should be no more than 35%. The high concentration of PN solutions can cause thrombosis so PN is normally infused via a central venous catheter (CVC). Peripheral administration can be considered when the final solution concentration is 10–12%,¹⁸⁸ but is not usually used in the context of critical illness because high volumes of PN would be required to meet caloric requirements.¹⁸⁹

TABLE 19.5 Components of TPN solutions

Component	Implication
Carbohydrate	• This should supply approximately 70% of the patient’s non-protein to prevent protein catabolism needs.¹⁹⁰ • Insulin production will usually be increased to maintain normoglycaemia, although some patients, such as those with diabetes, may require an insulin infusion to maintain normoglycaemia. • Glucose solutions over 25% are hyperosmolar and may cause thrombophlebitis. • Glucose solutions mixed with lipids can protect the vein from thrombophlebitis, provided osmolality is <800 mOsmol/kg.¹⁸⁹
Lipids	• More energy-dense than carbohydrate (9 kcal/g), and should provide 30–40% of the non-protein energy. • Available as a 10% (1 kcal/mL) or 20% (2 kcal/mL) solution. • Necessary to maintain cell wall integrity, prostaglandin synthesis and the absorption of lipid-soluble vitamins.¹⁹¹ • Isotonic, so can be given via a peripheral line if necessary.
Nitrogen	• A balance of crystalline amino acids supplying 0.2 g nitrogen per kg body weight is required to achieve a nitrogen balance in most patients, although some patients may utilise more nitrogen. • Some critically ill patients may utilise more nitrogen and thus have higher requirements.
Electrolytes	• Content varies in amino acid solutions, so content in relation to patient requirements needs to be considered. • Monitoring of electrolyte status is essential, particularly serum phosphate levels if the amino acid solution used is phosphate-free. • The balance between chloride and acetate is monitored, as administration of additional sodium or potassium may result in acid–base imbalances.

TABLE 19.6 Trace elements in TPN ¹⁹²

Trace element	Action
Zinc	Wound healing
Iron	Haemoglobin synthesis
Copper	Erythrocyte maturation and lipid metabolism
Manganese	Calcium and phosphorus metabolism
Cobalt	Essential constituent of vitamin B12
Iodine	Thyroxine synthesis
Chromium	Glucose utilisation

Catheter insertion, ongoing care and replacement are similar to that with any other CVC. A dedicated CVC, or lumen of a multilumen CVC, should be used for PN.^191,¹⁹³ Manipulation of the CVC and tubing should be avoided to minimise infection of the catheter.

Routine monitoring of the patient’s fluid balance, glucose, biochemical profile, full blood count, triglycerides, trace elements and vitamins is necessary. The patient is also assessed for signs of complications associated with the administration of PN (see Table 19.7).

TABLE 19.7 Short-term metabolic complications associated with total parenteral nutrition

Complication	Cause	Detection and treatment
Hyperosmolar coma	Occurs acutely if a rapid infusion of hypertonic fluid is administered. Infusion can cause severe osmotic diuresis, resulting in electrolyte abnormalities, dehydration and malfunction of the central nervous system.	Daily blood samples, accurate measurements of fluid balance, routine blood samples. Reduce infusion rate, correct electrolyte imbalances.
Electrolyte imbalance	Disturbances in serum electrolytes, particularly sodium potassium, urea and creatinine, may occur early in the treatment of TPN. Electrolyte imbalances can be caused by the patient’s underlying medical condition; requirements vary with individual patients’ needs. Can be caused by inadequate or excessive administration of intravenous fluids.	Daily blood samples taken early in treatment to detect abnormalities. Replacement fluid as required, extra intravenous fluids may be required during the stabilisation period.
Hyperglycaemia	Critically ill patients may be resistant to insulin because of the secretion of ACTH and adrenaline. This promotes the secretion of glycogen, which inhibits the insulin response to hyperglycaemia.	Monitor the patient’s blood sugar 4-hourly after commencement of treatment or as required. Monitor daily urinalysis for glucose and ketones. An insulin infusion may be required to keep blood sugar levels within prescribed limits.
Rebound hypoglycaemia	May occur on discontinuation of TPN because hyperinsulinism may occur after prolonged intravenous nutrition. A rise in serum insulin occurs with infusion, and thus sudden cessation of infusion can result in hypoglycaemia.	Glucose infusion rate should be gradually reduced over the final hour of infusion before discontinuing. Some patients may receive a 10% glucose solution after cessation of TPN.
Hypophosphataemia	Glucose infusion results in the continuous release of insulin, stimulating anabolism and resulting in rapid influx of phosphorus into muscle cells. The greatest risk is to malnourished patients with overzealous administration of feeding. Patients who are hyperglycaemic, who require insulin therapy during TPN or who have a history of alcoholism or chronic weight loss may require extra phosphate in the early stages of treatment.	Monitor phosphate levels daily. Hypophosphataemia will usually appear after 24–48 hours of feeding. Reduce the carbohydrate load and give phosphate supplementation.
Lipid clearance	Lipids are broken down in the bloodstream with the aid of lipoprotein lipase found in the epithelium of capillaries in many tissues. A syndrome known as fat overload syndrome can occur when infusion of lipid is administered that is beyond the patient’s clearing capacity, resulting in lipid deposits in the capillaries.	Blood samples should be taken after the first infusion commences (within 6 hours) to observe for lipid in the blood.
Side effects of lipid infusion	Some patients suffer symptoms either during or after an infusion of lipid mix parenteral nutrition. The exact cause is unknown. The patient may complain of headache, nausea or vomiting, and generally feels unwell.	Treat mild symptoms. If tolerated, the TPN solution of non-protein calories can be given in the form of glucose. However, it is essential that the regimen includes some fat to prevent the development of fatty acid deficiency.
Anaphylactic shock	This is a rare complication but may occur as a reaction to the administration of a lipid.	It may be necessary to administer adrenaline and/or steroids, and to provide supportive therapy as required.
Glucose intolerance	TPN using glucose as the main source of calories is associated with a rise in oxygen consumption and CO₂ production. The workload imposed by the high CO₂ production may precipitate respiratory distress in susceptible patients, particularly those requiring mechanical ventilation.	Observe patients for signs of respiratory distress. Provide non-protein calories in the form of glucose lipid mix. Slow initial rate of infusion.
Liver function	Abnormalities with liver function can be associated with TPN. May be attributable to hepatic stenosis with moderate hepatomegaly; patient may also develop jaundice. Liver function tests often return to normal after cessation of therapy; however, TPN can lead to severe hepatic dysfunction in neonates.	Monitor liver function tests twice weekly. There are several factors that may contribute to development of abnormal liver function tests. These most often occur after a period of time and appear to be more of a problem when there is an excess calorie intake or in glucose-based regimens.

ACTH = adrenocorticotrophic hormone.

Stress-Related Mucosal Disease

The reported incidence of stress-related mucosal damage is variable ¹⁹⁴ and complicated by definitions of end points, difficulty in measuring the end points, and the heterogeneity of the patient populations.¹⁹⁵ With occult bleeding (drop in haemoglobin level or positive stool occult blood test) as an endpoint, it is estimated that 15–50% of critically ill patients would be reported to have stress-related mucosal damage.^196,¹⁹⁷ Reported incidence is reduced to 25% or less when haematemesis or nasogastric lavage positive for bright red blood is used as an endpoint to describe clinically overt bleeding.^198,¹⁹⁹ The incidence of clinically significant bleeding, that is bleeding associated with hypotension, tachycardia, and a drop in haemoglobin level necessitating transfusion, is estimated to be 3–4%.¹⁹⁴

Factors influencing the development of stress-related mucosal disease include splanchnic hypoperfusion ²⁰⁰ which may influence mucosal ischaemia and reperfusion injury,²⁰¹ maintenance of the gastric mucosa by sufficient microcirculation and the mucus-bicarbonate gel layer,²⁰² decreased prostaglandin levels which impairs mucus replenishment and increased nitric oxide synthase which contributes to reperfusion injury and cell death.²⁰³ The protective mechanisms and factors which promote injury are detailed in Table 19.8.

TABLE 19.8 Factors contributing to stress-related mucosal disease ²⁰⁴

Factors	Mechanism	Action
Protective mechanisms	Mucosal prostaglandins	Protect the mucosa by stimulating blood flow, mucus and bicarbonate production²⁰⁵ Stimulate epithelial cell growth and repair
	Mucosal bicarbonate barrier	Forms a physical barrier to acid and pepsin, preventing injury to the epithelium²⁰⁶
	Epithelial restitution and regeneration	Epithelial cells rapidly regenerate but the process is highly metabolic and may be impaired by physiological stress²⁰⁶
	Mucosal blood flow	Mucosal blood flow helps remove acid from the mucosa, supplies bicarbonate and oxygen to the mucosal epithelial cells²⁰⁷
	Cell membrane and tight junctions	Tight junctions between mucosal epithelial cells prevents the back diffusion of hydrogen ions²⁰⁸
Factors promoting injury	Acid	Acid is a key issue in the pathogenesis of stress-related mucosal injury however not all critically ill patients hypersecrete acid.^14,²⁰⁸ However small amounts of acid may still cause injury and the prevention of acid secretion has led to a reduction in injury²⁰⁹
	Pepsin	May cause direct injury to the mucosa²¹⁰ Facilitates the lysis of clots²¹¹
	Mucosal hypoperfusion	Reduced mucosal blood flow results in reduced oxygen and nutrient delivery, making epithelial cells susceptible to injury.²⁰⁸ Contributes to mucosal acid-base imbalances Results in the formation of free radicals
	Reperfusion injury	Nitric oxide, which causes vasodilation and hyperaemia, is released during hypoperfusion and results in an increase in cell-damaging cytokines
	Intramucosal acid–base balance	The mucus layer protects the epithelium and traps bicarbonate ions that neutralise acid thus a decrease in bicarbonate secretion results in intramucosal acidosis and local injury²⁰⁶
	Systemic acidosis	Results in increased intramucosal acidity²⁰⁷
	Free oxygen radicals	Generated as a result of tissue hypoxia, free oxygen radicals cause oxidative injury to the mucosa²¹²
	Bile salts	Bile salts reflux from the duodenum into the stomach and may have a role in stress-related damage although the exact mechanism is uncertain²¹³
	Heliobacter pylori	Conflicting results about the role of H. pylori as a cause of stress-induced mucosal disease in the critically ill²¹⁴

Risk Factors for Stress-Related Mucosal Disease

A number of risk factors are associated with the development of stress-related mucosal disease, including respiratory failure requiring at least 48 hours of mechanical ventilation and coagulopathy,²¹⁵ acute hepatic failure, hypotension, chronic renal failure, prolonged nasogastric tube placement, alcohol abuse, sepsis and an increased serum concentration of anti-Helicobacter pylori (H. pylori) immunoglobulin A.²¹⁶

Mortality rates for critically ill patients who develop stress-related mucosal disease approximate 50–77% and higher than for those who do not develop this complication.²⁰⁰ Consequently, there is a strong imperative to implement stress-ulcer prophylaxis, particularly in those patients who are considered at risk.

Preventing Stress-Related Mucosal Disease

Prophylaxis for stress-related mucosal disease is often part of the care of the critically ill although evidence demonstrating an added benefit when this therapy is applied to those patients who are not identified as at risk for developing stress-related mucosal disease, is limited.²⁰¹ Nevertheless, it is common for the majority of critically ill patients to receive some form of stress-ulcer prophylaxis during their episode of critical illness. There are a variety of pharmacological strategies that can be used to prevent stress ulcers from developing. These include antacids, sucralfate, histamine-2-receptor antagonists and proton pump inhibitors (PPIs).²⁰¹

Antacids

Antacids directly neutralise gastric acid and have been shown to be effective in reducing significant stress-related bleeding.²¹⁷ One of the disadvantages of this therapy is the time-intensive nature of administering antacids every 1–2 hours. Furthermore, antacids can contribute to further complications (e.g. aluminium toxicity, hypophosphataemia, diarrhoea or hypermagnesaemia). These factors have led to their infrequent use within the critical care setting.^200,^218,²¹⁹

Histamine-2-Receptor Antagonists

Histamine-2-receptor antagonists (H₂RAs) are commonly used in the critically ill to inhibit the production of gastric acid, which is achieved by the drug binding to the histamine-2 receptor on the basement membrane of the parietal cell.¹⁹⁶ However, gastric acid secretion may also occur through stimulation of the acetylcholine or gastrin receptors present in parietal cells;²²⁰ therefore complete blocking of gastric acid production does not occur when H₂RAs are used. A further limitation of H₂RA is the development of tolerance that may occur within 72 hours of administration.²²¹ Nevertheless, this pharmacological strategy to prevent stress-related mucosal disease remains commonplace in critical care.²²²

The decrease in gastric acidity as a result of H₂RA use may be beneficial from the perspective of preventing stress-related mucosal disease, but changes in gastric pH could lead to bacterial overgrowth in the stomach, microaspiration, and consequently an increase in the incidence of nosocomial pneumonia,²²³ although there is some research that does not support this notion.²⁰⁹

Proton Pump Inhibitors

Proton pump inhibitors (PPIs) have a greater ability to maintain an increased intragastric pH than H₂RAs.²²⁴ These drugs work by irreversibly binding to the proton pump, effectively blocking all three receptors responsible for gastric acid secretion by the parietal cell.^196,²⁰¹ PPIs are also able to limit vagally-mediated gastric acid secretion.²⁰⁰

Clinical evaluation of the efficacy of PPIs is somewhat limited; few studies have specifically studied the prophylactic use of PPIs for stress-related mucosal diseases ^12,²²⁵^–²²⁷ and many are limited by small sample sizes. Although PPIs are similar to H₂RA in the ability to raise the gastric pH above 4, a level considered adequate to prevent stress ulceration, PPIs are more likely to maintain the pH at greater than 6, which may be necessary to maintain clotting in those patients at risk of rebleeding from peptic ulcer.²⁰¹

PPIs that may be administered intravenously include omeprazole, esomeprazole and pantoprazole. Omeprazole has the highest potential for drug interation and interferes with the metabolism of some drugs commonly used in intensive care, including cyclosporine, diazepam, phenytoin and warfarin.²⁰³ Pantoprazole has the lowest potential for drug interactions.²⁰⁰

Sucralfate

Sucralfate provides protection against stress-related mucosal disease through a number of mechanisms. Sucralfate provides a protective barrier on the surface gastric epithelium, stimulates mucus and bicarbonate secretion, stimulates epithelial renewal, improves mucosal blood flow and enhances prostaglandin release.¹⁹⁶ Given orally or via a nasogastric tube, sucralfate is well tolerated but appears to be less effective than H₂RAs in decreasing clinically significant bleeding.²²⁸ Earlier reports comparing sucralfate with ranitidine showed a decrease in the development of pneumonia in those patients receiving sucralfate; however, these findings were not supported in a subsequent Level I randomised controlled trial.²²⁸

Enteral Nutrition

It is thought that the presence of enteral feeding solution results in an increase in intragastric pH, thereby minimising acid injury. Several studies have demonstrated a lower incidence of stress-related bleeding in mechanically-ventilated ²²⁹ and burn patients,²³⁰ while others were unable to show a significant effect on increasing gastric pH.²³¹ A lack of well-designed prospective studies examining the role of enteral nutrition in stress-ulcer prophylaxsis prevents the use of this therapy as a sole therapeutic agent for this purpose.²⁰¹

Liver Dysfunction

The liver performs the vital functions of controlling metabolic pathways, participating in digestion, immunological protection, detoxifying chemicals and clearing toxins and drugs. Therefore, liver dysfunction can have broad-ranging consequences, for example alterations in metabolic processes (such as glucose homeostasis), failure to produce clotting factors (with resultant severe haemorrhage) and ‘other organ’ effects such as brain, lung and kidney dysfunction and injury. Accordingly, liver dysfunction can impact substantially on the nursing care needs of the critically ill patient.

Related Anatomy and Physiology

The liver is the largest internal organ, weighing approximately 1200–1600 g in the adult. It receives approximately 25% of total cardiac output through a dual vascular supply consisting of the hepatic artery and portal vein.²³² About 75% of the hepatic blood flow arises from the portal vein with the remaining 25% from the hepatic artery. Anatomically, the liver consists of 4 lobes: the major left and right lobes, and the minor caudate and quadrate lobes. The right lobe is considerably larger than the left lobe. Functionally, the liver is divided into eight segments each with their own inflow and outflow blood supply and biliary drainage. Hepatic lobules, or liver acini, are small units consisting of a single or double layer of hepatocytes arranged in plates interspersed with capillaries (sinusoids) that receive inflowing blood from the portal vein and hepatic artery. To safeguard the body from the entrance of toxins absorbed from the intestines, the sinusoids are lined by macrophages known as Kupffer cells. The hepatic vein then drains effluent blood from the liver into the general circulation.¹

The liver has a drainage system for bile (used in the breakdown and absorption of lipids from the intestine), which is secreted by the hepatocytes. Bile drains from the hepatocytes into bile ducts and then into the common hepatic duct, before passing into the gall bladder via the common bile duct.

The arrangement of the circulation to the liver with its rich vascular architecture enables it to perform the vital functions of carbohydrate, fat and protein metabolism; production of bile to aid in digestion; the production, conjugation and elimination of bilirubin; immunological and inflammatory responses; glycogen storage; and detoxification of toxins and drugs.¹

As the kidneys are responsible for clearance of water-soluble toxins from the body, the liver clears protein (largely albumin)-bound toxins and excretes them into the gastrointestinal tract for elimination, or reabsorption in water-soluble form for subsequent renal excretion.

Mechanisms of Liver Cell Injury

Liver cell injury and death can occur either as a direct result of injury to the cell, resulting in cell necrosis, or as a result of ‘cellular stress’ and the triggering of apoptotic pathways, leading to ‘programmed cell death’.²³³ Major factors for the triggering of the apoptotic pathway are hypoxia with resulting ischaemia and reperfusion; reactive oxygen metabolites resulting from alcohol or drug ingestion; accumulation of bile acids resulting from cholestasis; and inflammatory cytokines such as tumour necrosis factor alpha (TNF-α).²³³ The apoptotic pathway results in the deconstruction of the cellular structure from the inside out, while necrosis results in cell rupture and release of cellular contents. Although these processes may overlap, it is thought that the apoptotic pathway is a way of preventing the inflammatory response that is triggered with cell necrosis. The activation of the inflammatory response results in secondary liver cell injury and contributes to the multiple organ dysfunction seen in liver failure.^233,²³⁴

The degree and time course of liver cell damage from viral hepatitis depends on the immune response. Immune recognition and destruction of infected cells may result in either clearance of the virus or ongoing inflammation, cell death and fibrosis if the virus is not cleared. This process may progress over 20–40 years to cirrhosis and hepatocellular carcinoma.²³⁵ Chronic excessive alcohol intake may also result in a slower chronic course of liver injury that eventually results in cirrhosis, liver failure or hepatocellular carcinoma.²³⁶

Liver cells may also be injured by the toxic effects of drugs or their metabolites, as in paracetamol overdose, or by drugs at therapeutic doses (e.g. non-steroidal anti-inflammatory drugs, phenytoin, antimalarial agents). Other poisoning from the ingestion of mushrooms (e.g. Amanita phalloides), and from recreational drug use (e.g. ecstasy and amphetamines), may result in liver cell death and liver failure.²³⁷ Diseases of the biliary system such as primary biliary cirrhosis and primary sclerosing cholangitis also result in liver dysfunction and failure.²³⁸

The liver has a remarkable regenerative capacity. After injury and necrosis, liver cells rapidly regenerate around areas of surviving cells to restore the lost tissue whilst maintaining homeostasis during hepatic regeneration.^234,^239,²⁴⁰ However, with chronic injury, fibrosis or scarring occurs, resulting in the loss of the functional architecture and cell mass and ultimately in cirrhosis. Cirrhosis results in destruction of the normal liver vasculature, increased resistance to blood flow, and back pressure into the portal circulation. Dilation of the venous system leading into the liver results in the formation of varices.²⁴¹

Liver cell injury may occur to such a degree that a critical amount of hepatic necrosis results in the failure of the liver to maintain metabolic, synthetic and clearance functions leading to death. Liver cell injury may also occur more slowly, giving rise to chronic liver injury.²³⁶

Epidemiology of Viral Hepatitis

In developed countries such as Australia and New Zealand, viral infection, primarily from hepatitis B and hepatitis C viruses, is the major cause of liver cell injury leading to liver failure.^242,²⁴³ Although viral hepatitis can result in acute liver failure, it more often results in chronic disease that may lead to cirrhosis and hepatocellular carcinoma.²⁴³ While the prevalence of hepatitis B in Australia and New Zealand is generally low, infection rates among social subgroups, such as the socially disadvantaged, migrants from Asian countries, injecting drug users, homosexual males, and those with a history of incarceration, are high.^244,²⁴⁵ Hepatitis C is blood-borne, with intravenous drug use the cause of about 80% of hepatitis C infections. Blood screening has greatly reduced the incidence of hepatitis C infections.²⁴⁶ In Australia in 2009, approximately 217,000 people were living with chronic hepatitis C infection, with 46,000 in the moderate to severe liver disease category.²⁴⁷ However, about 25% of people with exposure to hepatitis C virus have cleared the virus and are not chronically infected. It is estimated that the number of people with hepatitis C will increase in Australia and New Zealand due to lack of access to antiviral therapy.²⁴⁷^–²⁴⁹ Vertical transmission (transmission from the mother to the child during the perinatal period) at birth is a major cause of such infections in children.²⁴³