Features of the metabolic response to injury

Historically, the response to injury was divided into two phases: ‘ebb’ and ‘flow’. In the ebb phase during the first few hours after injury patients were cold and hypotensive (shocked). When intravenous fluids and blood transfusion became available, this shock was sometimes found to be reversible and in other cases irreversible. If the individual survived the ebb phase, patients entered the flow phase which was itself divided into two parts. The initial catabolic flow phase lasted about a week and was characterized by a high metabolic rate, breakdown of proteins and fats, a net loss of body nitrogen (negative nitrogen balance) and weight loss. There then followed the anabolic flow phase, which lasted 2–4 weeks, during which protein and fat stores were restored and weight gain occurred (positive nitrogen balance). Our modern understanding of the metabolic response to injury is still based on these general features.

Factors mediating the metabolic response to injury

The metabolic response is a complex interaction between many body systems.

The acute inflammatory response

Inflammatory cells and cytokines are the principal mediators of the acute inflammatory response. Physical damage to tissues results in local activation of cells such as tissue macrophages which release a variety of cytokines (Table 1.1). Some of these, such as interleukin-8 (IL-8), attract large numbers of circulating macrophages and neutrophils to the site of injury. Others, such as tumour necrosis factor alpha (TNF-α), IL-1 and IL-6, activate these inflammatory cells, enabling them to clear dead tissue and kill bacteria. Although these cytokines are produced and act locally (paracrine action), their release into the circulation initiates some of the systemic features of the metabolic response, such as fever (IL-1) and the acute-phase protein response (IL-6, see below) (endocrine action). Other pro-inflammatory (prostaglandins, kinins, complement, proteases and free radicals) and anti-inflammatory substances such as antioxidants (e.g. glutathione, vitamins A and C), protease inhibitors (e.g. α₂-macroglobulin) and IL-10 are also released (Fig. 1.1). The clinical condition of the patient depends on the extent to which the inflammation remains localized and the balance between these pro- and anti-inflammatory processes.

Table 1.1 Cytokines involved in the acute inflammatory response

Cytokine	Relevant actions
TNF-α	Proinflammatory; release of leucocytes by bone marrow; activation of leucocytes and endothelial cells
IL-1	Fever; T-cell and macrophage activation
IL-6	Growth and differentiation of lymphocytes; activation of the acute-phase protein response
IL-8	Chemotactic for neutrophils and T cells
IL-10	Inhibits immune function

(TNF = tumour necrosis factor; IL = interleukin)

Fig. 1.1 Key events occurring at the site of tissue injury.

Consequences of the metabolic response to injury

Hypovolaemia

Reduced circulating volume often characterizes moderate to severe injury, and can occur for a number of reasons (Table 1.3):

• Loss of blood, electrolyte-containing fluid or water.

• Sequestration of protein-rich fluid into the interstitial space, traditionally termed “third space loss”, due to increased vascular permeability. This typically lasts 24–48 hours, with the extent (many litres) and duration (weeks or even months) of this loss greater following burns, infection, or ischaemia–reperfusion injury.

Table 1.3 Causes of fluid loss following surgery and trauma

Nature of fluid	Mechanism	Contributing factors
Blood	Haemorrhage	Site and magnitude of tissue injury Poor surgical haemostasis Abnormal coagulation
Electrolyte-containing fluids	Vomiting	Anaesthesia/analgesia (e.g. opiates) Ileus
	Nasogastric drainage	Ileus Gastric surgery
	Diarrhoea	Antibiotic-related infection Enteral feeding
	Sweating	Pyrexia
Water	Evaporation	Prolonged exposure of viscera during surgery
Plasma-like fluid	Capillary leak/sequestration in tissues	Acute inflammatory response Infection Ischaemia–reperfusionsyndrome

Summary Box 1.1 Factors mediating the metabolic response to injury

The acute inflammatory response

Inflammatory cells (macrophages, monocytes, neutrophils)

Proinflammatory cytokines and other inflammatory mediators

Endothelium

Endothelial cell activation

Adhesion of inflammatory cells

Vasodilatation

Increased permeability

Nervous system

Afferent nerve stimulation and sympathetic nervous system activation

Endocrine

Increased secretion of stress hormones

Decreased secretion of anabolic hormones

Bacterial infection

Decreased circulating volume will reduce oxygen and nutrient delivery and so increase healing and recovery times. The neuroendocrine responses to hypovolaemia attempt to restore normovolaemia and maintain perfusion to vital organs.

Fluid-conserving measures

Oliguria, together with sodium and water retention – primarily due to the release of antidiuretic hormone (ADH) and aldosterone – is common after major surgery or injury and may persist even after normal circulating volume has been restored (Fig. 1.2).

Fig. 1.2 The renin–angiotensin–aldosterone system.

(ACTH = adrenocorticotrophic hormone)

Secretion of ADH from the posterior pituitary is increased in response to:

• Afferent nerve impulses from the site of injury

• Atrial stretch receptors (responding to reduced volume) and the aortic and carotid baroreceptors (responding to reduced pressure)

• Increased plasma osmolality (principally the result of an increase in sodium ions) detected by hypothalamic osmoreceptors

• Input from higher centres in the brain (responding to pain, emotion and anxiety).

ADH promotes the retention of free water (without electrolytes) by cells of the distal renal tubules and collecting ducts.

Aldosterone secretion from the adrenal cortex is increased by:

• Activation of the renin–angiotensin system. Renin is released from afferent arteriolar cells in the kidney in response to reduced blood pressure, tubuloglomerular feedback (signalling via the macula densa of the distal renal tubules in response to changes in electrolyte concentration) and activation of the renal sympathetic nerves. Renin converts circulating angiotensinogen to angiotensin (AT)-I. AT-I is converted by angiotensin-converting enzyme (ACE) in plasma and tissues (particularly the lung) to AT-II which causes arteriolar vasoconstriction and aldosterone secretion.

• Increased adrenocorticotropic hormone (ACTH) secretion by the anterior pituitary in response to hypovolaemia and hypotension via afferent nerve impulses from stretch receptors in the atria, aorta and carotid arteries. It is also raised by ADH.

• Direct stimulation of the adrenal cortex by hyponatraemia or hyperkalaemia.

Aldosterone increases the reabsorption of both sodium and water by distal renal tubular cells with the simultaneous excretion of hydrogen and potassium ions into the urine.

Increased ADH and aldosterone secretion following injury usually lasts 48–72 hours during which time urine volume is reduced and osmolality increased. Typically, urinary sodium excretion decreases to 10–20 mmol/ 24 hrs (normal 50–80 mmol/24 hrs) and potassium excretion increases to > 100 mmol/24 hrs (normal 50–80 mmol/ 24 hrs). Despite this, hypokalaemia is relatively rare because of a net efflux of potassium from cells. This typical pattern may be modified by fluid and electrolyte administration.

Blood flow-conserving measures

Hypovolaemia reduces cardiac preload which leads to a fall in cardiac output and a decrease in blood flow to the tissues and organs. Increased sympathetic activity results in a compensatory increase in cardiac output, peripheral vasoconstriction and a rise in blood pressure. Together with intrinsic organ autoregulation, these mechanisms act to try to ensure adequate tissue perfusion (Fig. 1.3).

Fig. 1.3 Summary of metabolic responses to surgery and trauma.

Summary Box 1.2 Urinary changes in metabolic response to injury

↓ urine volume secondary to ↑ ADH and aldosterone release

↓ urinary sodium and ↑ urinary potassium secondary to ↑ aldosterone release

↑ urinary osmolality

↑ urinary nitrogen excretion due to the catabolic response to injury.

Increased energy metabolism and substrate cycling

The body requires energy to undertake physical work, generate heat (thermogenesis) and to meet basal metabolic requirements. Basal metabolic rate (BMR) comprises the energy required for maintenance of membrane polarization, substrate absorption and utilization, and the mechanical work of the heart and respiratory systems.

Although physical work usually decreases following surgery due to inactivity, overall energy expenditure may rise by 50% due to increased thermogenesis, fever and BMR (Fig. 1.4).

Fig. 1.4 Components of body energy expenditure in health and following surgery.

Thermogenesis: Patients are frequently pyrexial for 24–48 hours following injury (or infection) because pro-inflammatory cytokines (principally IL-1) reset temperature-regulating centres in the hypothalamus. BMR increases by about 10% for each 1°C increase in body temperature.

Basal metabolic rate: Injury leads to increased turnover in protein, carbohydrate and fat metabolism (see below). Whilst some of the increased activity might appear metabolically futile (e.g. glucose–lactate cycling and simultaneous synthesis and degradation of triglycerides), it has probably evolved to allow the body to respond quickly to altering demands during times of extreme stress.

Changes in red blood cell synthesis and coagulation

Anaemia is common after major surgery or trauma because of bleeding, haemodilution following treatment with crystalloid or colloid and impaired red cell production in bone marrow (because of low erythropoietin production by the kidney and reduced iron availability due to increased ferritin and reduced transferrin binding). Whether moderate anaemia confers a survival benefit following injury remains unclear, but actively correcting anaemia in non-bleeding patients after surgery or during critical illness does not improve outcomes.

Following tissue injury, the blood typically becomes hypercoagulable and this can significantly increase the risk of thromboembolism; reasons include:

Anabolism

Anabolism involves regaining weight, restoring skeletal muscle mass and replenishing fat stores. Anabolism is unlikely to occur until the processes associated with catabolism, such as the release of pro-inflammatory mediators, have subsided. This point is often temporally associated with obvious clinical improvement in patients, who feel subjectively better and regain their appetite. Hormones contributing to this process include insulin, growth hormone, insulin-like growth factors, androgens and the 17-ketosteroids. Adequate nutritional support and early mobilization also appear to be important in promoting enhanced recovery after surgery (ERAS).

Normal water and electrolyte balance

Water forms about 60% of total body weight in men and 55% in women. Approximately two-thirds is intracellular, one-third extracellular. Extracellular water is distributed between the plasma and the interstitial space (Fig. 1.5A).

Fig. 1.5 Distribution of fluid and electrolytes between the intracellular and extracellular fluid compartments.

A Approximate volumes of water distribution in a 70 kg man. B Cations and anions.

The differential distribution of ions across cell membranes is essential for normal cellular function. The principal extracellular ions are sodium, chloride and bicarbonate, with the osmolality of extracellular fluid (normally 275–295 mOsmol/kg) determined primarily by sodium and chloride ion concentrations. The major intracellular ions are potassium, magnesium, phosphate and sulphate (Fig. 1.5B).

The distribution of fluid between the intra- and extravascular compartments is dependent upon the oncotic pressure of plasma and the permeability of the endothelium, both of which may alter following surgery as described above. Plasma oncotic pressure is primarily determined by albumin.

The control of body water and electrolytes has been described above. Aldosterone and ADH facilitate sodium and water retention while atrial natriuretic peptide (ANP), released in response to hypervolaemia and atrial distension, stimulates sodium and water excretion.

In health (Table 1.7):

In the absence of sweating, almost all sodium loss is via the urine and, under the influence of aldosterone, this can fall to 10–20 mmol/24 hrs. Potassium is also excreted mainly via the kidney with a small amount (10 mmol/day) lost via the gastrointestinal tract. In severe potassium deficiency, losses can be reduced to about 20 mmol/day, but increased aldosterone secretion, high urine flow rates and metabolic alkalosis all limit the ability of the kidneys to conserve potassium and predispose to hypokalaemia.

In adults, the normal daily fluid requirement is ~30–35 ml/kg (~2500 ml/day). Newborn babies and children contain proportionately more water than adults. The daily maintenance fluid requirement at birth is about 75 ml/kg, increasing to 150 ml/kg during the first weeks of life. After the first month of life, fluid requirements decrease and the ‘4/2/1’ formula can be used to estimate maintenance fluid requirements: the first 10 kg of body weight requires 4 ml/kg/h; the next 10 kg 2ml/kg/h; thereafter each kg of body requires 1ml/kg/h. The estimated maintenance fluid requirements of a 35 kg child would therefore be:

The daily requirement for both sodium and potassium in children is about 2–3 mmol/kg.

Assessing losses in the surgical patient

Only by accurately estimating (Table 1.8) and, where possible, directly measuring fluid and electrolyte losses can appropriate therapy be administered.

Table 1.8 Sources of fluid loss in surgical patients

Intravenous fluid administration

When choosing and administering intravenous fluids (Table 1.10) it is important to consider:

Types of intravenous fluid

Crystalloids

Dextrose 5% contains 5 g of dextrose (d-glucose) per 100 ml of water. This glucose is rapidly metabolized and the remaining free water distributes rapidly and evenly throughout the body’s fluid compartments. So, shortly after the intravenous administration of 1000 ml 5% dextrose solution, about 670 ml of water will be added to the intracellular fluid compartment (IFC) and about 330 ml of water to the extracellular fluid compartment (EFC), of which about 70 ml will be intravascular (Fig. 1.6). Dextrose solutions are therefore of little value as resuscitation fluids to expand intravascular volume. More concentrated dextrose solutions (10%, 20% and 50%) are available, but these solutions are irritant to veins and their use is largely limited to the management of diabetic patients or patients with hypoglycaemia.

Fig. 1.6 Distribution of different fluids in the body fluid compartments 30–60 minutes after rapid intravenous infusion of 1000 ml.

Sodium chloride 0.9% and Hartmann’s solution are isotonic solutions of electrolytes in water. Sodium chloride 0.9% (also known as normal saline) contains 9 g of sodium chloride dissolved in 1000 ml of water; Hartmann’s solution (also known as Ringer’s lactate) has a more physiological composition, containing lactate, potassium and calcium in addition to sodium and chloride ions. Both normal saline and Hartmann’s solution have an osmolality similar to that of extracellular fluid (about 300 mOsm/l) and after intravenous administration they distribute rapidly throughout the ECF compartment (Fig. 1.6). Isotonic crystalloids are appropriate for correcting EFC losses (e.g. gastrointestinal tract or sweating) and for the initial resuscitation of intravascular volume, although only about 25% remains in the intravascular space after redistribution (often less than 30–60 minutes).

Balanced solutions such as Ringers lactate, closely match the composition of extracellular fluid by providing physiological concentrations of sodium and lactate in place of bicarbonate, which is unstable in solution. After administration the lactate is metabolised, resulting in bicarbonate generation. These solutions decrease the risk of hyperchloraemia, which can occur following large volumes of fluids with higher sodium and chloride concentrations. Hyperchloraemic acidosis can develop in these situations, which is associated with adverse patient outcomes and may cause renal impairment. Some colloid solutions are also produced with balanced electrolyte content.

Hypertonic saline solutions induce a shift of fluid from the IFC to the EFC so reducing brain water and increasing intravascular volume and serum sodium concentration. Potential indications include the treatment of cerebral oedema and raised intracranial pressure, hyponatraemic seizures and ‘small volume’ resuscitation of hypovolaemic shock.

Colloids

Colloid solutions contain particles that exert an oncotic pressure and may occur naturally (e.g. albumin) or be synthetically modified (e.g. gelatins, hydroxyethyl starches [HES], dextrans). When administered, colloid remains largely within the intravascular space until the colloid particles are removed by the reticuloendothelial system. The intravascular half-life is usually between 6 and 24 hours and such solutions are therefore appropriate for fluid resuscitation. Thereafter, the electrolyte-containing solution distributes throughout the EFC.

Synthetic colloids are more expensive than crystalloids and have variable side effect profiles. Recognized risks include coagulopathy, reticuloendothelial system dysfunction, pruritis and anaphylactic reactions. HES in particular appears associated with a risk of renal failure when used for resuscitation in patients with septic shock.

The theoretical advantage of colloids over crystalloids is that, as they remain in the intravascular space for several hours, smaller volumes are required. However, overall, current evidence suggests that crystalloid and colloid are equally effective for the correction of hypovolaemia (EBM 1.1).

1.1 Crystalloid vs colloid to treat intravascular hypovolaemia

‘There is no evidence that resuscitation with colloids reduces the risk of death, compared to resuscitation with crystalloids, in patients with trauma, burns or following surgery.’

Perel P. et al., Cochrane Database Syst Rev. 2007 Oct 17;(4):CD000567

‘The use of 4% albumin for intravascular volume resuscitation in critically ill patients is associated with similar outcomes to the use of normal saline.’

Finfer S. et al. The SAFE study. New Engl J Med 2004; 350:2247–2256.

Specific water and electrolyte abnormalities

Calcium

Clinically significant abnormalities in calcium balance in the surgical patient are most frequently encountered in endocrine surgery (See Chapter 24 of the 5th edition).

Magnesium

Hypomagnesaemia is common in surgical patients who have restricted oral intake and who have been receiving intravenous fluids for several days. It is frequently associated with other electrolyte abnormalities, notably hypokalaemia, hypocalcaemia and hypophosphataemia. Hypomagnesaemia appears to be associated with a predisposition to tachyarrhythmias (most notable torsades de pointes and atrial fibrillation), but many of the clinical manifestations of magnesium depletion are non-specific (muscle weakness, muscle cramps, altered mentation, tremors, hyper-reflexia and generalized seizures). As magnesium is predominantly intracellular, serum magnesium levels poorly reflect total body stores. Despite this limitation, serum levels are frequently used to guide (oral or parenteral) magnesium supplementation.

Phosphate

Phosphate is a critical component in many biochemical processes such as ATP synthesis, cell signalling and nucleic acid synthesis. Hypophosphataemia is common in surgical patients and if severe (< 0.4 mmol/l) causes widespread cell dysfunction, muscle weakness, impaired myocardial contractility and reduced cardiac output. Most hypophosphataemia results from the shift of phosphate into cells and most commonly occurs in malnourished and/or alcoholic patients commencing enteral or parenteral nutrition. The increased carbohydrate load leads to insulin secretion and this results in the rapid intracellular uptake of glucose and phosphate together with magnesium and potassium. For reasons that remain unclear, these changes are accompanied by fluid retention and an increase in ECF volume (refeeding syndrome). To avoid this syndrome, feeding should be established gradually and accompanied by regular measurement and aggressive supplementation of serum electrolytes (phosphate, magnesium and potassium). Micronutrient (notably B vitamin) deficiencies should also be corrected. Phosphate can be supplemented orally or by slow intravenous infusion.

Metabolic acidosis

Metabolic acidosis is characterized by an increase in plasma hydrogen ions in conjunction with a decrease in bicarbonate concentration. A rise in plasma hydrogen ion concentration stimulates chemoreceptors in the medulla resulting in a compensatory respiratory alkalosis (an increase in minute volume and a fall in P_aCO₂).

Metabolic acidosis can occur as a result of increased production of endogenous acid (e.g. lactic acid or ketone bodies) or increased loss of bicarbonate (e.g. intestinal fistula, hyperchloraemic acidosis). The commonest cause encountered in surgical practice is lactic acidosis resulting from hypovolaemia and impaired tissue oxygen delivery (see section on shock). Treatment is directed towards restoring circulating blood volume and tissue perfusion. Adequate resuscitation typically corrects the metabolic acidosis seen in this context.

Metabolic alkalosis

Metabolic alkalosis is characterized by a decrease in plasma hydrogen ion concentration and an increase in bicarbonate concentration. A rise in P_aCO₂ occurs as a consequence of the rise in bicarbonate concentration, resulting in a compensatory respiratory acidosis.

Metabolic alkalosis is commonly associated with hypo-kalaemia and hypochloraemia. The kidney has an enormous capacity to generate bicarbonate ions and this is stimulated by chloride loss. This is a major contributor to the metabolic alkalosis seen following significant (chloride-rich) losses from the gastrointestinal tract, especially when combined with loss of acid from conditions such as gastric outlet obstruction. Hypokalaemia is often associated with metabolic alkalosis because of the transcellular shift of hydrogen ions shift into cells and because distal renal tubular cells retain potassium in preference to hydrogen ions.

The treatment of metabolic alkalosis involves adequate fluid replacement and the correction of electrolyte disturbances, notably hypokalaemia and hypochloraemia.

Respiratory acidosis

Respiratory acidosis is a common postoperative problem characterized by increased P_aCO₂, hydrogen ion and plasma bicarbonate concentrations. In the surgical patient, respiratory acidosis usually results from respiratory depression and hypoventilation. This is common on emergence from general anaesthesia and following excessive opiate administration. Occasionally, respiratory acidosis occurs in the context of pulmonary complications such as pneumonia. This is more usual in very sick patients or those with pre-existing respiratory disease. Patients with this cause of respiratory acidosis frequently require ventilatory support as the hypercapnia observed reflects inadequate respiratory muscle strength to cope with an increased work of breathing.

Respiratory alkalosis

Respiratory alkalosis is caused by excessive excretion of CO₂ as a result of hyperventilation. P_aCO₂ and hydrogen ion concentration decrease. Respiratory alkalosis is rarely chronic and usually does not need specific treatment. It usually corrects spontaneously when the precipitating condition resolves.

Mixed patterns of acid–base imbalance

Mixed patterns of acid–base disturbance are common, particularly in very sick patients. In this situation acid–base nomograms can be very useful in clarifying the contributing factors (Fig. 1.8).

Fig. 1.8 Changes in blood [H⁺].

The rectangle indicates limits of normal reference ranges for [H⁺] and P_aCO₂. The bands represent 95% confidence limits of single disturbances in human blood in vivo. When the point obtained by plotting [H⁺] against P_aCO₂ does not fall within one of the labelled bands, compensation is incomplete or a mixed acid-base disturbance is present.

Definition

Shock exists when tissue oxygen delivery fails to meet the metabolic requirements of cells. An imbalance between oxygen delivery (DO₂) and oxygen demand can result from a global reduction in oxygen delivery, maldistribution of blood flow, impaired oxygen utilization or an increase in tissue oxygen requirements. Left unchecked, shock will result in a fall in oxygen consumption (VO₂), anaerobic metabolism, tissue acidosis and cellular dysfunction leading to multiple organ dysfunction and ultimately death. Although shock is sometimes considered to be synonymous with hypotension, it is important to realise that tissue oxygen delivery may be inadequate even though the blood pressure and other vital signs remain normal.

Types of shock

Septic shock

Septic shock results from complex disturbances in oxygen delivery and oxygen consumption and can be defined as sepsis-induced hypotension (systolic BP < 90 mmHg, mean arterial blood pressure [MAP] < 70 mmHg) and/or tissue hypoperfusion (elevated lactate or oliguria) that persist despite adequate fluid resuscitation (~30 ml/kg) (Fig. 1.9).

Fig. 1.9 The interrelationship between systemic inflammatory response syndrome (SIRS), sepsis and infection.

Adapted from The American College of Chest Physicians and Society of Critical Care Medicine Consensus Conference Committee definitions for sepsis 1992.

Sepsis usually arises from a localized infection, with Gram-negative (38%) and (increasingly) Gram-positive (52%) bacteria being the most frequently identified pathogens. The commonest sites of infection leading to sepsis are the lungs (50–70%), abdomen (20–25%), urinary tract (7–10%) and skin.

Infection triggers a cytokine-mediated proinflammatory response that results in peripheral vasodilation, redistribution of blood flow, endothelial cell activation, increased vascular permeability and the formation of microthrombi within the microcirculation. Cardiac output typically increases in septic shock to compensate for the peripheral vasodilation. However, despite a global increase in oxygen delivery, microcirculatory dysfunction impairs oxygen delivery to the cells. Compounding disturbances in oxygen delivery, mitochondrial dysfunction blocks the normal bioenergetic pathways within the cell impairing oxygen utilization.

Cardiogenic shock

This occurs when the heart is unable to maintain a cardiac output sufficient to meet the metabolic requirements of the body (pump failure) and can be caused by myocardial infarction, arrhythmias, valve dysfunction, cardiac tamponade, massive pulmonary embolism, and tension pneumothorax.

Anaphylactic shock

This is a severe systemic hypersensitivity reaction following exposure to an agent (allergen) triggering the release of vasoactive mediators (histamine, kinins and prostaglandins) from basophils and mast cells. Anaphylaxis may be immunologically mediated (allergic anaphylaxis), when IgE, IgG or complement activation by immune complexes mediates the reaction, or non-immunologically mediated (non-allergic anaphylaxis). The clinical features of allergic

and non-allergic anaphylaxis may be identical, with shock a frequent manifestation of both. Anaphylactic shock results from vasodilation, intravascular volume redistribution, capillary leak and a reduction in cardiac output. Common causes of anaphylaxis include drugs (e.g. neuromuscular blocking drugs, β-lactam antibiotics), colloid solutions (e.g. gelatin containing solutions, dextrans), radiological contrast media, foodstuffs (peanuts, tree nuts, shellfish, dairy products), hymenoptera stings and latex.

Neurogenic shock

This is caused by a loss of sympathetic tone to vascular smooth muscle. This typically occurs following injury to the (thoracic or cervical) spinal cord and results in profound vasodilation, a fall in systemic vascular resistance and hypotension.

Macrocirculation

When assessing a patient with shock, it is useful to remember that mean arterial blood pressure (MAP) is equal to the product of cardiac output (CO) and systemic vascular resistance (SVR) (Table 1.15).

Table 1.15 Haemodynamic and oxygen transport parameters

MAP = mean arterial pressure; CO = cardiac output; SVR = systemic vascular resistance; DO₂ = oxygen delivery; [Hb] = haemoglobin concentration in g/dl; SaO₂ = arterial oxygen saturations; VO₂ = oxygen consumption; SvO₂ mixed venous oxygen saturations (sampled from pulmonary artery)

Shock (inadequate tissue oxygen delivery) can occur in the context of a low, normal or high cardiac output.

In hypovolaemic shock there is catecholamine release from the adrenal medulla and sympathetic nerve endings, as well as the generation of AT-II from the renin–angiotensin system. The resulting tachycardia and increased myocardial contractility act to preserve cardiac output, whilst vasoconstriction acts to maintain arterial blood pressure and divert the available blood to vital organs (e.g. brain, heart and muscle) and away from non-vital organs (e.g. skin and gut). Clinically this manifests as pale, clammy skin with collapsed peripheral veins and a prolonged capillary refill time. The resulting splanchnic hypoperfusion is implicated in many of the complications associated with prolonged or untreated shock.

In septic shock, circulating proinflammatory cytokines (notably TNF-α and IL-1β) induce endothelial expression of the enzyme nitric oxide (NO) synthetase and the production of NO which leads to smooth muscle relaxation, vasodilation and a fall in systemic vascular resistance. The (initial) cardiovascular response is a reflex tachycardia and an increase in stroke volume resulting in an increased cardiac output. Clinically this manifests as warm, well-perfused peripheries, a low diastolic blood pressure and raised pulse pressure. Fit young patients may compensate for these changes relatively well even though oxygen delivery and utilization is compromised at the cellular level. However, as septic shock progresses endothelial dysfunction results in significant extravasation of fluid and a loss of intravascular volume. Ventricular dysfunction also impairs the compensatory increase in cardiac output. As a result, peripheral perfusion falls and the clinical signs may become indistinguishable from those associated with the low-output state described above

In neurogenic shock, traumatic disruption of sympathetic efferent nerve fibres results in loss of vasomotor tone, peripheral vasodilation and a fall in systemic vascular resistance. Loss of cardiac accelerator fibres (T1–4) and anhydrosis as a result of loss of sweat gland innervation also frequently occur, with patients typically presenting with hypotension, bradycardia and warm, dry peripheries.

Cardiogenic shock typically presents with signs of a low-output state although, unlike hypovolaemic shock, circulating volume is typically normal or increased with increased circulating AT-II and aldosterone. If associated with left ventricular failure, there may be pulmonary oedema.

Microcirculation

Changes in the microcirculation (arterioles, capillaries and venules) have a central role in the pathogenesis of shock.

Arteriolar vasoconstriction, seen in early hypovolaemic and cardiogenic shock, helps to maintain a satisfactory MAP and the resulting fall in the capillary hydrostatic pressure encourages the transfer of fluid from the interstitial space into the vascular compartment so helping to maintain circulating volume. As described above, high vascular resistance in the capillary beds of the skin and gut results in a redistribution of cardiac output to vital organs.

If shock remains uncorrected, local accumulation of lactic acid and carbon dioxide, together with the release of vasoactive substances from the endothelium, over-ride compensatory vasoconstriction leading to pre-capillary vasodilatation. This results in pooling of blood within the capillary bed and endothelial cell damage. Capillary permeability increases with the loss of fluid into the interstitial space and haemoconcentration within the capillary. The resulting increase in blood viscosity, in conjunction with reduced red cell deformability, further compromises flow through the microcirculation predisposing to platelet aggregation and the formation of microthrombi.

In sepsis, there is up-regulation of inducible NO synthetase and smooth muscle cells lose their adrenergic sensitivity resulting in pathological arterio–venous shunting. Endothelial and inflammatory cell activation results in the generation of reactant oxidant species, disruption of barrier function in the microcirculation and widespread activation of coagulation. Microthombi occlude capillary blood flow and the consumption of platelets and coagulation factors leads to thrombocytopenia, coagulopathy and DIC (Fig. 1.10).

Fig. 1.10 The effect of septic shock on the microcirculation.

Photomicrograph from a video clip of the normal microcirculation A and the microcirculation in septic shock B Septic shock is associated with an increased number of small vessels with either absent or intermittent flow.

Cellular function

Under normal (aerobic) conditions, glycolysis converts glucose to pyruvate which is converted to acetyl-coenzyme-A (acetyl-CoA) and enters the Krebs cycle. Oxidation of acetyl- CoA in the TCA cycle generates nicotinamide adenine dinucleotide (NADH) and flavine adenine dinucleotide (FADH₂), which enter the electron transport chain and are oxidized to NAD⁺ in the oxidative phosphorylation of adenosine diphosphate (ADP) to ATP.

The oxidative metabolism of glucose is energy efficient, yielding up to 38 moles of ATP for each mole of glucose, but requires a continuous supply of oxygen to the cell. Hypoxaemia blocks mitochondrial oxidative phosphorylation, inhibiting ATP synthesis. This leads to a decrease in the intracellular ATP/ADP ratio, an increase in the NADH/NAD⁺ ratio and an accumulation of pyruvate that is unable to enter the TCA cycle. The cytosolic conversion of pyruvate to lactate allows the regeneration of some NAD⁺, enabling the limited production of ATP by anaerobic glycolysis. However, anaerobic glycolysis is significantly less efficient, generating only 2 moles of ATP per mole of glucose and predisposing cells to ATP depletion (Fig. 1.11).

Fig. 1.11 Glycolysis.

Simplified diagram illustrating glycolysis, the Krebs cycle and oxidative phosphorylation. Aerobic metabolism yields up to 38 moles of ATP per mole of glucose oxidized. Anaerobic metabolism is considerably less efficient yielding only 2 moles of ATP per mole of glucose.

Under normal conditions, the tissues globally extract about 25% of the oxygen delivered to them, with the normal oxygen saturation of mixed venous blood being 70–75%. As oxygen delivery falls, cells are able to increase the proportion of oxygen extracted from the blood, but this compensatory mechanism is limited, with a maximal oxygen extraction ratio of about 50%. At this point, further reductions in oxygen delivery lead to a critical reduction in oxygen consumption and anaerobic metabolism, a state described as dysoxia (Fig. 1.12).

Fig. 1.12 The relationship between oxygen delivery, oxygen consumption and oxygen extraction (SaO₂–SvO₂).

As oxygen delivery falls in shock, oxygen extraction increases until it reaches maximal oxygen extraction (45–50%). Further reductions in oxygen delivery result in a fall in oxygen consumption and tissue dysoxia. As ATP supply falls below ATP demand this leads to cell dysfunction and ultimately to cell death.

Anaerobic metabolism leads to a rise in lactic acid in the systemic circulation. Indeed, in the absence of significant renal or liver disease, serum lactate concentration may be a useful marker of global cellular hypoxia and oxygen debt. Similarly, a fall in mixed venous oxygen saturations may reflect increased oxygen extraction by the tissues and an imbalance between oxygen delivery and oxygen demand.

In septic shock, cell dysoxia and lactate accumulation may reflect a problem with both oxygen utilization and oxygen delivery. The increased sympathetic activity occurring in sepsis leads to increased glycolysis and an increase in pyruvate generation. Coupled with dysfunction of the enzyme pyruvate dehydrogenase, this leads to accumulation of pyruvate and (hence) lactate. In addition, sepsis is associated with significant mitochondrial dysfunction and marked inhibition of oxidative phosphorylation. The phrase ‘cytopathic shock’ has been used to describe this condition.

The movement of sodium against a concentration gradient is an active process requiring ATP. Reduction in ATP supply leads to intracellular accumulation of sodium, an osmotic gradient across the cell membrane, dilation of the endoplasmic reticulum and cell swelling. When combined with the failure of other vital ATP-dependent cell functions and the reduction in intracellular pH associated with the accumulation of lactic acid, the result is disruption of protein synthesis, damage to lysosomal and mitochondrial membranes and ultimately cell necrosis.

Cardiovascular

As described above, cardiogenic shock leads to a fall in CO and neurogenic shock leads to vasodilation and reduced SVR. However, significant myocardial and vascular dysfunction frequently occur in other causes of shock.

Despite coronary autoregulation, severe (diastolic) hypotension results in an imbalance between myocardial oxygen supply and demand and ischaemia in the watershed areas of the endocardium. This impairs myocardial contractility. Hypoxaemia and acidosis deplete myocardial stores of noradrenaline (norepinephrine) and diminish the cardiac response to both endogenous and exogenous catecholamines. Acid–base and electrolyte abnormalities, combined with local tissue hypoxia, increase myocardial excitability and predispose to both atrial and ventricular dysrhythmias. As described above, circulating inflammatory mediators implicated in the pathogenesis of sepsis and SIRS depress myocardial contractility and ventricular function, increase endothelial permeability (resulting in intravascular volume depletion) and cause widespread activation of both coagulation and fibrinolysis (leading to DIC).

Respiratory

Tachypnoea driven by pain, pyrexia, local lung pathology, pulmonary oedema, metabolic acidosis or cytokines is one of the earliest features of shock. The increased minute volume typically results in reduced arterial PCO₂ and a respiratory alkalosis as described above. Initially this will compensate for the metabolic acidosis of shock but eventually this mechanism is overwhelmed and blood pH falls.

In hypovolaemic states, there is reduction in pulmonary blood flow and this leads to underperfusion of ventilated alveolar units so increasing ventilation–perfusion (V/Q) mismatch. In cardiogenic shock, left ventricular failure and pulmonary oedema often compromises the ventilation of perfused alveolar units increasing the shunt fraction (Qs/Qt) within the lung. Increased V/Q mismatch and shunt fraction also occur in sepsis. The net result is hypoxaemia that may be refractory to increases in inspired oxygen concentration.

Sepsis and hypovolaemic shock are both recognized causes of acute lung injury and its more severe variant, the acute respiratory distress syndrome (ARDS). This is characterized by the influx of protein-rich oedema fluid and inflammatory cells into the alveolar air spaces and appears to be cytokine-mediated (notably IL-8, TNF-α, IL-1and IL-6).

Renal

As a result of the mechanisms discussed above, reduced renal blood flow results in the production of low volume (< 0.5 ml/kg/h), high osmolality and low sodium content urine. If shock is not reversed, hypoxia leads to acute tubular necrosis (ATN) characterized by oligo-anuria and urine with a high sodium concentration and an osmolality close to that of plasma. With a fall in glomerular filtration, blood urea and creatinine rise; hyperkalaemia and a metabolic acidosis are also usually present.

Renal failure occurs in about 30–50% of patients with septic shock. In addition to the mechanisms responsible for the simple pre-renal failure described above, there is an imbalance in pre- and postglomerular vascular resistance, mesangial contraction and microvascular injury leading to glomerular filtration failure.

Nervous system

Due to the increased sympathetic activity, patients may appear inappropriately anxious. As compensatory mechanisms reach their limit and cerebral hypoperfusion and hypoxia supervene, there is increasing restlessness, progressing to confusion, stupor and coma. Unless cerebral hypoxia has been prolonged, effective resuscitation will usually correct the depressed conscious level rapidly. In septic shock, the clinical picture may be complicated by the presence of an underlying (septic) encephalopathy and/or delirium.

Gastrointestinal

As described above, the redistribution of cardiac output observed in shock leads to a marked reduction in splanchnic blood flow. In the stomach, the resulting mucosal hypoperfusion and hypoxia predispose to stress ulceration and haemorrhage. In the intestine, movement (translocation) of bacteria and/or bacterial endotoxin from the lumen to the portal vein and then systemic circulation is thought to be a key mechanism underlying the development of SIRS and multiple organ failure.

Hepatobiliary

Despite its dual blood supply, ischaemic hepatic injury is frequently seen following hypovolaemic or cardiogenic shock. An acute, reversible elevation in serum transaminase levels indicates hepatocellular injury, and typically

occurs 1–3 days following the ischaemic insult. Increases in prothrombin time and/or hypoglycaemia are markers of more severe injury. Significant ischaemic hepatitis is more frequent in patients with underlying cardiac disease and a degree of hepatic venous congestion.

General principles

The management of shock is based upon the following principles:

As with most clinical emergencies, treatment and diagnosis should occur simultaneously with the immediate assessment and management following an Airway, Breathing, Circulation (ABC) approach.

The early recognition and treatment of potentially reversible causes (e.g. bleeding, intra-abdominal sepsis, myocardial ischaemia, pulmonary embolus, cardiac tamponade) is essential and may be facilitated by a detailed history, a thorough clinical examination (Table 1.16) and focused investigations.

Table 1.16 Clinical assessment of shock

In isolation, single measurements are not helpful. Measurements are far more useful when used in combination with the findings of a detailed clinical examination. Observation of trends over time, together with the response to therapeutic interventions (e.g. a fluid challenge) is key to the successful management of shock.

Whilst shocked patients may be more sensitive to the effects of opiates, there is no justification for withholding effective analgesia if indicated and this should be titrated intravenously (e.g. morphine in 1–2 mg increments) to response during the initial assessment and treatment.

Most patients with shock will require admission to a high dependency (HDU) or intensive care unit (ICU).

Circulation

Initial resuscitation should be targeted at arresting haemorrhage and providing fluid (crystalloid or colloid) to restore intravascular volume and optimize cardiac preload. It is common practice to use blood to maintain a haemoglobin concentration > 10 g/dl (haematocrit around 0.3) during the initial resuscitation of shock if there is evidence of inadequate oxygen delivery, such as a raised lactate concentration or low central venous saturations (measured from a central venous catheter). A reduction in tachycardia, increasing blood pressure, and improving peripheral perfusion and urine output in response to a series of 250–500 ml fluid challenges indicate ‘fluid responsiveness’ and suggest that further fluid and optimization of preload may be required. Once parameters stop improving it is unlikely that further fluid will be beneficial, particularly if there is an associated fall in oxygen saturation and the development of pulmonary oedema. As resuscitation continues, more invasive monitoring allows the acid–base status, central venous pressure (CVP), pulmonary artery wedge pressure (PAWP), CO and mixed (S_vO₂) or central (Sc_vO₂) venous oxygen saturations to be used to further assess the response to fluid (Fig. 1.13).

Fig. 1.13 Frank–Starling curve.

Demonstrating the relationship between ventricular preload and stroke volume.

If blood pressure remains low and/or signs of inadequate tissue oxygen delivery persist despite fluid resuscitation and the optimization of preload, then inotropes and/or vasopressors may be required. Although there is a degree of crossover in their mechanism of action, vasopressors (e.g. noradrenaline) cause peripheral vasoconstriction and an increase SVR while inotropes (e.g. dobutamine) increase myocardial contractility, stroke volume and cardiac output. The initial choice of inotrope or vasopressor therefore depends upon the underlying aetiology of shock and an understanding of the main physiological derangements (Table 1.17). Adrenaline, which has both vasopressor and inotropic effects, is a useful first line drug in the emergency treatment of shock. Vasoactive drug administration should be continuously titrated against specific physiological end-points (e.g. blood pressure or cardiac output).

Table 1.17 Effects of commonly used vasoactive drugs

Hypovolaemic shock

The commonest cause of acute hypovolaemic shock in surgical practice is bleeding due to trauma, ruptured aortic aneurysm, gastrointestinal and obstetric haemorrhage (Table 1.14).

Normal adult blood volume is about 7% of body weight, with a 70 kg man having an estimated blood volume (EBV) of around 5000 ml. The severity of haemorrhagic shock is frequently classified according to percentage of EBV lost where class I (< 15%) represents a compensated state (as may occur following the donation of a unit of blood) and class IV (> 40%) is immediately life threatening (Table 1.18). The term ‘massive haemorrhage’ has a number of definitions including: loss of EBV in 24 hours; loss of 50% EBV in 3 hours; blood loss at a rate ≥ 150 ml/min.

Arrest of haemorrhage and intravascular fluid resuscitation should occur concurrently; there is little role for inotropes or vasopressors in the treatment of a hypotensive hypovolaemic patient. As described above, fluid therapy should be titrated to clinical and physiological response.

In the emergency situation, before bleeding has been controlled, a systolic blood pressure of 80–90 mmHg is increasingly used as a resuscitation target (permissive hypotension) as it is thought less likely to dislodge clot and lead to dilutional coagulopathy. Once active bleeding has been stopped, resuscitation can be fine-tuned to optimize organ perfusion and tissue oxygen delivery as described above. It remains unclear whether permissive hypotension is appropriate for all cases of haemorrhagic shock but it appears to improve outcomes following penetrating trauma and ruptured aortic aneurysm.

Rapid fluid resuscitation requires secure vascular access and this is best achieved through two wide-bore (14- or 16-gauge) peripheral intravenous cannulae; cannulation of a central vein provides an alternative means.

As discussed above, the type of fluid used (crystalloid or colloid) is probably less important than the adequate restoration of circulating volume itself. In the case of life-threatening or continued haemorrhage, blood will be required early in the resuscitation. Ideally, fully cross-matched packed red blood cells (PRBCs) should be administered, but type-specific or O Rhesus-negative blood may be used until it becomes available. A haemoglobin concentration of 7–9 g/dl may be sufficient to ensure adequate tissue oxygen delivery in stable (non-bleeding) patients, but a haemoglobin target of > 10 g/dl may be more appropriate in actively bleeding patients. Massive transfusion can lead to hypothermia, hypocalcaemia, hyper- or hypokalaemia and coagulopathy.

The acute coagulopathy of trauma (ACoT) is well recognized and multifactorial. Dilution of clotting factors and platelets as a result of fluid resuscitation, combined with their consumption at the point of bleeding, results in clotting factor deficiency, thrombocytopaenia and coagulopathy. Hypothermia, metabolic acidosis and hypocalcaemia also significantly impair normal coagulation. Resuscitation strategies aggressively targeting the ‘lethal triad’ of hypothermia, acidosis and coagulopathy appear to significantly improve outcome following military trauma and observational studies support the immediate use of measures to prevent hypothermia, early correction of severe metabolic acidosis (pH < 7.1), maintenance of ionized calcium > 1.0 mmol/l and the early empirical use of clotting factors and platelets.

Where possible, correction of coagulopathy should be guided by laboratory results (platelet count, prothrombin time, activated partial thromboplastin time and fibrinogen concentration). Thromboelastography (TEG) or rotational thromboelastometry (ROTEM) provide near-patient functional assays of clot formation, platelet function and fibrinolysis and are also now widely used to guide the management of coagulopathy. Clotting factor deficiency is normally treated by the administration of fresh frozen plasma (FFP) (10–15 ml/kg), thrombocytopenia or platelet dysfunction by the administration of platelets (usually one ‘pool’ or adult dose containing 2–3 × 10¹¹ platelets). Fibrinogen deficiency (< 1.0 g/l) is best treated with fresh frozen plasma or cryoprecipitate (usually one ‘pool’ of 10 single donor units). The antifibrinolytic, tranexamic acid, can be used to inhibit fibrinolysis and has been shown to reduce mortality from bleeding when used early (< 3 hours) and empirically following major trauma. Early administration is important for its beneficial effect.

In the case of rapid haemorrhage, it is often not possible to use traditional laboratory results to guide the correction of coagulopathy because of the time delay in obtaining these results. This has lead to a formula-driven approach to the use of PRBC, FFP and platelets targeting the early empirical treatment of coagulopathy. Although the evidence for these strategies is still emerging, current military guidelines advocate the administration of warmed PRBC and fresh frozen plasma (FFP) in a 1:1 ratio as soon as possible in the resuscitation of major haemorrhage following trauma in conjunction with platelet transfusions to maintain platelets > 100 × 10⁹.

A recombinant form of activated factor VII (rVIIa) is approved for the management of bleeding in haemophiliacs with inhibitory antibodies to factors VIII or IX. Although rVIIa has been used effectively in the treatment of life-threatening haemorrhage in other patient groups, its use is associated with a significant rate of arterial thromboembolic events and it remains unclear whether its unlicensed use in these groups is justified.

Septic shock

The principles guiding the management of septic shock are:

The Surviving Sepsis Campaign has published evidence-based guidelines on the management of severe sepsis and septic shock: http://www.survivingsepsis.org .

Early recognition of severe sepsis and septic shock is critical. This requires a high index of suspicion together with a detailed history and examination to identify signs of organ dysfunction and potential sources of infection. Hospital-acquired infection should always be considered as a cause of clinical deterioration in surgical patients.

As with all forms of shock, the initial assessment and management of septic shock should follow an A, B, C approach. However, in patients with septic shock there is evidence that protocolized early goal-directed therapy (EGDT) improves survival (EBM 1.2) and this should be started as soon as signs of sepsis-induced tissue hypoperfusion are recognized (hypotension, elevated lactate, low central venous saturations or oliguria). The widely accepted resuscitation goals for the first 6 hours of this strategy are:

As described above, septic shock is associated with both relative and absolute hypovolaemia as a result of profound vasodilation and extravasation of fluid from the intravascular space. Both crystalloid and colloid can be used to restore intravascular volume although HES solutions should probably be avoided because of concerns about inducing acute renal failure. Current guidelines suggest a target CVP of ≥ 8 mmHg and this frequently requires large volumes of fluid. Persistent hypotension (MAP < 65 mmHg) following restoration of circulating volume is best treated with a vasopressor such as noradrenaline in the first instance. While the titration of fluid and vasopressor to a MAP ≥ 65mmHg should be sufficient to preserve tissue perfusion in most patients, this may not be the case in all patients (e.g. those with hypertension) and it is important to supplement these simple resuscitation end-points with additional markers of global tissue perfusion (lactate and central venous saturations) to determine whether oxygen delivery is adequate. If serum lactate is elevated (> 2 mmol/l) and central venous saturations are low (< 70%) in the context of septic shock this suggests inadequate tissue oxygen delivery with increased oxygen extraction from the blood and anaerobic metabolism. In this situation, oxygen delivery can be increased by transfusion of PRBC to achieve a haemoglobin concentration of about 10 g/dl (haematocrit around 0.3) and/or increasing cardiac output using an inotrope such as dobutamine.

In patients with hypotension unresponsive to fluid resuscitation and vasopressors, intravenous hydrocortisone has been shown to promote reversal of shock. However, this does not appear to translate into a mortality benefit and the use of corticosteroids is associated with an increased risk of secondary infections. Because of this, the use of corticosteroids in the treatment of refractory septic shock remains contentious.

Treatment of infection involves adequate source control and the administration of appropriate antibiotics. Source control includes the removal of infected devices, abscess drainage, the debridement of infected tissue and interventions to prevent ongoing microbial contamination such as repair of a perforated viscus or biliary drainage. This should be achieved as soon as possible following initial resuscitation and should be performed with the minimum physiological disturbance; where possible, percutaneous or endoscopic techniques are preferable to open surgery.

Intravenous antibiotics must be administered as soon as possible (EBM 1.3), preferably in discussion with a microbiologist. The choice depends on the history, the likely source of infection, whether the infection is community- or hospital-acquired and local patterns of pathogen susceptibility. Covering all likely pathogens (bacterial and/or fungal) usually involves the use of empirical broad-spectrum antibiotics in the first instance, with these rationalized or changed to reduce the spectrum of cover once the results of microbiological investigations become available.

One or more (peripheral) blood cultures should be taken prior to the administration of antibiotics but this must not delay therapy. Culture of urine, cerebrospinal fluid, faeces and bronchoalveolar lavage fluid may also be indicated. Targeted imaging (CXR, ultrasound, computed tomography) may also help identify the source of infection.

In septic patients at high risk of death, most of whom will have an Acute Physiology and Chronic Health Evaluation (APACHE) II ≥ 25 or multiple organ failure, there is some evidence that the early use of recombinant activated protein C (rhAPC) reduces mortality. However, it is clear that the use of rhAPC is associated with a significant risk of serious bleeding complications and this risk may be higher in surgical patients. This expensive therapy should only be used under the supervision of an intensive care specialist.

Cardiogenic shock

The commonest cause of cardiogenic shock is acute (anterior) myocardial infarction. As with other forms of shock, the management of cardiogenic shock is based upon the identification and treatment of reversible causes and supportive management to maintain adequate tissue oxygen delivery. This involves active management of the four determinants of cardiac output: preload, myocardial contractility heart rate, and afterload.

Routine investigations to identify the cause of cardiogenic shock include serial 12-lead ECGs, troponin or creatinine kinase-MB (CK-MB) levels and a CXR. A transthoracic echocardiogram may provide useful information on (systolic and diastolic) ventricular function and exclude potentially treatable causes of cardiogenic shock such as cardiac tamponade, valvular insufficiency and massive pulmonary embolus.

General supportive measures include the administration of high concentrations of inspired oxygenation. In patients with cardiogenic pulmonary oedema, there is some evidence that continuous positive airway pressure (CPAP) improves oxygenation, reduces the work of breathing and provides subjective relief of dyspnoea. It remains unclear whether these advantages translate into a significant survival benefit.

For patients with acute myocardial ischaemia, intravenous opiates should be titrated cautiously to control pain and reduce anxiety. In addition to providing analgesia, opiates reduce myocardial oxygen demand and reduce afterload by causing peripheral vasodilation.

As with all forms of shock, correction of hypovolaemia and optimization of intravascular volume (preload) is of central importance in maximizing stroke volume, cardiac output and tissue oxygen delivery. However, the management of fluid balance in cardiogenic shock can be challenging. Patients with acute heart failure and cardiogenic shock are usually normovolaemic or relatively hypovolaemic as a result of intravascular fluid loss into the lungs and the development of pulmonary oedema. In contrast, patients with chronic heart failure are usually hypervolaemic as a result of long-standing activation of the renin–angiotensin system and salt and water retention. The key point is that some patients in cardiogenic shock are hypovolaemic and require fluid resuscitation. This is best achieved by careful titration of a fluid challenge and assessment of the clinical response in an appropriately monitored environment (see above). Once hypovolaemia has been corrected and cardiac preload optimized, refractory hypotension and/or signs of inadequate tissue perfusion may require treatment with vasoactive drugs. This frequently requires a careful balance of vasodilator, inotrope and vasoconstrictor.

The major derangements in cardiogenic shock are a reduction in cardiac output and a compensatory increase in systemic vascular resistance. The use of a vasodilator such as glyeryltrinitrate (GTN) may reduce SVR (afterload) and improve cardiac output, but vasodilation frequently results in a significant reduction in blood pressure compromising tissue perfusion. Adrenaline, an α- and β-agonist with both inotropic and vasoconstricting actions, is frequently used in the emergency management of cardiogenic shock, increasing both myocardial contractility and SVR. However, while adrenaline may increase blood pressure, it significantly increases myocardial workload, potentially worsening myocardial ischaemia and profound vasoconstriction further reduces already-compromised tissue perfusion. Frequently, the most appropriate choice of vasoactive drug in cardiogenic shock is one that has both inotropic and vasodilating properties such as the β-agonist dobutamine. Alternative ino-dilating agents include the calcium sensitizer levosimendan and the phosphodiesterase inhibitor milrinone. Noradrenaline is also an effective treatment for cardiogenic shock under some circumstances. Whenever a vasoactive drug is given the patient requires monitoring in a high dependency or critical care area.

The intra-aortic balloon pump (IABP) is increasingly used as an adjunct in the supportive management of cardiogenic shock. This device works by inflating a balloon in the thoracic aorta during diastole, with deflation occurring in systole. Inflation during diastole augments the diastolic blood pressure improving coronary perfusion and myocardial oxygen delivery; deflation in systole reduces afterload. While it still remains unclear which patient groups benefit from insertion of an IABP, they are generally used as a bridge to more definitive treatment such as percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG) or mitral valve repair.

Anaphylactic shock

The management of anaphylactic shock is illustrated in Table 1.19.

Table 1.19 The management of anaphylaxis