Essential Notes for MRCS - Book 2(A)

and solutes, and excreting others.

Structure and function of the glomerulus
The glomerulus is a coiled capillary bed nestling inside Bowman’s capsule. It is supplied with blood via
an afferent arteriole and initial filtration of the plasma occurs through the fenestrated capillary
endothelium and the basement membrane of the capillary. The major barrier to flow is the basement
membrane. The total area available for filtration in the kidney is 1 m2. The blood then passes to the
efferent arteriole, which forms a second capillary bed around the tubules (peritubular capillaries) to
allow for reabsorption from the filtrate. The peritubular bed lies in the renal cortex and has long looping
capillaries (vasa recta) which project down into the medulla along with the juxtamedullary nephrons. Of
the blood flow to the kidneys 1–2% passes through the vasa recta and flow here is relatively sluggish.
Blood then drains back into the renal venules.



Figure 3.33 M odifications of the filtrate in the re nal tubule

Structure and function of the renal tubule
This extends from Bowman’s capsule around the glomerulus to the collecting ducts (eventually draining
into the ureter). Initially ultrafiltrate from Bowman’s space drains through the podocyte ‘foot’ processes
of the capsule into the proximal convoluted tubule (PCT). The PCT leads to the loop of Henle, which has
both thin descending and ascending limbs followed by a thick ascending limb. Subsequently, the distal
convoluted tubule (DCT) joins the cortical collecting duct, which runs into the medulla, forming the
medullary collecting duct. At each stage the filtrate is progressively modified by secretion and resorption
of water and electrolytes (Figure 3.33).

There are two types of nephrons with different functions:
Superficial cortical nephrons (80%): these have glomeruli lying close to the kidney surface and short
loops of Henle reaching only the outer medulla
Deeper juxtamedullary nephrons (20%): these have long loops of Henle which plunge deep into the
medulla. They are accompanied by the vasa recta, which are capillary loops derived from the efferent
glomerular arterioles. The vasa recta are involved in a countercurrent system that maintains a high solute
concentration in the renal medulla. They are used to concentrate urine and thus preserve water

The ultrafiltrate is modified in the tubules by a combination of passive and active processes:
Three sodium ions are actively transported out of the lumen by exchange for two K+ ions via an ATP-
driven ion pump in the tubule wall
This creates an electrical sodium gradient, encouraging simple diffusion of sodium out of the filtrate. Other
compounds such as glucose, chloride and some urea are also reabsorbed in this way
Sodium carrier proteins pull additional molecules (eg amino acids or glucose) into the cell with the Na+
ions. This is called ‘co-transport’
Water is drawn out of the tubules by means of passive osmosis


SUMMARY OF FILTRATE MODIFYING ACTIONS WITHIN THE TUBULE

Concentration and dilution of urine
The degree of urinary concentration is controlled by ADH (see ‘Renal hormones and their actions’ page
259). In the absence of ADH, the ascending loop of Henle, the DCT and the collecting ducts are relatively
impermeable to water, so a higher proportion of the water in the filtrate is excreted. Concentration of
urine is performed by the countercurrent mechanism and occurs in the long loops of Henle of the
juxtamedullary nephrons and the vasa recta. The renal medulla has a very hyperosmolar interstitial fluid,
maintained by active transport of NaCl. As the filtrate passes down the loop of Henle, water is drawn out
by the high medullary osmotic pressure. In the ascending limb, additional sodium and chloride are
actively transported out of the filtrate. Under the influence of ADH, the distal convoluted tubule and
collecting ducts become highly permeable to water. This portion of the nephron passes through the
hyperosmolar medulla, so allowing resorption of additional water and concentration of the urine.

Glomerular filtration rate

This is the net flow of filtrate across the basement membrane per unit time. It is the most sensitive
indicator of renal function. There is great functional reserve within the human kidney, and plasma levels
of urea and creatinine may be preserved despite massive loss of functioning nephrons. A representative
value for GFR in adults is about 125 ml/minute or 180 litres/day. This value varies according to age, sex
and body surface area.

GFR depends on:
The difference in hydrostatic pressure between the glomerular capillary and Bowman’s space (fluid
hydrostatic pressure is higher in the capillary, promoting filtration of the plasma). Hydronephrosis causes
an increase in the hydrostatic pressure of Bowman’s capsule, reducing the difference between them and
effectively reducing GFR
The difference in colloid osmotic pressure between the glomerular capillary and Bowman’s space (the
colloid osmotic pressure is that pressure exerted by the protein content of the fluid; here this is effectively
the colloid pressure of the plasma because very few proteins are filtered into Bowman’s capsule – this
opposes filtration)
The ultrafiltration coefficient is a constant related to the area and conductivity of the basement
membrane; it may be altered in conditions such as glomerulonephritis

As the glomerular capillary bed has an arteriole at either end (a unique situation) the hydrostatic pressure
in the capillaries is determined by both afferent and efferent arteriolar resistance. This allows very
precise regulation of capillary pressure and therefore glomerular filtration.
Afferent arteriolar vasoconstriction decreases both GFR and glomerular plasma flow • Efferent
arteriolar vasoconstriction reduces glomerular plasma flow, and also increases glomerular pressure, so
increasing GFR

Autoregulation holds the glomerular filtration pressure relatively constant despite variation in mean
arterial blood pressure over the range 80–180 mmHg. The mechanism for autoregulation is not completely
understood. However, it still occurs in denervated and isolated perfused kidney preparations, suggesting
that it is intrinsic to the kidney.

If renal perfusion pressure increases, afferent arteriolar resistance also increases, so that glomerular
blood flow and GFR remain constant. Conversely, when blood pressure falls the afferent arteriole
decreases in resistance, but the efferent arteriolar resistance increases to maintain GFR.

Juxtaglomerular apparatus
Tubuloglomerular feedback is another mechanism by which GFR is regulated. This is a negative feedback
system whereby the GFR is inversely related to fluid delivery to the distal nephron. It is controlled by
specialist cells in the juxtaglomerular apparatus (JGA). The JGA is located in the initial portion of the
DCT where the DCT bends upwards, and is situated between the afferent and efferent arterioles of the
glomerulus.

The JGA contains three cell types:
Macula densa cells (cells of the tubule involved in feedback) • Juxtaglomerular cells (smooth muscle cells
of the arterioles which secrete renin) • Extraglomerular mesangial cells

Measurement of GFR
There are a number of ways of measuring GFR. Each requires the use of a solute that is:
Detectable in plasma and urine
Freely filtered by the kidney
Not absorbed or secreted
Not toxic
Does not alter renal blood flow
This solute may be administered exogenously (eg inulin, which requires continuous infusion for a steady
plasma state) or may be produced endogenously (eg creatinine, which fulfils most of these requirements
apart from a degree of tubular secretion).

Creatinine clearance therefore gives an approximation of GFR. To calculate GFR:
GFR = [U × V]/P

where V is the volume of urine produced, P is the concentration of the solute in the plasma and U is the
concentration of the solute in the urine.

The filtration fraction is the proportion of plasma filtered by the glomerulus. It is expressed as the
relationship between GFR and renal blood flow and is normally about a fifth of the value of GFR.

Renal blood flow (RBF) can be calculated if it is considered that renal plasma flow (RPF) is equal to the
GFR, thus:

RBF = RPF/(1 – haematocrit)

Diuretics
Diuretics work by increasing urine volume. This can be achieved either by increasing renal tubular
excretion of sodium and chloride, which draws water with it, or by giving an osmotically active
substance such as mannitol.

Thiazides (eg bendroflumethiazide)
These act by inhibiting NaCl resorption in the DCT (thus exchanging urinary sodium loss for potassium
loss) by acting on tubular ATPase ion pumps. Side effects include hypokalaemia, hyperuricaemia
(alteration in the excretion of uric acid), glucose intolerance and hyperlipidaemia.

Loop diuretics (eg furosemide, bumetanide)
These act by inhibiting the co-transport of sodium, chloride and potassium in the thick ascending loop of
Henle. Potassium is lost in preference to sodium and so the hypokalaemic effect can be pronounced.

Potassium-sparing diuretics (eg spironolactone, amiloride)
These act as aldosterone antagonists and therefore prevent resorption of sodium in the DCT. These drugs
do not cause the body to exchange sodium loss for potassium loss and therefore do not cause
hypokalaemia. Care must be taken in the elderly not to cause hyperkalaemia.

Renal hormones and their actions

ADH/arginine vasopressin (AVP)
This hormone is produced by the cells of the supraoptic nucleus of the hypothalamus and is stored in the
posterior pituitary gland.

It is released by a number of stimuli:
Increased plasma osmolality (sensed by osmoreceptors in the brain) • Decreased blood pressure (sensed
by baroreceptors in the great vessels) • Decreased circulating volume (stretch receptors and increased
ANP)

Alcohol, opiates, prostaglandins, oestrogens and stress all decrease ADH secretion. ADH (AVP) acts to
increase salt and thus water reabsorption in the DCT, and to increase the permeability of the collecting
system and thus increase the amount of water reabsorbed as the filtrate passes through the medulla. This
concentrates the urine and reduces its volume.

Renin–angiotensin–aldosterone system
Renin is produced and stored in the smooth muscle cells of the JGA. It is released when arterial pressure
falls. It has several intrarenal functions and acts enzymatically on a plasma protein, angiotensin I.

Angiotensin I is fast converted to angiotensin II by angiotensin-converting enzyme (ACE) in lung
endothelium. Angiotensin II has three major actions:
It is a powerful vasoconstrictor, increasing arterial pressure • It acts directly on the kidney to conserve
sodium and water and to decrease renal blood flow, which reduces urine volume, gradually increasing
arterial pressure
It stimulates the production of aldosterone by the adrenal glands

Aldosterone causes increased sodium retention by the kidney tubules, which expands the ECF
compartment by causing retention of water.

Atrial natriuretic peptide
Over-stretching of the atrial wall by high volumes is sensed by stretch receptors and results in the release
of ANP into the bloodstream. This acts on the kidneys to increase sodium and water excretion and thus
reduce blood volume by increasing urine output.

Renal failure



In a nutshell ...

Renal failure is defined as failure of the kidneys to maintain the correct composition and volume of the
body’s internal environment. Patients undergoing major surgery are at risk of developing renal failure,
particularly in the postoperative period, where inadequate fluid rehydration is not uncommon.
Anuria is the absence of urine output. In most surgical patients, sudden anuria is more likely to be due
to a blocked or misplaced urinary catheter rather than to acute renal failure.

Oliguria is defined as a urine output of <0.5 ml/kg per hour. This is a much more likely presentation of
impending renal failure in surgical patients than anuria. It is not uncommonly seen after inadequate fluid
replacement.
Non-oliguric renal failure can also occur. It has a much lower morbidity.

Acute renal failure (ARF) is a rapid reduction in renal function (best measured by decrease in GFR or
increase in serum creatinine) that may or may not be accompanied by oliguria. The abrupt decline in renal
function occurs over hours or days.

The most useful classification system divides renal failure into:
Prerenal
Renal
Postrenal

Prerenal causes of renal failure

Volume depletion (eg haemorrhage, GI losses, dehydration, burns) • Abnormal fluid distribution (eg
distributive shock, cirrhosis, congestive cardiac failure (CCF) • Local renal ischaemia, eg renal artery
stenosis or prostaglandin inhibitors such as NSAIDs • Low-output cardiac failure
Raised intra-abdominal pressure (abdominal compartment syndrome)

Inadequate perfusion of the kidneys is the most common cause of renal failure in hospital.

Hypovolaemia is classified according to aetiology:
Loss of whole blood (haemorrhage)
Loss of plasma (burns)
Loss of crystalloid (dehydration, diarrhoea, vomiting)

Note that as far as possible one should replace like with like, ie blood after haemorrhage or water (given
as 5% dextrose) in dehydration. However, in many hypovolaemic patients, the priority is initially to
rapidly replace lost circulating volume. This is with blood, colloid or isotonic crystalloid, such as 0.9%
saline. The remaining fluid deficit can be made up more slowly with whatever fluid most closely
resembles the fluid losses.

The typical mechanism is that hypoxaemia and hypoperfusion reduce sodium absorption in the ascending
loop of Henle, which is a high-energy-consuming process. Hence the JGA detects increased filtrate
sodium concentration, and so reduces renal blood flow to conserve blood volume, resulting in reduced
urine output. Appropriate treatment should reverse this process before ischaemic damage and acute
tubular necrosis (ATN) occurs.

Renal causes of renal failure

Intrinsic renal pathology:
ATN due to prolonged ischaemia or tubular toxins, including drugs (eg gentamicin) • Glomerulonephritis
or vasculitis (eg SLE, polyarteritis nodosa, Wegener’s granulomatosis) • Goodpasture syndrome (anti-
glomerular basement membrane antibodies) • Interstitial nephritis
Vascular lesions: hypertension, emboli, renal vein thrombosis • Infections such as pyelonephritis

Contrast-induced nephropathy

Postrenal causes of renal failure

Obstruction to the flow of urine along the urinary tract:
Pelvicalyceal: usually at pelviureteric junction (PUJ) (eg bilateral PUJ obstruction) • Ureteric:
luminal/intramural extrinsic obstruction; retroperitoneal fibrosis, stone • Bladder/urethral outflow
obstruction: urinary retention, prostatic enlargement, high pressure or atonic bladder, urethral stricture,
blocked catheter, cervical prostatic neoplasm



The most important causes of renal failure that must not be missed (because they are so easily
treatable) are prerenal, especially hypovolaemia/dehydration, and postrenal (particularly prostate or
catheter problems). Also, inadequate rehydration of a postobstructive diuresis commonly results in
prerenal failure.

Prevention of renal failure

Prevention of hypotension or hypovolaemia
Prevention of dehydration (especially in patients who continue to receive their ‘normal’ diuretic
medication) • Early treatment of sepsis
Caution with potentially nephrotoxic drugs (eg NSAIDs, gentamicin): in all cases monitor renal function
closely, substitute these drugs with non-nephrotoxic equivalents if there is any indication of deterioration
in renal function
Prophylactic intravenous fluid hydration 24 hours pre- and post-contrast administration in those with pre-
existing renal disease and consider use of an antioxidant, eg N-acetylcysteine

Assessment of acute renal failure

Differentiating causes: renal and prerenal failure
This is initially on the basis of a history and examination (postrenal failure is usually clinically evident
and the main differentiation exists between establishing renal from prerenal failure).
History
Examination
Serum urea and creatinine
Blood gases: a metabolic acidosis may occur • Paired urinary and serum measures of osmolality and
sodium • Response to fluid challenge: this may distinguish between prerenal and renal causes. If no
diuresis occurs with adequate fluid replacement, consider a renal cause
Bladder scanning for residual volume and catheterisation: this diagnoses retention • Renal tract
ultrasonography and Doppler: these show renal blood flow, and evidence and level of hydronephrosis



Urine analysis and serum biochemistry
Where there is still a query as to the cause of renal failure, an analysis of the urine and serum
biochemistry is performed. This is one of the simplest and most effective ways of differentiating
prerenal from intrinsic renal failure.

Measurement Prerenal Renal

Urinary sodium Low: High:

<20 mmol/l >40 mmol/l

Urine

Serum osmolarity ratio >1.2 <1.2

Serum creatinine ratio High: > 40 Low: <20

Urine osmolality >500 <350

Normally functioning kidneys, in the presence of hypotension or hypovolaemia, will concentrate urine and
conserve sodium (meaning that there will be less in the urine). If there is intrinsic renal pathology, the
kidney will be unable to concentrate the urine or conserve sodium.

Management of renal failure

The important steps in the management of oliguria are:
Exclude obstruction: insert catheter or flush existing catheter • Correct hypovolaemia and hypotension:
may need CVP ± PA catheter and assessment of response of CVP to fluid boluses. When optimally filled,
inotropes or vasopressor may be required to provide adequate perfusion pressure (perfusion pressure
may need to be increased in people with hypertension) • Fluid maintenance after resuscitation: includes
infusing volume equivalent to urine output each hour plus insensible losses (about 1000 ml/24 hours).
Insensible losses will be increased in pyrexia
Treat the cause or any contributing factors: eg stop NSAIDs and ACE inhibitors. Prostaglandin
inhibition by NSAIDs causes renal vasoconstriction

In addition, various treatments are often used to try to reverse/prevent renal failure. Examples of such
treatments are:
Dopamine or dopexamine: cause stimulation of dopamine receptors • Sodium loading with NaHCO3 to
reduce oxygen-dependent sodium retention by the nephron • Mannitol: increases urine output by osmotic
diuresis. Does not prevent renal failure; some evidence of nephrotoxicity. Used successfully to reduce
renal damage in jaundice and rhabdomyolysis. Be aware that induced diuresis can cause hypovolaemia
and reduce renal perfusion

However, none of these treatments has been proved to prevent renal failure and the other measures
described above are much more important.

Review of drug therapy for patients with renal failure

All drug therapy given to patients in renal failure needs to be regularly and thoroughly reviewed.
Drugs that may exacerbate renal failure or its complications (eg NSAIDs, ACE inhibitors, gentamicin and
potassium-sparing diuretics) should be avoided
Many drugs need dose adjustment to prevent overdosage because they, or their active metabolites, are
excreted by the kidneys (this includes most antibiotics)
If possible, serum drug levels should be checked and drug doses adjusted accordingly

Optimisation of serum biochemistry in renal failure

The following biochemical abnormalities commonly occur:
Progressive rise in urea and creatinine
Hyperkalaemia
Hyponatraemia (due to relative water overload)
Acidosis
Hypocalcaemia
Hyperphosphataemia
Hyperuricaemia

The abnormalities requiring most urgent correction are hyperkalaemia and acidosis.

Treatment of hyperkalaemia
10 ml IV 10% calcium chloride (does not reduce potassium levels but reduces risk of cardiac arrhythmia)
• 10 units IV insulin + 50 ml 50% dextrose
Sodium bicarbonate infusion
Salbutamol or other β agonist
Calcium resonium: orally or per rectum (reduces total body potassium, but poorly tolerated orally and
works slowly) • Stop potassium-containing infusions (which may include TPN or enteral feed) • Stop
drugs such as potassium-sparing diuretics

Insulin, β agonists and sodium bicarbonate do not reduce total body potassium. They increase
intracellular potassium and so reduce the serum potassium. This reduces the risk of a fatal arrhythmia, but
is only a short-term measure; haemofiltration/haemodialysis will be required medium/long-term to
prevent hyperkalaemia unless renal function improves.

Treatment of acidosis
If artificially ventilated, increase the minute ventilation • Sodium bicarbonate infusion (but this is
controversial; may paradoxically increase intracellular acidosis and is only a short-term measure)
Artificial renal support

Nutritional requirements in patients with renal failure
High-calorie diet needed, with adequate high-quality protein. Maximum of 35 kcal/kg per day (about
2500 kcal) plus 14 g nitrogen/day.

Treatment of infection in patients with renal failure
Infection and generalised sepsis may already be apparent as the cause or contributing factor in the
development of renal failure. If the cause of renal failure (or other organ system failure) is sepsis it is
unlikely to improve until the source of the sepsis is eradicated (eg intra-abdominal collection).

Renal replacement therapy

In established renal failure, artificial support may be required. This is commonly achieved by
haemodialysis.

Indications for renal replacement therapy

Hyperkalaemia (persistently >6.0 mmol/l)
Metabolic acidosis (pH <7.2) with negative base excess • Pulmonary oedema/fluid overload without
substantial diuresis • High urea (30–40 mmol/l)
Complications of chronic uraemia (eg pericarditis/cardiac tamponade) • Creatinine rising >100 μmol/l per
day
The need to ‘make room’ for ongoing drug infusions and nutrition, and to aid clearance of drugs already
given (eg sedatives)

Methods of renal replacement therapy

CAVH Continuous arteriovenous haemofiltration

CVVH Continuous venovenous haemofiltration

CVVHD Continuous venovenous haemodiafiltration

HD Haemodialysis

In the ITU, both haemofiltration and haemodiafiltration are commonly performed via a large-bore dual-
lumen central venous cannula (CVVH). As the flow of blood is both from and to the venous side of the
circulation, a pump is required. The blood flow is in the region of 250 ml/minute and alarms are
incorporated to prevent air embolism. Anticoagulation is needed and heparin is usually used as an
infusion or prostacyclin if thrombocytopenia develops. Previously, arteriovenous systems were used, but
a large-bore catheter needs to be placed in an artery and filtration depends on arterial pressure. These
techniques provide slow fluid shifts and maintain haemodynamic stability.



Figure 3.34 Hae mofiltration and hae modialys is

In haemofiltration the blood is driven under pressure through a filter (a semipermeable membrane). The
‘ultrafiltrate’ derived from the blood (which is biochemically abnormal) is disposed of and replaced with
a replacement fluid. Small molecules such as sodium, urea, creatinine and bicarbonate pass through the
filter with water but large molecules such as proteins and cells do not. The usual volume of filtrate
produced is 1–2 l/hour and this volume is replaced with an electrolyte solution containing ions and buffer.
The replacement fluid is buffered with lactate, acetate or freshly added bicarbonate. The system provides
a clearance equivalent to 10 ml/minute and if solute clearance is inadequate then augmentation with
dialysis can be used (CVVHD).

In haemodiafiltration (CVVHD) the dialysate augments clearance by diffusion by running an electrolyte
solution on the outside of the filter. The clearance increases to about 20 ml/minute. Fluid balance over 24
hours can be manipulated using these filters. If the patient is oedematous then removal of 2 litres may be
appropriate and can be achieved by replacing 84 ml less per hour than is filtered.

In HD blood is pumped through the machine on one side of a semipermeable membrane, in a manner
similar to haemofiltration. However, in HD dialysis fluid is also pumped through the machine, on the
other side of the semipermeable membrane, to the blood. The biochemistry of the blood equilibrates with
that of the dialysis fluid by diffusion, although some ultrafiltration also occurs.

HD tends to be more effective in terms of correcting acidosis and abnormal biochemistry in a short period
of time. However, it is associated with more circulatory instability; continuous haemofiltration is often
better tolerated in patients with circulatory instability.



Continuous ambulatory peritoneal dialysis (CAPD) is becoming more common. Fluid is instilled into
the peritoneum by a special catheter (eg Tenckhoff catheter). The peritoneum acts as the dialysis
membrane. Increasingly this method is chosen by patients because they can perform it at home, but it is
unsuitable for inpatients or those on ITU.

3.4 Systemic inflammatory response syndrome



In a nutshell ...

Systemic inflammatory response syndrome (SIRS) is a disseminated inflammatory response that may
arise as a result of a number of insults.
It is described as a syndrome because the symptoms and signs can be produced by processes other than
just infection.
SIRS is a harmful, excessive reaction of acute phase response. It is defined by two or more of the
following:
Tachycardia >90 beats/minute
Respiratory rate >20 breaths/minute or PaCO2 >4.3 kPa • Temperature >38°C or <36°C
WCC >12 or <4 × 103/mm3

Pathophysiology of SIRS

SIRS is a disseminated inflammatory response that may arise as a result of a number of insults:
Infection and sepsis
Ischaemia–reperfusion syndrome
Fulminant liver failure
Pancreatitis
Dead tissue

Any localised injury stimulates an inflammatory response. This response involves recruitment of
inflammatory cells (such as macrophages and neutrophils) to the area, release of inflammatory mediators
(eg cytokines, IL-1, IL-6, IL-8, TNF-α), and changes in vascular permeability.
These localised inflammatory responses are responsible for minimising further damage (eg from infection)
and optimising conditions for healing
Under certain conditions (eg major trauma) the extent of the inflammatory activity throughout the body is
activated in an apparently uncontrolled manner, with an imbalance between inflammatory and anti-
inflammatory responses
The widespread activity of this systemic inflammation (SIRS) and activation of a mediator network is such
that it damages organs throughout the body, potentially initiating MODS

Important components of the inflammatory response

Oxygen free radicals
Occur after initial hypoxic injury and subsequent reperfusion (ie reperfusion injury) • Mechanism involves
the formation of xanthine oxidase during ischaemia from xanthine dehydrogenase which converts
adenosine to hypoxanthine
When oxygen becomes available the hypoxanthine is metabolised to uric acid via the enzyme xanthine
oxidase and oxygen free radicals are formed in the process
Cause direct endothelial damage and increased permeability

Cytokines
Peptides released by various cell types which are involved in the immune response • Produced by
macrophages
TNF: central mediator in sepsis, produces deleterious effects similar to effects of infection; pivotal role in
host response • IL-1: synergistic with TNF; initiator of host response; stimulates T-helper cells • IL-6/IL-
8: reparative processes; production of acute phase proteins

Macrophages
Phagocytosis of debris and bacteria
Act as antigen-presenting cells to T lymphocytes
Release inflammatory mediators, endothelial cells and fibroblasts

Neutrophils
Migrate to inflamed tissue from the blood
Release mediators
Release proteolytic and hydrolytic enzymes, which cause vasodilatation, increased permeability,

myocardial depression and activation of clotting mechanisms

Inducible intercellular adhesion molecules (ICAMs)
Mediation of adhesion and migration of neutrophils through endothelium • Induced by lipopolysaccharides
(LPSs) and cytokines

Platelet-activating factor (PAF)
Released by neutrophils and monocytes
Cause hypotension, increased permeability and platelet aggregation

Arachidonic acid metabolites
Essential fatty acid
Metabolised by cyclo-oxygenase to form prostaglandins and thromboxane, and by lipoxygenase to form
leukotrienes (LTs)

Vascular endothelium
Increased permeability, allowing both inflammatory cells and acute phase proteins from the blood to reach
the injured (inflamed) area • Complex organ in its own right, involved in vascular tone, permeability,
coagulation, phagocytosis and metabolism of vascular mediators • Nitric oxide: induced form stimulated
by TNF and endotoxin via nitric oxide synthase; causes sustained vasodilatation • Endothelin-1: powerful
vasoconstrictor, increased in trauma and cardiogenic shock

Complement cascade
Occurs in early septic shock via the alternative pathway
Attracts and activates neutrophils

Vasodilatation
Allowing increased recruitment of inflammatory cells from the blood


In the systemic inflammatory response syndrome, it is these changes in the vascular endothelium which,
when widespread, cause circulatory failure and hypotension, contributing to MODS.

The ‘two-hit’ hypothesis and the role of the gut

The gut is thought to have an important role in the development of SIRS and a ‘two-hit’ theory has been
postulated. The initial cellular insult (cellular trauma or shock states) sets up a controlled inflammatory
response. A second insult is then sustained by the patient (eg repeated surgery, superimposed infection,
bacteraemia or persistent cellular damage). This creates a destructive inflammatory response and results
in loss of intestinal mucosal integrity, allowing translocation of bacteria and endotoxin into the portal
circulation which further feeds back into the immuno-inflammatory cascade.

3.5 Sepsis and septic shock

Definitions in sepsis

Infection: microbiologically proven clinical condition with host response • Sepsis: the body’s response to
infection in the presence of SIRS
Severe sepsis: sepsis with evidence of organ dysfunction or hypoperfusion • Septic shock: severe sepsis
with hypotension (<90 mmHg) despite fluid resuscitation • Septicaemia: clinical signs and symptoms
associated with multiplying bacteria in the bloodstream • Bacteraemia: bacteria in bloodstream but not
necessarily symptomatic or requiring treatment • Endotoxin: toxin that remains within the cell wall of
bacteria. Heat stable. Lipid A conserved among different organisms acts to trigger various mediators
responsible for sepsis
Exotoxin: toxin actively secreted by a bacterium, with specific effects according to organism • Carriage:
two consecutive surveillance samples of throat and rectum that are positive for microorganisms •
Colonisation: presence of microorganisms in a normally sterile organ without host response (eg throat,
gut)



Factors predisposing to sepsis in critical care
Impaired barriers
Loss of gag reflex – reduced level of consciousness, drugs • Loss of cough reflex – drugs, pain
Ciliary function – high inspired O2, dry O2, intubation • Gut mucosal barrier – ischaemia, change in gut
flora (antibiotics) • Urinary catheters predispose to urinary tract infection
IV/arterial lines breach skin barrier
Impaired defences
Cell-mediated immunity
Humoral immunity
Reticuloendothelial system
Caused by trauma, shock, postop, sepsis, age, malnutrition, malignancy, splenectomy (humoral),
immunosuppressive drugs

Gram-positive bacteria are the most common cause of infection (eg staphylococci), having taken over
from Gram negatives such as Pseudomonas spp., Escherichia coli and Proteus spp. Organisms such as
Acinetobacter spp. are a particular problem on ITUs after use of broad-spectrum antibiotics or in
immunosuppression, as are fungal infections (eg Candida and Aspergillus spp.).

Local antibiotic policy on ITUs should be formulated by collaboration with the microbiologist so that
appropriate antibiotics for local organisms are used, as well as being based on culture and sensitivity.

Typical policies follow patterns such as:


cephalosporin + metronidazole ± gentamicin (renal toxicity)

↓


If unsuccessful

↓

Broad-spectrum anti-pseudomonals such as:


piperacillin + tazobactam


ciprofloxacin


ceftazidime


or

imipenem/meropenem

Antibiotic policy should be guided by culture and sensitivity of sputum, blood, wound and urine samples,
but quite often these are not available, so broad-spectrum agents are used in the first instance. Take
advice from your microbiologist.
For MRSA: teicoplanin, or vancomycin (beware toxicity)
For fungal infections: fluconazole followed by amphotericin if resistant or Aspergillus spp.

Infection on ITUs

Community acquired: tend to be sensitive organisms
Nosocomial: tend to be resistant species
Gram-positive organisms are more common, but Pseudomonas spp. and other Gram negatives still occur •
EPIC (European Prevalence of Infection in Intensive Care) study showed 21% of infections are acquired
within ITUs

Septic shock

Classically this is a combination of high cardiac output, low systemic resistance, maldistribution of blood
flow and increased vascular permeability. There is suppression of cardiac contractility but tachycardia
increases the cardiac output. Vasodilatation results from nitric oxide production. The physiological effects
seen in septic shock result from the cytokines of the inflammatory response and therefore may also be due
to an inflammatory rather than infective stimulus (eg pancreatitis).

Clinical features of septic shock

Pyrexia
Tachycardia
Peripherally warm, flushed
Hypotensive, low CVP
Acidotic (lactic acidosis)

Note that NSAIDs and corticosteroids can mask pyrexia. Corticosteroids may also mask peritonitis.

Management of septic shock

Management of sepsis-induced shock, defined as tissue hypoperfusion (hypotension persisting after initial
fluid challenge or blood lactate concentration ≥4 mmol/l) essentially comprises:
Identify and treat the cause
Support organ function



The Surviving Sepsis Campaign and management of septic shock
The Surviving Sepsis Campaign has published international guidelines (2008) on the recognition and
management of severe sepsis in an attempt to decrease the high mortality rates. Its recommendations
are:
Initial resuscitation (first 6 hours)
Begin fluid resuscitation and high-flow oxygen immediately in patients with hypotension or elevated
serum lactate ≥4 mmol/l; aim to achieve haemodynamic goals of:
Central venous pressure 8–12 mmHg
Mean arterial pressure (MAP) ≥65 mmHg
Urine output ≥0.5 ml/kg per hour
Central venous (SVA) or mixed venous oxygen saturation ≥70% or ≥65%, respectively

If venous oxygen saturation target is not achieved:
Consider further fluid
Transfuse packed red blood cells if required to hematocrit of ≥30%, and/or • Start dobutamine infusion,

maximum 20 μg/kg per minute
Diagnosis
Obtain appropriate cultures before starting antibiotics provided that this does not significantly delay
antimicrobial administration • Obtain two or more blood cultures
One or more blood cultures should be percutaneous
One blood culture from each vascular access device inserted ≥48 hours ago • Culture other sites as
clinically indicated (urine, the tip from any line that you change, pus after drainage of collections, etc) •
Perform imaging studies promptly to confirm and sample any source of infection, if safe to do so
Antibiotic therapy
Begin IV antibiotics as early as possible and always within the first hour • Broad-spectrum: one or more
agents active against likely bacterial/fungal pathogens and with good penetration into presumed source •
Reassess antimicrobial regimen daily with culture results to optimise efficacy, prevent resistance, avoid
toxicity and minimise costs • Duration of therapy typically limited to 7–10 days, longer if response is
slow or there are undrainable foci of infection or immunological deficiencies
Stop antimicrobial therapy if cause is found to be non-infectious
Source identification and control
A specific anatomical site of infection should be established as rapidly as possible. Look for a focus of
infection amenable to active treatment such as surgical resection, percutaneous or open abscess drainage,
tissue debridement, etc (noted exception: infected pancreatic necrosis, where surgical intervention is
best delayed)
Remove intravascular access devices if potentially infected and send the tip for culture



Additional critical care management
Transfusion: give packed red cells if Hb <7 g/dl • Hyperglycaemia: should be managed with sliding-

scale IV insulin • Prophylaxis: use LMWH for DVT prophylaxis and H2-receptor blocker for stress
ulcer prophylaxis • Steroids: consider IV hydrocortisone (dose should be ≤300 mg/day) for septic

shock if hypotension responds poorly to fluid and vasopressors but do not use steroids to treat sepsis in
the absence of shock. Steroids can be stopped once vasopressors are no longer needed • Recombinant
human activated protein C (rhAPC): consider rhAPC in adult patients with sepsis-induced organ
dysfunction with clinical assessment of high risk of death (typically APACHE II ≥25 or multiorgan
failure) • Nutrition: use enteral nutrition unless not absorbing; consider TPN

Complications of sepsis and septic shock

Metabolic acidosis
DIC
MODS/MOF (multiorgan failure)
Hypercatabolic state and hyperglycaemia
Stress ulcers
Pulmonary hypertension

Septic shock has approximately a 50% mortality rate.

3.6 Multiorgan dysfunction syndrome

Definitions of individual organ system failure

Cardiovascular failure (one or more of the following)

Heart rate <54 beats/minute or symptomatic bradycardia • MAP <49 mmHg or (>70 mmHg requiring
inotropic support) • Occurrence of ventricular fibrillation or tachycardia (VT or VF) • Serum pH <7.24
with normal PCO2

Respiratory failure

Respiratory rate <5 or >49 breaths/minute
PaCO2 >6.65 kPa • Alveolar–arterial gradient >46.55
Ventilator-dependent on day 4 in ITU

Renal failure

Urine output <479 ml in 24 hours, or <159 ml in 8 hours • Urea >36 mmol/l
Creatinine >310 μmol/l
Dependent on haemofiltration

Haematological failure

White cell count <1/mm3
Platelets <20 × 109/l
Haematocrit <0.2%
DIC

Neurological failure

GCS <6 in the absence of sedation

Gastrointestinal failure

Ileus >3 days
Diarrhoea >4 days
GI bleeding
Inability to tolerate enteral feed in absence of primary gut pathology

Skin failure

Decubitus ulcers

Endocrine failure

Hypoadrenalism or abnormal thyroid function tests

Multiple system failures

MODS may also be referred to as MOF and is an important cause of death in intensive care. It refers to
the process whereby more than one organ system has deranged function and requires support. Patients do
not often die from single organ failure but from the development of MOF following the initial insult.

The degree of dysfunction can be difficult to quantify (eg dysfunction of the GI tract) or easily quantifiable
(eg renal dysfunction, quantified by the degree of oliguria, serum biochemistry and acid–base status).

When assessing the degree of dysfunction, account must be taken of the support being provided for the
organ system (eg for respiratory failure the concentration of inspired oxygen and ventilatory support must
be considered when assessing PaO2).

MOF is a process that develops over a period of time, and can be in response to an initial severe stimulus
(eg major burn, sepsis, multiple trauma, major surgery) or after several seemingly minor insults.

The development of MOF depends more on the pre-existing physiological reserve of the organs and the
body’s response to a given stimulus than the stimulus itself. This may explain why different patients, with
seemingly similar pathology or injuries, differ in their tendency to develop MOF.

Outcome of MOF

The prognosis of established multiorgan failure is extremely poor:
In two-organ failure, the mortality rate is in the region of 50% and increases to 66% on day 4
In three-organ failure, the mortality rate is around 80% on the first day, increasing to 96% if it does not
resolve • In four-organ failure, survival is unlikely

Pre-existing medical condition and age must be considered in the outcome of MOF.

Treatment and prevention of MOF

The emphasis must be on identifying at-risk patients early, and intervening quickly to prevent MOF.

In order to optimise the chances of recovery, the initial insult (eg intra-abdominal sepsis) must be treated
if possible. Supportive treatment for specific organ systems is the mainstay of treatment. Early nutritional
support, particularly via the gut (enteral feeding), is increasingly being recognised as important in
improving outcome.

Various anti-inflammatory treatments have been attempted, affecting different parts of the inflammatory
response (eg anti-endotoxin antibodies, IL-1 antibodies), but in clinical trials none seems to have any
effect on the outcome. This is due to the complex and multiple pathways involved.

CHAPTER 4

Infection and Inflammation

Claire Ritchie Chalmers

Inflammatory processes
1.1 Acute inflammation
1.2 Chronic inflammation
1.3 Clinical indicators of inflammation
1.4 Anti-inflammatory pharmacology

The immune system
2.1 Non-specific mechanisms of immunity
2.2 Specific mechanisms of immunity
2.3 Disorders of immunity
2.4 Management of the immunocompromised patient

Disease-causing organisms
3.1 Bacteria
3.2 Viruses
3.3 Fungi
3.4 Parasites

Surgical infections
4.1 Recognition of a septic patient
4.2 Fever in a postoperative patient
4.3 Abscess management
4.4 Necrotising fasciitis

4.5 Gangrene
4.6 Specimen collection

Prevention and control of infection
5.1 Infection control
5.2 Skin preparation
5.3 Asepsis and sterilisation
5.4 Surgical measures to reduce infection
5.5 Vaccination
5.6 Sharps injury

Antibiotic control of infection
6.1 Types of antibiotic
6.2 Empirical treatment
6.3 Antibiotic prophylaxis
6.4 Microbial resistance

SECTION 1

Inflammatory processes

In a nutshell ...

Inflammation is a stereotyped response of living tissue to localised injury. It may be acute or progress
to chronicity. It is not the same thing as infection (which is a cause of inflammation). There is a
spectrum of inflammation ranging through:
Acute inflammation
Characterised by dilated and leaky vessels
Mediated by neutrophils and multiple chemical mediators
Chronic inflammation
Mediated by T-helper cells
Recruits other cells of the immune system such as B cells, macrophages and eosinophils • Cells
involved in repair (fibroblasts and angioblasts) are involved

1.1 Acute inflammation



In a nutshell ...

Acute inflammation is a stereotyped response to local injury and an essential component of wound
repair. It occurs by a combination of: Changes in microcirculation (vasodilatation and increased
vascular permeability) Recruitment and activation of phagocytic cells (mediated by neutrophils)
These events are mediated by the release of chemical mediators:
Complement
Kinins
Arachidonic acid derivatives (prostaglandins, leukotrienes) • Histamine
Serotonin (5HT)
Interleukins, cytokines and monokines
Platelet-activating factor (PAF)
Acute inflammation results in resolution, regeneration, abscess formation, scarring or chronic
inflammation.

Causes of acute inflammation

Inflammation is the essential response of living tissue to trauma. It destroys and limits the injury and is
intimately related to the process of repair. It is therefore an integral component of the body’s defence
mechanisms, and without it there would be no defence against foreign organisms and no wound healing.

Acute inflammation is usually beneficial, although it can occasionally be harmful (eg anaphylaxis, acute
lung injury, systemic inflammatory response syndrome).



Causes of acute inflammation include:
Trauma (mechanical, thermal, radiation, chemical – includes stomach acid, bile and blood when free in

the peritoneal cavity) • Infection (bacteria, virus, parasite, fungus)
Ischaemic injury
Immunological attack (autoimmunity, graft vs host disease) • Foreign body response (eg mesh in hernia

repair)

Mechanism of acute inflammation

Vasodilatation and vascular permeability

After the initial injury there is a rapid and transient arteriolar vasoconstriction (reduces blood loss in
case of vascular injury). Damage to the vasculature results in a collection of blood and activation of the
clotting cascade. The resulting clot fills the wound and consists of a mesh-like fibrin plug in which are
trapped a number of activated platelets. Activation of the platelets results in the release of a number of
inflammatory mediators. Platelet activation may also activate the complement cascade.

The plasma contains four interlinked enzyme cascades – the clotting cascade, fibrinolysis cascade,
complement cascade and kinin system. These cascades are interrelated and can be activated by each
other’s products. They are discussed in detail in Chapter 3.



Important inflammatory mediators released by platelets
Prostaglandins
Leukotrienes
Histamine
Serotonin

The release of prostaglandins (PGs) and nitric oxide results in persistent arteriolar smooth muscle
relaxation and therefore increased local blood flow (‘rubor’ and ‘calor’); 5HT, histamine, leukotrienes
and complement proteins (C3a and C5a) cause activation of the endothelium, resulting in increased
vascular permeability and exudation of fluid and plasma proteins. Increased oncotic pressure in the
interstitial fluid draws water out from the vessels and causes tissue oedema – ‘umour’.

Vessel permeability

Due to three different responses
The immediate-transient response begins at once, peaks at 5–10 minutes, and is over by 30 minutes. It is
due to chemical mediators (prostaglandins, histamine, 5HT). It involves only the venules and is due to
contraction and separation of endothelial cells



Figure 4.1 Acute inflammation


The immediate-prolonged reaction is seen only when the injury is severe enough to cause direct
endothelial cell damage (eg trauma to the blood vessel). It persists until the clotting cascade ends it
The delayed-prolonged leakage phenomenon is seen only after hours or days. Venules and capillaries
exude protein because their junctions separate due to apoptosis of the endothelial cells
In addition, endothelial cells are damaged as the leucocytes squeeze through the capillary walls and there
is a degree of endothelial cell apoptosis. As the tissues heal, new blood vessels are formed which are, in
themselves, leaky. This leakage of fluid from the vessels causes sludging or stasis in the capillary blood
flow because there is a relative increase in the viscosity (thus the application of plasma viscosity
measurement in inflammatory states).

Cellular events in acute inflammation

Initially neutrophils, and later macrophages, rapidly migrate to the injured area. Their subsequent
activities involve the steps as shown in the box overleaf.


Recruitment of inflammatory cells
Margination: as blood flow decreases, leucocytes move from the centre of the vessel to lie against the
endothelium.

Pavementing: adhesion molecules on leucocytes (eg integrins) bind to corresponding molecules on the
endothelium (eg intercellular adhesion molecule 1 [ICAM-1] – see below); expression of these
adhesion molecules is upregulated by specific inflammatory mediators (C5a, interleukin 1 [IL-1],
tumour necrosis factor [TNF]) in the locality of the inflammation.
Diapedesis or emigration: adherent leucocytes pass through interendothelial junctions into the
extravascular space; neutrophils are the predominant cell type in the first 24 hours, after which
monocytes predominate.
Chemotaxis: leukocytes move to the injury site along a chemical gradient assisted by chemotactic
factors (bacterial components, complement factors, leukotriene [LT]–B4).
Phagocytosis and intracellular degradation: opsonised bacteria (opsonins IgG and C3b) attach via Fc
and C3b receptors to the surface of neutrophils and macrophages; the bacteria/foreign particle is then
engulfed to create a phagosome, which then fuses with lysosomal granules to form a phagolysosome,
and the contents of the lysosome degrade the ingested particle.

ICAM-1, ICAM-2 and integrins
ICAM-1 and ICAM-2 are cell adhesion molecules belonging to the Ig gene superfamily. They are
expressed on endothelial cells (upregulated by inflammatory mediators) and act as receptors for β2-
integrin (expressed on neutrophils, eosinophils and T cells). The integrin ‘hooks on’ to the ICAM
molecule and this interaction allows the leucocyte to adhere to the endothelium and emigrate into the
tissue from the bloodstream. Integrins thus allow cell–cell interactions and cell–extracellular matrix
(ECM) interactions.

The ICAM family is upregulated in certain disease states such as allergy (eg atopic asthma, allergic
alveolitis), autoimmunity (eg type 1 diabetes mellitus, systemic lupus erythematosus [SLE], multiple
sclerosis [MS]), certain cancers (eg bladder, melanoma), and infection (eg HIV, malaria, tuberculosis
[TB]), allowing increased leucocyte infiltration of non-inflamed tissue. Reduction in the numbers of
cellular adhesion molecules occurs in disease (eg diabetes, alcoholism, steroid treatment) and results in a
reduced immune response to bacterial infection.

Cellular components of the inflammatory infiltrate
The neutrophils are the predominant cell type in the inflammatory phase in the first 24 hours. They
degranulate, releasing their lysosomal contents, and also initiate phagocytosis of bacteria and cell debris.
Phagocytosis requires that the particle be recognised and attach to the neutrophil. Most particles must be
coated (opsonised) by IgG or complement protein C3b. There are receptors for both on the neutrophil
surface. The particle will then be engulfed and a lysosome membrane fused with the phagosome
membrane, causing digestion within the phagolysosome. Macrophages become the predominant cell type
after 48 hours. They continue the process of phagocytosis and secrete growth factors (cytokines) which
are instrumental in ECM production. Macrophages are also responsible for fibrosis, and heavy or
prolonged inflammatory infiltrates are associated with severe scarring.

Inflammatory mediators in acute inflammation

The inflammatory response to trauma is mediated by chemical factors present in the plasma and produced
by the inflammatory cells, as shown in the following table.

Mediators of the inflammatory response

Plasma Cells

Vasoactive amines (eg histamine, serotonin)

Complement system

Kinin system Lysosomal enzymes

Coagulation pathway Arachidonic acid derivatives

Cytokines (eg TNF-α, interleukins)

Fibrinolytic system

Free radicals



Important cytokines responsible for chemotaxis
Transforming growth factor β (TGF-β)
Basic fibroblast growth factor (bFGF)
Platelet factor 4 (PF-4)
β-Thromboglobulin (β-TG)
Vascular endothelial growth factor (VEGF)
Platelet-derived growth factor (PDGF)
Monocyte chemotactic protein 1 (MCP-1)
Keratinocyte growth factor (KGF)
Epidermal growth factor (EGF)
Fibroblast growth factor (FGF)

Complement system
The complement system consists of over 20 component proteins.
The classical pathway is initiated by antigen–antibody complexes • The alternative pathway is activated
by endotoxins, complex polysaccharides and aggregated immunoglobulins

Both pathways convert C3 to C3a and C3b.
C3b initiates the lytic pathway that produces the membrane attack complex (MAC), which forms
destructive pores in the membranes of target cells
C3a and C5a increase vascular permeability by causing release of histamine from granulocytes, mast cells
and platelets. C5a is also chemotactic

The biological functions of complement are as follows:
It yields particles that coat microorganisms and function as adhesion molecules for neutrophils and
macrophages (opsonins) • It leads to lysis of bacterial cell membranes via the MAC
It yields biologically active fragments that influence capillary permeability and chemotaxis

Kinin system
Activation of coagulation factor XII produces factor XIIa. This converts prekallikrein into the active
enzyme kallikrein, which produces bradykinin from high-molecular-weight kininogen. Bradykinin is a
potent vasodilator and increases vascular permeability.



Figure 4.2 Activation of the comple me nt pathways – clas s ical and alte rnative

Coagulation and fibrinolysis
The clotting cascade and fibrinolysis are discussed in detail in Chapter 3.

Vasoactive amines

Histamine and serotonin
Mast cells, basophils and platelets contain the amines histamine and 5HT
Release from mast cell granules is stimulated by C3a and C5a, IgE immunological reactions and IL-1
Release from platelets is caused by contact with collagen, thrombin, ADP and by PAF
Both amines cause vasodilatation and increased vascular permeability

Nitric oxide (NO)
Found to be of increasing importance in health and disease • Synthesised by nitric oxide synthase (NOS)
during oxidation of arginine to citrulline • Produced by three NOS genes in neurones, endothelial cells
and the immune system • Acts to reduce intracellular calcium (smooth muscle dilatation, decreased
cardiac contractility, reduced platelet and inflammatory cell activation)
Appears to have protective beneficial effects when produced in neurones and endothelial cells, but
pathological activity in inflammatory states:
Has multiple actions in inflammation:
• Local vasodilator
• Bactericidal activity
• Downregulatory effects on neutrophil function
• Prolongs neutrophil lifespan
• Causes apoptosis in macrophages

Lysosomal enzymes
Leucocytes degranulate at the site of infection, setting up a cycle of bacterial phagocytosis, tissue
destruction and recruitment of increasing numbers of immune cells.
Cationic proteins: increase vascular permeability and act as chemotactants • Acid proteases: most active at
about pH 3
Neutral proteases: degrade extracellular matrix

Arachidonic acid metabolism
Arachidonic acid is a 20-carbon polyunsaturated fatty acid present in cell membranes. After activation,
arachidonic acid is released from the membrane by phospholipases. It is then metabolised via two main
pathways: the cyclooxygenase (COX) pathway and the lipoxygenase pathway.



Figure 4.3 Arachidonic acid me tabolis m

COX pathway prostaglandins PGE2 and PGI2
Cause vasodilatation and increased vascular permeability • The E-series prostaglandins are hyperalgesic

Lipoxygenase pathway leukotrienes
Produced by all of the inflammatory cells except lymphocytes • LTC4 (plus products LTD4 and -E4)
increase vascular permeability and constrict smooth muscle • LTB4 makes neutrophils adhere to
endothelium and is a potent chemotactic agent
See section 1.4 for a discussion of anti-inflammatory pharmacology.

Interleukins, cytokines and monokines
Polypeptides: produced by activated monocytes (monokines), lymphocytes (lymphokines) and other
inflammatory cells • Interferons: viral infection induces the synthesis and secretion of interferons; they
confer an antiviral state on uninfected cells
Interleukins:
• IL-8 is a chemokine produced by monocytes, T lymphocytes, endothelial cells and platelets, which
mediates the rapid accumulation of neutrophils in inflamed tissues
• IL-1 is secreted by numerous cell types (monocytes, macrophages, neutrophils, endothelial cells); it
promotes T- and B-cell proliferation, tissue catabolism and the acute phase response, and also acts as a

pyrogen (see Section 2, The immune system) • TNF-α
• Produced by monocytes and macrophages, particularly if stimulated by bacterial endotoxins • Plays an
important part in host defence against Gram-negative sepsis • When endotoxin present at a low dose TNF-
α enhances macrophage killing, activation of B white blood cells and cytokine production
• When endotoxin is present at a high dose TNF-α is an extremely potent mediator in the pathogenesis of
endotoxin-related shock • PAF:
• A wide variety of cells produces PAF, including mast cells, neutrophils, platelets and macrophages • It
has a multitude of effects and increases vascular permeability, leucocyte aggregation and exudation,
smooth muscle constriction and cellular degranulation
• Research into anti-PAF agents is ongoing

Free radicals
Neutrophils release collagenase, alkaline phosphatase, elastase, myeloperoxidase, acid hydrolases, α1-
antitrypsin and lysozyme
Monocytes produce acid hydrolases, collagenase and elastase

Outcomes of acute inflammation


Outcomes of acute inflammation
Resolution
Abscess and pus formation
Scarring and fibrosis
Chronic inflammation

Resolution

Resolution occurs when no structural tissue component has been lost, with restoration of normal cellular
and tissue function.

Abscesses and pus formation

Pus is a body fluid containing neutrophils and necrotic debris • Chemicals and enzymes released by
inflammatory cells damage surrounding tissue and may even cause liquefaction necrosis – the mediators
released by neutrophils are the worst offenders (predominantly these are proteases and free radicals) •
Collections of pus tend to find their own way out through tissue planes as the pressure inside the abscess
builds; there is an increase in osmotic pressure due to the increasing number of molecular products being
generated by the continuous action of proteases (eg formation of sinuses in osteomyelitis)

Scarring and fibrosis

Scarring means laying down of dense (type I) collagen in chronic inflammation ± wound healing. Degree
of scarring is determined by repair vs regeneration.
Repair occurs by laying down of fibrous tissue (fibroblasts produce ground substance, fibronectin and
initially type III collagen, which is replaced with type I collagen as the scar matures)
Regeneration can occur only in certain cell types: • Labile cells are continuous replicators (eg intestinal
mucosa, hair follicles) • Stable cells are discontinuous replicators and can divide when required to do so
(eg fibroblasts and endothelial cells) • Permanent cells are non-replicators and cannot divide (eg
neurones)

1.2 Chronic inflammation



In a nutshell ...

Chronic inflammation is characterised by three features:

Infiltration of tissue with mononuclear inflammatory cells (monocytes, lymphocytes ± plasma cells) •
Ongoing tissue destruction

Evidence of healing (scarring, fibroblast proliferation, angioblast proliferation, angiogenesis)
It can be non-specific, autoimmune or granulomatous. Granulomatous disease includes TB, syphilis,
leprosy and schistosomiasis.

Chronic inflammation results from:
Persistence of the acute inflammatory stimulus (eg cholangitis leading to chronic liver abscess) • Deranged
inflammatory response (eg autoimmune conditions such as rheumatoid arthritis or SLE) • Recurrent
episodes of acute inflammation (eg recurrent cholecystitis or pancreatitis resulting in pseudocyst
formation)

Non-specific chronic inflammation

This is when acute inflammation fails to end in resolution or repair, as a result of:
Persistence of injurious agent (eg chronic osteomyelitis, peptic ulcer due to Helicobacter pylori) • Failure
of removal of pus and foreign material (eg undrained abscess) • Inadequate blood supply or drainage (eg
ischaemic or venous ulceration) • Inadequate drainage of an exocrine gland (eg chronic sialoadenitis)

Pathology of non-specific chronic inflammation

Tissue macrophages are almost all recruited directly from bloodstream monocytes • T-helper cells activate
B lymphocytes to produce plasma cells (via IL-4) • Plasma cells produce antibodies against the persistent
antigen or the altered tissue components; they divide under the influence of IL-1 from macrophages
Some degree of scarring always occurs in chronic inflammation; IL-1 also activates fibroblasts, resulting
in scarring • Fibrosis is stimulated by TGF-β

Cellular response to chronic inflammation

The predominant cell in the inflammatory infiltrate varies according to the cause of inflammation:
Neutrophils predominate in inflammation caused by common bacteria • Lymphocytes predominate in
viral infections and autoimmune diseases • Plasma cells predominate in spirochaetal diseases (syphilis
and Lyme disease) • Macrophages predominate in typhoid fever, TB and fungal infections (except
candidiasis) • Eosinophils predominate in inflammation secondary to allergic reactions, parasites (ie
worms) and in most inflammations of the gut

Autoimmune chronic inflammation

Autoimmune diseases are characterised by the production of antibodies against ‘self’. These antibodies
cause chronic tissue damage and necrosis, and may be deposited as antibody complexes. This feeds a
state of chronic inflammation. In autoimmune diseases the primary immune cell in the inflammatory
infiltrate is the lymphocyte.

Autoimmunity is discussed in detail in section 2.3 of this chapter.

Granulomatous chronic inflammation

This is characterised by small collections (granulomas) of modified macrophages called ‘epithelioid
cells’. T-helper cells are stimulated by the persistent antigen to produce activating cytokines, which
recruit and activate macrophages (eg by interferon [IFN]-α, TNF-α, etc). Persistence of the causative
organism or substance causes the macrophages to surround the offending particle, effectively walling it
off. These are then termed ‘epithelioid cells’. Epithelioid cells may fuse over several days to form giant
multinucleated cells (Langerhans’ or foreign-body giant cells).

Granulomatous inflammation may be associated with suppuration (pus-filled cavity), caseation or a
central foreign body. It is usually a low-grade smouldering response, occurring in the settings listed in the
box.



Causes of granulomatous inflammation
Persistent infection
Mycobacteria (TB, syphilis, leprosy)
Atypical fungi
Prolonged exposure to non-degradable substances
Pulmonary asbestosis
Silicosis
Talc
Immune reactions
Autoimmune disorders (eg rheumatoid arthritis)
Wegener’s granulomatosis
Sarcoidosis
Reactions to tumours (eg lymphomas and seminomas)

Tuberculosis

Organism
Mycobacterium tuberculosis hominis or Mycobacterium bovis.
Identified as acid-fast bacilli (AFBs) in sputum or pus smears by Ziehl–Neelsen stain • Needs special
growth conditions (grow very slowly) so must be specifically requested • Three consecutive samples
required (bacteria often sparse) • Early-morning samples best (sputum or urine)
Waxy, hard to kill and resistant to drying (they remain infectious)

Transmitted commonly by droplet inhalation or dust containing dried sputum; can also be ingested.

Demographics of TB
Incidence increasing worldwide (increased drug resistance, HIV, non-compliance with treatment). WHO
data show that TB is common in Southeast Asia (33% of cases) and is increasing in sub-Saharan Africa
(secondary to HIV causes highest mortality per capita). There is an increased risk in populations who are
malnourished, overcrowded and economically deprived, in those who have HIV and are
immunosuppressed (eg due to steroids), and in alcoholism.
Bacille Calmette–Guérin (BCG) vaccination (live attenuated virus) is used in some countries and is most
effective in protecting children from TB meningitis
Tuberculin (or Mantoux/Heaf) tests for infection or previous effective immunisation. Intracutaneous
injection or topical application of purified tuberculin protein causes a type IV hypersensitivity reaction if
there has been previous exposure. (Note that very immunosuppressed patients cannot mount this response
and so the test may be negative despite florid TB.) The interpretation of the result of these tests also
depends on whether the patient has been immunised with BCG

Symptoms and signs of TB
TB is a multisystem disease, with the following signs and symptoms:
General: weight loss, night sweats, fever, malaise, ‘consumption’
Pulmonary: caseating cavities, empyema, progressive lung destruction, miliary form; cough, haemoptysis
(chest radiograph: granulomas and thickening of pleura in upper lobes; diffuse shadowing in miliary form)
Gastrointestinal: commonly ileocaecal; features similar to Crohn’s disease ± RLQ (right lower quadrant)
mass • Adrenal: usually bilateral. Tissue destruction can lead to Addison’s disease • Peritoneal: primary
peritonitis • Urinary: sterile pyuria, renal involvement, predisposes to transitional cell carcinoma (TCC)
in bladder • Hepatic: miliary involvement • Skin: may look like carcinoma • Bone: Pott’s disease is
vertebral TB (± neurological compromise); joints (commonly knee and hip) • CNS: meningeal pattern
involving base of brain (cranial nerve signs) • Lymph nodes: lymphadenitis of the cervical nodes
(scrofula) • Cardiovascular: usually pericarditis

Primary TB
Often occurs in childhood
Caseating granuloma surrounds primary infective focus (often subpleural); associated hilar
lymphadenopathy and the initial granuloma together are referred to as the Ghon complex
Disease may resolve, calcify or remain dormant and reactivate later in life (often due to subsequent
immunocompromise) • Rarely florid

Secondary TB
Seen commonly in adults (re-infection/reactivation when bacilli escape the walled-off Ghon focus) •
Commonly at apex of lung
Active florid infection with spread throughout the pulmonary tree and sequelae such as haemoptysis,
erosion into bronchioles and ‘open infection’

‘Cold abscess’
Develops slowly so very little associated inflammation (ie ‘cold’) • Becomes painful when pressure
develops on surrounding areas • Often affects musculoskeletal tissues
Pus may track down tissue planes and present as a swelling some distance away • Can be drained by
percutaneous catheter or surgically

Treatment of TB
Multiple drug therapy (rifampicin, isoniazid, pyrazinamide, ethambutanol) given as triple or quadruple
therapy initially • Requires directly observed therapy to ensure compliance
Should also give pyridoxine to avoid isoniazid-induced neuropathy

Syphilis

Organism
Treponema pallidum
Transmitted: sexually (bacterium is fragile and moves from open genital sore to skin/mucous membrane of
recipient); vertically (transplacental); via blood transfusion
Risks: increases risk of transmitting HIV three- to fivefold; teratogenicity

Symptoms of syphilis
These are divided into primary, secondary and tertiary stages.
Primary syphilis
• Ulceration at site (chancre) within 2–6 weeks
• May occur on genitalia, lips, tongue or cervix
• Chancre disappears after a few weeks regardless of treatment • 30% progress to chronicity
Secondary syphilis
• Skin rash (large brown sores) on palms and soles of feet • Fever, headache, sore throat,
lymphadenopathy
• Lasts for a few weeks and may recur over next 1–2 years • Tertiary syphilis
• Damage to heart, eyes, brain, nervous system, bones and joints • Development of gummas (granulomas
with coagulative necrosis; often in liver, testes, bridge of the nose)

Diagnosis of syphilis
In early stages the disease mimics many others (called ‘the great imitator’) • Diagnosed by two separate
blood tests on different occasions (VDRL test)

Treatment of syphilis
Intravenous (IV) penicillin

Leprosy (Hansen’s disease)

Organism
Mycobacterium leprae
Multiplies very slowly (difficult to culture)

Demographics of leprosy
WHO data show 90% of cases are in Brazil, Madagascar, Ethiopia, Mozambique, Tanzania and Nepal •
Transmission probably involves respiratory droplet infection

Symptoms of leprosy
Disfiguring skin lesions, peripheral nerve damage (sensory loss and muscle weakness), loss of sweating
and progressive debilitation (loss of sensation results in repeated injury and damage to hands and feet)
Predisposes to amyloidosis A