Secondary assessment

After the initial assessment and resuscitation, the patient should have a secure airway, adequate ventilation, and cardiovascular resuscitation should have commenced. These need to be rechecked regularly. The priorities during the next phase are:

• Fill in the gaps in the patient's acute and past medical history.
• Perform a full physical examination by system.
• Perform relevant investigations (see below).
• Communicate with the other teams involved in the patient's management (e.g. general surgeons for intra-abdominal infection, gynaecologists for gynaecological sepsis).
• Continue resuscitation.

Perform investigations to confirm or clarify problems that are clinically evident, or to look for complications that are likely in each particular clinical setting. Investigations will be governed by the availability of these tests in each centre and the time available. For example, for a septic patient with abdominal signs in a centre with no access to radiological facilities, diagnostic laparotomy may be the definitive investigation (and treatment). Table 2 shows common initial investigations.

Monitoring is not dependent on expensive equipment, but it requires the continuous presence of trained nursing staff. Clear documentation aids the assessment of subtle changes in the patient's clinical state. Patients with severe SIRS / sepsis should have observations recorded hourly. Record body temperature, pulse, blood pressure, urine output, CVP, respiratory rate and SpO2 (if available). Accurate fluid balance is essential - insensible losses may be very significant in hot climates. Ideally measure the patient's temperature centrally (rectal or nasopharyngeal). Other sites include the axilla or mouth. Of these, the axilla is the least accurate but most convenient; whilst the rectal route is the most accurate but least convenient. Always use the same site. 

Treatment of the underlying problem

Clearly this depends on the nature of the initial insult and may be straightforward (oxygen, antibiotics and chest physiotherapy for a lobar pneumonia), or complex involving different specialities (orthopaedics, general and plastic surgery for major trauma). Infection is common, either as cause, or as a secondary complication. Treatment of infection may involve:

Antibiotic therapy. The initial antibiotic prescription is a 'best guess', and will depend on the clinical picture of the patient, local patterns of antibiotic resistance and the local availability of antibiotics. It should be broad enough to cover the most likely pathogens, but not so broad as to encourage antibiotic resistance. The advice of a local microbiologist or infectious diseases specialist is valuable.

Surgical debridement. Pus-filled cavities (abscess, empyema), necrotic tissue, infected tissue or gross tissue contamination (open wounds, peritonitis) cannot be treated by antibiotics alone and must be treated surgically at the earliest opportunity. The surgical team should assess the patient as soon as possible. Anaesthesia for these patients is discussed later in this article. 

Therapeutic strategies for preserving organ function

Organ failure results from inadequate organ oxygenation due to poor perfusion. Strategies to maintain or restore organ function are general, aimed at improving delivery of oxygen and nutrients to all tissues, or organ-specific (e.g. the kidney and gut).

Improving Oxygen Delivery

Oxygen delivery to the tissues, (DO2 ) is defined as: DO2 = cardiac output x haemoglobin level x oxygen saturation

Each of these three factors should be optimised to improve oxygen delivery.

Cardiac output. In SIRS the cardiac output may be low, high or normal. Whilst cardiac output at normal or supranormal levels is required to maintain oxygen delivery, maintenance of blood pressure itself is also important to ensure perfusion pressure is adequate (eg filtration at the kidney). Although most organs are capable of some autoregulation, this mechanism cannot always compensate for the circulatory disturbance in sepsis. This is why a vasodilated patient with a high cardiac output needs intervention to elevate their blood pressure.

The main treatments for maintaining cardiovascular function are correction of hypovolaemia with fluid therapy, inotropes and vasopressor agents.

• Correction of hypovolaemia (fluid therapy). Vasodilation causes blood to pool in the periphery, and abnormal capillary permeability results in fluid leak into the tissues. These changes decrease the relative blood volume (by vasodilation) and absolute blood volume (by capillary leak) causing a fall in the preload of the heart and therefore a decrease in cardiac output. Monitor progress clinically: a satisfactory response to fluid therapy is suggested by a falling heart rate, increase in the blood pressure, decrease in the capillary refill time and improvement in organ function. A central venous catheter may be helpful if the clinical picture is hard to interpret or mixed (co-existent cardiac disease).
  Clear benefits of colloid over crystalloid have not been demonstrated, but crystalloid redistributes rapidly into the whole extracellular volume (about 14 litres in a 70 kg man) and so larger volumes must be given for intravascular resuscitation. In anaemic patients blood is often required.
• Use of inotropic and vassopressor (vasoconstrictor) agents. If the blood pressure remains low after the patient is judged to be adequately intravascularly filled, the patient either has inadequate myocardial 'pump' function or has a degree of vasodilation which cannot be overcome by fluid therapy alone. Sometimes patients present as clear-cut examples of one of these two syndromes, but more often patients have a mixture of clinical signs. If the patient appears vasodilated with a hyperdynamic circulation an agent with vasopressor (a adrenoreceptor agonist) properties, such as noradrenaline (norepinephrine) is appropriate to elevate the blood pressure.
  If the patient is cool peripherally (has a large core to peripheral temperature difference), has signs of poor organ perfusion and/or a low blood pressure then an agent with more positive inotropic properties is the best choice. Examples are adrenaline (epinephrine), dobutamine or dopamine.
  Inotropes should be given through a central venous catheter and direct intra-arterial blood pressure measurement is preferable for accurate, continuous readings. Proposed regimens for use of these drugs are shown below. In practice few of these drugs have 'pure' effects; noradrenaline also has positive inotropic effects via stimulation of b1-adrenoreceptors. Combinations of vasopressor and inotropic drugs are often used.

If the clinical picture is difficult to interpret, other means of investigation are available in some centres. Pulmonary artery flotation catheters (Swan-Ganz catheters) indirectly measure the left atrial pressure, which may be a more accurate measure of intravascular volume status. The saturation of blood sampled from the pulmonary artery gives the mixed venous blood oxygen saturation which can be used to assess adequacy of oxygen delivery. Use of trans-oesophageal doppler is increasing.

Oxygen saturation and gas exchange. The majority of patients with severe sepsis require intubation and ventilation and almost 50 % go on to develop problems with gas exchange. Lung problems associated with SIRS is termed 'Acute Lung Injury' (ALI). 'Acute Respiratory Distress Syndrome' (ARDS) describes the most severe form of ALI. In both cases the lungs become oedematous and damaged and are less able to take up oxygen or eliminate carbon dioxide. ALI may resolve with treatment of the underlying cause of the SIRS, or progress to a stage where lung fibrosis takes place. Steroids may have a role in the treatment of late refractory ALI / ARDS, but are thought to be ineffective in the early stages. Some of the lung damage sustained during critical illness may be due to mechanical ventilation: excessive driving pressure causes over-expansion of and damage to alveoli. In patients with ALI, ventilators should be set at a more protective ventilation strategy in patients with:

• Limitation of plateau pressure to less than 35 cm H2O
• Use of smaller tidal volumes (up to 8 ml/kg)
• Lower target minute volumes resulting in PaCO2 values higher than normal (so called 'permissive hypercapnia'). This results in a respiratory acidosis which is usually well tolerated, provided the arterial pH does not fall below 7.2.
• Use of pressure-control rather than volume-control ventilation.
• Higher positive end-expiratory pressures (PEEP, 10 or 12 cm H2O instead of 5 or 6cm H2O)
• Longer inflation phase with I:E ratio of approximately 1:1, to improve the distribution of gas within the lung.
• Avoid an FiO2 above 60% if possible - aim for SpO2 93-95%.

Ventilator-associated pneumonia (VAP) is a frequent complication of ventilation. This is thought to arise from contamination of the respiratory tract by aspiration of material regurgitated from the stomach ('micro-aspiration' around the endotracheal tube cuff). Techniques which are thought to reduce the incidence of VAP include:

• Aseptic technique when suctioning patients
• Nursing the patient semi-recumbent instead of completely flat
• Avoiding the use of proton-pump inhibitors or H2- antagonists which encourage bacterial growth in the stomach due to loss of acidity. Establishing early nasogastric feeding
• Ensuring that the cuff of the endotracheal tube is correctly inflated
• Avoiding re-intubation or manipulation of the airway circuit

Treatment of anaemia. Recent studies show that transfusion of blood to critically ill patients to maintain a haemoglobin level of greater than 10 g/dl does not alter the patients outcome. With the multiple potential problems associated with blood transfusion, in the absence of ischaemic heart disease, it is reasonable to allow the haemoglobin to remain at 7 to 9 g/dl.

Nutrient supply and hormonal changes in SIRS. Insulin secretion is reduced with the stress of severe illness whilst cortisol and growth hormone secretion both increase. Patients are prone to hyperglycaemia due to the insulin-antagonism of these hormones and drugs such as adrenaline (epinephrine). A slow intravenous infusion of an insulin solution (1 unit per ml) may be required to maintain normal blood sugar levels (5 to 9 mmol/l), but if this is not practical then adequate glycaemic control can be achieved with intermittent subcutaneous injections of insulin. Check the blood sugar at regular intervals.

During a prolonged illness the patient's metabolic requirements will be increased by the effects of fever and infection, and the patient will become catabolic, breaking down their own tissues (especially muscle) to use as metabolic fuel. This process cannot be reversed, but can be limited to some extent by supplying the patient with appropriate quantities of energy (in the form of fat and carbohydrate), nitrogen (in the form of protein, peptides or amino acids), minerals and vitamins. Feeding via the enteral route (e.g. via a nasogastric tube) is preferable; proposed benefits include reduced 'stress' ulceration in the stomach, preservation of bowel mucosal function and reduction of bacterial translocation from the bowel lumen into the circulation (see below). Some conditions preclude enteral feeding (recent bowel resection) but other problems may be overcome (e.g. nasojejunal tube for pancreatitis or percutaneous gastrostomy for oesophageal disease). Intravenous nutrition may be used if enteral feeding is not possible, but is expensive, and associated with a number of significant complications (most notably infection).

Organ-specific Strategies

Gastrointestinal tract. The bowel may act as the 'motor' for MODS, by the mechanism of bacterial translocation across damaged mucosa whose integrity has been damaged by hypoxia. As described above, early enteral feeding is the main preventative measure to counter this.

H2-antagonists (e.g. ranitidine) and proton pump inhibitors (e.g. omeprazole) have been used to reduce mucosal damage in patients who cannot be fed enterally. The disadvantage is that by reducing gastric acidity these drugs allow bacterial overgrowth and may increase the likelihood of ventilator associated pneumonia and bacterial translocation. Sucralfate is a cheaper alternative which gives some mucosal protection without reducing gastric acidity.

Liver. In the acute phase of sepsis (within the first 24 or 48 hours) the liver may be damaged by periods of low blood pressure, reflected in sharp rises in circulating liver enzymes (lactate dehydrogenase and both aspartate and alanine transaminase). With adequate resuscitation this damage is self-limiting and reversible. Maintenance of liver function depends on effective resuscitation, rapid removal of the septic focus, appropriate antibiotic treatment, early nutritional support and the avoidance of further damage. Hepatic damage may cause encephalopathy, coagulapathy and hypoglycaemia.

Kidneys. The ion channels in the tubular epithelium of the renal medulla are energy (and therefore oxygen) dependent and so particularly sensitive to episodes of hypotension and hypoxia. Up to 65 % of patients with sepsis develop abnormalities of renal function and if renal replacement therapy (haemofiltration or haemodialysis) is required the mortality is as high as 75 %. Indications for renal replacement therapy include, severe or refractory hyperkalaemia, severe metabolic acidosis, low or absent urine output or symptomatic uraemia (e.g. pericardial effusion).

If a patient is oliguric, consider the following:

• Exclude obstructive causes- flush the urinary catheter, consider urethral damage in trauma.
• Fluid resuscitation. Reduction in blood volume stimulates the release of renin, anti-diuretic hormone and activation of the sympathetic nervous system, reducing the volume of urine produced by the kidney. These effects may be reversed by adequate fluid resuscitation guided clinically and, if necessary, using a central venous catheter.
• Blood pressure. The kidney autoregulates the filtration pressure in the glomerulus by altering the resistance of afferent and efferent arterioles. Autoregulation fails if the mean arterial blood pressure falls below about 60mm Hg and urine flow decreases or stops. Correction of hypovolaemia may not restore the blood pressure. Use an inotrope or vasopressor as described above.
• Nephrotoxic agents. Stop non-steroidal anti-inflammatory drugs, angiotensin-converting enzyme (ACE) inhibitors and avoid radiographic contrast media. Levels of aminoglycoside antibiotics (gentamicin, netilmicin) and vancomycin should be checked.
• Diuretics. Loop diuretics such as frusemide may establish a diuresis but should only be used after optimal restoration of intravascular volume. By inhibiting the active transport of ions in the loop of Henle loop diuretics may offer some protection to tubular cells from hypoxic damage.

If these strategies do not restore urine flow, then acute renal failure has occurred. In the absence of specific nephrotoxic agents the cause is likely to be acute tubular necrosis, which in most cases is reversible. The time to return of renal function is variable (from a few days to several weeks) and in the interim some form of renal replacement is necessary to control hypervolaemia, acidosis, hyperkalaemia and uraemia. The choice is largely dependant on local availability and transfer to another centre may be necessary. Monitor the patient using daily weight, and measurement of electrolytes, urea and creatinine.

Complications following sepsis
Complications of intubation and mechanical ventilation	Pneumonia Pneumothorax Vocal cord damage Tracheal stenosis Difficulty weaning from ventilatory support
Hospital-acquired (nosocomial) infections	Cellulitis at the site of venous or arterial cannulae Cannula-related septicaemia Urinary-tract infections Blood and blood-product infections (HIV, hepatitis B)
Complications secondary to immobility and severe illness	Pressure sores Peripheral nerve palsies Corneal abrasions Pulmonary emboli and/or deep vein thromboses Malnutrition and weakness
Drug-related	Kidney damage (aminoglycoside antibiotics)
Disturbance of sleep / wake cycle

(Continued ...)

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