- Email: [email protected]
Organization of critical care services
INTENSIVE CARE
comfortable environment than road ambulance or fixed-wing aircraft. Helicopters are expensive and have a poorer safety record than fixed-wing aircraft. Fixed-wing aircraft, preferably pressurized, should be selected for transfer distances over 150 miles, but they expose the patient to higher acceleration and deceleration forces during take off and landing. The problems associated with aeromedical transfers are altitude, temperature control, noise, vibration, visibility and unfamiliar environments. Changes in barometric pressure are hazardous, because a small pneumothorax expands by 20% with an increase in altitude of 6000 ft; most aircraft are pressurized to only 8000 ft. The aircraft noise may be excessive, especially in military airframes, therefore the patient must wear ear defenders at all times, even though sedated. Tissues may swell and so casts should be split. Staff should be aware of the physical, physiological and psychological stresses they will experience as a result of flying.
Organization of critical care services Simon Mackenzie
Critical care services may be provided in separate intensive care (ICU) and high dependency (HDU) units or in a combined area. The level of care required by an adult patient can be categorized using the classification in Figure 1, which should be read in conjunction with the definitions of organ system monitoring and support used in the Augmented Care Period dataset (Figure 2). There is an increasing emphasis on seamless care and on ‘outreach’ services.
Children and neurosurgical patients: the special considerations required for transferring children are described in Anaesthesia and Intensive Care Medicine 3:12: 446 and those for neurosurgical patients are described in Anaesthesia and Intensive Care Medicine 3:4: 134.
Intensive care Intensive care is ‘a service for patients with potentially reversible conditions who can benefit from more detailed observation and invasive treatment than can safely be provided in general wards or high dependency areas’. ICUs require a nurse:patient ratio of 1:1, a resident doctor without other duties and consultant cover throughout 24 hours. Consultants should not have other duties while covering the ICU. Most ICUs are ‘general’, though some support a specific specialty. In the UK, a typical unit contains six beds; this is small in comparison with those in other European countries and the USA. An ICU where care is provided by a team of intensivists, supported by other clinicians when requested, is described as a ‘closed’ unit. A unit in which patient care is delivered by more than one group of doctors is termed an ‘open’ unit. The former may be associated with better outcomes.
Quality and audit Transfer forms are vital to record physiological changes and therapy before and during transfer. Regular audit of transfers is necessary to maintain and improve standards. The responsible consultant should review all transfers in and out of the hospital and a similar process should be established at a network level. The referring hospital, the receiving hospital, the ambulance service and any external auditing system should retain copies of the transfer documentation.
High dependency care HDUs provide a level of care intermediate between an ordinary ward and an ICU. HDUs are more likely to be specialty based, though general units are preferable. HDUs provide greater monitoring and nursing input than is given on general wards, may provide support for single-organ failure (but not ventilation) and can act as a ‘step down’ area for patients between the ICU and the general ward. The nurse:patient ratio on an HDU is 1:2. There is seldom a resident doctor and patients are usually cared for by their referring team, the members of which will probably also have duties elsewhere. FURTHER READING Association of Anaesthetists of Great Britain and Ireland. Recommendations for the transfer of patients with acute head injuries to neurosurgical units. London: Association of Anaesthetists of Great Britain and Ireland, 1996. Intensive Care Society. Guidelines for transport of the critically ill adult. London: Intensive Care Society, 2002. Morton N S, Pollack M M, Wallace P G M. Stabilization and transport of the critically ill. New York: Churchill Livingstone, 1997. Runcie C J, Reeve W R, Wallace P G. Preparation of the critically ill for interhospital transfer. Anaesthesia 1992; 47: 327–31.
ANAESTHESIA AND INTENSIVE CARE MEDICINE
Admission Admission criteria: the decision to admit a patient to ICU is a clinical one, based on the patient’s present condition, the treatment possible, the likely response, co-morbidities and the patient’s
Simon Mackenzie is Consultant in Anaesthesia and Intensive Care at the Royal Infirmary, Edinburgh, UK. His research interests include cardiovascular support, acute liver failure and the use of severity scoring systems in critical illness.
23
© 2004 The Medicine Publishing Company Ltd
INTENSIVE CARE
Levels of care
Classification of organ system monitoring and support
Level 0 • Patients whose needs can be met through normal ward care in an acute hospital
Advanced respiratory support • Mechanical ventilatory support (excluding mask continuous positive airway pressure or non-invasive ventilation) • Possibility of sudden, precipitous deterioration in respiratory function requiring immediate tracheal intubation and mechanical ventilation Basic respiratory monitoring and support • Need for more than 40% oxygen via a fixed performance mask • Possibility of progressive deterioration to the point of needing advanced respiratory support • Need for physiotherapy to clear secretions at least 2-hourly • Patients recently extubated after prolonged intubation and ventilation • Need for continuous positive-airway pressure by mask or noninvasive ventilation • Patients intubated to protect the airway but not requiring ventilation Circulatory support • Need for vasoactive drugs to support arterial pressure or cardiac output • Support for circulatory instability due to hypovolaemia from any cause that is unresponsive to modest volume replacement • Patients resuscitated after cardiac arrest when intensive or high dependency care is considered clinically appropriate Neurological monitoring and support • CNS depression, from whatever cause, sufficient to prejudice the airway and protective reflexes • Invasive neurological monitoring Renal support • Need for acute renal replacement therapy
Level 1 • Patient recently discharged from a higher level of care • Patients in need of additional monitoring, clinical input or advice • Patients requiring critical care outreach service support • Patients requiring staff with special expertise and/or additional facilities for at least one aspect of critical care delivered in a general ward environment Level 2 • Patients requiring single-organ system monitoring and support • Patients requiring preoperative optimization • Patients needing extended postoperative care • Patients needing a greater degree of observation and monitoring • Patients moving to step down care • Patients with major uncorrected physiological abnormalities Level 3 • Patients needing advanced respiratory monitoring and support • Patients needing monitoring and support for two or more organ systems • Patients with chronic impairment of one or more organ systems sufficient to restrict daily activities (co-morbidity) and who require support for an acute reversible failure of another organ system Source: Intensive Care Society. Levels of critical care for adult patients. London: Intensive Care Society, 2002.
Source: DoH. Guidelines on admission to and discharge from intensive care and high dependency units. London: HMSO, 1996.
1
2
wishes. Chronological age influences survival after intensive care, but should not be the sole arbiter for ICU admission. Indeed, limited physiological reserve means that elderly patients may require admission to the ICU or HDU in situations where younger patients would not. Similar considerations apply to patients with chronic disease, but patients with irreversible progression of chronic disease should not be admitted. Scoring systems used for ICU audit (e.g. APACHE, SAPS or MPM; see page 29) cannot be used to determine an individual patient’s prognosis or need for admission. One example of criteria for referral is given in Figure 3.
Outreach services: the objectives of outreach services are to: • avert admissions to critical care • facilitate timely admission to critical care and discharge back to the wards • share critical care skills and expertise through an educational partnership • promote continuity of care • ensure thorough audit and evaluation of outreach services. Outreach services are a recent development and it is too early to say which is the most effective model, or indeed if they provide any benefit. Outreach services are not a substitute for lack of critical care beds or adequate ward staffing.
When to admit: in principle, patients should be referred early and by a consultant. This may be difficult to achieve. Many patients are referred late in their illness, after potentially avoidable deterioration, which may include cardiac arrest. Doctors outside the ICU may fail to appreciate what an ICU can offer or may see referral as an admission of failure. Doctors in the ICU may give the impression that they are too busy to be bothered with patients who are not ‘really sick’. The concept of ‘outreach’ attempts to address this, by using scoring systems to identify those at risk and providing a team from the critical care department to respond.
ANAESTHESIA AND INTENSIVE CARE MEDICINE
Identification of patients at risk: the concept of outreach depends on identifying patients at risk of deterioration; those at level 1 in Figure 1. While levels of care do not necessarily define staffing levels or geographical location, most patients requiring level 3 care are likely to be admitted to the ICU, while the needs of those requiring level 2 care are often met in the HDU. Many hospitals still lack adequate arrangements for providing level 1 care and this can lead to inappropriate placement. Several tools have been devel-
24
© 2004 The Medicine Publishing Company Ltd
INTENSIVE CARE
Although oxygen and fluids are almost invariably required, the underlying cause of shock must be diagnosed and treated. Patients requiring fluid replacement with large volumes, central venous pressure monitoring or vasoactive drugs should be admitted to an HDU or ICU. Neurological – many patients with impaired consciousness (e.g. caused by head injuries, intracranial haemorrhage, meningitis, encephalitis, drug overdose, hepatic encephalopathy, hypoxia) require admission to the ICU or HDU. Airway obstruction, absent airway reflexes, hypoxaemia or hypoventilation are all indications for intubation and controlled ventilation. Patients with severe head injuries require ventilation and intracranial pressure monitoring. Patients with neuromuscular diseases (e.g. Guillain–Barré syndrome, myasthenia gravis) may require ventilatory support if airway reflexes are impaired or vital capacity is reduced to less than 1000 ml. High-risk surgery – the perioperative risk of major non-cardiac surgery is high, as is the risk of more modest surgery in patients with significant cardiorespiratory disease. Surgery produces a predictable, but temporary, physiological stress, and such patients can benefit greatly from postoperative critical care. Some advocate admission before surgery for ‘pre-optimization’, aiming for a cardiac index of 4.5 litre/minute/m2 and oxygen delivery of 600 ml/minute/m2. This remains controversial, but the value of good perioperative care is not.
Specific criteria for ICU referral Airway • Actual or threatened airway obstruction • Impaired ability to protect airway Breathing • Respiratory rate < 8 or > 30 breaths/minute • Respiratory arrest • Oxygen saturation < 90% with FiO2 of 0.5 • Worsening respiratory acidosis Circulation • Pulse < 40 or > 140/minute • Systolic blood pressure < 90 mm Hg • Cardiac arrest • Metabolic acidosis [H+] > 62 nmol/litre (pH 7.20) • Urine output < 0.5 ml/kg/hour Neurological • Repeated or prolonged seizures • Decreasing conscious level General • Patient causing concern to medical, nursing or physiotherapy staff
Who not to admit: patients should not be admitted to the ICU if they are too well, if they refuse, or if they are too ill to benefit. Admitting patients who are too well wastes resources and exposes the individuals to potential complications. Patients have the same right to refuse intensive care as they do any other treatment. If they are unable to express a view (e.g. because of coma), discussion with the relatives may be helpful in ascertaining the patient’s wishes. Any advance directive should be respected, but, in practice, these are uncommon and may be ambiguous. Patients should not be admitted if further treatment is futile, whether this is because of co-morbidity or the acute illness. This is often difficult to judge and may be best resolved by a trial of therapy. There is increasing concern that patients may survive but have a poor quality of life. However, doctors should be careful not to make decisions based on their own opinion of another individual’s existing or future quality of life.
Note Much depends on whether there is an identified and easily remediable cause. The start of an adverse trend despite treatment is important Source: McQuillan et al. Br Med J 1998; 316: 1853–8.
3
oped to identify patients at risk, including the Medical Emergency Team Calling Criteria, the Patient at Risk Team, the Early Warning Score and the Modified Early Warning Score (MEWS). Key to them all is the use of simple bedside physiological observations to identify patients at risk. Increasingly hospitals are modifying ward observation charts to alert staff to patients at risk using these criteria. Respiratory – patients may be referred with hypoxaemia or ventilatory failure. The decision to ventilate a patient may be based on blood gas results, but is usually made on clinical criteria. Patients who are clearly exhausted (e.g. confused, unable to talk, using accessory muscles) and not responding to treatment should be ventilated before respiratory arrest ensues, irrespective of their blood gases. Some patients with hypoxaemia and dyspnoea may respond well to continuous positive-airway pressure. Cardiovascular – patients with deteriorating tissue perfusion (e.g. cool peripheries, peripheral cyanosis, reduced skin turgor, slow capillary refill, oliguria, reduced conscious level and metabolic acidosis) should be referred to ICU. Metabolic acidosis is often overlooked when interpreting blood gas or biochemistry results. Patients in shock may have surprisingly normal blood pressure.
ANAESTHESIA AND INTENSIVE CARE MEDICINE
FUTHER READING Department of Health. Guidelines on admission to and discharge from intensive care and high dependency units. London: HMSO, 1996. Intensive Care Society. Levels of critical care for adult patients. London: Intensive Care Society, 2002. Intensive Care Society. Guidelines for the introduction of outreach services. London: Intensive Care Society, 2002. Smith G, Nielsen M. Criteria for admission. Br Med J 1998; 318: 1544–7.
25
© 2004 The Medicine Publishing Company Ltd
comfortable environment than road ambulance or fixed-wing aircraft. Helicopters are expensive and have a poorer safety record than fixed-wing aircraft. Fixed-wing aircraft, preferably pressurized, should be selected for transfer distances over 150 miles, but they expose the patient to higher acceleration and deceleration forces during take off and landing. The problems associated with aeromedical transfers are altitude, temperature control, noise, vibration, visibility and unfamiliar environments. Changes in barometric pressure are hazardous, because a small pneumothorax expands by 20% with an increase in altitude of 6000 ft; most aircraft are pressurized to only 8000 ft. The aircraft noise may be excessive, especially in military airframes, therefore the patient must wear ear defenders at all times, even though sedated. Tissues may swell and so casts should be split. Staff should be aware of the physical, physiological and psychological stresses they will experience as a result of flying.
Organization of critical care services Simon Mackenzie
Critical care services may be provided in separate intensive care (ICU) and high dependency (HDU) units or in a combined area. The level of care required by an adult patient can be categorized using the classification in Figure 1, which should be read in conjunction with the definitions of organ system monitoring and support used in the Augmented Care Period dataset (Figure 2). There is an increasing emphasis on seamless care and on ‘outreach’ services.
Children and neurosurgical patients: the special considerations required for transferring children are described in Anaesthesia and Intensive Care Medicine 3:12: 446 and those for neurosurgical patients are described in Anaesthesia and Intensive Care Medicine 3:4: 134.
Intensive care Intensive care is ‘a service for patients with potentially reversible conditions who can benefit from more detailed observation and invasive treatment than can safely be provided in general wards or high dependency areas’. ICUs require a nurse:patient ratio of 1:1, a resident doctor without other duties and consultant cover throughout 24 hours. Consultants should not have other duties while covering the ICU. Most ICUs are ‘general’, though some support a specific specialty. In the UK, a typical unit contains six beds; this is small in comparison with those in other European countries and the USA. An ICU where care is provided by a team of intensivists, supported by other clinicians when requested, is described as a ‘closed’ unit. A unit in which patient care is delivered by more than one group of doctors is termed an ‘open’ unit. The former may be associated with better outcomes.
Quality and audit Transfer forms are vital to record physiological changes and therapy before and during transfer. Regular audit of transfers is necessary to maintain and improve standards. The responsible consultant should review all transfers in and out of the hospital and a similar process should be established at a network level. The referring hospital, the receiving hospital, the ambulance service and any external auditing system should retain copies of the transfer documentation.
High dependency care HDUs provide a level of care intermediate between an ordinary ward and an ICU. HDUs are more likely to be specialty based, though general units are preferable. HDUs provide greater monitoring and nursing input than is given on general wards, may provide support for single-organ failure (but not ventilation) and can act as a ‘step down’ area for patients between the ICU and the general ward. The nurse:patient ratio on an HDU is 1:2. There is seldom a resident doctor and patients are usually cared for by their referring team, the members of which will probably also have duties elsewhere. FURTHER READING Association of Anaesthetists of Great Britain and Ireland. Recommendations for the transfer of patients with acute head injuries to neurosurgical units. London: Association of Anaesthetists of Great Britain and Ireland, 1996. Intensive Care Society. Guidelines for transport of the critically ill adult. London: Intensive Care Society, 2002. Morton N S, Pollack M M, Wallace P G M. Stabilization and transport of the critically ill. New York: Churchill Livingstone, 1997. Runcie C J, Reeve W R, Wallace P G. Preparation of the critically ill for interhospital transfer. Anaesthesia 1992; 47: 327–31.
ANAESTHESIA AND INTENSIVE CARE MEDICINE
Admission Admission criteria: the decision to admit a patient to ICU is a clinical one, based on the patient’s present condition, the treatment possible, the likely response, co-morbidities and the patient’s
Simon Mackenzie is Consultant in Anaesthesia and Intensive Care at the Royal Infirmary, Edinburgh, UK. His research interests include cardiovascular support, acute liver failure and the use of severity scoring systems in critical illness.
23
© 2004 The Medicine Publishing Company Ltd
INTENSIVE CARE
Levels of care
Classification of organ system monitoring and support
Level 0 • Patients whose needs can be met through normal ward care in an acute hospital
Advanced respiratory support • Mechanical ventilatory support (excluding mask continuous positive airway pressure or non-invasive ventilation) • Possibility of sudden, precipitous deterioration in respiratory function requiring immediate tracheal intubation and mechanical ventilation Basic respiratory monitoring and support • Need for more than 40% oxygen via a fixed performance mask • Possibility of progressive deterioration to the point of needing advanced respiratory support • Need for physiotherapy to clear secretions at least 2-hourly • Patients recently extubated after prolonged intubation and ventilation • Need for continuous positive-airway pressure by mask or noninvasive ventilation • Patients intubated to protect the airway but not requiring ventilation Circulatory support • Need for vasoactive drugs to support arterial pressure or cardiac output • Support for circulatory instability due to hypovolaemia from any cause that is unresponsive to modest volume replacement • Patients resuscitated after cardiac arrest when intensive or high dependency care is considered clinically appropriate Neurological monitoring and support • CNS depression, from whatever cause, sufficient to prejudice the airway and protective reflexes • Invasive neurological monitoring Renal support • Need for acute renal replacement therapy
Level 1 • Patient recently discharged from a higher level of care • Patients in need of additional monitoring, clinical input or advice • Patients requiring critical care outreach service support • Patients requiring staff with special expertise and/or additional facilities for at least one aspect of critical care delivered in a general ward environment Level 2 • Patients requiring single-organ system monitoring and support • Patients requiring preoperative optimization • Patients needing extended postoperative care • Patients needing a greater degree of observation and monitoring • Patients moving to step down care • Patients with major uncorrected physiological abnormalities Level 3 • Patients needing advanced respiratory monitoring and support • Patients needing monitoring and support for two or more organ systems • Patients with chronic impairment of one or more organ systems sufficient to restrict daily activities (co-morbidity) and who require support for an acute reversible failure of another organ system Source: Intensive Care Society. Levels of critical care for adult patients. London: Intensive Care Society, 2002.
Source: DoH. Guidelines on admission to and discharge from intensive care and high dependency units. London: HMSO, 1996.
1
2
wishes. Chronological age influences survival after intensive care, but should not be the sole arbiter for ICU admission. Indeed, limited physiological reserve means that elderly patients may require admission to the ICU or HDU in situations where younger patients would not. Similar considerations apply to patients with chronic disease, but patients with irreversible progression of chronic disease should not be admitted. Scoring systems used for ICU audit (e.g. APACHE, SAPS or MPM; see page 29) cannot be used to determine an individual patient’s prognosis or need for admission. One example of criteria for referral is given in Figure 3.
Outreach services: the objectives of outreach services are to: • avert admissions to critical care • facilitate timely admission to critical care and discharge back to the wards • share critical care skills and expertise through an educational partnership • promote continuity of care • ensure thorough audit and evaluation of outreach services. Outreach services are a recent development and it is too early to say which is the most effective model, or indeed if they provide any benefit. Outreach services are not a substitute for lack of critical care beds or adequate ward staffing.
When to admit: in principle, patients should be referred early and by a consultant. This may be difficult to achieve. Many patients are referred late in their illness, after potentially avoidable deterioration, which may include cardiac arrest. Doctors outside the ICU may fail to appreciate what an ICU can offer or may see referral as an admission of failure. Doctors in the ICU may give the impression that they are too busy to be bothered with patients who are not ‘really sick’. The concept of ‘outreach’ attempts to address this, by using scoring systems to identify those at risk and providing a team from the critical care department to respond.
ANAESTHESIA AND INTENSIVE CARE MEDICINE
Identification of patients at risk: the concept of outreach depends on identifying patients at risk of deterioration; those at level 1 in Figure 1. While levels of care do not necessarily define staffing levels or geographical location, most patients requiring level 3 care are likely to be admitted to the ICU, while the needs of those requiring level 2 care are often met in the HDU. Many hospitals still lack adequate arrangements for providing level 1 care and this can lead to inappropriate placement. Several tools have been devel-
24
© 2004 The Medicine Publishing Company Ltd
INTENSIVE CARE
Although oxygen and fluids are almost invariably required, the underlying cause of shock must be diagnosed and treated. Patients requiring fluid replacement with large volumes, central venous pressure monitoring or vasoactive drugs should be admitted to an HDU or ICU. Neurological – many patients with impaired consciousness (e.g. caused by head injuries, intracranial haemorrhage, meningitis, encephalitis, drug overdose, hepatic encephalopathy, hypoxia) require admission to the ICU or HDU. Airway obstruction, absent airway reflexes, hypoxaemia or hypoventilation are all indications for intubation and controlled ventilation. Patients with severe head injuries require ventilation and intracranial pressure monitoring. Patients with neuromuscular diseases (e.g. Guillain–Barré syndrome, myasthenia gravis) may require ventilatory support if airway reflexes are impaired or vital capacity is reduced to less than 1000 ml. High-risk surgery – the perioperative risk of major non-cardiac surgery is high, as is the risk of more modest surgery in patients with significant cardiorespiratory disease. Surgery produces a predictable, but temporary, physiological stress, and such patients can benefit greatly from postoperative critical care. Some advocate admission before surgery for ‘pre-optimization’, aiming for a cardiac index of 4.5 litre/minute/m2 and oxygen delivery of 600 ml/minute/m2. This remains controversial, but the value of good perioperative care is not.
Specific criteria for ICU referral Airway • Actual or threatened airway obstruction • Impaired ability to protect airway Breathing • Respiratory rate < 8 or > 30 breaths/minute • Respiratory arrest • Oxygen saturation < 90% with FiO2 of 0.5 • Worsening respiratory acidosis Circulation • Pulse < 40 or > 140/minute • Systolic blood pressure < 90 mm Hg • Cardiac arrest • Metabolic acidosis [H+] > 62 nmol/litre (pH 7.20) • Urine output < 0.5 ml/kg/hour Neurological • Repeated or prolonged seizures • Decreasing conscious level General • Patient causing concern to medical, nursing or physiotherapy staff
Who not to admit: patients should not be admitted to the ICU if they are too well, if they refuse, or if they are too ill to benefit. Admitting patients who are too well wastes resources and exposes the individuals to potential complications. Patients have the same right to refuse intensive care as they do any other treatment. If they are unable to express a view (e.g. because of coma), discussion with the relatives may be helpful in ascertaining the patient’s wishes. Any advance directive should be respected, but, in practice, these are uncommon and may be ambiguous. Patients should not be admitted if further treatment is futile, whether this is because of co-morbidity or the acute illness. This is often difficult to judge and may be best resolved by a trial of therapy. There is increasing concern that patients may survive but have a poor quality of life. However, doctors should be careful not to make decisions based on their own opinion of another individual’s existing or future quality of life.
Note Much depends on whether there is an identified and easily remediable cause. The start of an adverse trend despite treatment is important Source: McQuillan et al. Br Med J 1998; 316: 1853–8.
3
oped to identify patients at risk, including the Medical Emergency Team Calling Criteria, the Patient at Risk Team, the Early Warning Score and the Modified Early Warning Score (MEWS). Key to them all is the use of simple bedside physiological observations to identify patients at risk. Increasingly hospitals are modifying ward observation charts to alert staff to patients at risk using these criteria. Respiratory – patients may be referred with hypoxaemia or ventilatory failure. The decision to ventilate a patient may be based on blood gas results, but is usually made on clinical criteria. Patients who are clearly exhausted (e.g. confused, unable to talk, using accessory muscles) and not responding to treatment should be ventilated before respiratory arrest ensues, irrespective of their blood gases. Some patients with hypoxaemia and dyspnoea may respond well to continuous positive-airway pressure. Cardiovascular – patients with deteriorating tissue perfusion (e.g. cool peripheries, peripheral cyanosis, reduced skin turgor, slow capillary refill, oliguria, reduced conscious level and metabolic acidosis) should be referred to ICU. Metabolic acidosis is often overlooked when interpreting blood gas or biochemistry results. Patients in shock may have surprisingly normal blood pressure.
ANAESTHESIA AND INTENSIVE CARE MEDICINE
FUTHER READING Department of Health. Guidelines on admission to and discharge from intensive care and high dependency units. London: HMSO, 1996. Intensive Care Society. Levels of critical care for adult patients. London: Intensive Care Society, 2002. Intensive Care Society. Guidelines for the introduction of outreach services. London: Intensive Care Society, 2002. Smith G, Nielsen M. Criteria for admission. Br Med J 1998; 318: 1544–7.
25
© 2004 The Medicine Publishing Company Ltd