June 2009

CORE SKILLS IN LAPAROSCOPIC SURGERY

Contact: Mrs. Kelly Westlake Tel: 011-44-29-2068-2131 Email: westlakekm@cf.ac.uk Website: www.rcseng.ac.uk/education/courses/course_list.html
Surgery
June 15-17, 2009 United Kingdom / Cardiff
 
BASIC SKILLS IN HAND SURGERY
Contact: Royal College of Surgeons of England Tel: 011-44-20-7869-6336 Email: plastic@rcseng.ac.uk Website: www.rcseng.ac.uk
Plastic Surgery
June 15-17, 2009 United Kingdom / London 
 
BRITISH FERTILITY SOCIETY PELVIC ULTRASOUND STUDY DAY
Contact: British Fertility Society Secretariat Tel: 011-44-454-642-217 Fax: 011-44-454-642-222 Email: bfs@bioscientifica.com Website: www.britishfertilitysociety.org.uk
Obstetrics/Gynecology / Radiology/Imaging
June 15-16, 2009 United Kingdom / London 
 
REPRODUCTIVE AGEING IN OLDER MOTHERS
Contact: Royal College of Obstetricians & Gynaecologists Tel: 011-44-20-7772-6245 Fax: 011-44-20-7772-6388 Email: conference@rcog.org.uk Website: www.rcog.org.uk/events
Family Medicine / Obstetrics/Gynecology / Other Specialties
June 15, 2009 United Kingdom / London 
 
BASIC TECHNIQUES IN ARTHROSCOPIC SURGERY BASK/RCS
Contact: Royal College of Surgeons of England Tel: 011-44-20-7869-6337 Email: orthopaedic@rcseng.ac.uk Website: www.rcseng.ac.uk/education/courses/course_list.html
Orthopedics / Surgery
June 16, 2009 United Kingdom / London 
 
SPECIALTY SKILLS IN EMERGENCY SURGERY & TRAUMA
Contact: Royal College of Surgeons of England Tel: 011-44-20-7869-6328 Email: trauma@rcseng.ac.uk Website: www.rcseng.ac.uk/education/courses/course_list.html
Emergency Medicine / General Medicine
June 16-17, 2009 United Kingdom / Nottingham 
 
CARE OF THE CRITICALLY ILL SURGICAL PATIENT
Contact: Royal College of Surgeons of England Tel: 011-44-20-7869-6311 Email: ccrisp@rcseng.ac Website: www.rcseng.ac.uk/education/courses/course_list.html
Surgery
June 17-19, 2009 United Kingdom / London 
 
HOW TO PRACTICE EVIDENCE-BASED HEALTH CARE
Contact: Dr. Jane Ilsley, Western General Hospital Tel: 011-44-131-537-3355 Email: wtcrf.education@ed.ac.uk Website: www.rcpe.ac.uk
Other Specialties
June 18-19, 2009 United Kingdom / Edinburgh 
 
BRITISH MATERNAL & FETAL MEDICINE SOCIETY 2009 ANNUAL CONFERENCE
Contact: Hampton Medical Conferences Tel: 011-44-20-8979-8300 Email: fetal@hamptonmedical.com Website: www.bmfms.org.uk
Obstetrics/Gynecology
June 18-19, 2009 United Kingdom / Liverpool 
 
WRIST & HAND ARTHROPLASTY
Contact: Royal College of Surgeons of England Tel: 011-44-20-7869-6336 Email: plastic@rcseng.ac.uk Website: www.rcseng.ac.uk
Plastic Surgery
June 18, 2009 United Kingdom / London 
 
HOW DOES RHEUMATOID ARTHRITIS NEED TO BE MANAGED?
Contact: Meetings & Events Office, Royal College of Physicians Tel: 011-44-20-7034-4900 Email: conferences@rcplondon.ac.uk Website: www.rcplondon.ac.uk/event
General Medicine / Orthopedics / Rheumatology
June 18, 2009 United Kingdom / London 
 
3RD SYMPOSIUM ON ACETABULAR RECONSTRUCTION
Contact: Furlong Research Charitable Foundation Tel: 011-44-207-436-1919 Email: furlong@frcf.org.uk Website: www.rcseng.ac.uk/education/courses/course_list.html
Orthopedics / Surgery
June 19, 2009 United Kingdom / London 
 
ROAD TRAFFIC FATALITIES, PASSENGERS, PEDESTRIANS, PATHOLOGISTS & POLICE
Contact: Conference Department, Royal College of Pathologists Tel: 011-44-20-7451-6715 Email: meetings@rcpath.org Website: www.rcpath.org
Pathology
June 19, 2009 United Kingdom / London 
 
MANAGEMENT OF COMMON PROBLEMS IN OLDER PEOPLE
Contact: Joyce Achampong, Senior Regional Events Co-ordinator, Royal Society of Medicine Tel: 011-44-20-7290-2980 Fax: 011-44-20-7290-2989 Email: joyce.achampong@rsm.ac.uk Website: www.rsm.ac.uk/academ/condiary.php
Family Medicine / General Medicine / Internal Medicine
June 19, 2009 United Kingdom / York 
 
UK THALASSAEMIA SOCIETY CONFERENCE
Contact: UK Thalassaemia Society Tel: 011-44-20-8882-0011 Fax: 011-44-20-8882-8618 Email: office@ukts.org Website: www.rsm.ac.uk/academ/condiary.php
Hematology
June 20, 2009 United Kingdom / Wilmslow 
 
2009 ANNUAL MEETING OF BRITISH ASSOCIATION OF UROLOGICAL SURGEONS (BAUS)
Contact: BAUS Tel: 011-44-20-7869-6950 Fax: 011-44-20-7404-5048 Email: admin@baus.org.uk Website: baus.meeting.org.uk
Surgery / Urology
June 22-25, 2009 United Kingdom / Glasgow 
 
GASTROENTEROLOGY FOR THE PCP BRITISH ISLES/NORWEGIAN FJORDS CRUISE
Contact: Continuing Education, Inc. Tel: 800-422-0711 (US) or 727-526-1571 Email: contactus@continuingeducation.net Website: www.continuingeducation.net
Family Medicine / Internal Medicine
June 22-July 04, 2009 United Kingdom / Harwich 
 
BASIC PRACTICAL SKILLS IN OBSTETRICS & GYNAECOLOGY
Contact: Conference Office, Royal College of Obstetricians & Gynaecologists Tel: 011-44-20-7772-6245 Fax: 011-44-20-7772-6388 Email: conference@rcog.org.uk Website: www.rcog.org.uk/meetings
Obstetrics/Gynecology
June 22-24, 2009 United Kingdom / London 
 
BYPASS, BALLOON PUMPS & CIRCULATORY SUPPORT
Contact: Royal College of Surgeons of England Tel: 011-44-20-7869-6340 Email: cardiothoracics@rcseng.ac.uk Website: www.rcseng.ac.uk
Surgery
June 22, 2009 United Kingdom / London 
 
WORKSHOP IN PELVIC SURGERY
Contact: TMB Marketing and Communications, Conference Desk Tel: 011-44-1306-877-000 Fax: 011-44-1306-877-777 Email: info@wips-intl.com Website: www.wips-intl.com
Obstetrics/Gynecology
June 22-26, 2009 United Kingdom / London 
 
SPECIALTY SKILLS IN VASCULAR SURGERY
Contact: Royal College of Surgeons of England Tel: 011-44-20-7869-6340 Email: vascular@rcseng.ac.uk Website: www.rcseng.ac.uk
 Surgery
June 22-23, 2009 United Kingdom / London
                                                                                                                                                   

5TH INTERNATIONAL CONFERENCE ON CHILDREN'S BONE HEALTH
Contact: Clare Moloney, Oxford International  Tel: 011-44-1865-511-550 Fax: 011-44-1865-511-570 Email: clare.moloney@oxfordint.co.uk Website: www.iccbh5.org
Endocrinology / Orthopedics / Pediatrics
June 23-26, 2009 United Kingdom / Cambridge 
 
9TH ANNUAL INTERNATIONAL ASSOCIATION OF FORENSIC MENTAL HEALTH SERVICES (IAFMHS)
Contact: IAFMHS Tel: 604-924-5026 Fax: 604-924-5027 Email: tmoropito@iafmhs.org Website: www.iafmhs.org
Psychiatry
June 24-26, 2009 United Kingdom / Edinburgh 
 
ADVANCED SKILLS IN VASCULAR SURGERY
Contact: Royal College of Surgeons of England Tel: 011-44-20-7869-6340 Email: vascular@rcseng.ac.uk Website: www.rcseng.ac.uk/education/courses/course_list.html
Surgery
June 24-26, 2009 United Kingdom / London 
 
INTERMEDIATE THORACIC SURGERY
Contact: Royal College of Surgeons of England Tel: 011-44-20-7869-6340 Email: Cardiothoracics@rcseng.ac.uk Website: www.rcseng.ac.uk/education/courses/course_list.html
Surgery
June 24-25, 2009 United Kingdom / London 
 
ASSOCIATION OF BREAST SURGERY AT BASO TRAINEES MEETING 2009
Contact: Krysia Cruickshank Tel: 011-44-141-211-6248 Email: krysia.cruickshank@northglasgow.scot.nhs.uk Website: www.baso.org
Oncology / Surgery
June 25-26, 2009 United Kingdom / Glasgow 
 
RECENT ADVANCES IN MEDICINE
Contact: Sue Dent, University Hospital of North Tees Tel: 011-44-164-262-4791 Fax: 011-44-164-226-4918 Email: sue.dent@nth.nhs.uk Website: www.rcpe.ac.uk
Family Medicine / General Medicine / Internal Medicine
June 26, 2009 United Kingdom / Stockton-on-Tees 
 
SYSTEMATIC TRAINING IN ACUTE ILLNESS RECOGNITION & TREATMENT FOR SURGERY
Contact: Royal College of Surgeons of England Tel: 011-44-20-7869-6311 Email: ccrisp@rcseng.ac.uk Website: www.rcseng.ac.uk
Surgery
June 27, 2009 United Kingdom / London 
 
13TH CONFERENCE OF NATIONAL OSTEOPOROSIS SOCIETY
Contact: Sarah Phillips or Kelly Hall, Events Dep’t., National Osteoporosis Society Tel: 011-44-1761-473-106 or 011-44-1761-473-123 Fax: 011-44-1761-471-104 Email: s.phillips@nos.org.uk or k.hall@nos.org.uk Website: www.nos.org.uk
Other Specialties
June 29-July 01, 2009 United Kingdom / Manchester 
 
2009 ANNUAL MEETING OF BRITISH SOCIETY FOR ALLERGY & CLINICAL IMMUNOLOGY (BSACI)
Contact: BSACI Tel: 011-44-207-340-9614 Email: info@bsaci.org Website: www.bsaci.org
Immunology/Allergy
June 29-July 01, 2009 United Kingdom / Nottingham 
 
PATHOLOGICAL SOCIETY OF GREAT BRITAIN & IRELAND SUMMER MEETING 2009
Contact: Pathological Society of Great Britain & Ireland Tel: 011-44-20-7976-1260 Fax: 011-44-20-7930-2981 Email: admin@pathsoc.org Website: www.pathsoc.org
Pathology
June 30-July 03, 2009 United Kingdom / Cardiff 
 
UPDATE IN MANAGEMENT OF DETRUSOR OVERACTIVITY
Contact: Royal College of Surgeons of England Tel: 011-44-20-7869-6340 Email: urology@rcseng.ac.uk Website: www.rcseng.ac.uk
Surgery / Urology
June 30, 2009 United Kingdom / London 
 
CARDIOTHORACICS FOR SURGICAL ASSISTANTS
Contact: Royal College of Surgeons of England Tel: 011-44-20-7869-6340 Email: Cardiothoracics@rcseng.ac.uk Website: www.rcseng.ac.uk/education/courses/course_list.html
Surgery
June 30, 2009 United Kingdom / London 
 
RECONSTRUCTIVE TECHNIQUES IN UROLOGY
Contact: Royal College of Surgeons of England Tel: 011-44-20-7869-6340 Email: urology@rcseng.ac.uk Website: www.rcseng.ac.uk/education/courses/course_list.html
Surgery / Urology
June 30, 2009 United Kingdom / London 
 
CARE HOME MEDICINE
Contact: Meetings & Events Office, Royal College of Physicians of Edinburgh Tel: 011-44-20-7034-4900 Email: conferences@rcplondon.ac.uk Website: www.rcplondon.ac.uk/event
General Medicine / Geriatrics / Other Specialties / Pain Management
June 30, 2009 United Kingdom / London 
 
SOUTH ASIA DAY: JOINT RCOG/AICC RCOG/SAFOG MEETING
Contact: Royal College of Obstetricians & Gynaecologists Tel: 011-44-20-7772-6245 Fax: 011-44-20-7772-6388 Email: conference@rcog.org.uk Website: www.rcog.org.uk/events
Obstetrics/Gynecology
July 03, 2009 United Kingdom / London 
 
CANCER IN WOMEN BALTIC SEA CRUISE
Contact: Continuing Education, Inc. Tel: 800-422-0711 (US) or 727-526-1571 Email: available through web page Website: www.continuingeducation.net
Family Medicine / Internal Medicine / Obstetrics/Gynecology
July 04-16, 2009 United Kingdom / Harwich 
 
6TH INTERNATIONAL ASSOCIATION FOR BIOLOGICALS SYMPOSIUM ON ADVANCES IN TRANSFUSION SAFETY
Contact: Department of Haematology, Cambridge Institute for Medical Research Tel: 011-44-122-354-8044 Email: jpa1000@cam.ac.uk Website: www.iabs.org
Hematology / Other Specialties
July 06-07, 2009 United Kingdom / Cambridge 
 
4TH NATIONAL AUTISM TODAY
Contact: Mark Allen Group Tel: 011-44-20-7501-6762 Fax: 011-44-20-7733-8174 Email: conferences@markallengroup.co.uk Website: www.mahealthcareevents.co.uk
Family Medicine / General Medicine / Neurology / Pediatrics / Psychiatry
July 06-07, 2009 United Kingdom / London 
 
MRCOG PART 1 REVISION COURSE
Contact: Royal College of Obstetricians & Gynaecologists Tel: 011-44-20-7772-6245 Fax: 011-44-20-7772-6388 Email: conference@rcog.org.uk Website: www.rcog.org.uk/events
Obstetrics/Gynecology
July 06-10, 2009 United Kingdom / London 
 
CURRENT CONCEPTS IN EXTERNAL FIXATION IN TRAUMA
Contact: Royal College of Surgeons of England Tel: 011-44-20-7869-6337 Email: orthopaedics@rcseng.ac.uk Website: www.rcseng.ac.uk/education/courses/course_list.html
Orthopedics / Surgery
July 06, 2009 United Kingdom / London 
 
WORKSHOP ON THE MOLECULAR PHARMACOLOGY & THERAPEUTICS OF BONE DISEASE
Contact: National Association for the Relief of Paget's Disease Tel: 011-44-161-799-4646 Fax: 011-44-161-799-6511 Email: director@paget.org.uk Website: www.paget.org.uk
Endocrinology / Other Specialties
July 06-09, 2009 United Kingdom / Oxford 
 
89TH ANNUAL MEETING OF BRITISH ASSOCIATION OF DERMATOLOGISTS
Contact: Conference & Events Services, British Association of Dermatologists Tel: 011-44-20-7391-6358 Fax: 011-44-20-7388-0487 Email: conference@bad.org.uk Website: www.bad.org.uk
Dermatology
July 07-10, 2009 United Kingdom / Glasgow 
 
13TH BRITISH ACADEMIC CONFERENCE IN OTOLARYNGOLOGY AND ENT EXPO
Contact: ENT UK Tel: 011-44-20-7404-8373 Fax: 011-44-20-7420-4200 Email: conferences@entuk.org Website: www.bacouk.org
Otolaryngology
July 08-10, 2009 United Kingdom / Liverpool
 
HANDS ON GYNAECOLOGICAL ENDOSCOPY SKILLS WORKSHOP
Contact: Therese Eleftheriou, Course Secretary Tel: 011-44-20-7795-0500 ext. 33863 Fax: 011-44-20-7431-1321 Email: courses@gynendo.com Website: www.gynendo.com/dates.htm
Obstetrics/Gynecology / Surgery
July 08-10, 2009 United Kingdom / London 
 
INTERNATIONAL SYMPOSIUM ON PAGET’S DISEASE
Contact: National Association for the Relief of Paget's Disease Tel: 011-44-161-799-4646 Fax: 011-44-161-799-6511 Email: director@paget.org.uk Website: www.paget.org.uk
Endocrinology / Other Specialties
July 08-09, 2009 United Kingdom / Oxford 
 
11TH NATIONAL CONFERENCE: THE DIABETES EPIDEMIC
Contact: Mark Allen Group Tel: 011-44-20-7501-6762 Fax: 011-44-20-7733-8174 Email: conferences@markallengroup.co.uk Website: www.mahealthcareevents.co.uk
Endocrinology
July 13-14, 2009 United Kingdom / London 
 
DEFINITIVE SURGICAL TRAUMA SKILLS FOR THE GENERAL SURGEON
Contact: Royal College of Surgeons of England Tel: 011-44-20-7869-6336 Email: trauma@rcseng.ac.uk Website: www.rcseng.ac.uk/education/courses/course_list.html
Surgery
July 14-15, 2009 United Kingdom / London 
 
3RD NATIONAL CRITICAL CARE SYMPOSIA
Contact: Mark Allen Group Tel: 011-44-20-7501-6762 Fax: 011-44-20-7733-8174 Email: conferences@markallengroup.co.uk Website: www.mahealthcareevents.co.uk
Internal Medicine
July 15-17, 2009 United Kingdom / London 
 
BRITAIN PACIFIC MEDICAL AND LEGAL CONFERENCE
Contact: Lorenzo Boccalbella Tel: 011-61-07-3254-3331 Fax: 011-61-07-3254-3332 Email: info@educationcpe.com Website: www.conferences21.com
Legal/Ethics
July 17-24, 2009 United Kingdom / Oxford
 
BRITAIN PACIFIC MEDICAL & LEGAL CONFERENCE
Contact: Continuing Professional Education Pty Ltd. Tel: 011-61-7-3254-3331 Fax: 011-61-7-3254-3332 Email: info@conferences21.com Website: www.conferences21.com
Legal/Ethics
July 17-24, 2009 United Kingdom / Stratford-upon-Avon 
 
BASIC SCIENCE: CELL SIGNALLING AND THE GUT
Contact: United European Gastroenterology Federation Secretariat Tel: 011-43-1-997-1639 Fax: 011-43-1-997-1639 ext. 10 Email: office@uegf.org Website: www.uegf.org
Gastroenterology
July 19-21, 2009 United Kingdom / Cambridge 
 
MRCOG PART 2 REVISION COURSE
Contact: Royal College of Obstetricians & Gynaecologists Tel: 011-44-20-7772-6245 Fax: 011-44-20-7772-6388 Email: conference@rcog.org.uk Website: www.rcog.org.uk/events
Obstetrics/Gynecology
July 20-22, 2009 United Kingdom / London 
 
FRCS (PLAST) AESTHETIC STUDY DAY
Contact: Royal College of Surgeons of England Tel: 011-44-20-7869-6336 Email: aesthetic@rcseng.ac.uk Website: www.rcseng.ac.uk/education/courses/course_list.html
Plastic Surgery
July 21, 2009 United Kingdom / London 
2009 BRITISH ASSOCIATION FOR PSYCHOPHARMACOLOGY (BAP) SUMMER MEETING
Contact: Lynne Harmer, BAP Tel: 011-44-1223-358-421 Email: lynne@bap.org.uk Website: www.bap.org.uk
Clinical Pharmacology / Psychiatry
July 26-29, 2009 United Kingdom / Oxford                                                                                                                                                                    
 
BASIC PRACTICAL SKILLS IN OBSTETRICS & GYNAECOLOGY
Contact: Royal College of Obstetricians & Gynecologists Tel: 011-44-20-7772-6245 Fax: 011-44-20-7772-6388 Email: conference@rcog.org.uk Website: www.rcog.org.uk/events
Obstetrics/Gynecology
July 27-29, 2009 United Kingdom / London 
 
CORE SKILLS IN LAPAROSCOPIC SURGERY
Contact: Julie Bradley Tel: 011-44-121-424-1488 Email: julie.bradley@heartofengland.nhs.uk Website: www.rcseng.ac.uk/education/courses/course_list.html
Surgery
August 19-21, 2009 United Kingdom / Birmingham 
 
11TH NATIONAL CONFERENCE: PARKINSONS DISEASE
Contact: Mark Allen Group Tel: 011-44-20-7501-6762 Fax: 011-44-20-7733-8174 Email: conferences@markallengroup.co.uk Website: www.mahealthcareevents.co.uk
Neurology
August 25, 2009 United Kingdom / London 

The patient's right to autonomy should always be respected and steps shall be taken to make consent truly informed. There is, however, no absolute right to consent on the basis of philosophical, ethical, legal and practical considerations.

Introduction

Consent to investigations and treatment is considered a cornerstone in the doctor-patient relationship.¹ The Oxford Dictionary (1998) defines consent as “permission for something to happen or agreement to do something”.² This definition does not entail understanding of the action agreed to and for medical purposes the term ”informed consent” meaning “permission granted in the knowledge of possible consequences” has been developed.² General Medical Council (GMC) guidance requires the ability to comprehend and weigh up information as well the ability to communicate for informed consent.³

Most authors describe consent as a principle relatively new to medicine.^4-6 This is however incorrect as even Plato and Hippocrates used consent in their medical practice.⁷

This review addresses the issue whether the right to consent is an absolute right by exploring the ethical and legal framework of consent or more specifically informed consent. Whereas most of the ethical issues are universally applicable, the legal aspects and guidance by the regulatory authorities apply only to the United Kingdom (UK). Where law differs between Scotland and the rest of the UK, I have focused on the laws for the latter.

Ethical principles around consent

The four main principles of medical ethics are justice, non-malificence, autonomy and beneficence.⁸ Autonomy is the main ethical consideration underlying informed consent. The patients’ right to determine what investigations and treatment to undergo must be respected by all doctors.³ For consent to be informed patients rely on the information provided by their doctor. Honesty and truthfulness are required to make the process of consent valid.³ The ethical principle of justice needs to be applied when deciding what treatments are offered to or withheld from patients. This touches the process of informed consent and is further explored when the right to demand certain treatments is discussed.

Philosophical aspects

The debate whether a right or a principle is absolute not only involves ethical and legal aspects. It also touches on the philosophical argument of absoluteness. Freedom as an example can’t exist as an absolute principle because granting one individual absolute freedom will infringe the freedom of a second individual considerably. Person A’s freedom to take any good will influence the freedom of person B to have property. When applying these principles to autonomy the same problem arises: Total autonomy of one individual has a negative effect on autonomy of other individuals. The modern democratic society has designed rules and laws to create a fair way of living. On the one hand this restricts autonomy, while on the other hand this same restricted autonomy guarantees the same amount of it to all members of this society.

I argue therefore that on a philosophical basis the principle of total autonomy contradicts itself when applied to society. As autonomy is the main ethical principle for informed consent an absolute right to consent cannot exist.

Requirements of informed consent

The basic difference between consent and informed consent is the patients’ knowledge behind the consent decision. Informed consent requires the patient to understand the diagnosis and uncertainties about it as well as the different treatment options (including doing nothing) and their advantages, disadvantages and achievable outcomes.³ The amount of information required to make consent informed may vary depending on complexity and risks of treatment as well as the patient’s wishes.³ Furthermore individual patients will have different intellectual capabilities and understanding of their illness. It is therefore mandatory to tailor information provided to the individual patient and the current situation. An emergency like acute myocardial infarction for example will allow less time to discuss diagnosis and treatment than an elective endoscopy.

To judge whether a patient has really understood the information provided can be difficult and often little of the information is retained (see practical aspects chapter). This leaves physicians in doubt whether their patient’s consent is truly informed. Consent based on partial information may be invalid but this may go unnoticed by patient and treating physician.

The principal of an absolute right to consent could be easily undermined by partial information. It is highly dependant on the willingness to provide full information and the patient’s capability to understand it and weigh up the options.

Legal framework

A medical intervention without valid informed consent is a criminal offence and the physician can be charged with battery. Examples of such situations include treatment against the patient’s will, different treatment than the one consented for and treatment after consenting deliberately with wrong information.⁹

Guidance for consent has been set up by the regulatory body (GMC). While no one can consent for a competent adult UK laws are regulating consent for minors, patients with acutely or permanent incapacity and patients suffering form severe mental illness.

Minors

At the age of 16 persons are to be considered as adults and can therefore be presumed to have capacity. Children younger than 16 years may have capacity depending on their understanding. When a competent child refuses treatment persons with parental responsibility may authorise this or a court may overrule the child’s decision.³ Incompetent children will be treated with consent from a person with parental responsibility.

Acute and permanent incapacity

The presumption that every adult patient has capacity applies unless the opposite can be clearly demonstrated.^{3, 10} Patients lacking capacity due to an acute (i.e loss of consciousness after an accident or patients on mechanical ventilation) or chronic illness (i.e dementia) cannot make decisions about their treatments themselves. In those situations it is the doctor’s duty to act in the “best interest of the patient”. Views about the patient’s preferences may be sourced from a third party (relatives for example). This third party can however not consent or object to treatment.³ If a patient has clearly given an advance directive while still competent, the treating physician is bound to respect this (see advance directive).

To give informed consent a patient needs to have mental capacity and the ability to communicate.¹¹ The physician needs to establish the patient’s “ability to understand, retain, believe, evaluate, weigh and use information that is relevant to a medical intervention or its withdrawal”.¹¹ This test of capacity has been supported by several court rulings^{10, 12, 13} and is embedded in the Mental Capacity Act (2005).¹⁴

Making an irrational choice does by no means constitute lack of capacity and a competent patient’s irrational decision has to be accepted even if this leads to an adverse outcome (including death).³

Mentally ill patients

The Mental Health Act (1983) regulates the treatment and hospital admission of mentally ill patients not volunteering to undergo assessment and/or treatment.¹⁵ These patients can only be admitted to hospital if due to their mental illness they pose a threat to themselves or others. Patients can be detained against their wishes to conduct an assessment and if their condition is deemed treatable they can be detained to receive such treatment. While this allows treatment for psychiatric conditions, the treatment of physical conditions not related to mental illness cannot be undertaken against the patient’s wishes. If needed, a court can decide on treatment of non-psychiatric illnesses in those patients.

This aspect of the law can leave physicians in difficult situations. If a depressed patient takes an overdose of an anti-inflammatory drug he can be detained in hospital using section 5.2 of the Mental Health Act. A resulting medical complication like severe gastrointestinal bleeding is however not covered by the mental health act. The patient therefore still remains competent to refuse a life-saving endoscopy or blood transfusion.

Protecting the public: infectious diseases, infection control and confidentiality

In order to protect the public form contagious infectious diseases the Public Health (Control of Disease) Act (1984) regulates notification of diseases and mandatory treatment of conditions like tuberculosis (TB).¹⁶ The individual’s right to consent is severely restricted in two areas: Firstly information about the patient’s diagnosis has to be given to the relevant authorities. The patient should be informed about this step. Section 11 regulates the disclosure of information. It is mandatory for a medical practitioner to disclose personal details of the patient and the diagnosis to the relevant authorities even if the patient does not agree to this. The list of notify-able diseases ranges from food poisoning and viral hepatitis to tuberculosis.

Secondly patients suffering from communicable diseases can be forced to take their medication by supervised administration or involuntary inpatient treatment. Sections 37 and 38 of the Public Health (Control of Disease) Act have recently been used to detain a man for inpatient treatment of TB against his will at North Manchester General Hospital.¹⁷ The act was used to prevent the spread of TB to the wider public by forcing treatment onto an individual, who was not compliant.

While above regulations are clearly set out by law, a physician might encounter situations in which no clear guidance is given. If a patient confesses a crime or a planned crime to a doctor, it is left to him to decide whether to pass on this information to the police. This decision requires careful weighing up whether the right to consent on passing on information is more important than the right of the public to be protected. GMC guidance (Confidentiality: Protecting and Providing Information, 2004) gives general advice on disclosure, but leaves the ultimate decision with the medical practitioner.¹⁸

The legislative has given clear laws stating when a right to consent does not apply to a patient. Incompetent minors, adults lacking capacity and some mentally ill patients do not have an absolute right to consent. Furthermore patients suffering from some infectious diseases have limited right to consent and can be detained and treated against their will. Using the principles of capacity and justice towards other individuals the right to autonomy has been cut in a few well-defined circumstances.

Advance directives

When an adult becomes incompetent he loses the right to decide on his medical care. To allow patients to express their ideas and wishes before they become incapacitated the Mental Capacity Act was introduced in 2005.¹⁹ Patients can give an advance directive or “living will” to outline the treatments they wish or wish not to receive. A physician is required to act within this advanced directive unless there is evidence that the patient revoked the will when still competent. A “living will” does not necessarily apply to all situations and it has to be checked whether the patient’s current condition is covered by his will.

Practical application of advance directives can be difficult: Unclear wording like “no life-prolonging treatment” leaves room for interpretation and the same intervention might have different outcomes depending on underlying conditions. A healthy patient might set up an advance directive to not receive mechanical ventilation without discussing the merits of this intervention with a health care professional. This generally prohibits any doctor from administering such treatment in any situation. While this might be the patient’s wish should he suffer a devastating stroke (very little chance of recovery), it could be argued that his view would be different if the merits of ventilation after major emergency surgery (reasonably good chance of full recovery) would have been explained to him.

Furthermore the act established the lasting power of attorney (LPA) concept. This enables the patient to grant rights of consent and refusal to a LPA while still competent. The LPA then takes over these powers when the patient loses capacity.

Research without consent

While consent should always be sought for including patients in clinical research, there are conditions that do not allow a delay: Unconscious patients, patients in shock and studies with short therapeutic windows. While including those patients without consent infringes their right to autonomy society as a whole benefits from such research. The European Union (EU) allows such studies to recruit patients without their consent under strict regulation.²⁰

The right to refuse or demand treatment

British law clearly gives competent patients the right to refuse any treatment (the very few exceptions have been outlined in the chapter legal framework). In contrast, however, no patient has a right to demand certain treatments. GMC regulation (2008) states that if a patient wishes treatment that in the doctor’s view is clinically not indicated there is no ethical or legal obligation to provide such treatment.²¹

Burke, who suffers from a chronic and progressing neurological illness, challenged this guidance. He wishes to receive artificial nutrition and hydration (ANH) when he loses his ability to swallow and he does not want doctors to make decisions on his behalf. Arguing that the relevant GMC guidance infringes his human rights he took the case to court achieving a favourable ruling initially. Mr Justice Munby ruled in Burke²² that the Human Rights Act (1998)²³ entitles a person to demand life-prolonging treatments such as ANH. He based his decision on article 2, 3 and 8 arguing that a competent person’s right to life and autonomy constitute an entitlement to ANH.¹¹

The Court of Appeal overturned this ruling although the right-based analysis of Munby’s decision was acknowledged. Two lines of argument were used to justify the decision. Firstly the case of Bland²⁴ (Airedale NHS Trust 1993), an advance directive to withdraw treatment in a case of persistent vegetative state must be respected, does not automatically lead to a reverse decision in opposite cases.¹¹

Secondly an advanced directive demanding life-prolongueing treatment would not be in consistence with the Mental Capacity Act, which requires the doctor to take the incompetent patient’s best interest into consideration.¹¹

Another aspect of demanding treatment is the effect on the wider community. Graber and Tansey argue that demanding certain (more expensive, equally effective) treatments leads to injustice.²⁵ While doctors may feel pressured to please their patient’s wishes, financial and organisational constraints in society (and a public health care system) will mean that other patients might not get treatments they require.

Currently there is no legal right in the UK to demand treatment. Furthermore such demands infringe justice by prohibiting resources to be allocated by need.

Practical aspects of consent: understanding and retention of information provided

Informed consent requires the ability to understand and weigh up information. Several studies have addressed the issue of understanding and retention of information provided. Even in a research setting where rigorous measures for consent are applied severe defiencies have been identified: in a randomized drug trial 44% of participants did not know that they were assigned to treatment or placebo by chance.²⁶ A capsule endoscopy study recruited healthy volunteers, of whom 90% had university education and 60% were medical students. Still vital information (drugs used, potential risks) given during the consent was only completely recalled by around 20%.²⁷ These examples show that most patients or research participants do not have a good understanding and/or recall of the information provided by standard consent procedures. Despite that treating doctors and researcher had treated or included patients based on this “informed” consent.

Methods like enhanced consent forms and multimedia interventions during informed consent have shown mixed results, while only additional time spent in one-on-one interviews significantly improved understanding and recall of information.²⁸

Discussion

Informed consent is required for any investigation or treatment proposed to a patient. Understanding of the nature of procedure, benefits and risks are the cornerstones of informed consent. While autonomy is one of the four main ethical principles, I argue that there is no absolute right to autonomy or consent.

On a philosophical basis an absolute right to autonomy and consent contradicts itself.

Several restrictions in the right to consent are set by the legal framework in the United Kingdom (or England). The main statuary instruments concerned are: Mental Health Act, Mental Capacity Act and Public Health Act. UK Law regulates the right to consent for minors, mentally ill patients, patients with incapacity and patients with communicable diseases. Their rights to consent are restricted and in special circumstances not granted. Disclosure of information without consent is mandatory in infectious diseases cases and legal in cases where the doctor believes that non-disclosure will leave the public in danger. Furthermore patients can be recruited to studies of emergency medical treatment without consent under strict EU regulation. On a legal basis there is no absolute right to consent therefore.

Patients with anticipated incapacity can set advance directives to guide their future treatment while still competent or a LPA can be given the right to decide on treatment on the patient’s behalf. While this increases the right of consent and improves patient autonomy to refuse treatment, there is no right to demand treatment if this is considered medically inappropriate (futile for example) by the treating medical practitioner.

Looking at the practical aspects of consent shows that the information provided is often poorly understood and retained. Patients giving consent are doing so without being truly informed. In other words they can’t give informed consent due to their lack of understanding. As shown in the chapter practical aspects this will often not be noticed by the treating doctor or researcher. It is difficult to conceive an absolute right to consent in practice, when the effort to supply information required for informed consent fails so often.

In summary the patient’s right to autonomy should always be respected and step shall be taken to make consent truly informed. On the basis of philosophical, ethical, legal and practical considerations, however, there is no absolute right to consent.

References

1. Habiba MA (2000) Examining consent within the patient-doctor-relationship. Journal of Medical Ethics 26:183-87
2. The Oxford Dictionary of new English, Oxford. Oxford University Press, 1998
3. GMC (1998) Seeking patients’ consent: The ethical considerations, General Medical Council, London
4. King J (1986) Informed consent: A review of empirical evidence. Institute of Medical Ethics Bulletin supp 3: 1-17
5. Kour NW, Rauff A (1992) Informed consent – historical perspective and a clinician’s view. Singapore Medical Journal 33:44-46
6. Nelson-Marten P, Rich RA (1999) A historical perspective of informed consent in clinical practice and research. Oncology Nursing 15:81-8
7. Dalla-Vorgia P, Lascaratos J, Skiadas P et al. (2001) Is consent in medicine a concept only of modern times? Journal of Medical Ethics 27:59-61
8. Gillon R. Medical ethics: Four principles plus attention to scope. BMJ 1994; 309:184-8<br>
9. MRHA guidance (2007): http://www.mhra.gov.uk; as accessed on 01/06/2008
10. Re C (adult refusal of treatment) [1994] 1WLR 290
11. Samata A, Samata B (2006) Advance directives, best interests and clinical judgement: shifting sands at the end of life. Clinical Medicine 6:274-78
12. Re MB (an adult: medical treatment) [1997] 2 FLR 426
13. Re B (consent to treatment: capacity) [2002] EWCH 429
14. Mental Capacity Act 2005. The Stationary Office, 2005
15. Mental Health Act 1983. The Stationary Office, 1983
16. Public Health (Control of Disease) Act (1984). The Stationary Office, 1984
17. Crook A (2007) TB patient under guard. Manchester Evening News 9/10/2007
18. GMC (2004) Confidentiality: Protecting and Providing Information, General Medical Council, London
19. Mental Capacity Act 2005. The Stationary Office, 2005
20. Lecouturier J, Rodgers H, Ford GA, et al. (2008) Clinical research without consent in adults in the emergency setting: a review of patient and public views. BMC Medical Ethics 9:9
21. GMC (2008) Withholding and withdrawing life-prolonging treatments: Good practice in decision making, General Medical Council, London
22. Re (Burke) v General Medical Council (defendant) and Disability Rights Comission (interested party) and the Official Solicitor (intervenor) [2004] EWHC 1879
23. Human Rights Act (1998). The Stationary Office, 1998
24. Airedale NHS Trust v Bland [1993] A.C. 789
25. Graber MA, Tansey JF (2005) Autonomy, consent, and limiting healthcare costs. Journal of Medical Ethics 31:424-426
26. Howard JM, DeMets D (1981) How informed is informed consent: the BHAT experience. Controlled Clinical Trials 2: 287-303
27. Fortun P, West J, Chalkley L, Shonde A, Hawkey C (2008) Recall of informed consent information by healthy volunteers in clinical trials. QJM an international journal of Medicine in press, available online at: http://qjmed.oxfordjournals.org/cgi/content/abstract/hc
28. Flory J, Emanuel E (2004) Interventions to improve research participants’ understanding in informed consent for research. Journal of the American Medical Association 292: 1593-1601

Case report

An 82 year old lady, who had suffered multiple strokes in the past and was currently on long term percutaneous endoscopic gastrostomy( PEG) feeding, was admitted as an emergency from a nursing home with a two week history of productive cough and fever. She had been on PEG feeding since her first stroke six years previously. The first PEG tube (placed in 2001) subsequently fell out of position, and a second tube (15 French Frecka PEG tube) was inserted in 2003.

On admission, she was pyrexial, dehydrated, and hypoxic on room air. Chest examination revealed bilateral crackles and neurological examination revealed expressive dysphasia, and spastic weakness in both lower limbs. Abdominal examination revealed an inflamed PEG site with purulent discharge. Blood tests revealed raised inflammatory markers with neutrophilia (WBC 20 x 10⁹ /L with a neutrophil count of 12 x 10⁹/L) and a raised C-reactive protein at 193 mg/L.

She was managed with intravenous fluids and antimicrobial therapy (tazocin and metronidazole) for possible aspiration pneumonia. Vancomycin was subsequently commenced as methicillin resistant staphylococcus aureus (MRSA) was isolated from the PEG site. As she remained stable, PEG feeding was recommenced.

A week following her admission she became unwell with an episode of vomiting and choking following PEG feeding. This was associated with difficulty in infusing feeds and medications through the PEG tube. Multiple flushes through the tube were unsuccessful. The tube was found to be persistently blocked and lacked free mobility within the tract.

Urgent upper gastro intestinal endoscopy revealed a buried bumper as the cause of blockage of the PEG tube. This necessitated insertion of a new PEG tube (9 French Frecka) for enteral feeding. The old PEG tube was removed surgically under local anaesthesia in due course. As the removal of the buried bumper was found to be very difficult endoscopically, and surgical intervention was deemed to be inadvisable in view of co morbidities, the bumper was left in situ. Feeding was recommenced through a new tube. In view of persistent discharge through the PEG site, abdominal ultrasound examination was performed, revealing a possible gastro-cutaneous fistula. No local collection was seen around the PEG wound.

As the patient remained clinically stable, she was discharged home with necessary instructions to her carers for regular flushing of the PEG tube with water, before and after each feed, to prevent further blockages.

Fig 1: Buried bumper (stomach-lower body)


Fig 2: New peg and buried bumper

Discussion

PEG is primarily used for long term (longer than 6 weeks) enteral alimentation for patients with impaired swallowing (e.g. from stroke, degenerative neurological disease, head injury, and oropharyngeal malignancy). However numerous complications have been reported since its introduction in 1980.

Buried bumper syndrome (BBS) is an uncommon but well documented complication of PEG insertion, first described in 1988 ¹. It is usually a late complication occurring up to 3 years post PEG insertion and reported to occur in 0.3-2.4 % of patients².

The internal bumper of the PEG tube should normally sit snugly against the anterior gastric wall, and this is confirmed endoscopically at the time of initial placement. BBS develops when there is migration of the internal bumper/flange through or into the anterior abdominal wall. This probably occurs as a result of excessive tension between the internal and external bumpers, from over-tightening of the external flange, leading to gastric wall erosion. During migration it becomes lodged along the gastrostomy tube tract between the gastric and abdominal walls. Once epithelialisation occurs the bumper gets covered with gastric mucosa³.

The diagnosis of BBS should be suspected if localised abdominal pain, peri-tubal leakage or inability to infuse feed occurs. Initial measures to deal with a blocked tube include flushing with warmed water, and occasionally passage of a flexible wire through the lumen, in order to unblock any obstruction. Tube obstruction is usually related to the administration of protein-enriched formulae or medications, especially if the tube size is 9 French. Fungal colonisation may also lead to tube blockage, requiring specific solutions for flushing the tube⁴. Tube exchange should only be considered if the gastrocutaneous tract is mature (6 weeks or longer after placement of the tube).

Endoscopy is confirmatory in cases of BBS. The internal bumper is not seen, and the site of the PEG is indicated by an elevated area of submucosa with a central depression. Failure to recognise BBS can result in gastric perforation and gastrointestinal haemorrhage or intra abdominal sepsis, peritonitis and even death⁵.

Ideally, the buried bumper should be removed even if the patient is asymptomatic, to avoid potential complications from continued tube migration until it is completely impacted in the abdominal wall. The literature describes various methods of dealing with this complication. Endoscopic ultrasound of the gastric wall with a catheter US probe can facilitate the localisation of the bumper and also provides information regarding feasibility of surgical or endoscopic removal of PEG tube⁶.

Regular and optimal PEG care has been vital in identifying and prevention of this complication. During daily cleaning of the external PEG site, the PEG should be pushed in approximately 1 cm and rotated prior to repositioning of the external bumper. The length of the tube outside the abdominal wall should be examined at regular intervals so that migration can be recognised⁵.

This report reinforces the fact that physicians should be aware of this recognised risk of PEG feeding and prompt referral for endoscopy is necessary to avoid serious consequences including gastro-intestinal bleeding, peritonitis and death. Similarly specific instructions should be given to carers for prevention of BBS.

References

1. Shallman RW, Norfleet RG, Hardache JM. Percutaneous endoscopic gastrostomy feeding tube migration and impaction in the abdominal wall. Gastrointest Endosc 1988; 34: 367–68.
2. Venu RP, Brown RD. Pastika BJ Erickson LW. The buried bumper syndrome: a simple management approach in two patients. Gastrointest Endosc 2002; 56: 582–84.
3. Anagnostopoulos GK, Kostopoulos P, Arvanitidis DM. Buried Bumper Syndrome with a fatal outcome, presenting early as gastrointestinal bleeding after percutaneous endoscopic gastrostomy placement. J Postgrad Med 2003; 49:325–27
4. Iber, FL, Lusak, A, Patel, M Importance of fungus colonization in failure of silicone rubber percutaneous gastrostomy tubes (PEGs) Dig Dis Sci, 1996, 41: 226-231
5. Braden B, Brandstaetter M, Caspary WF, Seifert H. Buried bumper syndrome: treatment guided by catheter probe US. Gastrointest Endosc 2003;57:747-51
6. Ma MM, Semalacher EA, Fedorak RN, Llor EA, Duerksen DR et al The buried gastrostomy bumper syndrome: prevention and endoscopic approaches to removal. Gastrointest Endosc 1995 ; 41:505-8

The significance of disturbed subjective sleep quality in the general population is important because of high prevalence rates (of up to 30%)¹ and the association with decreased quality of life.² Poor sleep affects cognitive and physical functioning, and insomnia is associated with a greater risk of falls and accidents,³ higher rates of absenteeism⁴ and increased health care utilization.⁴

Insomnia is commonly encountered in primary and secondary care settings, and can be symptomatic of many medical, neurological, substance abuse or primary sleep disorders.

Epidemiological and clinic-based studies consistently demonstrate high rates of psychiatric comorbidity.^5,6 Sleep disturbance is an important clinical construct in psychiatry. It represents formal diagnostic criterion in mental illnesses such as affective and anxiety disorders.^7,8

Insomnia is broadly defined as the subjective experience of poor or unrefreshing sleep, with some objective evidence of reduced time asleep or delayed sleep-onset. The subjective nature of such complaints remains key, because sleeping is a private event, and there is often no informant history. Furthermore, it is the perceptual aspects of sleep that influence patients’ help-seeking behaviour, such as consultation requests, demands for night sedation, and medication and substance use. It is noteworthy that despite the wide-ranging implications and subjectively distressing nature of this phenomenon, it remains arguably one of the least satisfying symptoms to treat. Seeking a better understanding of the extent and nature of patients’ sleep perception can help optimise appropriate therapeutic strategies.

This is the first study assessing the subjective sleep quality of a sample of psychiatric disordered in-patients in a UK psychiatric hospital setting, using the Pittsburgh Sleep Quality Index (PSQI).⁹ This study is framed in the context of increasing the awareness of the significance of patients’ complaints of insomnia and addressing the wider psychosocial issues that this raises.

Method

Design: This was a cross-sectional survey of the self-reported quality of sleep in a population of psychiatric in-patients on the acute adult wards of a London psychiatric hospital.

Participants and Procedure:Participants consisted of psychiatric in-patients (ages 18-65) on all five of the acute adult open psychiatric wards of the Highgate Mental Health Centre, London, currently admitted for the assessment or treatment of mental illness. Financial compensation was not provided for any subject.

Subjects were approached on the ward by a member of nursing staff and asked if they were interested in participating in a study about sleep. The researcher was then introduced to explain further details with the aid of the participant information sheet. After a minimum of 24 hours, patients were approached again by the researcher and asked if they were willing to participate. Recruitment of subjects took place if the patient was agreeable to take part and did not meet any of the exclusion criteria (listed below). A scheduled time and date was made with participants in order to obtain written informed consent and to administer the questionnaire. Questionnaire data was collected from each subject by the researcher in a private interview room located on the patient’s psychiatric ward. Demographic and clinical data required from the patient’s medical notes was recorded on the day of sampling. Exclusion criteria were: the presence of severely disturbed behaviour, or having received rapid tranquilisation for such behaviour on the day of sampling; a significant impairment in physical condition (e.g. infection, trauma); a history of a sleep disorder (e.g. obstructive sleep apnoea); the presence of organic illness including dementia; and lack of capacity to give informed consent.

Quality of Sleep:Subjects' quality of sleep was assessed by the administration of the Pittsburgh Sleep Quality Index (PSQI).⁹ This is one of the most widely used questionnaires employing standardised measures to assess subjective sleep quality in clinical and research settings. It assesses sleep quality and disturbances over a 1-month time interval. 19 individual items are used to generate 7 component scores (with a range of possible subscale scores from 0 to 3): 1) overall subjective sleep quality; 2) sleep latency; 3) sleep duration; 4) habitual sleep efficiency; 5) sleep disturbances 6) use of hypnotic or sedative medication; 7) daytime dysfunction. Higher scores indicate greater sleep disturbances. The sum of the component scores yields a global score (ranging from 0 to 21), which was used as the primary outcome measure in this study. A global PSQI score cut off score of 5 discriminates between good and bad sleepers and the PSQI gives acceptable measures of internal homogeneity, consistency (test-retest reliability) and validity.^9,10

Other Variables:Demographic and clinical data recorded concurrently from participant's medical notes included: sex (male/female); age (years); ethnicity (Asian/Black/Mixed//Other); body mass index (BMI) (calculated as the ratio between weight [kilograms] and squared height [metres]); primary psychiatric diagnosis (based on ICD-10 criteria); duration of psychiatric illness (years); past medical history; number of currently prescribed medications; length of admission to date (days); current admission status (informal/detained under Section 2 of the Mental Health Act (MHA) (1983) (this is for a maximum period of 28 days for further assessment)/detained under Section 3 MHA (1983) (this is for a maximum period of 6 months for psychiatric treatment). A further category (detained under another type of section) was dropped as this did not apply to any of the subjects.

Ethics Committee Approval:Ethical and research governance authorisations were granted from Camden and Islington Community Local Research Ethics Committee, and from the North Central London Research Consortium, respectively.

Statistical Analysis:The aim was to compare clinical, demographic and PSQI data between the poor sleepers and good sleepers. The prevalence (%) of poor sleep was determined by the proportion of subjects with global PSQI score of 5 or more. Statistical analyses were predominantly performed using the software package Stata, version 9.2.

Results

Sample Characteristics

77 patients were initially identified as potentially eligible subjects. Of these, 31 (40%) were excluded due to: the presence of disturbed behaviour (n=1); inability to give informed consent (n=9); unwillingness to participate (n=19); absence from ward (either on leave or absent without leave) (n=2).

This left a total of 46 patients who were enrolled in to the study. Subject characteristics are given in Table 1.
Table 1: Demographic and clinical characteristics of study subjects

s.d.: standard deviation

As defined by ICD-10 criteria, the most common subdivisions of patients’ psychiatric diagnoses in descending order were: paranoid schizophrenia, F20.0, (n=16); emotionally unstable personality disorder, F60.3, (n=6); depressive disorder, F32, (n=6); bipolar affective disorder, F31 (n=5). Other subdivisions of subjects’ diagnoses included: organic mood disorder, F06.3 (n=1); organic personality disorder, F07, (n=1); residual and late onset psychotic disorder due to alcohol use, F10.7, (n=1); persistent delusional disorder, F22, (n=1); acute and transient psychotic disorder, F23, (n=1); unspecified non-organic psychosis, F29, (n=1); post traumatic stress disorder, F43.1, (n=1). One patient was undergoing psychiatric evaluation and therefore had no formal diagnosis.

Medications prescribed regularly were: antipsychotics (for 40% of the total sample of patients), mood stabilizers (16%), antidepressants (14%) and benzodiazepines (7%). In terms of regular night time sedation, two patients out of a total of 46 were prescribed zopiclone and diazepam respectively. Zopiclone was prescribed on an “as required” basis for 15 patients (33% of the total sample).

Overall sleep quality evaluated by the PSQI revealed a mean score of 9.74 (standard deviation= 5.11). Poor sleep quality (defined as a global PSQI score of 5 or more) was present in 36 out of the total of 46 subjects (78% of the sample).

Comparison between good and poor sleepers

Comparison of numerical measurements between the two sleep groups is presented in Table 2. For the normally distributed variables the figures reported for each group are the mean (standard deviation) and the p-value from the t-test. For the non-normally distributed variables the figures reported are the median (inter-quartile range) and the p-value from the Mann-Whitney test.

Table 2: Comparison of demographic and clinical data between good and poor sleepers.

(total PSQI <5)

Mean (SD)

Poor sleepers

(total PSQI ≥5)

Mean (SD)

P-value

Age (years)41.0 (12.1)37.2 (10.9)0.34BMI (kg/m²)23.0 (2.5)26.7 (5.2)0.15Duration of psychiatric illness (years) ^(*)10 (8, 12)9.5 (3, 12)0.70Duration of admission (days) ^(*)44 (13, 111)15 (5, 41)0.06Medications ^(*)2 (1, 3)2 (1, 4)0.55Psychiatric medications ^(*)1.5 (1, 2)2 (1, 2)0.68

(*) Median (Inter-quartile range) reported. Analysis performed using Mann-Whitney test

The results indicate that there was no strong evidence of a statistically significant difference between good and poor sleepers for any of the variables examined. However, there was a possible difference for duration of admission, although this result was only of borderline statistical significance (p=0.06). The results indicate a median duration of admission of 44 days for good sleepers and 15 days for poor sleepers.

The difference between sleep groups for the categorical variables was examined using Fisher’s exact test. Results, presented in Table 3, show the number (and percentage) of subjects falling into each category, with the p-value indicating the significance of the results.

Table 3: Comparison of categorical data between good and poor sleepers

There was a significant difference between sleep groups with regard to their admission status. Almost all (90%) of the good sleepers were detained under Section 3 MHA (1983), whilst this applied to only half of those in the poor sleepers group. Being detained under Section 2 MHA and informal admission were more commonly found amongst those categorised as poor sleepers.

There was no significant difference between groups in terms of sex or the presence of physical comorbidities.

The final set of analyses compared the differences between groups for the PSQI measures, and the results are summarised in Table 4. The figures reported are the mean (standard deviation) score for each group. For the individual components the Mann-Whitney test was used to compare between groups, and the p-values from this analysis are reported. For the PSQI total score, the unequal variance t-test was used to compare between groups.

Table 4: Comparison of PSQI measures between the good and poor sleepers

(*) Analysis performed using Mann-Whitney test

There was a statistically significant difference between good and poor sleepers for all PSQI components and for the PSQI total. The PSQI component values and PSQI total scores for poor sleepers were significantly higher than for good sleepers.

A profile of the mean PSQI individual component scores between the two groups (good sleepers versus poor sleepers) is displayed in Figure 1.

Figure 1: Mean component PSQI scores of good and bad sleepers

Profiles of the PSQI represent group differences of individual component scores. Mann-Whitney test, *p<0.05).

Subjective Patient Comments

The PSQI also comprises an open ended question, providing subjects with the opportunity to cite “other” (subjective) reasons for difficult sleep. The most common response was anxiety (n=8). Other examples included: medication alterations (n=3); environmental noise (n=2); “thinking excessively” (n=1); “a desire to be creative” (n=1); hard mattress (n=1); “food eaten” (n=1); “sedentary lifestyle” (n=1); alcohol (n=1); hunger (n=1); asthma (n=1); symptoms of the menopause (n=1); and “voices”(n=1).

Discussion

Main Results

This is the first study to examine the subjective quality of sleep among a population of psychiatric in-patients in the UK. The prevalence of poor sleep, as defined by a cut off PSQI score of 5 or more, was present in 78% of the patients sampled. Patients detained under Section 3 MHA (1983) were more likely to report sleeping well when compared to informal patients or those detained under section 2 MHA (1983). There was some evidence of good subjective sleep quality being related to a longer duration of admission, but this requires further investigation.

There were no significant differences between good and poor sleepers for any of the other demographic and clinical variables studied, including age, body mass index, duration of psychiatric illness, number of prescribed medications, sex, and physical comorbidities.

Individual PSQI component scores and global scores were significantly lower for good sleepers compared to poor sleepers. This would be expected given that higher scores indicate more severe sleep complaints, and this supports the consistency of the PSQI as a research instrument.

Factors Affecting Sleep

In-patients’ disturbed sleep may be caused by a variety of exogenous factors such as unfamiliar surroundings, environmental noise, bright lighting and staff interactions or monitoring. Physical and psychological factors, such as the side-effects of medication and substance use, may also have a detrimental effect on sleep quality. In the added presence of a psychiatric disorder, each of these factors may act synergistically on the relationship between mental illness and sleep. Despite substantial research supporting the robust associations between insomnia and comorbid conditions, specific mechanisms linking sleep, medical and psychiatric factors have not been well established.

Sleep complaints may represent early symptoms and risk factors for new episodes of mental illness rather than simply representing phenomena secondary to experience of mental illness. For example, longitudinal studies have found insomnia to be a substantial risk factor for the development of a depressive disorder^5,11,12 and the risk for developing new anxiety disorders and alcohol abuse is also greater for insomniacs.⁶

Stepanski & Rybarczyk¹³ present research arguing against the more traditional conceptualisation of insomnia as simply a consequence of another disorder. They propose the need for a revised model to understand insomnia that is comorbid with medical and/or psychiatric illness. Abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis may represent the underlying pathophysiological process in many chronic insomnia patients.¹⁴ This may signify a common risk factor for insomnia and depression, thus predisposing the individual to a vulnerability to both conditions.¹⁵

In this study, detained patients (under Section 3 MHA (1983)) were significantly more likely to be classified as good sleepers. A suggestion for this finding could be that these patients may be less resisting of remaining and sleeping on the ward due to the involuntary nature of their admission. Alternatively these patients may represent the group with the most severe mental illnesses and with the least insight, and therefore less able to accurately recall their (poor) sleeping habits over the previous month.

There was also a potential association between longer admission status and better sleep quality. Explanations for this observation might include: patients’ acceptance over time of their admission and the consequent conditioning to, and familiarisation with, the ward environment; achievement of stability in mental state over time; or the adaptation of the perception of sleep quality to the sleep disturbances that accompany mental illness.

Limitations

This study is based on cross-sectional data and the relationship between the course of mental illness and sleep perception cannot be determined. In order to verify the direction of causality, it is necessary to demonstrate longitudinally that improvement in symptom severity is accompanied by an increase in subjective sleep quality.

This study was not designed to look at the prevalence of poor sleep across the different classes of psychiatric illnesses and dual diagnoses were not considered. It did not measure psychopathology or self-reported psychological distress. Possible confounding factors were not taken in to account, such as concurrent use of caffeine, alcohol, nicotine, illicit substances, hypnotics or other medications known to affect sleep.

The PSQI measures sleep quality averaged over the previous month. In cases where patients had only very recently been admitted to hospital, measurements would have been unlikely to accurately reflect the perspective of an in-patient’s experience. The mean length of admission for this population however was longer than one month (42 days).

These results were drawn from a small sample, with a fairly high proportion of excluded patients (40%). This may explain why this study did not identify factors previously found to more frequently affect sleep adversely such as female gender, the elderly and those with chronic medical conditions.¹⁶ In addition the population sample has little ethnic diversity which limits the generalisability of the results.

Implications

This study found that the prevalence of poor sleep quality was more common than previously reported in the general population¹⁷ and more comparable to the higher rates reported in similar patient populations. Two previous studies investigating subjective sleep quality using the PSQI, found prevalence rates of poor sleepers to be 45.5%¹⁸, and 91.22%¹⁹ among a population of schizophrenia patients and psychiatric in-patients respectively.

Complaints of poor sleep are important for diagnostic purposes and also raise the need to address the adequacy of therapeutic strategies, given the consequent adverse impact on patients’ mental state, physical health, daytime function and quality of life.

Improving Sleep

Hypnotics such as benzodiazepines and benzodiazepine receptor agonists can be efficacious for the treatment of insomnia.^20,21 However the clinical benefits must be weighed against well known adverse effects, such as daytime sedation, agitation, memory impairment, confusion and ataxia. This, together with the recommendation that hypnotics should only be used for short periods of time because of the risk of drug tolerance and dependence,²² highlights the need for suitable non-pharmacological alternatives.

Recent reviews support the notion of the effectiveness of Cognitive Behavioural Therapy for insomnia in the treatment of people with psychiatric or medical conditions.^13,23 Modified, lower cost education initiatives to promote good sleep could be employed by utilising the skills of the mental health professionals caring for patients on the ward, supplemented by the provision of clear written material.

Environmental variables to consider include adherence to regular ward routines including bedtime and awakening times, attention to ward layout and design (including the provision individual bedrooms), lighting, ambient noise, temperature, and the provision of comfortable mattresses and appropriate bed linen. Medication scheduling times, regular medication reviews, and avoidance of non-prescribed substances such as caffeine, alcohol and illicit substances are also important. Physical health problems, pain and psychological distress should be optimally managed. Moderate intensity exercise programs have also been found to bring about significant improvements in self-rated sleep quality.²⁴ Finally, increased staff awareness and sensitivity to the sleep problems on the ward, supplemented with objective recording of such disturbances, would be informative in gaining a further understanding of patients’ insomnia experiences.

Future Directions for Research

The PSQI is simple and inexpensive to perform. Results could be followed longitudinally in order to examine the course of sleep problems throughout an episode of acute mental illness, or to examine the effects of specific therapeutic interventions for sleep disorders. Sleep diaries have been shown to provide reliable estimates of subjective sleep parameters²⁵ and could be used as an adjunct to the PSQI. Ideally, concomitant objective measures such as polysomnography or wrist actigraphy (which detects physical motion), as well as cognitive and behavioural measures could be used to provide additional data.

This study represents the first attempt to examine the degree of self-reported poor sleep quality in a UK-based population of psychiatric in-patients and results suggest unsatisfactory sleep is a common finding. Large prospective longitudinal studies of sleep quality with control for confounding factors are needed to confirm the high prevalence rates in psychiatric in-patients. Studies comparing psychiatric patients with healthy controls, and also with insomniacs without psychiatric comorbidity, would further clarify the role of psychopathology in sleep disturbance.

References

1. Ancoli-Israel S, Roth T. Characteristics of insomnia in the United States: results of the 1991 National Sleep Foundation Survey. I. Sleep 1999;22 Suppl 2:S347-53.

2. Leger D, Scheuermaier K, Philip P, et al. SF-36: Evaluation of quality of life in severe and mild insomniacs compared with good sleepers. Psychosom Med 2001;63:49-55.

3. Roth T. Prevalence, associated risks, and treatment patterns of insomnia. J Clin Psychiatry 2005;66 suppl 9:10-13.

4. Leger D, Guilleminault C, Bader G, et al. Medical and socio-professional impact of insomnia. Sleep 2002;25(6):625-629.

5. Ford DE, Kamerow DB. Epidemiologic study of sleep disturbances and psychiatric disorders. An opportunity for prevention? JAMA 1989;262:1479-84.

6. McCall WV. A psychiatric perspective on insomnia. J Clin Psychiatry 2001;62 Suppl 10:27-32.

7. World Health Organisation. The ICD-10 Classification of Mental and Behavioural Disorders: Diagnostic Criteria for Research. Geneva: World Health Organisation, 1993.

8. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (4th edn) (DSM-IV). Washington, DC: American Psychiatric Association, 1994.

9. Buysse DJ, Reynolds CF 3rd, Monk TH, et al. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res 1989;28:193-213.

10. Doi Y, Minowa M, Uchiyama M, et al. Psychometric assessment of subjective sleep quality using the Japanese version of the Pittsburgh Sleep Quality Index (PSQI-J) in psychiatric disordered and control subjects. Psychiatry Res 2000;97:165-172.

11. Breslau N, Roth T, Rosenthal L, et al. Sleep disturbance and psychiatric disorders: a longitudinal epidemiological study of young adults. Biol Psychiatry 1996;39:411-418.

12. Chang PP, Ford DE, Mead LA, et al. Insomnia in young men and subsequent depression. The Johns Hopkins Precursors Study. Am J Epidemiol 1997;146:105-114.

13. Stepanski EJ, Rybarczyk B. Emerging research on the treatment and etiology of secondary of cormorbid insomnia. Sleep Med Rev 2006;10:7-18.

14. Richardson GS, Roth T. Future directions in the management of insomnia. J Clin Psychiatry 2001;62 suppl 10:39-45.

15. Roth T, Roehrs T. Insomnia: Epidemiology, Characteristics, and Consequences. Clin Cornerstone 2003;5(3):5-15.

16. Morin CM, Hauri PJ, Espie CA, et al. Nonpharmacologic treatment of chronic insomnia: an American Academy of Sleep Medicine review. Sleep 1999;22:1134-56.

17. Doi Y, Minowa M, Uchiyama M, et al. Subjective sleep quality and sleep problems in the general Japanese adult population. Psychiatry Clin Neurosci 2001; 55(3): 213-215.

18. Ritsner M, Kurs R, Ponizovosky A, et al. Perceived quality of life in schizophrenia: Relationships to sleep quality. Qual Life Res 2004;13:783-791.

19. Prieto-Rincón D, Echeto-Inciarte S, Faneite-Hernández P, et al. [Quality of sleep in hospitalized psychiatric patients]. Invest Clin 2006;47:5-16.

20. Nowell PM, Mazumdar S, Buysse DJ, et al. Benzopdidazepines and zolpidem for chronic insomnia: a meta-analysis of treatment efficacy. JAMA 1997;278:2170-7.

21. Holbrook AM, Crowther R, Lotter A, et al. Meta-analysis of benzopdiazepine use in the treatment of insomnia. CMAJ, 2000; 162: 225-233.

22. National Institute for Health and Clinical Excellence. Guidance on the use of zaleplon, zolpidem and zopiclone for the short-term management of insomnia. London: NICE, 2004. (Technology Appraisal 77.) Available from: URL: http://www.nice.org.uk/TA077guidance

23. Smith MT, Huang MI, Manber R. Cognitive behavior therapy for chronic insomnia occurring within the context of medical and psychiatric disorders. Clin Psychol Rev 2005;25:559-92.

24. King AC, Oman RF, Brassington GS, Bliwise DL, Haskell WL. Moderate-Intensity Exercise and Self-rated Quality of Sleep in Older Adults. A Randomized Controlled Trial. JAMA 1997;277:32-37.

25. Coates TJ, Killen JD, George J, et al. Estimating sleep parameters: A multitrait-multimethod analysis. J Consult Clin Psychol 1982;50:345-52.

Laparoscopic fundoplication (LF) has been emerging as the procedure of choice for selected patients with symptomatic and problematic reflux disease since the first described case by Dallemagne in 1991 (1). This was followed by a rapid expansion into routine clinical practice shortly afterwards. With increased acceptance and availability of laparoscopy as a safe surgical modality there has been a huge increase in the number of patients undergoing LF. This has probably been due to increased willingness of patients and referring doctors to consider the less invasive procedure, rather than the older ‘open’ surgical treatment, with its more rapid recovery, smaller incisions and earlier return to work and to normal daily activities.

Patient referral patterns have also changed over the last decade with the main indication for consideration of LF being patient choice, a general unwillingness to take long term medication as well as ineffective or intolerance of medications and relapse of symptoms (5-6). Several advantages of LF have been described by recent data including shorter hospital stay, less requirement for analgesia, and sooner return to work (7-9). These have to be offset against procedure specific complications including gastro-oesophageal perforation, pneumothorax, dysphagia, and bleeding (2-4). However, the other main downside to LF is the learning curve during which there are an increased number of complications. Previous reports have suggested the learning curve to be around 20 for an individual surgeon and 50 for an institution (10-12).

In a recent meeting of the Upper GI group at the Royal College of Surgeons there was discussion concerning the incidence and management of dysphagia following laparoscopic fundoplication (13 Bill Owen Day RCS (Eng) 2004). There is a paucity of data available in this regard with a general paucity of negative or unequivocal results in the literature equating to a selection bias towards only positive data and positive reporting of good results.

Therefore the aim of the present study was to look critically at the learning curve and, with respect to operative complications, with specific regard to the incidence and management of dysphagia in a personal series of patients who underwent a laparoscopic fundoplication in a District General Hospital in the United Kingdom.

Patients and Methods

From December 1997 to February 2004, 75 patients who underwent laparoscopic fundoplication under the care of a single consultant surgeon in a district general hospital were included in this study. It became routine practice for LF to be performed by one dedicated surgical team (JMT) who kept a complete prospective list of procedures. This series was complete and the hand written records of all the procedures were used to identify patients undergoing operations for LF with or without reduction and repair of Para-oesophageal hernia during the study period. These records were cross-checked with the theatre logbook, hospital computer system as well as with the surgeon’s own record. This ensured full inclusion in the analysis of patients.

The groups were not randomised and ‘all comers’ where included in the study. However, Group 1 consisted of the first 20 LF whereas Group 2 included LF (numbers 21-75). Informed consent was obtained in writing prior to surgery. At least a single dose of prophylactic antibiotics (of either a third generation cephalosporin or co-amoxiclav) was administered at induction; all patients received standard thromboprophylaxis (subcutaneous clexane, TEDS, intermittent pneumatic calf compression).

Patients underwent a laparoscopic fundoplication as briefly described below. The patient was placed in the lithotomy position with reversed Trendelberg tilt; a pneumoperitoneum was created and 4 ports inserted. The liver was elevated using a ‘Nathanson’ liver retractor placed through a 5 mm epigastric incision. Initially the right and left limbs of the right crus are dissected alongside the pancreaticogastric and phrenogastric ligaments. A window is created behind the distal oesophagus. A Penrose drain is passed through the gap. The short gastric vessels are divided using a harmonic scalpel (Ethicon, USA), if required. The crural limbs are approximated using 2, 2-0 ethibond sutures to leave a hiatus 1 cm wider than the oesophagus. A laparoscopic babcock is placed behind the oesophagus and the gastric fundus is brought left to right behind the oesophagus and bought round to meet with the remaining portion of the fundus anteriorly. Two (or rarely three) sutures of 2-0 ethibond were used for the fundoplication. The upper suture included a bite of the anterior hiatal margin to anchor the wrap. Of note, the important feature of the procedure is the creation of a ‘floppy’ tension free fundoplication. This is hugely aided by good mobilisation of the gastric fundus with its associated ligaments and if required, division of the short gastric vessels. Notably, one must carefully create a window behind the oesophagus and an overlap of no longer than 3 cms length and one must stay high up on the fundus in order to avoid the creation of a ‘2’ compartment stomach syndrome’.

Post-operatively all patients were treated in an identical manner. As soon as tolerated after the operations the patients were allowed the consumption of water; diet and analgesia were made available as soon after surgery as required by individual patients. Complications were noted as they occurred during the follow-up period. Both general and specific complications were documented for at least 6 months. Furthermore, patient demographics, details of operations, all complications and follow-up data were kept. Follow up for the purpose of this audit involved completion of a proforma at a minimum post operative period of one year and a maximum of eight years.

All patients where regularly reviewed daily on the ward whilst they were in-patients and in the outpatients at 4-6 week intervals or sooner should the need arise by the surgical team. Thereafter they were given a “see on request” appointment. Data on patient and procedure related morbidity and acceptability was also collected.

At the time of the study contact was made via the telephone and a questionnaire was completed. A telephone survey asking the patient four questions,

1. Where they happy with the operation
2. Would they reccomend the procedure to a friend
3. Had there symptoms resolved
4. If they had had post op dysphagia had it resolved

The data was reviewed and analysed in conjunction with our department of medical statistics. Analysis was performed using the Mann-U test. Multivariate analysis of the means was performed using the Kruskal-Wallis Test.

Results

Overall the 75 patients who underwent laparoscopic fundoplication consisted of 44 males (59%) and 31 females (41%). The mean age was 47.0 years (range 22-80 years). Group 1, which consisted of the first 20 LF cases included 11 male and 9 females. The mean age was 53.25 years (range 32-80). Group 2, which consisted of the LF cases numbering 21-75 included 33 male and 22 females. The mean age was 44.8 years (range 22-78). Both groups were well matched across the above parameters with no statistical differences (Table A). Only 4 patients were obese (5%), smoker (n=10, 14%), 7 patients suffering with Hypertension (10%) and one with diabetes mellitus (2%) and were equivalently represented in both groups (data not shown).

Presenting features are shown in Table B. Notably, the commonest presenting complaints included regurgitation of acid/ food in 79% (n=59), heartburn in 73% (n=55) and pain and discomfort 53% (n=35). Other complaints included dysphagia 21% (n=16), cough/wheeze 19% (n=14) and excess salivation 18% (n=13).

Table A: Patient Demographics

Table B: Presenting Features

Patients underwent pre-operative evaluation with Upper GI endoscopy 88% (n=66), pH manometry 47% (n=35) and barium swallow 32% (n=24). Previous to this procedure all patients (100%) were on or had been during some part of their illness on therapeutic doses of proton pump inhibitors.

There was a significant difference between the operating times in the two groups. Thus in Group 1 the average operating time was 190 minutes (range120-240 minutes) whereas in Group 2 the average operating time was 144 minutes (range 75-195 minutes, P <0.05).

Table C: Post Op Mild and Moderate Complications<

One of the major aims of the study was to record post-operative complications. Table C shows all mild and moderate complications which resolved completely with conservative management. Of note Table F shows that dysphagia occurred in up to 40 of our patients. Table F shows the distribution of dysphagia in both groups. In group A (n=20) the are 15 patients who complained with dysphagia (75%) of which 5 settled spontaneously and 10 required further investigation with OGD +/- dilation. in group B (n=55), 25 patients suffered with dysphagia all of which settled with conservative management. Our initial policy was to perform an OGD and dilate prophylactically; however, this was abandoned halfway through the study. It was found that the dysphagia settled in all patients with conservative management. Furthermore, other mild/moderate complications, of note included regurgitation of stomach contents (7/75) and port-site discomfort (6/75), all of which also resolved spontaneously

Table D: Major Complications Groups 1 & 2

Table E: Conversion to Open Surgery

Major complications are shown in Table D. Of note there are three conversions to ‘Open’ surgery in Group 1 and five in Group 2 (Table E). In detail, four cases (two in each group) were converted early because of poor or very difficult access. They included difficulty in reducing the stomach and omentum from the mediastinum into the abdomen, unable to reach the hiatus despite placing the ports as high as possible, dense adhesions between the liver and stomach and G-O junction thereby leaving no access to the hiatus and simply impossible access to the upper stomach. Further, oesophageal perforation which was caused by intra-operative insertion of a nasogastric bougie (Group 1), this was repaired laparoscopically with no sequelae. Other reasons for conversions included perforation of the greater curve of the stomach due to the fact that there was thickened fatty tissue around the greater curve of the stomach and spleen which produced a perforation while dissecting the stomach free. Also in Group 2 there was one pneumothorax and in another patient there was marked desaturation on creation of the pneumoperitoneum and in both cases it was deemed safer to open the patient.

Table F: Dysphagia Group

Relaparotomy occurred in three patients; one developed severe pain and clinical shock at 24 hours and it was found on laparotomy to have a perforated oesophagus, the second patient we found disruption of the wrap (requiring re-operation and refashioning the wrap) and a final patient developed small bowel obstruction.

Finally a telephone survey at the conclusion of the study managed to contact 70/75 patients. It was found that overall 68/70 patients were satisfied with their procedure and would recommend the procedure to a relative or friend.

Discussion

Gastro-oesophageal reflux disease (GORD) is the commonest disorder of the Upper GI tract affecting approximately between 10-40% of most western populations and with rising incidence (11). In Australia it has shown to consume around 10% of the national expenditure on prescription drugs. Fortunately the majority of patients settle with simple measures including weight loss and reductions in smoking, caffeine and chocolate consumptions. Furthermore, better timing of meals as well as increasing the number of pillows and raising the head end of the bed can lead to improved symptoms. The advent of H₂- receptor antagonist (H₂RA) and later proton pump inhibitors (PPIs) has led to symptom control in the majority of patients. However, patients on maximum therapy who remain symptomatic or who develop complications (i.e. haemorrhage, oesophagitis, strictures) or those who refuse long term medication are deemed candidates for surgical intervention.

LF has emerged as the procedure of choice for GORD. The present study, which is a personal single surgeon series, shows that laparoscopic fundoplication is a safe and effective procedure with low rates of long-term complications. Importantly, post operatively these patients may develop dysphagia which settles with conservative measures in the vast majority of cases (13).

There is no doubt that for LF a ‘learning curve’ exists but there is debate about the actual numbers. Most studies suggest that it is around 20 for an individual and around 50 for a department (12), thus in the present study we compared our first 20 (classically thought to be within the learning curve) with the next 55 in order to assess major complications, conversions to open procedure. We found that in Group 1 there were 3 major complications (15%) whereas in the next 55 cases there were five (9%). Indeed only one major complication in Group 1 and two in Group 2 could be considered as technical, they were oesophageal and gastric perforations the rest being post operative pneumonia, PE and major desaturation. There were no deaths in either group. This was in keeping with previously published series (14-16).

Previously published data and our own observations revealed that there were significant post operative rates of dysphagia. In the present series dysphagia was the single commonest complication experienced by 53% of patients (n=40). Initially these were investigated with barium swallow and OGD and treated aggressively with early dilation (Group 1) however this strategy was abandoned after it was found that the vast majority of our patients resolved their dysphagia with conservative treatment. From thereon we adopted a very conservative approach reassuring the patient and keeping within close contact until the dysphagia resolved. We reserved dilatation for only highly resistant dysphagia or patients who where non-compliant with conservative treatment. We found that clear explanations pre-operatively, regular reassurance and assessment was generally all that was required. In Group 2 (21-75) none of the patients required dilation for dysphagia. It is almost universal that patients undergoing LF will have a degree of dysphagia. However what is now accepted and reflected from the experience from the present study is that dysphagia after LF should only cause concern if severe, presenting with severe pain, uncontrolled retching and vomiting requiring immediate surgical revision (17). Most commonly this is due to over-tightening of the hiatus or with poor mobilisation and a 360 degree wrap. This may be related to the learning curve, being more common in the earlier cases in a personal series. In our series 53% of patients (n=40) experienced dysphagia. This is comparable to previous reported data (2,16). Notably, Fontaumard et al reported a dysphagia rate of 78% (40/51). The reason for this post operative dysphagia has been thought to be related to the type of procedure. In our series all patients underwent a Nissen type of repair however evidence is now emerging that the incidence of dysphagia and gas related complications are reduced following anterior partial fundoplication (19,20). This is shown from the data of two recent randomised controlled studies. Baigrie et al (18) in a double-blind, randomized study compared laparoscopic Nissen total fundoplication and anterior partial fundoplication. There were no differences in mean heartburn scores between groups but dysphagia scores for both liquids and solids were lower after anterior fundoplication. Also Ludemann et al (19) compared total fundoplication for gastro-oesophageal reflux disease with an anterior 180 degrees partial fundoplication. Both achieved effective reflux control but the partial wrap was associated with fewer side-effects in the short term than total fundoplication. After 5 years, dysphagia, measured by a visual analogue score for solid food and a composite dysphagia score, was worse at 5 years after total fundoplication.

Our study confirms what has previously been shown with the learning curve for LF and its acceptability. It has also clearly highlighted that post operative dysphagia is common and affects a significant number of patients post operatively. However in our study we found that this was best managed conservatively and the almost all resolved spontaneously. There is no evidence to support early intervention unless the symptoms are very severe and occur very soon after surgery, when the patient should be taken back to theatre for another look. The specific causes of the dysphagia are not known but it is postulated that it is due to increased pressure as the upper part of the wrap augments the pressure of the lower oesophageal sphincter causing it to become over competent. Over time this mechanism relaxes leading to an improvement in dysphagia with simple conservative therapy. Furthermore, there was a hugely positive satisfaction score on a simple telephone survey suggesting symptom control from this procedure.

References

1. Dallemagne B, Weerts JM, Jehacs C, Markiewid S, Lombard R. Laparoscopic Nissens Fundoplication: preliminary report. Surg Laparosc Endosc 1991:1;138-143.
2. Watson DI, Johnson AG, Reed MWR, Stoddard CJ. Laparoscopic Fundoplication for gastroesophageal reflux. Ann R Coll Surg Engl 1994:76; 264-68.
3. Schauer PR, Meyers WC, Eubanks S et al. Mechanisms of avoidance of esophageal perforation during laparoscopic Nissens fundopliaction. Ann Surg 1996; 223:43-52.
4. Reid DB, Winning T, Bell G. Pneumothorax during laparoscopic dissection of the diaphragmatic hiatus. Br J Surg 1993;80:670
5. Perdikis G, Hinder RA. Lund J. Laparoscopic Nissens Fundoplication: where do we stand? Surg Laparosc Endosc 1997; 7; 17-21.
6. Laine S, Rantala A, Gullichsen R, Ovaska J. Laparoscopic vs. conventional Nissens Fundoplication. Surg Endosc 1997; 11:441-44.
7. Zacharoulis D, O'Boyle CJ, Sedman PC, Brough WA, Royston CM. Laparoscopic fundoplication: a 10-year learning curve. Surg Endosc. 2006; 20(11):1662-70.
8. Martin RC 2nd, Kehdy FJ, Allen JW. Formal training in advanced surgical technologies enhances the surgical residency. Am J Surg. 2005 Aug; 190(2):244-8.
9. Hwang H, Turner LJ, Blair NP. Examining the learning curve of laparoscopic fundoplications at an urban community hospital. Am J Surg. 2005 ;189(5):522-6;
10. 7th Bill Owen Oesophago-Gastric Symposium 'Meet-the-Experts' The Royal College of Surgeons of England, London March 2005.
11. Speechler SJ. Barrett's esophagus. Semin Oncol. 1994 Aug; 21(4):431-7.
12. Watson DI, Baigrie RJ, and Jamieson GG. A learning curve for laparoscopic fundoplication. Definable, avoidable, or a waste of time? Ann Surg. 1996 August; 224(2): 198–203.
13. Champault GG, Barrat C, Rozon RC, Rizk N, Catheline JM. The effect of the learning curve on the outcome of laparoscopic treatment for gastroesophageal reflux. Surg Laparosc Endosc Percutan Tech. 1999 Dec; 9(6):375-81.
14. Cuschieri A, Hunter J, Wolfe B, Swanstrom LL, Hutson W. Multicenter prospective evaluation of laparoscopic antireflux surgery. Preliminary report. Surg Endosc. 1993; 7(6):505-10.
15. Jones NJ, Soper DB. Laparoscopic Nissens Fundoplication. Surg Rounds 1994:17;573-81
16. Gotley DC, Smithers BM, Rhodes M, Menzies B, Branicki FJ, Nathanson L. Laparoscopic Nissen fundoplication--200 consecutive cases.
    Gut. 1996 Apr; 38(4):487-91.
17. Watson DI, Jamieson GG, Mitchell PC, Devitt PG, Britten-Jones R.Stenosis of the esophageal hiatus following laparoscopic fundoplication. Arch Surg. 1995 Sep;130(9):1014-16.
18. Baigrie RJ, Cullis SN, Ndhluni AJ, Cariem A. Randomized double-blind trial of laparoscopic Nissen fundoplication versus anterior partial fundoplication. Br J Surg. 2005 Jul; 92(7):819-23.
19. Ludemann R, Watson DI, Jamieson GG, Game PA, Devitt PG. Five-year follow-up of a randomized clinical trial of laparoscopic total versus anterior 180 degrees fundoplication. Br J Surg. 2005 Feb; 92(2):240-3.
20. Watson DI, Jamieson GG, Lally C, Archer S, Bessell JR, Booth M, Cade R, Cullingford G, Devitt PG, Fletcher DR, Hurley J, Kiroff G, Martin CJ, Martin IJ, Nathanson LK, Windsor JA; International Society for Diseases of the Esophagus--Australasian Section. Multicenter, prospective, double-blind, randomized trial of laparoscopic nissen vs anterior 90 degrees partial fundoplication. Arch Surg. 2004 Nov; 139(11):1160-7.

Ventilator Associated Pneumonia (VAP) is defined as pneumonia occurring in a patient within 48 hours or more after intubation with an endotracheal tube or tracheostomy tube and which was not present before^{1, 2}. Early onset VAP occurs within 48 hours and late onset VAP beyond 48 hours of tracheal intubation.

Incidence

Between 5-15% of hospital in-patients develop infection during admission to ICU³. Patients are 5-10 times more likely to acquire nosocomial infections than patients in the wards⁴and approximately 86% of hospital associated pneumonia is linked with mechanical ventilation⁵.

Approximately 10-28% of critical care patients develop VAP⁶. VAP is also the most common and fatal infection of ICU^7,8 and in the United States it affects 9-27% of intubated patients and doubles the risk of mortality as compared with similar patients without VAP^9-13.

VAP may account for up to 60% of all Healthcare-Associated Infections¹⁴. VAP increases length of ICU stay by 28%¹⁶ and each incidence of VAP is estimated to generate an increased cost of £6000- £22000¹⁵.

Diagnosis

Despite the high incidence, diagnosis remains challenging because many conditions common to ICU patients like ARDS, sepsis, cardiac failure and lung atelectasis have similar clinical signs. More than 50% of patients diagnosed with VAP do not have the disease whereas upto one-third are not diagnosed^{17, 18}. Unfortunately there is no clearly accepted gold standard for diagnosis of VAP¹⁹.

Histological landmark of VAP is multifocal disease favouring dependant lung segments, often at different stages of development and severity with cultures growing heterogenous microbial flora.^20,21

Pathogenesis:

VAP that occurs within 48 hours after tracheal intubation is usually termed as early onset often resulting from aspiration, which complicates intubation process²². VAP occurring after this period is late onset. Early onset VAP is often due to antibiotic sensitive bacteria (eg oxacillin-sensitive Staphylococcus aureus, Hemophilious influenza and Streptococcus pneumoniae), whereas late onset VAP is frequently caused by antibiotic resistant pathogens (eg.oxacillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, acinetobacter species and enterobacter species) ^23,24,25

The pathogenesis of VAP usually requires that two important processes take place:

1. Bacterial colonisation of the aero-digestive tract
2. Aspiration of contaminated secretions into the lower airway²⁶.

Therefore, the strategies to prevent VAP usually focus on reducing the burden of bacterial colonisation in the aero-digestive tract, decreasing the incidence of aspiration or both.

The presence of invasive medical devices is an important contributor to the pathogenesis and development of VAP²⁷. Many patients have nasogastric tubes that predispose them to gastric reflux and increase the potential for aspiration. Endotracheal tubes facilitate bacterial colonisation of the tracheo-bronchial tree and lower airway aspiration of contaminated secretions through mucosal injury, pooling of contaminated secretions above the endotracheal tube cuff and elimination of the cough reflex²⁶. The ventilator circuit and the respiratory-therapy equipment may also contribute to the pathogenesis of VAP if they become contaminated with bacteria, which usually originate in the patient’s secretions^{26, 28}.

Prevention:

The National Institute of Clinical Excellence (NICE) in collaboration with National Patient Safety Agency (NPSA) is examining four technical patient safety solutions for the prevention of VAP and in the process of publishing guidelines. The latest technical patient safety solutions for VAP was published in August 2008 which says

1. Body position-mechanically ventilated and intubated patients should be positioned with their upper body elevated for as long as possible. This may be inappropriate in some patients. eg. spinal injuries.
2. Oral antiseptics e.g. 2% chlorhexidine should be included as part of oral hygiene regimen for all patients who are intubated and ventilated. There is insufficient evidence to recommend any particular antibiotic regimen.
3. Use of kinetic beds - a lack of robust evidence meant the Committee was unable to make recommendations for action on the use of kinetic beds.
4. Care bundles - although the evidence supported the use of elements of care bundles; there was insufficient evidence to recommend a care bundle of any specific design.

The Department of Health published the following ‘High impact intervention’ for ventilated patients in June 2007

• Elevation of the head of bed to 35-40 degrees
• Sedation holding
• Deep Vein Thrombosis prophylaxis
• Gastric ulcer prophylaxis
• Appropriate humidification of inspired gas
• Appropriate tubing management
• Suctioning of respiratory secretions (including use of gloves and decontaminating hands before and after the procedure)
• Routine oral hygiene as per local policy

In addition the following also may contribute to the prevention of VAP

• Prolonged nasal intubation (more than 48hrs) should be avoided because of the association between nosocomial sinusitis and ventilator-associated pneumonia²⁹.
• Several investigations have suggested that secretions that pool above the inflated endotracheal tube cuffs may be a source of aspirated material and thus VAP. Endotracheal tubes with separate dorsal lumen above the cuff to suction pooled secretions from the subglottic space are now available. The pressure of the endotracheal tube cuff should be adequate to prevent the leakage of colonised subglottic secretions into the lower airway^26,30.

Antibiotic Administration:

Previous administration of antibiotics is an important risk factor for VAP because of the presence of antibiotic-resistant bacteria³¹. In an attempt to reverse the trend towards increasing rates of antimicrobial resistance among hospital acquired infections, more effective strategies for using antibiotics have been advocated that restrict antibiotic use or offer guidelines for their use ^{32, 33}. Eliminating or reducing the unnecessary use of antibiotics should be the primary goal in reducing antibiotic-resistant nosocomial infections³².

The routine use of prolonged courses of empirical therapy i.e. therapy not supported by results of clinical cultures should be avoided to minimise the subsequent development of antibiotic-resistant infections.

The use of aerosolised antibiotics for the prevention of VAP has been abandoned because of its lack of efficacy and subsequent emergence of antibiotic-resistant infections²⁸.

Similarly the routine use of selective digestive tract decontamination has not gained acceptance in the UK and USA because of its lack of demonstrated effect on mortality, emergence of antibiotic resistant infections and additional toxicity. NICE is currently in consultation for selective decontamination of digestive tract guidelines. The technical patient safety solutions for VAP in adults were published in August 2008.

The Committee examined evidence, which suggested that selective decontamination of the digestive tract (SDD) using topical antibiotics may reduce the incidence of VAP and that SDD regimes that include systemic antibiotics may also reduce mortality. However, Specialist Advisers stated that UK intensive care specialists had particular concerns about the risk of infection with Clostridium difficile and the induction and/or selection of resistant, including multiresistant, microorganisms as a result of SDD. Therefore the Committee recommended further research into SDD in a UK setting.

Use of broad-spectrum antibiotics is also not recommended for the prevention of VAP because of increasing antibiotic resistance among subsequent hospital acquired infections. Targeted antibiotic therapy with appropriate dose of appropriate antibiotic is the sensible thing to do.

Vaccines:

Various vaccination programmes in adults and children have reduced the incidence of pneumonia caused by specific pathogens including H.influenzae type B, Streptococcus Pneumoniae and Influenza virus ^{34, 35}.Vaccinations against these may prevent some hospital acquired infections. Pneumococcal and influenza vaccination must be considered before hospital discharge or included in the discharge planning for all patients at increased risk for subsequent respiratory infections including VAP.

Newer Developments:

There have been new advances in equipment and techniques to help prevention of VAP

1. Endotracheal and tracheostomy tubes with an extra subglottic port to clear pooled secretions above the endotracheal and tracheostomy tube cuff.
2. Continuous suctioning of the subglottic secretions.
3. Endotracheal tubes with specially designed cuffs that do not allow pooled secretions above the cuff to trickle down causing micro-aspiration and ultimately leading to VAP. eg. Endotracheal tubes with microthin polyurethane cuff.
4. Specially designed closed Tracheal Suctioning Systems (TSS) as compared to open tracheal suctioning systems. However a meta analysis of randomised controlled trial showed that closed suctioning system is not associated with a lower incidence of VAP or mortality as compared to open suctioning³⁶

References

1. Prevention of ventilator-associated pneumonia: consultation NICE, Sept 2007
2. Ventilator associated-pneumonia JAMA 2007; 297: 1616-1617
3. Eggimann P, Pittet D. Infection control in the ICU. Chest 2001; 120: 2059-93
4. Weber DJ, Raasch R, Rutala WA. Nosocomial infections in the ICU: the growing importance of antibiotic-resistant pathogens. Chest 1999; 115: 34S-41S
5. Richards MJ, Edwards JR, Culver DH, Gaynes RP. Nosocomial infections in medical intensive care units in the United States. National Nosocomial infections Surveillance System.Crtic Care Med.1999 May; 27950: 887-92
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Introduction

Adjuvant modes of breast cancer therapy following surgical intervention mainly revolve round radiation therapy, chemotherapy, or hormone therapy designed to eliminate residual cancer cells. The increase in the incidence of breast cancer with age has sharply focused attention on the link between incidence and progression. It follows from this that approaches to successful treatment and patient management would converge on hormonal status as a beneficial mode of targeted therapy. A number of growth factors, besides the steroid hormones oestrogen and progesterone, are closely involved in the growth and metastatic spread of breast cancer. Recent years have seen intensive studies of the mechanisms of function of growth factors and the pathways by which they stimulate the growth of cancer cells. These studies have led the way to the targeting growth factor function as a means of controlling breast cancer development and secondary spread.

The growth factor receptors are transmembrane proteins. The binding of growth factors to the external domain activates these receptors which have tyrosine kinase activity. This activation therefore leads to the phosphorylation of signalling proteins down stream in the signalling cascade. This in turn leads to the expression of genes associated with cell proliferation and often also to the inhibition of apoptotic loss of cells.

Growth factors, growth factor receptors and tumour growth and progression

Growth factors and their receptor play a major part in normal growth and differentiation and also in tumour development and progression. Growth factors promote proliferation and induce cancer invasion. Certain growth factors, e.g. the insulin-like growth factor (IGF) might promote tumour growth by inhibiting apoptotic loss of cells¹. Mutations or over-expression of growth factor receptors is associated with aggressive cancers and poor prognosis for patients. Growth factor receptor genes are amplified in a number of human cancers and this is reflected in the expression of the respective receptor proteins in the cancers. Growth factor receptors are transmembrane tyrosine kinase proteins and transduce the signals imparted by the binding of the growth factors to their specific receptors; this signal transmission ultimately results in the induction of cell proliferation.

Among growth factors of note in the context of this editorial are the epidermal growth factor (EGF) and the Heregulins constituting a family of EGF related growth factors. There are several isoforms of Heregulin generated by alternative RNA splicing of the heregulin gene; these isoforms bind to their receptors with different degree of affinity. The epidermal growth factor receptor (EGFr) family (also often referred to as the erb family) includes HER1 (human epidermal growth factor receptor 1 also called EGFr), HER2, HER3 and HER4. These receptor proteins significantly resemble one another in aminoacid sequence². Heregulin can bind HER3 and HER4 receptors but the ligand for HER2 has not been identified³ and so HER2 is often described as an orphan receptor. The receptor protein consists of an external domain that binds growth factors, a transmembrane domain and an intracellular domain which possesses tyrosine phosphorylation sites⁴. Growth factors and their paralogues bind to these receptors and induce receptor oligomerisation. This activates the cytoplasmic kinase domains, which phosphorylate and activate target proteins that induce the expression of genes responsive to the growth factors. The binding and activation of the receptors is a highly specific process, but often more than one receptor might be involved in the signalling process. In this event heterodimerisation would occur between different receptors; this seems to enhance the affinity of ligand binding⁵. This process of engagement of co-receptors to enhance growth factor signalling has been described as cross-talk between the receptors. HER2 is known to be involved in cross-talk with EGFr, HER3 as well as HER4. So HER2 seems to occupy a pre-eminent position in the signalling cascade, but recently it has been suggested that HER3 might also be a prominent participant⁶.

The EGFr family of receptors have been intensively investigated for their potential relationship to cancer progression and prognosis and as a potential route for treatment and patient management. Approximately 25% of breast cancers show HER2 gene amplification and this correlates aggressive behaviour and poor prognosis^7-10. However, on the positive side the presence of HER2 receptors has provided a new treatment modality for many patients.

Monoclonal antibodies (Herceptin) have been raised against the external domain of HER2. Herceptin has provided a highly successful mode of treatment for metastatic breast cancer showing high HER2 expression and HER2 gene amplification^11-13. Blocking receptor function with Herceptin inhibits tumour growth and possibly also microvascular density associated with tumours and vascular permeability. Furthermore, Herceptin treatment appears to reduce VEGF (vascular endothelial growth factor) expression, tumour associated microvascular density and cell proliferation in breast cancers xenografted into mice¹⁴. Also in murine tumour models, Herceptin reduces the number of circulating cancer cells even under circumstances where the tumour is resistant to Herceptin treatment¹⁵, which could be a manifestation of its effects on the vasculature independently of its inhibition of HER2 signalling.

HER2 expression and tamoxifen resistance

Breast cancer growth is influenced by the sex steroid hormones oestrogen and progesterone and growth factors such as EGF and HER2 ligands. Patients with tumours that are oestrogen receptor (ER) positive are treated with tamoxifen. The latter binds ER and competitively blocks oestrogen signals. In the context of the deployment of Herceptin to treat HER2+ patients, it has emerged that tumours over-expressing HER2 are resistant to tamoxifen. These patients could benefit from anti-oestrogen therapy combined with blockade of HER2 signalling¹⁶. A randomized trial has indicated that post-menopausal patients with advanced breast cancer can benefit significantly from this combination therapy¹⁷.

Among other factors that might confer tamoxifen resistance is AIB1, the steroid receptor co-activator, which is often amplified in breast cancers. In vitro studies with breast cancer cells and in vivo investigations of murine tumours have suggested the involvement of AIB1 in tamoxifen resistance¹⁸ and in HER2 signalling¹⁹. In primary breast cancer also AIB1 has been linked with tamoxifen resistance^{20, 21}. A second factor deserving discussion in this context is the possibility that EGFr and HER2 signalling systems might interact and contribute in this way to resistance to hormonal therapy. As mentioned elsewhere in this review, EGFr does recruit HER2 as a co-receptor in signal transduction. This is of some significance for patients with ER-negative tumours. For, we showed some years ago that a proportion of ER-ve tumours tended to be EGFr+ve^22-24. So this would suggest the possibility that patients with ER-ve/EGFr+ tumours could conceivably benefit from Herceptin treatment (see below).

Another possible means by which tamoxifen resistance might arise has been suggested by the finding that tamoxifen and Fulvestrant, also an anti-oestrogen, appear to be able to induce breast cancer cell invasion in the absence of E-cadherin²⁵. Cadherins are transmembrane proteins, which have considerable influence on cancer invasion because they alter intercellular and cell-substratum adhesion. E-cadherin is regarded as a suppressor of invasion and growth of carcinomas as the loss or mutation of E-cadherin leads to the acquisition of invasiveness. Borley et al.²⁵ showed that both tamoxifen and Fulvestrant induced invasion in E-cadherin deficient MCF7 breast cancer cells, but this did not occur after oestrogen depletion. These findings add a new dimension to tamoxifen resistance as potentially being mediated by recurrence resulting from induced invasive ability.

HER2 expression and adjuvant chemotherapy

It has been recognised of late that combination of Herceptin with chemotherapy might yield considerable benefits in terms of reduction of recurrence and mortality. So HER2 expression has come into the reckoning when considering the use of adjuvant chemotherapy. Combining Herceptin with either an anthracycline plus cyclophosphamide or with Paclitaxel, as first-line therapy for metastatic breast cancer over expressing the HER2 receptor, has provided significant benefits in terms of objective response, duration of response and survival as compared with chemotherapy alone. Furthermore, the benefits were related to the degree of HER2 over-expression²⁶. A review of 35 clinical trials has indicated that patients with HER2+ cancers might benefit more from anthracycline-based and taxane-based adjuvant chemotherapy than those with HER2-negative cancers²⁷. Indeed, anti-HER2 antibody combined with chemotherapy is superior to HER2 anitibody and anti-oestrogen combination¹⁷. The benefits of adjuvant chemotherapy with anthracyclines to patients with HER2 over-expressing tumours seem to be beyond reasonable doubt. Gennari et al.²⁸ have provided a combined analysis of eight studies. HER2+ patients on anthracyclines had superior disease-free as well as overall survival in comparison with patients on non-anthracycline regimen. No such benefits emerged for HER2-ve patients, suggesting that one can exclude these patients from anthracycline adjuvant therapy. Also being investigated is potential synergy between antibodies against other growth factor receptors and anti-HER2 antibodies.

Attempts are also currently in progress to test the efficacy of conjugates of anti-HER2 antibodies with cytotoxic drugs to achieve targeted delivery of the cytotoxic agents. Laboratory studies are underway with Herceptin-platinum(II) complexes²⁹ and Herceptin-microtubule-depolymerising agents³⁰.

Contraindications of Herceptin regimen

The toxic side-effects of the administration of monoclonal antibodies were recognised some years ago. Cardiotoxicity, pulmonary toxicity and infusion-related problems such as anaphylaxis occur, albeit infrequently with monoclonal antibody therapies ^{31, 32}. These toxicities have been described with Herceptin treatment, more so in patients on anthracycline and cyclophosphamide combined with Herceptin²⁶. Cardiotoxicity could occur in some patients when Herceptin is administered with anthracyclines^{33, 34}. Herceptin itself can be cardiotoxic in patients receiving concurrent or prior anthracyclines^{35, 36}. Cardiotoxicity is not due to structural abnormalities but Herceptin might cause myocardial dysfunction. The toxicity of anthracyclines and Herceptin could be brought about by different routes³⁷. As Dinh et al.³⁸ have emphasised, many questions relating to Herceptin treatment still remain unanswered, e.g. optimising treatment, and combination with conventional chemotherapeutic agents, among others. Even with these caveats Herceptin may be regarded as a most efficacious agent in the treatment of HER2+ breast cancers.

EGFr inhibitor Lapatinib (Tykerb) in breast cancer treatment

As stated earlier, EGFr is over expressed in a proportion of breast cancers that are ER-negative. EGFr expression also correlates with the expression of metastasis promoting genes. Further, in the light of the function of EGFr in conjunction with HER2, it would be of considerable clinical benefit to test the effects of EGFr inhibitors in breast cancer treatment. Lapatinib is a powerful dual inhibitor of EGFr and HER2 with marked pharmacological potential.

Lapatinib is a protein kinase inhibitor (a 4-anilinoquinazoline derivative), which inhibits growth factor signalling by binding to the ATP-binding pocket of both EGFr and HER2 receptor proteins and so prevents autophosphorylation of the receptor and inhibits the signalling cascade leading to the suppression of the growth of tumours, including advanced or metastatic breast cancers resistant to Herceptin³⁹. Objective responses have been achieved in 28% of patients with untreated HER2-positive tumours⁴⁰. Clinical trials have provided promising results; Lapatinib is clinically very effective especially in advanced or metastatic breast cancer and patients with brain metastases. A phase III trial assessing the efficacy of combination of Lapatinib with Capecitabine, which is converted to 5-Flurouracil and inhibits DNA synthesis, seems to suggest a significant slowing down of disease progression by the combination as compared with capecitabine alone⁴¹. The efficacy of combining Lapatinib with other conventional chemotherapeutic agents is being evaluated. First-line Paclitaxel-Lapatinib combination gave significant benefits to HER-2-positive patients⁴².

Lapatinib could be functioning synergistically with HER2 inhibitors, for its effect on prominently EGFr over-expressing cancers, such as colorectal cancer or squamous cell carcinoma of the head and neck, is said to be unexceptional and moderate⁴³. According to Press et al.⁴⁴ the benefits of Lapatinib appear to be restricted to patients with HER2 over-expressing cancers. Lapatinib has no cardiac toxicity but does produce other toxic effects⁴⁵. However, its toxicity whilst administered in combination with other anticancer agents has not been appraised.

Avastin in breast cancer treatment

A different route to control of tumour growth and metastatic spread has been afforded by inhibitors that target the microvasculature associated with tumours. Tumours induce the formation of neovascularisation so that tumour cells can access the vascular system and become disseminated to form distant metastases. The neovasculature is induced by VEGF, which transduces its effects by binding specifically to its receptors VEGFr (see⁴⁶). A strategy similar to that adopted with EGF family growth factors has been used to target VEGFr, inhibit its function and inhibit the signalling by VEGF. Avastin (Bevacizumab), a humanised monoclonal anti-VEGFr antibody, is such an inhibitor. Avastin with Paclitaxel chemotherapy has been found to enhance progression-free survival and improve response rate in patients with advanced breast cancer⁴⁷. However, on account of possible side effects, there is some reluctance to the use of Avastin. It has been approved in Europe for first line treatment of women with metastatic breast cancer, but has not been approved for use by the National Institute for Health and Clinical Excellence UK⁴⁸.

ACKNOWLEDGEMENTS

The author thanks Professor Leif Bergkvist of the Department of Surgery and Centre for Clinical Research of Uppsala University Central Hospital at Västerås, and Dr M.S. Lakshmi for reading the manuscript and making helpful suggestions, and Professor Bayan Sharif and Professor Satnam Dlay for research and literary facilities

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