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Published on 25 January 2010

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United Kingdom Clinical Pharmacy Association report

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Managing anticoagulation, opioid-induced bowel dysfunction and surviving sepsis were all topics discussed at the recent UKCPA residential symposium held in Stratford, UK, in November

Christine Clark
BSc MSc PhD FRPharmS FCPP(Hon)
Editor
HPE

Managing anticoagulation, opioid-induced bowel dysfunction and surviving sepsis were all topics discussed at the recent UKCPA residential symposium held in Stratford, UK, in November

Hospital pharmacists can make a positive impact on the morbidity and mortality of sepsis, in the opinion of Paul Wade (consultant pharmacist, infectious diseases, Guy’s and St Thomas Hospitals).

The spectrum of infectious disease ranges from systemic inflammatory response syndrome (SIRS) to septic shock. SIRS includes fever, tachycardia and raised respiratory rate. Severe sepsis is usually associated with organ dysfunction and septic shock is associated with raised levels of lactic acid, oliguria and lack of response to fluid resuscitation.

Worldwide there are 750,000 cases of sepsis annually and it is estimated to be the 10th leading cause of death. UK data show that the numbers of people admitted to intensive care units (ICUs) with sepsis in the first 24 hours increased from 24% to 28% between 1996 and 2004. The majority of these were medical patients, commented Mr Wade.

In the UK there are 37,000 deaths from sepsis each year and this exceeds the combined total of deaths from cancer of the bowel and breast. Organ failure is a major factor; patients with severe sepsis usually have two or three failing organs and mortality increases by 15% for each organ that fails. The cost burden of sepsis is estimated to be £2 billion per annum, he added.

Sepsis is not linked to any specific pathogens, but can be caused by any organism including fungi, viruses and parasites. Gram-positive organisms are now more common than Gram-negative organisms and this seems to be associated with additional factors such as long-term indwelling lines.

The sequence of events is much the same regardless of the organism and the patterns of systemic response are similar, suggesting that there is a final common disease pathway. The guiding principles of treatment are to provide aggressive circulatory support, optimisation of ventilatory support and prompt control of the source of infection. Key management recommendations include resuscitation, diagnosis of infection, antibiotic treatment, control of the source of infection, fluid therapy, haemodynamic support using vasopressors and inotropes, treatment with steroids, activated protein C and blood products and supportive treatment. “The aim is to keep the patient alive while the infection is treated”, said Mr Wade.

It is essential to take samples for culture before antibiotic treatment is started. Two or more blood cultures should be drawn, both directly and through any vascular access devices that are present. Imaging may also be may be required, for example, to identify abscesses.

Controlling the source of infection can be a critical step and removal of infected cannulae is essential. Intravenous antibiotic treatment should be started in the first hour using a broad-spectrum agent. Patients should be reassessed daily, and treatment should normally be continued for seven to 10 days. Antibiotic treatment should be discontinued if the cause of the illness is found to be non-infectious.

The concept of the golden hour is important in the management of sepsis. Research has shown that aggressive, early, goal-directed treatment is associated with a mortality of about 30% whereas conventional treatment has a mortality of 47%, emphasised Mr Wade. One study showed that if antibiotics were given in the first 30 minutes, 80% of patients survived but mortality increased by 7.5% for every hour that antibiotics treatment was delayed. Many studies show that the impact of early antibiotic treatment is “very reproducible” said Mr Wade.

It has been calculated that if antibiotics were given for sepsis within four hours, an overall mortality reduction of 0.6% is possible and this equates to 720 lives saved in the UK annually. “A relatively small intervention that could have a big result”, said Mr Wade.

In order to bring this about medical emergency teams will be needed in hospitals. The College of Emergency Medicine has called for performance standards to be implemented in this area” 50% of septic patients should receive antibiotics within one hour and 90% within two hours. This will be audited next year, said Mr Wade.

Mr Wade acknowledged that there are practical problems associated with making broad-spectrum antibiotics available on hospital wards because of anxiety about Clostridium difficile. What is needed is a system that prioritises the first dose of antibiotics, along with suitable empiric guidelines and available broad-spectrum antibiotics. Patients should be closely monitored and switched to narrow-spectrum antibiotics when the infecting organism is identified. As the infection is brought under control, switching of IV to oral therapy is important as is remembering to remove the intravenous cannula. Implementation of these measures is a role for everyone – not just the infectious diseases pharmacist, concluded Mr Wade.

Opioid-induced constipation
Opioid induced constipation is “more than just defaecation– it is a whole constellation of features”, said Steve Allen (consultant in chronic pain management, Churchill Hospital, Oxford, UK) speaking at a satellite meeting held by the UKCPA pain interest group. Peripheral GI side-effects are all associated with the physiology of opioid receptors. Constipation is the most common and most troublesome effect but it is important to recognise that it is often accompanied by other GI effects such as anorexia, cramps, bloating and incomplete evacuation.

Opioid receptors are found in the myenteric plexus and the submucosal plexus both of which are located in the bowel wall. When opioids are absorbed from the gut they bind to opioid receptors in the myenteric plexus and the result is reduced gut motility and constipation. Some of the absorbed opioid is carried via the hepatic portal system to the systemic circulation and produces an analgesic effect. Parenteral opioids can also cause constipation because some of the dose will diffuse into the gut wall from the bloodstream, noted Dr Allen.

Opioid receptors (μ receptors) are found throughout the gastrointestinal tract and they are involved in gut motility, sphincter control and secretory activity. Water flux is as important as motility and yet the importance of this key activity of the submucosal plexus is rarely considered. Some 10 litres of fluid are secreted into the gut each day and most of this is reabsorbed in the small and large bowel. Opioids reduce secretion of water and increase absorption from mucosal cells – the result is hard, dry stools that are difficult to move along the gut lumen. Opioids also increase sphincter tone, leading to gastric reflux (gastric and oesophageal) and incomplete evacuation (anal sphincter). There is no evidence that any one opioid is less toxic than any other on the gut, he said.

Opioid-induced constipation is the result of pathological gut motility and enhanced fluid absorption. Much of the management of this condition is unsatisfactory because the agents used are ineffective and in practice fewer than 50% of patients get any help from laxatives. Moreover, one study showed that only 37% of patients prescribed regular opioids were also prescribed laxatives. Dr Allen said that laxatives treat the symptom not the cause and they do not address all of the opioid mediated effects.

A better approach would be to treat the cause rather than the symptoms by using a peripherally-acting opioid antagonist, he suggested. One option here is to use methylnaltrexone, which does not cross the blood-brain barrier and therefore does not reverse the analgesic effects of opioids. As it is not absorbed from the gut it is given subcutaneously. It is licensed for “opioid-induced constipation in advanced illness patients receiving palliative care” and is usually given on alternate days. Methylnaltrexone displaces opioids from gut receptors and provokes a laxative effect within four hours of administration. The response can be so rapid and vigorous that it has been described as “injectable Picolax”, commented Dr Allen.

An alternative approach is to use Targinact – a product which combines prolonged release oxycodone and prolonged release naloxone in 2:1 ratio in a single tablet. Naloxone has a greater affinity for the opioid receptor than oxycodone, and so after an oral dose of Targinact the gut opioid receptors are quickly occupied and the oxycodone (which is simultaneously released) enters the hepatic portal system and then the general circulation. The small amount of naloxone that is absorbed is rapidly metabolised in the liver. The net result is satisfactory analgesia without impairment of gut motility.

Studies have shown that Targinact and prolonged release oxycodone alone produce the same level of analgesia. Targinact is tolerable and effective during prolonged use (up to one year). Detailed bowel function studies have shown that patients taking Targinact require significantly fewer doses of rescue laxatives.

Anticoagulant special interest
Linda Hirst described how she had become a Pharmacist with a Special Interest (PhwSI) in anticoagulation. In 2004 she set up a health promotion clinic in her pharmacy, operating one evening per week. At this clinic she performed blood pressure measurement and blood glucose testing and provided lifestyle advice. When the new community pharmacy contract came into effect in 2005 she became involved, together with colleagues, in cardiovascular screening work at festivals for the British Heart Foundation. It was after this that her local PCT asked for pharmacists to train in anticoagulation and to set up community clinics. She received training in the theory and practice of anticoagulation under pharmacists experienced in running anticoagulant services at Bradford and Airedale hospitals. She also learned how to use the Coagucheck device, and became familiar with EMIS/System 1 software used in general practice and INRstar – anticoagulation management software.

In October 2005 she started to run a community pharmacy-led anticoagulation clinic jointly with her colleague, Marta Hildebrandt. The clinical was funded by the local Primary Care Trust and ran for a half-day on alternate weeks. Patients liked the service because it was much more convenient for them than the previous arrangement and it was quickly found that there were too many patients for the time available. Moroever, more complex patients and housebound patients were being referred to the clinic.

The Primary Care Trust then decided that in future the service should be run by accredited pharmacists with special interests (PhwSIs) through a practicebased commissioning scheme. Ms Hirst and Ms Hildebrandt then had to demonstrate that they met all the specialist competences required. They also had to ensure that appropriate infrastructure was in place for the service to operate including items such as indemnity insurance, referral pathways and appropriate documentation. This culminated in their appearance before a PCT panel for accreditation. “Many GPs with special interests had been accredited in the past but we were the first pharmacists”, said Linda.

In April 2008 she was accredited as a PhwSI in anticoagulation for level 1 patients and in April 2009 she was accredited for level 1 and 2 patients. Level 2 patients include, for example patients who have recently undergone cardioversion.

Ms Hirst and Ms Hildebrandt now have more than 70 patients attending the clinic, which runs for one full day each week. They also manage housebound patients and some patients in nursing homes. “It is possible that in future we will take on warfarin initiation” said Ms Hirst. In summary she said that they had received “fantastic support” from the staff at Willesden Medical Centre, where the clinic is based.



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