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You are here: BAILII >> Databases >> Scottish Sheriff Court Decisions >> Frame, Re Inquiry Into the Death of [2005] ScotSC 30 (24 May 2005) URL: http://www.bailii.org/scot/cases/ScotSC/2005/30.html Cite as: [2005] ScotSC 30 |
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UNDER THE FATAL ACCIDENTS AND SUDDEN DEATHS INQUIRY (SCOTLAND) ACT 1976
INTO THE DEATH OF
EMMA AGNES FRAME (DATE OF BIRTH: 30 April 1996)
Held at LANARK and HAMILTON on: 20,21,22,23,28,29 and 30 September, 1,4,5,6,7,8,11,12,13,15 October and 1 November 2004
Hamilton: 24 May 2005
The Sheriff, having considered all the evidence adduced,
DETERMINES:
In terms of section 6(1)(a) of the Fatal Accidents and Sudden Deaths Inquiry (Scotland) Act 1976 that Emma Agnes Frame, born 30 April 1996, died at 04.35 hours on 24 November 2001 within Wishaw General Hospital;
In terms of section 6(1)(b) of the Act that the cause of her death was adrenal insufficiency due to inhaled steroid therapy prescribed for chronic asthma;
In terms of section 6(1)(c) of the Act that there were reasonable precautions whereby Emma Frame's death might have been avoided, namely:
In terms of section 6(1)(e) of the Act other facts which are relevant to the circumstances of Emma Frame's death are:
SHERIFF
Emma's death
Emma Agnes Frame died on 24 November 2001 at Wishaw General Hospital. She was five years old.
Emma was born on 30 April 1996, the younger child of Stewart and Karen Frame.
When she was 7 weeks old Emma was taken to her GP, Dr Frank Shapiro, with a cough. Thereafter she had recurring respiratory symptoms. She was diagnosed by Dr Shapiro as possibly asthmatic. When she was about 19 months old, Dr Shapiro treated Emma's respiratory symptoms with budesonide, an inhaled corticosteroid drug, and a short course of the oral steroid, Prednisolene. About 7 weeks later, her prescription was changed to 1,500 micrograms per day of another inhaled corticosteroid drug, fluticasone propionate (hereinafter referred to as fluticasone). Thereafter, apart from a further period of approximately 6 weeks when she was again prescribed budesonide, Emma remained on a prescription for fluticasone of between 500 micrograms and 2,000 micrograms throughout her life.
Dr Shapiro referred Emma to the Royal Hospital for Sick Children at Yorkhill, Glasgow (Yorkhill) for specialist advice about her respiratory symptoms and his treatment of them. Emma was seen by Dr Dominic Cochran at Yorkhill on four occasions during her life.
On occasion Emma had a very bad cough, to the extent that she would vomit. On one occasion she was admitted to hospital with possible dehydration due to vomiting. She also sometimes had problems with her ears. Otherwise, Emma was generally a healthy child who led a normal life and took part in normal childhood activities. .
On 23 November 2001, Emma woke up complaining of a sore stomach. She was vomiting and appeared to be generally unwell. Later in the day, she became extremely lethargic and an emergency appointment was arranged at her GP's surgery where arrangements were made for her to be admitted to Wishaw General Hospital.
By around 7 pm when Emma arrived at hospital she had deteriorated further. On arrival in the ward, she had a convulsive fit. On examination she was noted to have large, red tonsils. Blood tests showed no obvious abnormalities
At approximately 10 pm, Emma's respiratory rate, breathing, blood pressure, heart rate, peripheral perfusion and cardiac function were all normal, she was a little dehydrated and her score on the Glasgow Coma Scale was 14 out of a possible 15. She was given fluids intravenously and treated with antibiotics. Dr Catherine Lees, consultant paediatrician in charge of Emma's care, thought that Emma may have meningitis.
Emma's condition continued to deteriorate and she had a further convulsion. Paediatric intensive care support was requested from the Royal Hospital for Sick Children in Glasgow (Yorkhill), where arrangements were made for the paediatric unit at the Royal Hospital for Sick Children in Edinburgh to attend at Wishaw General Hospital. Around 1:10 am, Emma had a respiratory arrest. She was intubated and seemed to stabilise. Treatment was administered to control convulsions. The paediatric intensive care unit team from the Royal Hospital for Sick Children in Edinburgh, arrived at 3:20 am. Emma continued to deteriorate. Her blood pressure was difficult to control. A variety of drugs and other methods of stabilisation were tried.
Emma did not respond to any treatment. The medical staff informed Emma's parents that nothing further could be done for her. The breathing tube was removed and at 4:35am Emma was pronounced dead.
A post-mortem examination of Emma was carried out on 28 November 2001 by Dr Howatson at Yorkhill. A preliminary report was sent to the procurator fiscal to advise that the cause of death was not established at that time and a full range of additional investigations were arranged with a view to making a more precise diagnosis. A report was sent to the procurator fiscal to this effect.
Calum Frame, Emma's brother had also been diagnosed as asthmatic by Dr Shapiro and had been on a prescription of high dose corticosteroid inhalants to treat the symptoms. About one month after Emma's death, on 21 December 2001, Calum, then aged seven, complained of a sore stomach and was very sick. Because of what had happened to Emma, Mr and Mrs Frame took him immediately to the Strathaven Medical Centre from where he was referred to Wishaw General Hospital.
At Wishaw General Hospital, tests were carried out on Calum and two doctors from Yorkhill attended and examined him but the cause of his illness was not established.
Calum was transferred to Yorkhill where he was given a CT scan which showed that his brain was swelling. He was transferred to the intensive care unit. He remained there for three days, was ventilated and sedated and the swelling in his brain reduced. On 29 December 2001 he returned home where he made a full recovery.
After Calum's discharge from Yorkhill, a member of staff at the hospital noticed that the results of the blood tests taken when Calum was in hospital showed that he had a lower level of cortisol than would have been expected. It was arranged that Calum be recalled for synacthen tests to check this.
Dr Howatson prepared a second report for the procurator fiscal on 8 February 2002 in which he detailed the results of the additional investigations, stated that Emma's death appeared to have been the result of natural causes, as yet undetermined and concluded that death certification should remain unchanged as "Ia Not Ascertained". Dr Howatson noted in this report that Emma's brother had been admitted to Yorkhill Hospital intensive care unit "in a state of acute onset unconsciousness with a symptom complex almost identical to that of his sister sometime after her death". He went on to say that: "Investigations of adrenal function are not yet complete and I am unaware of any other specific information."
In March 2002, Calum was recalled to Yorkhill hospital for synacthen tests to be carried out. The results of these tests showed that Calum had severe adrenal suppression. On 19 March 2002 Dr Malcolm Donaldson examined Calum at the endocrine clinic at Yorkhill. Dr Donaldson concluded from the results of the synacthen tests, the fact that Calum had been on high dose fluticasone and that his sister had died and that she had been on high dose fluticasone, that both Calum's illness and Emma's death were related to acute adrenal insufficiency.
On 5 April 2002, Dr Howatson wrote to the procurator fiscal about Calum's illness and the diagnosis of adrenal insufficiency probably secondary to drug treatment which he was receiving for asthma. He said that Emma had been receiving similar therapy and in the light of that and the small adrenal glands which he had identified at the post-mortem examination, and which he had thought to be stress-related, he was of the view that Emma's death "would now appear to be the result of a similar aetiology, i.e. adrenal insufficiency and suppression due to inhaled steroid treatment for asthma."
The fatal accident inquiry
In terms of section 1(1)(b) of the Fatal Accidents and Sudden Deaths Inquiry (Scotland) Act 1976, it appeared to the Lord Advocate that it was expedient in the public interest that an inquiry be held into the circumstances of Emma Frame's death.
At the inquiry the procurator fiscal was represented by Mr Houston. Mrs Dougall, advocate, instructed by Drummond and Miller, WS and Mr Pugh, solicitor, appeared on behalf of Calum Frame, representing Emma's family. Mr Holmes, solicitor, appeared on behalf of the Medical Defence Union in Scotland, representing the interests of Emma's general practitioner, Dr Shapiro. Mrs Robertson, solicitor, appeared on behalf of NHS Lanarkshire and NHS Greater Glasgow, representing the interests of the relevant consultants at Wishaw General Hospital and the Royal Hospital for Sick Children at Yorkhill, Glasgow. Mr Lindsay, advocate, appeared for the Advocate General's office, representing the Medicines and Healthcare Products Regulatory Agency. Mrs Abernethy, solicitor, and Miss Hill, solicitor, appeared on behalf of GlaxoSmithKline, the current manufacturers of the drug, fluticasone.
The inquiry lasted approximately four weeks. The following witnesses gave evidence:
Mr Stewart Frame, Emma's father
Dr Catherine Lees, consultant paediatrician at Wishaw General Hospital, Wishaw
Dr Frank Shapiro, GP, Strathaven Health Centre, Strathaven
Dr Alan Howatson, consultant paediatric and perinatal pathologist, Royal Hospital
for Sick Children,Yorkhill, Glasgow
Dr Dominic Cochran, consultant respiratory paediatrician at Royal Hospital for
Sick Children,Yorkhill, Glasgow and Southern General Hospital, Glasgow
Dr James Paton, consultant paediatrician at Royal Hospital for Sick Children,
Yorkhill, Glasgow
Mr John Milne, lead pharmacist in cancer services, Lanarkshire Acute Hospitals,
NH Trust
Dr Geoffrey Todd, consultant chest physician, Antrim Area Hospital, Northern
Ireland
Dr Jeremy Rafe Suvarna, senior medical assessor in the Pharmacovigilance Risk
Assessment Unit, Medicines and Healthcare Products Regulatory Agency, London
Dr David Leather, director of primary care, GlaxoSmithKline, UK Ltd
Professor Peter Helms, Professor of Child Health at the University of Aberdeen and
Honorary Consultant Paediatrician at the Royal Children's Hospital, Aberdeen
Dr Peter William Thornton, GP, Carnoustie, Angus
Dr Malcolm Donaldson, senior lecturer in child health at the Department of Child
Health, Royal Hospital for Sick Children, Yorkhill, Glasgow
Many of these witnesses are experts in their own specialised field of medicine. The evidence was not only lengthy but often complex and technical.
Many issues were raised regarding facts and circumstances which may, to a greater or lesser degree, have contributed or been relevant to Emma's death.
At the conclusion of the hearing of evidence parties' representatives addressed me on a substantial number of issues of relevance to the determination in this case.
SUMMARY OF EVIDENCE
In order to facilitate a full understanding of the matters raised in relation to Emma's death I have set out the evidence before the inquiry, which has been accepted by me, regarding the facts and issues which I consider to be of relevance and the background information which has substantially informed my determination in this matter.
Details of the care and management of Emma by her general practitioner
Dr Frank Shapiro qualified as a doctor in 1976 and has practised as a general practitioner for most of the time since then. He is currently one of the partners in the Strathaven Medical Centre.
The other doctors in the practice refer asthma cases which are difficult to manage to Dr Shapiro. He cares for approximately 90% of the child asthma patients and 50/60% of the adult asthmatics within the practice. The practice has an asthma nurse.
Dr Shapiro has had a particular interest in the diagnosis and management of asthma for 25 years dating from a period of GP training in a paediatric unit and a period working as a locum in a paediatric unit.
Dr Shapiro himself decides upon the management and the treatment of asthma patients whenever possible but he refers these patients to a consultant when he requires reassurance regarding his management of particularly difficult cases. He refers child patients in this category to Dr James Paton who is a consultant respiratory paediatrician at Yorkhill.
Dr Shapiro's first contact with Emma Frame was on 17 June 1996 when Emma was 7 weeks old. He noted that she was "chesty already" and had a marked cough and that there was a strong family history of atopic disease.
Dr Shapiro saw Emma again on 8 November when he noted that she had "chestiness".
Dr Shapiro's next consultation with Emma in relation to respiratory problems was on 8 May 1997, when he took a history of Emma's respiratory symptoms since birth, noted that she was sometimes chesty with colds and prescribed a non-steroid combined lung opener, Combivent.
The next relevant consultation was on 10 October 1997, when Dr Shapiro noted that Emma had had a cough for 10/14 days and was chesty with every cold. He prescribed a non-steroid lung stabiliser, Sodium Cromoglycate and requested a review in three weeks.
On 28 October 1997, Dr Shapiro noted that Emma was better and should be continued for six months on the Sodium Cromoglycate inhaler.
On 5 November 1997 Dr Shapiro had a consultation with Emma when he noted that she was feverish but that her chest was normal. He suspected that she may have a virus and that cold and smoke from a fireworks display was triggering asthma. He prescribed steroids for Emma for the first time, namely budesonide (brand name Pulmicort), an inhaled corticosteroid, via an aerochamber at a daily dose of 800 micrograms and also prescribed the lung opener Salbutamol, to be taken if she was symptomatic. He asked to see Emma again in 48 hours.
On 7 November 1997 Dr Shapiro noted that Emma was breathless and using accessory muscles of respiration. He prescribed a short course of Prednisolone, an oral steroid.
On 12 November 1997, at the end of the oral steroid course, Emma's condition was reviewed and she was noted to be "not much better but coping". A chest x-ray was arranged, which proved to be normal, and a further review was arranged.
On 26 November 1997 Emma was noted to have had a cough for 24 hours but to be otherwise well. As she was still symptomatic she was put back on Combivent. A treatment plan was devised whereby if Emma was still coughing in one week then either the dose of budesonide should be doubled or her inhaled corticosteroid prescription should be changed to fluticasone.
On 4 December 1997 Emma was noted to be less chesty but with still "the odd cough" and Dr Shapiro put the treatment plan on hold.
On 22 December 1997, Emma was seen by Dr Shapiro's partner, Dr Hassall who prescribed antibiotics.
On 29 December 1997 Dr Shapiro noted that Emma had been prescribed an antibiotic by his partner. Dr Shapiro did not consider that the use of antibiotics was appropriate in the management of asthma. As Emma was coughing and wheezing Dr Shapiro reverted to his treatment plan of 26 November and prescribed the inhaled cortisosteroid, fluticasone (brand name Flixotide) for Emma for the first time. The dose prescribed was 1,500 micrograms daily. A review was arranged for three weeks time.
On 20 January 1998, Dr Shapiro saw Emma again and noted that she was better but not symptom free. He decided that it was now necessary to refer Emma for specialist assessment.
On 21 January 1998 a referral letter was sent by Dr Shapiro to Dr Paton at Yorkhill Hospital in which Dr Shapiro stated inter alia that Emma's "symptoms are reduced on a dose of 1,500 micrograms of Flixotide a day via an aerochamber but she still easily becomes chesty. I think in view of her age and the doses we are using it would be worthwhile you seeing her for reassurance. As always, I am trying to use the lowest dose of steroid that keeps the child free [of symptoms]. I wonder if it might be useful sometimes to send you photocopies of my notes as since you only see the child once it is often difficult with this snapshot to assess the level of problem. I therefore have taken the liberty this time of sending a photocopy of the A4 pink sheets".
At each of his next two consultations with Emma, on 19 March and 13 May 1998, Dr Shapiro noted that Emma was "well" and reduced the total daily dosage of fluticasone to 1,000 micrograms and 750 micrograms respectively, with a two month review requested on each occasion.
On 2 June 1998 Emma was noted to be "not thriving". She was not gaining weight at the rate Dr Shapiro would have expected and she looked unwell. Upon examination, Dr Shapiro noted that Emma had enlarged glands, which suggested infection. He therefore arranged haematology investigations to check iron and blood sugar levels. The results were normal.
On 29 September 1998, Emma was reviewed and was noted to be well. The therapy was again reduced to a total of 500 micrograms daily. A further review was requested for the beginning of December.
On 1 December 1998 Dr Shapiro saw Emma and noted that she had been symptomatic for 2 or 3 weeks with a marked cough. Accordingly, Dr Shapiro increased the fluticasone prescription to 1,000 micrograms daily and prescribed Galpseud, a decongestant. An early review was arranged for four weeks. Dr Shapiro noted a plan to add Serevent, a long acting lung opener and decrease the steroid again at review if possible.
On 17 December 1998, Dr Shapiro saw Emma and noted that she was "miserable". She had been taking 1,000 micrograms of fluticasone daily for two weeks but despite that was coughing so severely that she was vomiting at the end of the cough. Her chest was clear. Dr Shapiro commenced a "rescue" course of the oral steroid, Prednisolone, which he hoped would produce a response within 24 hours. He increased Emma's dose of fluticasone to 2,000 micrograms per day and also prescribed Serevent. He asked to see Emma again the following week.
On 22 December 1998, Dr Shapiro reviewed Emma and noted that she was 75% better but was still symptomatic. He set out a plan to continue the therapy for four weeks, when he would review the situation with a view to decreasing the fluticasone prescription.
On 11 January 1999, Dr Shapiro noted that Emma was still symptomatic but that he would need to decrease the steroid. He prescribed 60 milligrams 12 hourly of Slophylline, an anti-inflammatory drug, with a view to reducing Emma's symptoms and reducing the steroid dose. He noted a further treatment plan to reintroduce sodium cromoglycate if that did not work.
On 20 January 1999, Dr Shapiro noted that Emma was "chesty until she vomits". Nevertheless he decreased the fluticasone dose to 1,500 micrograms daily. He also prescribed sodium cromoglycate. He also noted a treatment plan to the effect that he needed to use less steroid again. He arranged to see Emma in four weeks. Dr Shapiro also noted that his referral of Emma to Yorkhill the previous year had not resulted in contact with the hospital. He wrote again to the hospital requesting an urgent appointment.
On 6 February 1999, Dr Shapiro saw Emma and noted "little new medically, bit grumpy, afebrile, chest is clear". He did not change the therapy.
On 29 March 1999, Dr Shapiro saw Emma for review. By that time, Dr Cochran at Yorkhill had seen Emma and had written to Dr Shapiro. Dr Shapiro reduced the fluticasone dose to 1,000 micro-grams daily. He also followed Dr Cochran's recommendation and stopped the sodium cromoglycate prescription and changed Emma over from an aerochamber to a volumatic inhaler device.
On 23 June 1999 Dr Shapiro saw Emma for review. Prior to that, she had been seen by Dr Cochran at Yorkhill again but the letter sent by Dr Cochran after that consultation had not yet arrived at Dr Shapiro's surgery. Dr Shapiro decreased the fluticasone prescription to 750 micrograms daily with a view to reviewing this at Christmas when he intended to reduce it further to 500 micrograms daily if Emma was well.
On 7 October 1999, Dr Shapiro saw Emma and noted that she had become increasingly symptomatic over a month but had had seven good months out of eight. Dr Shapiro increased the dose of fluticasone to 2,000 micrograms daily, with a review in 17 or 18 days, at which time if she was symptom free, the dose should be reduced to 1,500 micro-grams daily for two or three weeks then reduced further again to 1,000 micro-grams daily over the winter.
On 28 October 1999 Emma was seen by a locum and the fluticasone was reduced to 1,500 micrograms daily, in accordance with Dr Shapiro's plan.
On 3 December 1999, Dr Shapiro noted that Emma had fever and was shaky, her drinking had increased and that she was otherwise alert and well. Due to the reference to increased drinking, Dr Shapiro arranged a test of Emma's urine to check that she was not diabetic. The results were negative. Dr Shapiro continued Emma's prescription for Montelukast which had been prescribed by Dr Cochran on 11 November 1999. Dr Shapiro noted a plan to see Emma in January with a view to decreasing the steroid dose.
On 2 February 2000, Dr Shapiro saw Emma, who had an upper respiratory tract infection. He noted that she had had two days of cough in the last two months. He noted that they should wait 2 weeks and then decrease the steroid to 1,000 micrograms daily.
Dr Shapiro did not see Emma until 26 June 2000 when he noted that she had been well for two months. He reduced the Flixotide to 750 micrograms daily. He noted that there were problems with volumatic spacer. He arranged to review Emma in 12 weeks.
However, he subsequently saw Emma again (date not noted) when he found that she had deteriorated on this dose and he increased the dosage to 2,000 micrograms per day, provided that if she was symptom free within two weeks, the dosage should be reduced to 1,500 micrograms daily. He arranged to see her in five weeks.
On 17 August 2000, the Flixotide was reduced to 1,500 micrograms.
On 30 August, it was noted that she had become symptomatic on this dosage. Dr Shapiro did not increase the steroid dose but he provided two types of dry powder breath activated inhalers, in the hope that this would improve the delivery of the steroid to the lungs, thereby allowing a decrease in the steroid dose.
On 14 September 2000, Dr Shapiro saw Emma using the inhaler devices and noted that she seemed to be able to use a turbohaler. He therefore changed her steroid prescription to budesonide as Flixotide is not available with a turbohaler device. He prescribed 1,600 micrograms daily.
On 10 October 2000, Dr Shapiro noted that Emma was doing well and was symptom free. He reduced the budesonide dose to 800 micrograms daily. He arranged to see her in two weeks, with a plan to convert to 500 micrograms Seretide, which is a combination of the lung opener, Salmeterol, and fluticasone, administered by accuhaler.
On 26 October 2000, Dr Shapiro noted that Emma had become symptomatic on the decreased steroid dose and that her mother had increased the budesonide to 1,600 micrograms daily. Dr Shapiro changed Emma to a prescription of Seretide which provided a dose of 1,000 micrograms of fluticasone daily. He requested a two week review.
On 8 November 2000, at review, Dr Shapiro noted that Emma was well and decided not to change her therapy at that stage.
Dr Shapiro saw Emma on 16 February 2001. She was well. Dr Shapiro reduced Emma's Seretide accuhaler therapy to 500 micrograms of fluticasone daily. He requested a review in 12 weeks.
Emma returned on 26 April 2001, having not tolerated the decrease in steroid, which had been increased by her parents to the original Seretide accuhaler dose of 1,000 micrograms daily of fluticasone. Dr Shapiro also prescribed a nasal steroid, as treatment for Emma's catarrh. He requested a review in two months.
In May 2001 Emma was referred by one of Dr Shapiro's partners to an ear, nose and throat specialist.
Dr Shapiro next saw Emma on 20 November 2001 when she presented with a bulging right eardrum. He prescribed the decongestent, Galpseud and doubled her nasal steroid prescription. He requested a review in four weeks.
On 23 November 2001, Emma was seen by Dr Shapiro's partner, Dr Campbell and was admitted acutely to Wishaw General Hospital where she died in the early hours of the following morning.
Details of the care and management of Emma at Yorkhill
On 20 January 1998, Emma was referred by Dr Shapiro to Dr Paton at Yorkhill Hospital. This referral did not result in Emma being seen at Yorkhill. (This matter will be dealt with at another part of this determination.)
On 25 February 1999, following upon a further referral by Dr Shapiro, Emma was seen at Yorkhill by Dr Cochran.
Dr Cochran is a consultant in paediatric respiratory medicine and in paediatric neonatal medicine at Yorkhill and at the Southern General Hospital in Glasgow.
Dr Cochran noted, mainly from the history given by Dr Shapiro and by Emma's parents, that Emma had quite significant persistent chest symptoms which were consistent with a diagnosis of asthma despite quite intensive asthma therapy.
He arranged a chest x-ray and a sweat test for Emma to exclude the possibility of other chest conditions and cystic fibrosis. The results of these tests were normal.
Dr Cochran recommended that delivery of the fluticasone and salmeterol which was being prescribed for Emma by Dr Shapiro be changed from an aerochamber to a large volume spacer, as that there was some evidence that a larger volume spacer gave better delivery of treatment into the lungs, thereby getting the best benefit from the treatment which was already been given.
At that time, Emma was being prescribed 1,500 micrograms of fluticasone daily by Dr Shapiro. In the letter which he sent to Dr Shapiro after his first consultation with Emma, Dr Cochran's comment in relation to this level of medication was that "given there has been such a poor response to intensive treatment it would seem reasonable to reduce Emma's current treatment to minimise unnecessary medication. In particular I note her dose of fluticasone is high and at this dose there is the potential for significant systemic absorptions. A high dose of Flixotide would be worthwhile if it was producing improved control but this does not seem to be the case". His letter also stated "consider reduction in dose of fluticasone".
On 3 June 1999 Emma had a further appointment with Dr Cochran to review her progress. During the three month review period, Emma's asthma symptoms had been less severe and her dosage of fluticasone had been reduced by Dr Shapiro.
Dr Cochran found that Emma's height and weight had increased appropriately, indicating a normal growth velocity.
A further appointment was arranged at the request of Emma's parents.
On 9 November 1999, Dr Cochran had a further consultation with Emma. Her symptoms had deteriorated and she was again receiving 1,500 micrograms of fluticasone daily. She had a very severe cough, which sometimes resulted in vomiting. Dr Cochran advised that if the symptoms lasted more than a few days, the only additional treatment likely to help was a short course of the oral steroid, Prednisolone. He also recommended Montelukast for a trial period.
On 9 November 2000, Dr Cochran saw Emma again. He noted in his follow-up letter to Dr Shapiro that "Emma has quite a heavy load of chronic asthma symptoms which fluctuate from month to month. I note that you have successfully managed to reduce the dose of fluticasone without any evidence of deterioration in Emma's asthma control".
At that time, Emma's treatment was 1,000 micrograms of fluticasone and 100 micrograms of salmeterol daily, both drugs given as a combined Seretide preparation. She was also being prescribed 5 micrograms of Montelukast and 120 micrograms of Slophyllin daily.
At that time, Dr Cochran did not recommend any change in Emma's treatment but noted "as previously, I would comment that she is receiving a relatively high dose of inhaled steroids. Although this is certainly acceptable if it leads to better symptom control, I also feel we should try to reduce the dose whenever possible since there is no benefit from her being on very high doses of steroid if they do not produce superior symptom control to lower doses".
Dr Cochran also noted that Emma was using a dry power accuhaler device and said that he "would have a low threshold for returning to a large volume spacer if her asthma deteriorated particularly since large volume spacers minimise systemic absorption of high dose inhaler steroids when compared to dry power devices".
Dr Cochran arranged to see Emma in one year's time, at the request of her parents. Emma did not attend her appointment on 8 November 2001 and shortly afterwards Dr Cochran heard about her death on 24 November 2001.
Details of the care of Emma at Wishaw General Hospital
Dr Catherine Lees is a consultant paediatrician at Wishaw General Hospital. She has 13 years experience in paediatrics. She was the consultant paediatrician on call at the time of Emma's acute admission to Wishaw General Hospital. She gave evidence regarding Emma's care from the time of her admission.
Emma was admitted to Wishaw General Hospital around 7.30pm on 23rd November 2001, with a history of vomiting all day and coughing. She was noted to have large, red tonsils on which there were exudates, which is evidence of infection. As she arrived in the ward, Emma had a generalised convulsion.
Blood tests were taken from which the following was ascertained:
sodium level was a little low, a fairly common pattern when a patient has been vomiting;
blood sugar was normal;
potassium level was low/normal;
white-cell blood count was high at 20.73, with a high neutrophil count of 17.14, suggestive of bacterial infection
When Emma was examined by Dr Lees at approximately 10 pm, she was noted to be pale and quite unwell. Her respiratory rate and breathing, blood pressure and heart rate, peripheral perfusion and cardiac function were all normal. She was a little, but not severely, dehydrated. Mrs Frame felt that Emma was not recognising. Her score on the Glasgow Coma Scale was 14 out of a possible 15. Dr Lees assessed that Emma had infection, perhaps meningitis. However, there was no restriction of her neck movement.
She had been receiving continuous intravenous fluids from the time of her arrival at hospital. She had also been given antibiotics. Dr Lees changed that prescription to broad spectrum antibiotics, to cover the possibility of more serious nervous system infection.
Over the next two hours, Emma became worse and her mother felt that she was becoming more confused and agitated.
Around midnight, she had a further convulsion, predominantly affecting the left side of the body, which led Dr Lees to suspect meningitis or encephalitis. Emma's condition was such that a lumbar puncture test to check for meningitis could not be carried out and therefore that could not be excluded as a diagnosis.
Dr Lees then focused on controlling Emma's airways. She contacted the intensive care unit at Yorkhill Hospital to arrange for paediatric intensive care support. Yorkhill Hospital was unable to provide this but arranged that the paediatric unit at the Royal Hospital for Sick Children in Edinburgh would attend.
In the meantime, arrangements were made to have Emma intubated so that breathing support could be given.
During that time, around 12:40 am, following upon discussion with the consultant at the paediatric intensive care unit at Edinburgh, 11 mg of the steroid dexamethasone was administered to Emma as part of the standard treatment when brain swelling is suspected.
While Emma was being prepared for intubation, around 1:10 am, she had a respiratory arrest. After intubation she seemed to stabilise and her blood pressure and heart rate were fairly normal. Further advice was sought from the consultant at the paediatric intensive care unit at Edinburgh, who suggested maintenance treatment with the drug phenytoin to control the convulsions.
The team from the paediatric intensive care unit at the Royal Hospital for Sick Children in Edinburgh, consisting of a doctor and a nurse, arrived from Edinburgh Royal hospital for sick children at 3:20 am. Emma continued to deteriorate. Her blood pressure was difficult to control. A variety of drugs and other methods of stabilisation were tried. It was not possible to transfer Emma to Edinburgh until she had been stabilised. There was further consultation with the consultant on call from the intensive care unit at the Royal Hospital for Sick Children in Edinburgh. Emma did not respond to any treatment. The breathing tube was removed and at 4:35 am Emma was pronounced dead.
Emma showed none of the indications of a typical adrenal suppression presentation, namely hypoglycaemia, high potassium levels and low blood pressure.
During 13 years of working in paediatrics, Dr Lees had never seen a child with an acute presentation of adrenal insufficiency.
Post-mortem and diagnosis of cause of Emma's death
Dr Alan Howatson is a consultant pathologist, specialising in paediatric and perinatal pathology. He is based at the Royal Hospital for Sick Children at Yorkhill in Glasgow.
On 28 November 2001 Dr Howatson carried out a post-mortem examination of Emma. The opinion in his preliminary report, dictated on 30 November 2001, was that death appeared to have been the result of natural causes, as yet undetermined and in the first instance cause of death was certified as "not ascertained (pending results of further investigations)".
In this preliminary report, Dr Howatson commented inter alia that: "Two organ systems reveal pathology. Within the lungs there is marked pulmonary oedema with associated pleural effusion. At this stage there is no convincing evidence of a primary lung infection (ie pneumonia) but this will be further assessed on histological examination. The pulmonary oedema and associated effusions could be the result of the brain pathology and also of the need to provide fluid support to maintain cardiac output. The second and more significant pathology lies within the brain. There is very severe brain swelling in the absence of any focal abnormality or sign of trauma. It is possible that the cause of the presentation and subsequent demise lies with the pathology affecting the brain."
He also stated that: "The adrenal glands (right 1.5 g, left 1.6 g) appear unremarkable both externally and on sectioning. The adrenal glands are not unduly haemorrhagic."
In the preliminary report Dr Howatson said that: "In circumstances such as this it would be essential for the brain to be submitted to a detailed neuropathology examination which takes several weeks. Unfortunately authorisation and consent for this procedure was not granted by the procurator fiscal and the examination which has been performed represents an incomplete study which may not permit a definitive diagnosis to be made in this important case."
Dr Howatson detailed a full range of additional investigations which were under way in an effort to ascertain a more precise diagnosis and said that the results of these investigations would take several weeks and would be transmitted to the procurator fiscal in a second and full report.
Dr Howatson prepared a second report, which was dictated on 8 February 2002. In that report it was again stated that death appeared to have been results of natural causes, as yet undetermined and that death certification should remain unchanged as "Ia Not Ascertained". The results of the histology, bacteriology, virology, biochemistry, toxicology and neuropathology investigations were detailed.
The findings set out in the preliminary report in respect of the adrenal glands were repeated. It was noted that when Emma was admitted to Wishaw Hospital, biochemical analysis revealed a low blood sodium level, which was attributed to sodium loss as a result of recurrent vomiting. The other blood tests revealed nothing out of the ordinary.
Dr Howatson stated in this second report that the ancillary investigations had contributed little to any greater understanding of the cause of Emma's death. The biochemical investigations had not identified any obvious deficiency of adrenal gland function or any obvious metabolic abnormality which could explain Emma's death.
Dr Howatson noted in this report that Emma's brother had been admitted to Yorkhill Hospital intensive care unit some time after Emma's death "in a state of acute onset unconsciousness with a symptom complex almost identical to that of his sister sometime after her death". He went on to say that: "Investigations of adrenal function are not yet complete and I am unaware of any other specific information."
In this second report, Dr Howatson repeated his concern that limitations had been imposed on the examination due to the procurator fiscal not granting authorisation for a full neuropathology examination.
On 5 April 2002, Dr Howatson sent to the procurator fiscal at Hamilton a letter in which he referred to Calum's admission to Yorkhill with "an identical symptom complex" and said that it had "been identified that Calum has suffered from adrenal insufficiency probably secondary to drug treatment which he was receiving for asthma."
Dr Howatson said in his letter that "Emma was also receiving similar therapy and in the light of that the small adrenal glands which I identified at the post-mortem examination, and which I thought were stress-related because her biochemical derangement was not unduly severe, would now appear to be the result of a similar aetiology, i.e. adrenal insufficiency and suppression due to inhaled steroid treatment for asthma."
In the light of this, Dr Howatson recommended an alteration in the notification of death to the Registrar General from the original certification: Ia Not Ascertained, to: Ia Adrenal insufficiency, Ib Inhaled steroid therapy, Ic Chronic asthma.
Action taken at Yorkhill after diagnosis of adrenal suppression in Calum
Following upon Calum's diagnosis of adrenal suppression, meetings were held at Yorkhill with the hospital medical director and it was agreed that all children and adolescents who had at some point attended Yorkhill and who were receiving inhaled fluticasone in doses of 500 micrograms or more would be recalled for synacthen testing.
The respiratory and endocrine teams at Yorkhill carried out this undertaking. 426 children were identified as receiving fluticasone from January 2000 onwards. 140 of these children were receiving fluticasone within licence and it was assumed that they had never been outwith licence. The patients who did not attend for testing in response to two written requests to do so had letters sent to them to warn them that they should assume that they had adrenal impairment until proved otherwise and that they should make emergency provisions. 214 children were tested with low dose synacthen testing.
By the time the children were tested, 78 of these 214 children were receiving fluticasone within licensed doses. 34 of these 78 children had impaired adrenal function, with cortisol peaks of between 250 and 499 nanomols per litre, 44 had normal readings. None of these children had severe impairment of adrenal function.
Of the 214 children tested 136 children were on fluticasone of 500 micrograms or more at the time of testing. 6 of these children had severely impaired adrenal function, with cortisol peaks of less than 250, 51 had impaired adrenal function, including a child who was symptomatic, and 79 had normal readings.
The children who were taking doses of fluticasone above 500 micrograms daily were evaluated for the potential to reduce the dose. Only in those patients in whom it was as clear as it possibly could be that their symptoms were intolerable on lower doses was the need for high dose accepted. Those patients who remained on a higher dose were kept under regular review at Yorkhill.
Of all the children tested 3%, that is 6 children, had cortisol peak levels indicating severe impairment of cortisol production. All of these children were on a dose of 1,000 micrograms or greater. One of these six children was Calum. The other five children with severe impairment were asymptomatic at the time of diagnosis.
A further 40 % of the children showed cortisol levels which were impaired but not severely impaired with readings of between 250 and 500 nanomals. All of these children were asymptomatic except one child who remains under the care of Dr Donaldson at Yorkhill as he has not yet shown a normal response to synacthen testing, although he is no longer taking steroids regularly. None of the children had obvious cushingoid features.
Asthma
Asthma is a very common illness and in its more severe form, it is a disease that still has significant mortality.
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A definition of asthma is recurrent episodes of coughing and/or wheezing in the absence of any specific explanation. There is no single feature or test. Diagnosis is reached by building a list of a number of features until there is sufficient in the doctor's judgement to justify diagnosis.
The underlying mechanism of asthma is intermittent or variable constriction of the air passages and inflammation or irritability of the lining of the air passages.
Asthma is a condition which is predominantly treated in general practice. All general practitioners have to have skills in treating asthma. Advice and treatment on a week to week basis will come from the general practitioner. The hospital specialist integrates specialist advice and management with the treatment and frequent appointments that the patient has with the general practitioner.
Asthma in children
In the 2001 Asthma Audit compiled by the National Asthma Campaign (now known as Asthma UK) it was estimated that about one in nine children in Scotland were receiving treatment for asthma. Acute asthma is the most common single cause for admission to children's hospitals. Approximately 1% of children with asthma are seen at specialist centres.
There is a separate body of information on aspects of asthma which are specific to children as opposed to adults, such as the child's use of an inhaler and growth and development issues.
Treatment of asthma with inhaled corticosteroids
Asthma is treated by trying to firstly, dilate the bronchi and, secondly, relieve the inflammation or irritability. Inhaled corticosteroid therapy is designed to do the latter.
Corticosteroids are analogues of the body's own natural steroid hormones. They have an anti-inflammatory action and are used to treat inflammatory conditions.
Inhaled corticosteroids were developed in the early 1970s. They are used to treat asthma and other respiratory complaints in both adults and children. They are administered through an inhaler device. The drug goes to the lining of the respiratory tract and is absorbed into the cells that line the respiratory tract where it binds with the steroid receptors inside the cells. Airways inflammation is one of the key features of asthma. The anti-inflammatory action of the inhaled corticosteroids reduces inflammation in the cells lining the lungs. Reduction of inflammation of the airways reduces the likelihood of the airways becoming narrowed by asthma or other respiratory diseases.
One would expect to wait a minimum of two to four days before seeing an improvement in asthma symptoms treated with inhaled corticosteroids. Often, two to four weeks pass before any benefit is apparent. There is evidence that there is further long term improvement over months of treatment.
Step up and step down practices of prescribing inhaled corticosteroids
With the step up practice of prescribing, the patient is started at a low dose of medication and, if the patient remains symptomatic, the dose of medication is increased in stages with a view to reaching the lowest possible dose at which the patient is symptom-free. The perceived disadvantage of this system of prescribing is that the patient remains symptomatic for the period of time during which the appropriate dose is being identified. This may also potentially result in the patient losing confidence in the treatment.
In around the mid-1990s, a step down practice of prescribing began to be advocated. With the step down practice of prescribing, the patient is started at a much higher dose of medication with a view to rapidly obtaining full control of symptoms then quickly reviewing the patient with a view to reducing the therapy in stages to the lowest possible level at which the symptoms remain controlled.
Hypothalamus/pituitary/adrenal axis
There are three tiers to the adrenal axis, namely the hypothalamus, which is the gland at the base of the brain, the pituitary glands, which lie just below the hypothalamus and the adrenal glands themselves.
The hypothalamus receives messages from the higher centres and elements such as fear, excitement, illness and fever are recognised by the hypothalamus, which stimulates the pituitary glands, which in turn secrete the hormone called ACTH. This hormone then stimulates the cortisol production in the adrenal glands.
The adrenal glands are situated adjacent to the kidneys. One of the functions of the adrenal glands is to produce the steroid cortisol to assist the body in coping with what might be putting it under stress, such as infection or trauma.
Adrenal suppression/adrenal insufficiency/adrenal excess
Adrenal suppression may occur if, as a result of steroids being given (exogenous steroids), the body does not require to produce its own (endogenous) steroids in order to maintain the necessary level of hormones and, as a result, the body's ability to produce its own steroids diminishes.
If the body is unable to produce appropriate amounts of cortisol, this results in adrenal insufficiency. Insufficiency may occur when cortisol levels are not high enough for the body's needs under normal circumstances or it may occur when there is a sufficient level of cortisol to deal with normal conditions but an inability to produce sufficient cortisol to respond to stress situations.
Adrenal insufficiency may be due to genetic abnormality. It may also occur as a result of adrenal suppression due to the introduction of exogenous steroids. It may also occur due to the sudden cessation of exogenous steroids. For example, a patient who is using exogenous steroids such as inhaled corticosteroids and has adrenal suppression, may become unwell with vomiting and diarrhoea and stop using the inhaler. As the inhaler is not being used, the supply of exogenous steroids stops. At the same time, due to the stress of the illness, additional steroids are necessary. In these circumstances, adrenal insufficiency may result.
Adrenal excess can occur when the body produces too much endogenous steroids for internal reasons, for example a tumour of the adrenal glands, or it can be due to the fact that exogenous steroids have been introduced into the body. An excessive amount of cortisol can lead to features of Cushing's syndrome, which includes weight gain, increased body hair and, in children, poor growth. These features, which come about as the result of excess steroid may therefore be present both in a person whose body produces too much steroid and in a person who has been given too much exogenous steroid, as a result of which the body's endogenous steroid production is suppressed.
The more steroids are absorbed into the system the more likely is suppression of the body's own steroid production. Topical steroids, which are applied directly to the affected area, such as the skin, nose or lining of the lungs are less likely to cause side-effects than oral steroids which distribute a much larger dose of steroid to the whole body.
Synacthen test
Synacthen is short for synthetic ACTH. ACTH is the hormone produced by the pituitary glands which stimulates the adrenal glands to produce cortisol.
In a low dose synacthen test the patient is given a low dose of synthetic ACTH in order to ascertain the extent to which the adrenal glands can produce cortisol with a hormone stimulus at a natural level.
In a standard dose synacthen test the dose of hormone administered is closer to that which would be produced by the body when it is under great stress.
Off-licence prescribing of drugs
Doctors are not restricted to prescribing drugs within the dosages for which they have a licence.
Doctors may also prescribe for children drugs which are not licensed for use with children or may prescribe drugs for children who are outwith the licensed age range for that drug.
It is common for drugs to be prescribed off-licence in paediatric medicine, considerably more than in adult medicine. This is a cause for concern for paediatricians but is accepted by them as unavoidable.
Clinical need is the reason for off-licence prescribing. The clinician takes responsibility for prescribing medication off-licence for the benefit of the patient, taking the risks and benefits into consideration.
Drugs Regulation
The Medicines and Healthcare Products Regulatory Agency (MHRA) is the Government Agency responsible for inter alia approving the initial licensing of medication and, once a drug is licensed, monitoring and supervising its use. Its predecessor was the Medicines Control Agency (MCA).
The Committee on Safety of Medicines (CSM) is a Committee comprising medical specialists who advise the Government on the safety of medicines.
When new medicines are authorised, they are given a black triangle designation and the drug companies are requested to place a black triangle on the Summary of Product Characteristics (SPCs) and all promotional material, next to the name of the product, usually for two years but sometimes longer.
The yellow card scheme is a system whereby health care professionals report suspected drug reactions on a yellow card to the MHRA.
In respect of new medicines, recognised by the inverted black triangle, medical practitioners are asked to report suspected reactions, however minor, which could conceivably be attributed to the medicine, even if the reaction is well recognised or if the practitioner is unsure of the causal relationship.
In respect of established medicines, medical practitioners are asked to report serious suspected reactions, including those which are fatal, life threatening, disabling, incapacitating or which result in prolonged hospitalisation, even if the reaction is well recognised. There is no need to report minor reactions for established medicines.
The companies which market licensed medicines are required to submit safety update reports six monthly after the grant of the initial licence for the first two years, then every year for five years, then five yearly after that. The information for these safety reports comes from reports of adverse drug reactions, studies which the drugs companies have conducted and any relevant published literature.
The pharmacovigilance unit of the MHRA also examines the medical literature for details of any new clinical trials or epidemiological studies.
If a potential safety issue is identified from assessment and prioritisation of the information obtained, an assessment report is compiled by MHRA, based on all relevant data sources and this, together with recommendations and a draft of regulatory action is submitted to the CSM for consideration. After deliberation the CSM gives advice to the MHRA as licensing authority.
If the CSM is of the view that a safety issue does require to be addressed, a range of actions might be taken, including an update of the SPC and the patient information leaflet (PIL) relating to the drug, adding an adverse drug reaction to the list contained in the SPC, adding a warning containing more detail of precautions which clinicians should take, adding a contraindication for the drug or, when the risk/benefit balance is no longer positive, the licence may be varied or may be completely revoked.
When there are matters which the MHRA wishes to bring to the attention of health care professionals, this may be done in various ways including the following:
Monitoring of drug safety by the manufacturer of fluticasone
GlaxoSmithKline was represented at the inquiry as the manufacturer of the drug, fluticasone. Fluticasone was originally manufactured by Glaxo Wellcome. Subsequently, Glaxo Wellcome and Smith Kline Beecham amalgamated and the new company, which now manufactures fluticasone, is GlaxoSmithKline. The drugs company which owns the drug, fluticasone, will be referred to throughout the remainder of this determination as Glaxo, it being understood that this refers to whichever of Glaxo Wellcome or GlaxoSmithKline is the relevant company name for the appropriate time frame.
Glaxo monitors the safety of drugs through its pharmacovigilance department. That department performs a safety review every six months for the first two years after a drug has been licensed, then every year for the next two years, then every five years thereafter.
During safety reviews, the literature is searched for reports of side-effects. Case reports on side-effects or adverse events which have been submitted to the company are examined and professional expert opinions may be sought. The information obtained is submitted to the MHRA for review.
In addition, publications and reports which have a potential link to one of Glaxo's medicines are investigated.
Sources of information about drugs
When a drug is licensed, the licensing agency also issues a Summary of Product Characteristics (SPC), which summarises inter alia the diseases which the drug is suitable to treat, the licensed dose ranges, the presentations in which the drug is available and warnings about potential side-effects.
The SPC is contained within:
Information from the SPC is incorporated within:
Fluticasone
Fluticasone is an inhaled corticosteroid. It is used to treat asthma. It was produced by Glaxo Wellcome, the predecessor of GlaxoSmithKline. The brand name of the drug is Flixotide.
The other two inhaled corticosteroids are beclomethasone and budesonide. Beclomethasone is also manufactured by Glaxo.
Fluticasone has been marketed worldwide over the last ten years.
Fluticasone is considered to be more, perhaps twice as, potent as the other inhaled corticosteroids. The reasons for this which were given to the inquiry include its having a higher receptor affinity, that is, a greater attraction to the steroid receptor, and having a more rapid and prolonged lung residency, being very fat-soluble and therefore well absorbed and thereby staying on the receptor for a longer period of time.
Licensing of fluticasone
Before the licence for fluticasone was granted, Glaxo submitted a regulatory dossier to the MCA, containing information about the drug.
Flixotide, the brand name for fluticasone was licensed by the MCA in 1993 for use with adults and with children between 4 and 16 years, with 200 micrograms specified as the maximum daily dose for children.
Flixotide was available initially in two inhaler devices, namely: a metered dose inhaler, which is an aerosol device available in 25, 50, 125 and 500 microgram strengths, the latter two licensed only for use in adults; and a dry powder device known as a disk inhaler which releases the drug from a blister of powder, in 50, 100, 250 and 500 microgram strengths, the latter two doses licensed only for use in adults.
In 1995, the Accuhaler was introduced. This is another dry powder device, licensed for use in 50, 100, 250 and 500 microgram strengths, the latter two licensed for use only in adults.
The earliest SPC for fluticasone which was made available to the inquiry was the 1995 SPC for the Flixotide Accuhaler. Included in this SPC was the following information:
Under the heading "Posology and Method of Administration" and subheading "Children aged four years and over", the dosage was stated to be 50 to 100 micrograms twice daily. It was specified that 'the starting dose should be appropriate for the severity of the disease. The dose should be adjusted until control is achieved or reduced to the minimum effective dose according to individual response.' and it was further stated that 'Flixotide Accuhaler 250 micrograms and Flixotide Accuhaler 500 micrograms are not suitable for use in children'.
Under the heading "Special Warnings and Precautions for Use" it was stated that 'Adrenal function and adrenal reserve usually remain within the normal range on inhaled fluticasone propionate. However, some systemic effects may occur in a small proportion of adult patients after prolonged treatment at the maximum recommended daily dose. Patients transferred from other inhaled steroids or oral steroids remain at risk of impaired adrenal reserve for a considerable time after transferring to inhaled fluticasone propionate.'
'Patients in a medical or surgical emergency, who in the past have required high doses of other inhaled steroids and/or intermittent treatment with oral steroids, remain at risk of impaired adrenal reserve for a considerable time after transferring to inhaled fluticasone propionate....... The possibility of residual impaired adrenal response should always be borne in mind in emergency and elective situations likely to produce stress and appropriate corticosteroid treatment must be considered.'
'In children taking recommended doses of inhaled fluticasone propionate adrenal function and adrenal reserve usually remain within the normal range. Very rarely biochemical changes suggestive of systemic effects have been reported. The clinical relevance of these changes has not been substantiated and, in particular, no stunting of growth in children has been observed. The possible effects of previous or intermittent treatment with oral steroids should not be discounted. The benefits of inhaled fluticasone propionate should minimise the need for oral steroids.....'
In 1996 the drug manufacturer applied to increase the licensed dose of fluticasone for children but the application was refused by the MCA.
In 2000 a further application was made and in 2001 the MCA licensed an increase in the maximum daily dose of fluticasone for children between 4 and 16 years to 400 micrograms and a new SPC was issued in which these doses were specified.
Promotion of fluticasone
Product monograph
At the time of the launch of Flixotide the product monograph, which contained 68 references to studies or data on file, was issued by the manufacturers. This included the following information:
Under the heading "Systemic side-effects" was stated inter alia:
'Mean plasma cortisol concentrations remained within the normal range for adults and children demonstrating that, even at high doses (2,000 micrograms), fluticasone propionate is well tolerated with regard to systemic effects, When fluticasone propionate was compared with beclomethasone dipropionate, the mean serum cortisol concentrations did not decrease in any study following fluticasone propionate but was found to fall in one study during beclomethasone dipropionate 1,000 micrograms twice-daily treatment. In the substantial majority of patients, even at daily doses of fluticasone propionate of 2,000 micrograms, no adverse effect on adrenal function or reserve has been shown'.
Advertising material
This included leaflets with teddy bears, teddy bears standing beside measuring rules and slogans such as :
"Designed For Control With Safety In Mind",
"Putting A Smile On The Face Of Asthma",
"An inhaled steroid to grow up with"
"A good friend in childhood asthma "
"For children, Flixotide"
and text such as:
"Formulated with safety in mind, Flixotide combines high topical anti-inflammatory activity with negligible oral systemic availability. Flixotide is effective where it is needed in the lungs with minimal potential for steroid side-effects from the swallowed portion."
Monitoring the safety of corticosteroids, including fluticasone
The MCA assessed that some yellow card reports and also some reports in the medical literature, including Dr Todd's 1996 report in the Lancet, of suspected adrenal suppression and adrenal insufficiency, raised a safety issue which required to be addressed. Many of these reports related to very high, off-licence doses of steroids. Accordingly, in 1997 the MCA conducted a review of all the possible systemic side effects of all inhaled and nasal steroids. The review was submitted to the CSM at the beginning of 1998 and thereafter the CSM gave advice on this issue.
Representatives of Glaxo and the MCA met to discuss the MCA review in April 1998. It was agreed that changes would be made to the SPC and the PIL for fluticasone, in accordance with the advice of the CSM.
The May 1998 Current Problems in Pharmacovigilance bulletin focused on corticosteroids and recorded the advice and recommendations of the CSM following upon the MCA review.
In the bulletin, under the heading "Withdrawal of Systemic Corticosteroids", was inter alia the following:
'Topical administration of corticosteroids (e.g. inhaled) may allow disease control to be maintained while systemic corticosteroids are being withdrawn. There is evidence that inhaled corticosteroids are absorbed and that they have some systemic activity including suppression of the HPA-axis. Although this activity is less than systemically administered corticosteroids, the precise long term effects are unknown.'
Under the heading "The Safety of Inhaled and Nasal Corticosteroids" is the following:
'Many patients, both adults and children, are now prescribed inhaled and nasal corticosteroids for the prophylactic treatment of asthma and rhinitis respectively. By delivering the drugs directly to the airways, these products maximise the beneficial therapeutic effects of corticosteroids whilst minimising the adverse systemic effects. Following a review of the available evidence, we have concluded that clinically important systemic adverse effects can occur at licensed doses of these products. The risks of these effects occurring are increased following long, high dose therapy, although susceptibility to these effects varies between individuals. The risks with intranasal corticosteroids are generally lower than with inhaled steroids as the doses used in clinical practice are lower. Five main areas of concern were identified: adrenal suppression, osteoporosis or changes in bone mineral density, growth retardation in children, cataracts and glaucoma. Following our assessment of these areas the following conclusions have been reached:
The dose should be titrated to the lowest dose at which effective control of asthma or rhinitis is maintained.
Potency of corticosteroids varies between individual drug substances. Greater potency does not however necessarily equate with greater efficacy. All inhaled corticosteroids have the potential to cause systemic side effects, the frequency and severity of which will be dependent upon the dose and duration of treatment.
Systemic effects of inhaled and nasal corticosteroids may occur, particularly at high doses prescribed for prolonged periods. Possible systemic effects with inhaled corticosteroids include adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma. In children receiving nasal corticosteroids at licensed doses growth retardation has been reported.
It is recommended that the height of children receiving prolonged treatment with inhaled or nasal corticosteroids is regularly monitored. If growth is slowed, therapy should be reviewed with the aim of reducing the dose of inhaled or nasal cortisosteroid, if possible, to the lowest dose at which effective control of asthma or rhinitis is maintained. In addition, consideration should also be given to referring the patient to a paediatric specialist.
Prolonged treatment with high doses of inhaled corticosteroids, or higher than recommended doses of nasal corticosteroids may result in clinically significant adrenal suppression. Additional systemic cortisosteroid cover should be considered during periods of stress and elective surgery.
It is important to emphasis that inhaled and nasal corticosteroids provide proven, effective control of asthma and rhinitis respectively and may, in some patients, remove the necessity for oral cortisosteroid therapy. The recognition that systemic effects may occur and that the lowest effective dose should be used, does not alter the favourable risk-benefit profile of these medicines.'
In July 1998, the wording of SPC for the Flixotide Accuhaler was changed, to read as follows:
Under the heading 'Special Warnings and Precautions for Use' was stated:
'Systemic effects of inhaled corticosteroids may occur particularly at high doses prescribed for long periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma. It is important therefore that dose of inhaled corticosteroid is titrated to the lowest dose at which effective control of asthma is maintained.
It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored. If growth is slowed, therapy should be reviewed with the aim of reducing the dose of inhaled corticosteroid, if possible to the lowest dose at which effective control of asthma is maintained. In addition, consideration should be given to referring the patient to a paediatric respiratory specialist.
Prolonged treatment with high doses of inhaled corticosteroids, particularly higher than recommended doses, may result in clinically significant adrenal suppression.
Additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.'
This wording was inserted in the BNF and MIMS within nine months of the change to the SPC. This wording was also contained in the datasheet published in the Data Sheet compendium for Fluticasone for 1999/2000.
The PIL was also changed for the Flixotide Accuhaler to read as follows:
"The usual starting dose is one blister of Flixotide Accuhaler, 50 micrograms twice a day. This can be increased to one blister of Flixotide Accuhaler, 100 micrograms twice a day. This medicine is not recommended for children below four years of age."
It was also stated that: "it is very important that you keep to your doctor's instructions as to how many blisters to inhale and how often to use your Flixotide Accuhaler. Do not use more often than you are told to".
There was reference to side-effects which included the following: "In very rare instances, treatment with Flixotide Accuhaler may affect the normal production of steroids in the body. This is more likely to happen if high doses are being used over a long period of time. One of the rare effects is that children and adolescents may grow more slowly than others. Children and adolescents who are receiving treatment over a long period of time will have their height checked regularly by their doctor. Other effects are thinning of the bones and certain eye disorders known as cataracts and glaucoma. Your doctor will help prevent this by prescribing the lowest dose of steroid at which your asthma is well controlled."
In 1999, on the advice of the CSM that this information be made available to interested prescribers or scientists, the review which the MCA had carried out relating to the potential for inhaled and nasal corticosteroids to cause systemic adverse effects was published in a journal called Pharmacology and Therapeutics, Volume 83.
At the section of the review headed 'Hypothalmic-pituitary-adrenal-axis suppression in children' was stated inter alia the following:
'Discussion- From the evidence reviewed in the previous sections it is possible that HPA axis suppression may occur at currently licensed doses in children. However, the literature is far from consistent, with a number of well-designed studies showing no effect at licensed doses. However, children with severe chronic asthma are increasingly being prescribed high doses of inhaled corticosteroids to control their symptoms as an alternative to oral corticosteroids and possibly in the belief that this is a safe alternative with few system effects. At these high doses there is convincing evidence that significant adrenal suppression, with clinically relevant sequelae, occurs.
In children with early onset of asthma, and hence, early use of inhaled corticosteroids, systemic side effects are of particular concern. Alveolar development is probably complete by 18 months of age, after which, lung and body growth occurs in a highly proportional fashion. Paediatric dosage recommendations, however, often apply to children 4-16 years of age, and, therefore, there will be a greater potential for systemic activity in very young children, in whom blood volume is smaller. Assessment of the dose in terms of micrograms per squared meter per day, as opposed to absolute dose, may, therefore, provide a more valid comparison amongst young children of different ages and weights. As such, Prifits et al (1990) reported that although only one child in their study population was taking greater than 800 micrograms per day of inhaled beclamethasone, 13 were taking greater than 460 micrograms per square metre per day, which is considered the upper limit of the conventional adult dose. It is particularly important, therefore, that in children, the dose is titrated to the lowest possible dose at which effective control of symptoms is maintained.
Subsequently, the MCA carried out a review of the safety of fluticasone, in particular the balance of its risks and benefits in adult doses, particularly in the range of 1,000 to 2,000 micrograms a day. The review was prompted because of evidence of some degree of adrenal suppression at high licensed doses of fluticasone, which is licensed for adults at up to 2,000 micrograms daily. Following upon the review, an article entitled 'Reminder: Fluticasone propionate (Flixotide): use of high doses (greater than 500 micrograms twice daily)' was published by the MCA and CSM in the August 2001 bulletin of Current Problems in Pharmacovigilance.
The article stated inter alia the following:
'Different inhaled corticosteroids have different potencies. The dose required for disease control with fluticasone propionate may be lower than that required with some other inhaled corticosteroids.
New advice:
To minimise the risk of systemic adverse effects at very high doses of fluticasone propionate, the following important new advice for prescribers will be included in the product information of all fluticasone propionate inhaler products.
This advice is specific to fluticasone propionate, doses of which are higher in potency terms than equivalent doses of any other licensed inhaled corticosteroid.
......For patients with mild asthma an appropriate starting dose is 100 micrograms fluticasone propionate twice daily. In moderate and more severe asthma, starting doses may need to be between 250 to 500 micrograms fluticasone propionate twice daily.
....Due to the risk of systemic effects, doses above 500 micrograms twice daily should be prescribed only for patients with severe asthma where additional clinical benefit is expected and is demonstrated by either an improvement in pulmonary function and/or in symptom control, or by the ability to reduce oral corticosteroid therapy. Such doses should be initiated by a specialist in the management of asthma (such as a consultant physician or a general practitioner with appropriate experience).'
In 2001, after application by the drugs manufacturer, the licensed dose of fluticasone for children between 4 and 16 was increased by the MCA and the SPC was amended. The wording of the SPC for the Flixotide Accuhaler gave information regarding the new licensed dose for 'Children aged 4 years and over' namely 50 to 200 micrograms twice daily and the information contained under 'Special Warnings and Precautions for Use' remained the same as in the 1998 SPC.
Action taken in relation to fluticasone after Emma's death
On 22nd March 2002 one of Glaxo's representatives became aware of the death of a child and that the drug fluticasone might be involved. A second representative obtained a medically substantiated report around 22nd April 2002 confirming that a child had died while taking fluticasone.
Glaxo submitted a safety report to the MCA on 25th April 2002, in accordance with the requirement that a serious unexpected adverse event be submitted to the regulatory authority within 14 days.
In April 2002, the MCA was advised through the yellow card scheme of the fatal and very serious cases of adrenal suppression involving Emma and Calum Frame respectively. Around the same time, the MCA was also informed of a publication of a survey (referenced Zahra S et al Arch Dis Child 2002; 86 Suppl 1:A39) of endocrinologists and paediatricians on the extent to which adrenal suppression and adrenal insufficiency had been noted in patients receiving inhaled corticosteroids. These gave rise to concern that there may have been previous undetected or unreported cases of adrenal suppression and, in particular, a possible concern over the use of high doses of fluticasone. After an initial investigation it was decided that a full review should be carried out.
On 27 April 2002 a Glaxo medical adviser met with Dr Paton, consultant paediatrician at Yorkhill to obtain full details of the death of Emma Frame and the case of Calum Frame.
In May 2002 Glaxo wrote to the MCA suggesting that Glaxo write to all doctors in the UK to remind them of the licensed dose of Flixotide and to give appropriate advice about its use.
The representatives of the MCA and of Glaxo met in August 2002 at which the MCA asked Glaxo to provide specific information about the use of fluticasone in practice in asthma in the UK. A risk management plan was prepared, which included the distribution by Glaxo of a letter of advice and guidance to all healthcare professionals in the UK, in relation to the issue of adrenal suppression in children associated with inhaled corticosteroids, and a programme of meetings across the UK to reinforce the BTS guidelines with GPs and secondary care physicians.
An assessment report was compiled by the MCA and presented to the CSM in around September 2002. The CSM gave its advice regarding amendments to the product information for fluticasone and the advice of the CSM was summarised in the October 2002 Current Problems in Pharmacovigilance bulletin, which included the following information in an article entitled 'Inhaled corticosteroids and adrenal suppression in children':
'Adrenal suppression is a well-established adverse reaction of all inhaled corticosteroids. There have been rare reports of adrenal suppression leading to adrenal crisis. Symptoms and signs associated with adrenal suppression and crisis may be under-recognised, particularly in children receiving higher than licensed doses of inhaled corticosteroids. .........
Adrenal suppression is a dose related class effect of all inhaled corticosteroids. Adrenal crisis has been observed more frequently following the use of fluticasone, possibly because higher than licensed doses of fluticasone are prescribed more widely in children than other inhaled corticosteroids. All inhaled corticosteroids are associated with an increased risk of adrenal crisis when used at higher than licensed doses but prescribers are reminded that fluticasone should normally be used at half the dose of beclomethasone.. or budesonide because of its greater potency.
Although case reports have highlighted children taking fluticasone at higher than recommended doses, (typically greater than or equal to 1,000 micrograms/day of fluticasone) prescribers are reminded that these are dose related class effects and are strongly advised that the paediatric licensed dosages of all inhaled corticosteroids should not be exceeded.
Prescribers are reminded that:
...it is important to review therapy regularly and titrate down to the lowest dose at which effective control of asthma is mintained
....if a doctor considers that a child's asthma is not controlled on the maximum licensed dose of their inhaled corticosteroid, despite the addition of other therapies, the child should be referred to a specialist in the management of paediatric asthma.'
[The maximum licensed doses of inhaled corticosterids in children were then set out]
The letter to the healthcare professionals, which had been agreed by the MCA and GlaxoSmith Kline was sent out by Glaxo to healthcare practitioners on 20th November 2002 and was in the following terms:
'Dear Healthcare Professional
Re: Inhaled Corticosteroids and adrenal suppression in children - Current Problems in Pharmacovigilance Article
We would like to draw your attention to the recent article in the Current Problems in Pharmacovigilance. This article, which we have enclosed for your reference, discusses the issue of adrenal suppression and adrenal crisis in children following the use of higher than licensed doses of inhaled corticosteroids.
As a company we would like to highlight the following points for medicines:
the maximum licensed dosage of fluticasone propionate and beclomethasone dipropionate (CFC containing) for children in the UK is 400 mcg/day.
GlaxcoSmithKline does not endorse the use of any of its medicines at doses in
excess of those stated in the Summary of Product Characteristics.
It is important to review therapy regularly and titrate down to the lowest dose of inhaled corticosteroid at which effective control of asthma is maintained.
If a doctor considers that a child's asthma is not controlled on the maximum licensed dose of their inhaled corticosteroid, despite the addition of other therapies, the child should be referred to a specialist in the management of paediatric asthma.
All inhaled corticosteroids may cause side-effects, even at licensed doses. However, when these drugs (beclomethasone dipropionate, budesonide and fluticasone propionate) are used at doses greater than those that are licensed, the risk of side-effects is increased.
The risk of adrenal suppression and crisis in children is associated with the use of higher than licensed doses of inhaled corticosteroids.
Situations that produce metabolic stress (e.g. infection, trauma, major surgery or a sudden withdrawal of inhaled corticosteroid therapy) may precipitate adrenal crisis. The symptoms of adrenal suppression and crisis are initially non-specific such as anorexia, abdominal pain, weight lost, tiredness, headache, nausea, vomiting but can progress to include decreased level of consciousness, hypoglycaemia and seizures. Any child receiving high dose inhaled corticosteroid therapy in whom adrenal suppression and crisis is suspected should be referred for urgent medical assessment in hospital.
Prescribers should be aware that fluticasone propionate is as effective as other inhaled steroids, at half the mcg daily dose. For example, a 100 micrograms of fluticasone propionate is approximately equivalent to 200 micrograms dose of beclomethasone dipropionate (CFC containing) or budesonide.
The above guidance will be reinforced in the forthcoming BTS/SIGN asthma guidelines, which will also clearly differentiate between adults and children in terms of dosage requirements for inhaled corticosteroids.'
A telephone number was given for any questions regarding the use of fluticasone propionate in paediatric patients.
The product information for fluticasone was amended and the SPC for the Flixotide Accuhaler include the following information under the heading 'Special Warnings and Precautions for Use' :
'Prolonged treatment with high doses of inhaled corticosteroids may result in adrenal suppression and acute adrenal crisis. Children aged less than 16 years taking higher than licensed doses of fluticasone (typically equal to or greater than 1,000 micrograms/day) may be at particular risk......... '
Full references and brief summary of articles, reports and other publications referred to at the inquiry and in the determination
(N.B. Many publications were cited and quoted from in the inquiry. Detailed below are only those referred to in the determination)
(1) Issues in Chest Medicine, a publication highlighting topics arising during a two-day meeting of UK chest physicians on 28-30 January 1994
Under the heading "Fluticasone propionate: pre-clinical pharmacology" is included the following:
FP has low oral bioavailability and is effectively metabolised in the liver to an inactive metabolite. If FP does enter the circulation, either from the intestine or from the lungs, it is rapidly metabolised during the first passage through the liver and thus becomes inactive. Further, as the other inhaled corticosteroids, about 80 percent of the dose is swallowed, but very little FP is absorbed from the intestine into the bloodstream. These properties mean that the potential for systemic effects is minimised. FP has also been shown to have a high specificity for the glucocorticoid receptor.
(2) Professor George Russell, Editorial in Thorax 1994;49:1185-1188 - Inhaled corticosteroid therapy in children: an assessment of the potential for side effects
Professor George Russell, now retired, was a consultant paediatrician at Aberdeen Children's Hospital. He was at respiratory specialist with a research record in asthma and other conditions and expertise in different aspects of asthma, including its treatment.
In the introductory section of this article, Professor Russell wrote:
"In the United Kingdom both beclomethasone and budesonide are licensed for administration to children in doses of up to 400 micrograms daily and numerous studies testify to the apparent safety of such doses.... However, childhood asthma is by no means always controlled by conventional doses of inhaled corticosteroid therapy and higher doses may have to be used especially in younger children with recurrent wheeze and in children with otherwise intractable asthma."
In the section headed "Adrenal Suppression", Professor Russell wrote:
"Any papers on adrenal function in children receiving inhaled corticosteroid therapy were reassuring, reporting either no adrenal suppression or adrenal suppression only on high doses. Most recent studies have continued to offer reassurance although caution has been advised in the use of higher doses.... Adrenal stimulation tests are by no means physiological but Law et al measuring nocturnal cortisol secretion in asthmatic children receiving inhaled corticosteroid therapy reported reduced adrenal secretion, a delayed rise from the nocturnal nadir and low early morning cortisol levels.... Although these effects were more significant in higher doses, they occurred at all dosage levels, cortisol secretion being reduced on daily doses as low as 400 micrograms. Other authors have also found that relatively modest doses of inhaled corticosteroid therapy can cause adrenal suppression... There is therefore good evidence that inhaled corticosteroid therapy, even when given in normally recommended doses, can produce adrenal suppression. There is no firm evidence that any child has ever come to harm as a result of adrenal suppression induced by inhaled corticosteroid therapy.... In most stimulation studies it has been notable that basal cortisol is much more sensitive than stimulated cortisol to the effects of inhaled corticosteroid therapy. This suggests that an adequate adrenal reserve is maintained in most cases, a suggestion which has been confirmed in adults with acute severe asthma"
(3) Dr Todd et al, Article in Lancet 1996;348:27-29 - Growth and adrenal suppression in asthmatic children treated with high-dose fluticasone propionate
This article was published in the Lancet in July 1996 by Dr Geoffrey Todd and colleagues. Dr Todd gave evidence at the inquiry.
The article reported upon a study in which growth retardation was seen in six severely asthmatic children after the introduction of high-dose fluticasone propionate treatment and assessment of cortisol response was by one of three methods.
The interpretation of the results, as stated in the article, was that when high doses of fluticasone propionate are used, growth may be retarded and adrenal suppression may occur.
(4) Cade et al, Letter to The Lancet, published 21 September 1996;348:819
This letter was submitted by Alan Cade and colleagues at the Department of Paediatrics at Leeds General Infirmary in response to Dr Todd's article.
It criticises Dr Todd's study as 'anecdotal and failed to demonstrate in a scientific and controlled way the relation between growth, adrenal suppression and high dose inhaled steroids'. It hihglighted several perceived limitations to this study, including lack of data control or control patients and deficiencies in growth measurement.
(5) Lenney, Letter to The Lancet, published 21 September 1996;348:819-820
This letter was submitted by Warren Lenney of the Academic Department of Child Health at City General Hospital, Stoke-on Trent.
It criticised the methodologies and lack of statistical analysis in the Todd study.
(6) Paper entitled 'Adrenal Suppression With Inhaled Budesonide And Fluticisone Propionate Given By A Large Volume Spacer to Asthmatic Children', Thorax, September 1996, by Clark, Clark and Lipworth.
The results of this study were summarised as follows:
"The results of the study show that when given by large volume spacer to asthmatic children single inhaled doses of fluticisone propionate of 400 to 1250 micrograms produces suppression of urinary cortisol compared with a placebo whereas corresponding doses of budesonide do not".
The conclusion of the study included following:
"Our study provides clear evidence of adrenal suppression with single doses of inhaled fluticisone propionate given by spacer to asthmatic children. It is likely that with repeated dosing the differences between fluticisone and budesonide would be greater due to the longer plasma half-life and receptor binding affinity as well as enhanced systemic tissue retention for fluticisone than for budesonide. Further chronic dose ranging studies are now indicated to resolve this issue."
(7) Article entitled "Drug companies criticised for exaggeration", published in BMJ volume 318, dated 10 April 1999
This article reported that complaints against pharmaceutical companies for breaching the industry's voluntary advertising code of practice remained at high levels in 1998, according to a report from the Prescription Medicines Code of Practice Authority.
One of the examples referred to in the article was as follows: "A consultant chest physician took Glaxo to task for claiming that fluticasone (Flixotide) given at half the daily dose of budesonide was more effective than budesonide at improving morning peak flow. His complaint was upheld."
(8) Brutsche et al, the Lancet, 12 August 2000; Comparison of Pharmacokinetics and
Systemic Effects of Inhaled Fluticasone Propionate in Patients with Asthma and Healthy Volunteers: A Randomised Cross-over Study
This was a double blind, randomised, cross-over study in eleven patients with asthma and thirteen matched healthy controls, receiving 1,000 micrograms intravenous dose or 1,000 micrograms daily for seven days inhaled fluticasone propionate, with monitoring of plasma fluticasone propionate and cortisol concentrations.
Under the heading "Interpretation" was the following:
Systemic availability of fluticasone propionate is substantially less in patients with moderate to severe asthma than in healthy controls. Inhaled cortisosteroids that are absorbed through the lungs need to be assessed in patients who are receiving doses appropriate for decease severity, and not in normal volunteers.
(9) Paper entitled "Dose response relation of inhaled fluticisone propionate in adolescents and adults with asthma: meta-analysis", by Holt et al published in the British Medical Journal, on 4 August 2001
The conclusion in this paper is that:
In adolescent and adult patients with asthma most of the therapeutic benefit of inhaled fluticasone is achieved with a total daily dose of 100 to 250 micrograms and the maximum effect is achieved with a dose of around 500 micrograms a day. However, these findings were limited by the lack of data on individual patients and by the paucity of dose-response studies that included doses of greater than 500 micrograms per day.
A commentary was written on this paper by Andrew Herxheimer entitled "Dosage needs systematic and critical review". Included in this commentary were the following observations:
'With any new drug that has therapeutic activity an appropriate dosage regimen must be worked out from a clear understanding of the pharmacokinetics and the dose response relation. ...
Why did it take until now, from the first marketing of fluticasone in 1993, to discover that the maximum useful dosage from most cases is only about half of that hitherto recommended by guidelines and the manufacturer? ...
My guess is that the scientists at GlaxoWellcome (sponsor of the trials in the meta-analysis) and at the Medicines Control Agency and the clinicians and academics working on asthma had not appreciated the need for and value of systematic reviews and appropriate meta-analysis."
(10) Patel et al: Symptomatic adrenal insufficiency during inhaled corticosteroid treatment, Arch. Dis. Child. 2001; 85: 330-4, and commentary by Professor Russell
This article describes 8 children, 5 of whom had received fluticasone in doses of 500-1,000 micrograms daily (one of whom had received another inhaled steroid previously) and 3 of whom were on other inhaled steroids. 3 children had dosages of 500 micrograms fluticasone daily, 1 child had a dosage of 1,000 micrograms of fluticasone daily, 1 child had previously been prescribed 400 micrograms of budesonide daily and was then prescribed a dose of 500 micrograms of fluticasone daily, 2 children were receiving a licensed dose of 400 micrograms of budesonide daily and one was receiving a licensed dose of 600 micrograms of beclomethasone daily. Six of the children had impaired cortisol response levels in standard dose synacthen testing and 2 children did not have stimulation testing but did have low cortisol levels.
Professor George Russell's commentary states inter alia:
".....A common feature in reports from the mid-1980s onwards has been dose related adrenal suppression, a side-effect that has generally been regarded as benign, representing nothing more than a physiological response to exogenous corticosteroid. Clinical symptoms of hypoadrenalism have not appeared to be a problem. It is therefore surprising that after more than a quarter of a century's relatively trouble free use of ICS, Patel et al should report no fewer than eight cases of clinically significant adrenal suppression in children on ICS therapy.
.... We can only guess the prevalence of clinically significant adrenal suppression in children on inhaled corticosteroids but clearly we can no longer claim that it is non-existent, nor can we be sure that the distribution of the individual corticosteroid molecules used by these children is anything other than a child's phenomenon. The authors are rightly cautious in refusing to comment but it can hardly pass unnoticed that only one of these 8 children was on beclomethasone whereas the others were on what is sometimes described as second or even the third generation inhaled corticosteroids. Beclomethasone was the first and is still the most widely used inhaled corticosteroid in the United Kingdom. In England in 1998, 8.43 million National Health Service prescriptions were filled for beclomethasone compared to only 1.88 million of budesonide and 1.54 million of fluticasone. We too are cautious in our interpretation of these proportions but await with interest further reports of inhaled corticosteroid related adrenal suppression. So what are the conclusions to be drawn from this report? In our current state of knowledge it would be quite wrong to suggest a major change in established practice. Inhaled corticosteroid treatment has been of immense value to literally millions of children and other anti-asthma therapies best regarded as steroid sparing rather than a true alternative to inhaled corticosteroids. Nevertheless, we should review our practice and pay more attention to existing recommendations on the importance of stepping down as well as stepping up inhaled corticosteroids and as everyone must be constantly vigilant to unforeseen side-effects in even the best established drugs. Whatever else we do, we must not panic and endanger the lives of the countless children whose respiratory and endocrine systems coexist happily on inhaled corticosteroids."
(11) National Asthma Campaign, Asthma Audit 2001; "Out In The Open, A True Picture Of Asthma In The United Kingdom Today": The Asthma Journal, Special Supplement, September 2001
This paper is a summary of information about asthma in the UK from an audit compiled in 2001 and produced by the National Asthma Campaign (now known as Asthma UK).
Under the heading 'Mortality' is stated inter alia:
'... around 1500 people still die from asthma each year in the UK.'
(12) Asthma Audit 2001 Summary: Scotland; Factsheet 40, Updated February 2003
This paper provides a summary of data relating to Scotland from the 2001 National asthma campaign audit .
Under the heading 'How many people in Scotland have asthma?' is stated inter alia:
'Statistics from the recent Scottish Health Survey indicate that there are 400,000 people receiving treatment for asthma: 1 in 15 adults and 1 in 9 children. We estimate that 636,000 people in Scotland will be diagnosed with asthma at some point in their lives'.
Under the heading 'How many people die from asthma?' is stated inter alia:
'Over 1200 people died from asthma in Scotland between 1990 and 1999 of which 43 % were under the age of 65'.
(13) National Asthma Campaign, Asthma Audit 2002; "Starting As We Mean To Go On": An Audit Of Children's Asthma In The UK": The Asthma Journal, Special Supplement, May 2002
This document was produced by the National Asthma Campaign.
Under the heading 'Prevalence' is stated inter alia:
Respiratory disease is the most commonly reported long term illness in children accounting for over 40% of all long term illnesses' and
'Over 80 % of long-term respiratory illnesses (and nearly a third of all long-term illnesses) in childhood are due to doctor-diagnosed asthma'.
(14) Todd et al (also referred to as Zahra et al): Survey of adrenal crisis associated with inhaled corticosteroids in the United Kingdom, Arch Dis Child 2002;87:457-461, and commentary by Professor Russell
This paper reports upon a UK survey of 3000 patients of whom 33 were identified as having acute adrenal insufficiency. Of those 33 patients, 30 were on fluticasone. 80% of the 33 patients were being prescribed within the dosages set out in the BTS guidelines. Under the heading 'Methods' is stated:
Questionnaires were sent to all consultant paediatricians and adult endocrinologists registered in the UK Medical Directory asking whether they had encountered asthmatic patients with acute adrenal crisis associated with ICS. Those responding positively completed a more detailed questionnaire. Diagnosis was confirmed by symptoms/signs with normal hypothalmic pituitary adrenal axis function test results.
Professor Russell wrote an editorial in which he referred to this study and in which he said inter alia:
'...... complacency was shattered with the publication of the three papers describing acute adrenal failure cited by Todd et al. These papers were multi-author and multi-centre and did not give the reader a feel for the frequency of this complication. This deficiency has now been remedied by Todd et al...who in addition to showing that this problem is alarmingly common have also implicated fluticasone propionate (FP) the least frequently prescribed form of ICT in the great majority of their cases ....
What are the implications for the practising clinician? The findings of this survey cannot be ignored but nor should they be used for an excuse for a further outbreak of steroid phobia. Nevertheless, there are implications both for patients already on high dose FP and for those for whom this therapy is contemplated.'
(15) Cochrane Review: Inhaled fluticasone versus inhaled beclomethasone or inhaled budesonide for chronic asthma, published in: The Cochrane Library, Issue 3, 2004. Chichester, UK
The objective of this review was to compare the efficacy and safety of fluticasone to beclomethasone or budesonide in the treatment of chronic asthma.
The review carried out a meta-analysis of randomised trials in children and adults comparing fluticasone to either beclomethasone or budesonide in the treatment of chronic asthma in a dose ratio of 1:2, i.e. using fluticasone at half the microgram dose of budesonide or beclomethasone.
Fluticasone was found to produce a significantly greater improvement in lung function in all drug doses, age groups and delivery services although subgroup analysis suggested that the relative benefit of fluticasone may be greater in more severe patients treated with higher doses of inhaled corticosteroid. No difference between fluticasone and beclomethasone or budesonide were seen for trial withdrawals. A higher likelihood of pharyngitis was apparent when patients were treated with fluticasone at twice the dose of beclomethasone or budesonide.
FINDING IN TERMS OF SECTION 6(1)(a): WHERE AND WHEN EMMA'S DEATH TOOK PLACE
All parties were agreed that a finding should be made in terms of section 6(1)(a) that Emma died at 4.35 am on 24 November 2001 at Wishaw General Hospital, Wishaw.
Dr Catherine Lees, consultant paediatrician at Wishaw General Hospital, testified to this and her evidence was supported by Emma's hospital case notes. Emma's father, Mr Stuart Frame, also gave evidence regarding the place and time of Emma's death. He agreed with the procurator fiscal's proposition that the time of death was 4.45 am but I accepted the evidence of Dr Lees, who certified Emma's death, in relation to this detail.
FINDING IN TERMS OF SECTION 6(1)(b): THE CAUSE OR CAUSES OF EMMA'S DEATH
I was invited by the procurator fiscal and those representing the NHS, Glaxo and the MHRA to find that the cause of Emma's death was adrenal insufficiency due to inhaled steroid therapy prescribed for her chronic asthma, as concluded by Dr Howatson and set out in his letter to the procurator fiscal of 5 April 2002.
Mrs Dougal agreed that this finding should be made and submitted that an amendment to this effect should be made in Emma's death certificate, as this has not yet been done, despite Dr Howatson's recommendation in his letter of 5 April 2002.
Mr Holmes said that none of the skilled witnesses who gave evidence at the Inquiry took issue with the finding as to cause of death as set out by Dr Howatson in his letter to the procurator fiscal of 5 April 2002 and he expected that the Inquiry's determination as to the cause of Emma's death would be to that effect. However, he submitted that such a finding should be subject to appropriate qualification to reflect the unique circumstances of Emma's death, her atypical presentation and the incomplete understanding of the mechanisms that led to her death. He referred to the fact that Dr Howatson had said in evidence that he had been able to undertake about 80 percent of his investigations, that only about 10 percent of the brain substance had been sampled and that it is recognised that limited examinations can miss encephalopathic or inflammatory changes elsewhere. He also referred to the fact that in his evidence Dr Howatson expressed the mistaken belief that Calum recovered without Acyclovir, the standard therapy for encephalitis.
I have given full consideration to the evidence relating to Mr Holmes's submission that the finding as to the cause of Emma's death should be subject to certain qualifications.
The evidence regarding the cause of Emma's death came principally from Dr Howatson and Dr Donaldson.
Dr Howatson confirmed that his conclusion regarding cause of death was based on the fact that Emma's presentation was consistent with that of her brother whose chemical results, clinical presentation and proven adrenal suppression led clinicians to conclude that he had been suffering from adrenal insufficiency due to inhaled steroid therapy. He agreed that, in reaching this conclusion, the results of his post-mortem examination of Emma were inconsistent with what he would normally expect to find in a case of adrenal suppression.
Dr Howatson and the colleagues whom he consulted were of the view that the results of Emma's blood tests carried out at Wishaw General Hospital were not diagnostic of adrenal insufficiency. Dr Howatson said that, at the time he prepared his second report, on 8th February 2002, while he may have had some suspicion that adrenal suppression was involved, he had no evidence of this. In fact, the evidence which he had was contrary to this conclusion.