Gary Ash

Our ref: 

Ms Nadia Persaud 
Area Coroner 
East London Coroner’s Court 
Queens Road 
Walthamstow  
E17 8QP 

By email: 

Dear Ms Persaud, 

Minister of State for Health 

39 Victoria Street 
London 
SW1H 0EU 

08 August 2024 

Thank you for the Regulation 28 report to prevent future deaths of 15 May 2024 about the 
death of Mr Gary David Ash. I am replying as Minister of State for Health (Secondary Care). 

Firstly, I would like to say how saddened I was to read of the circumstances of Mr Ash’s 
death, and I offer my sincere condolences to their family and loved ones. The circumstances 
your report describes are concerning and I am grateful to you for bringing these matters to 
my attention.  

The report raises concerns over: 

•  Management  of  the  condition  neuroleptic  malignant  syndrome,  including  the 

inappropriate, off licence, use of Dantrolene; 

•  The role of Dantrolene in the development of pulmonary oedema in the presence of 

intravenous fluid overload;  

•  The  potential  interaction  between  Dantrolene  and  Labetalol  in  relation  to  the 

reduction of cardiac contractility; 

•  The lack of knowledge around the diagnosis of serotonin syndrome and the risk of it 
developing  following  the  combined  use  of  Fentanyl  and  Ondansetron  as  part  of 
anaesthesia. 

In preparing this response, Departmental officials have made enquiries with the Medicines 
and Healthcare products Regulatory Agency (MHRA), NHS England and the Care Quality 
Commission (CQC). 

In your report, you raised a concern regarding the lack of knowledge around the diagnosis 
of serotonin syndrome and the risk of it developing, following the combined use of 
Fentanyl and Ondansetron as part of anaesthesia. 

The Medicines and Healthcare products Regulatory Agency (MHRA) is an Executive Agency 
of the Department of Health and Social Care (DHSC) with responsibility for the regulation of 
medicinal  products  in  the  UK.  The  MHRA  ensures  that  medicines  are  efficacious  and 

 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
  
 
 acceptably safe, and that any possible side effects which have been recognised to occur 
with use of a medicine are appropriately described in the authorised product information. 

Information  from  MHRA  advises  that  serotonin  syndrome  and  neuroleptic  malignant 
syndrome (NMS) share similar symptoms, and as a result serotonin syndrome has generally 
been  under-diagnosed.  Serotonin  syndrome  is  caused  by  the  increased  activation  of 
serotonin receptors found in nerve synapses (in which nerve cells connect with other nerve 
cells),  whereas  NMS  is  more  closely  associated  with  dopamine  activity.  Diagnosis  of 
serotonin syndrome was not universally harmonised until 2003 with the introduction of a set 
of diagnostic criteria known as Hunters Serotonin Toxicity Criteria. The diagnostic criteria 
include altered mental status, neuromuscular excitation and dysfunction of the autonomic 
nervous  system  which  controls body  systems  including  the  heart, respiratory and  urinary 
systems. These effects can typically occur rapidly within 1 to 6 hours after exposure to a 
relevant trigger. A similar feature of NMS relating to rigidity is reported only to occur several 
days after exposure to medication. It can be more difficult to diagnose serotonin syndrome 
in a patient under general anaesthesia because the signs and symptoms are similar to other 
perioperative conditions. 

The  MHRA  has  also  provided  information  regarding  Serotonin  Syndrome  warnings  in 
medicinal  product  information.  The  Summary  of  Product  Characteristics (SmPC)  is  a 
summary  of  a  medicinal  product’s  properties  and  the  conditions  for  use,  written  for 
healthcare professionals and is available online on the MHRA website and in the Electronic 
Medicines Compendium (EMC). The use of opioids such as fentanyl and the risk of serotonin 
syndrome when used concomitantly with serotonergic medicines is known and highlighted 
within the fentanyl Summary of Product Characteristics (SmPC).  

The  warning  was  added  to  the  SmPC  for  fentanyl  medicinal  products  across  Europe 
including  in  the  UK  by  the  European  Medicines  Agency’s  Pharmacovigilance  Risk 
Assessment Committee (PRAC) in 2015. Whilst the warning does not specifically refer to a 
potential  for  interaction  between  fentanyl  and  ondansetron,  it  should  be  noted  that 
ondansetron is a serotonin receptor blocker and will prevent the binding of serotonin to its 
receptor resulting in excess synaptic serotonin. This makes an interaction between fentanyl 
and ondansetron potentially biologically plausible. 

A  warning  is  also  included  in  the  patient  information  leaflet  provided  with  all  fentanyl 
medicines  advising  patients  to  inform  their  healthcare  professional  if  they  are  taking  any 
antidepressants, especially those similar to serotonergic medicines including SSRIs, SNRIs 
or MAOIs. Patients who are using fentanyl patches are also advised to tell their doctor if they 
are  going  to  have  an  operation.  This  enables  health  care  professionals  to  be  aware  of 
possible signs of serotonin syndrome which can be more difficult to diagnose in a patient 
under general anaesthesia.  

The risk of serotonin syndrome when used in combination with serotonergic drugs is also 
highlighted in the SmPC for ondansetron. 

One SmPC (PL 04569/0656) for ondansetron that was harmonised with its licence in Ireland 
in June 2020, contains the additional warning: 

There are also reports of serotonin syndrome when ondansetron is used concomitantly with 
opioid/opiate medicines, e.g. buprenorphine.  

 
 
 
 
 
 
 The British National Formulary (BNF) is a joint publication of the British Medical Association 
and the Royal Pharmaceutical Society and aims to provide prescribers, pharmacists, and 
other  healthcare  professionals  with  up-to-date  information  about  the  use  of  medicines. 
Information is drawn from the manufacturers' product literature, medical and pharmaceutical 
literature, UK health departments, regulatory authorities, and professional bodies and advice 
is constructed from clinical literature and reflects, as  far as possible, an evaluation of the 
evidence from diverse sources.  

The  BNF  also  takes  account  of  authoritative  national  guidelines  and  emerging  safety 
concerns, in addition, to receiving advice on all therapeutic areas from expert clinicians to 
ensure that the BNF's recommendations are relevant to practice. 

The interaction between fentanyl and ondansetron is included in the BNF under interactions 
for both ondansetron and fentanyl Ondansetron | Interactions | BNF | NICE.  

The  MHRA’s  Yellow  Card  Scheme  primarily  acts  as  an  early  warning  system  for  the 
identification  of  previously  unrecognised  adverse  reactions  and  also  provides  valuable 
information  on  recognised ADRs,  allowing  the  CHM  and  MHRA  to identify  and  refine  the 
understanding of risk factors that may affect the clinical management of patients.   

Up  to  21  May  2024,  two  Yellow  Card  reports  of  suspected  serotonin  syndrome  with 
concomitant  use  of  fentanyl  and  ondansetron  are  on  the  MHRA  Yellow  Card  database. 
However,  neither  report  provides  sufficient  information  to  enable  confirmation  that  the 
serotonin syndrome resulted from a fentanyl-ondansetron interaction in either patient. The 
MHRA will continue to undertake signal detection on its database of reports. 

Getting  It  Right  First  Time  (GIRFT)  is  a  national  programme  designed  to  improve  the 
treatment  and  care  of  patients  through  in-depth  review  of  services,  benchmarking,  and 
presenting a data-driven evidence base to support change. GIRFT is part of an aligned set 
of programmes within NHS England. 

The GIRFT Pre op team have advised that due to the limited information on what anaesthetic 
was used, what happened and the time scale of the event, it would be difficult to comment. 
They have also advised that Serotonin syndrome and malignant hyperpyrexia (MH) are both 
rare. These conditions have similar symptoms. When they precipitate a life-threatening crisis 
there is no simple test available to make a certain diagnosis. It can be made retrospectively 
for MH.  

I  understand  that  the  Barking,  Havering  and  Redbridge  University  Hospitals  NHS  Trust 
contacted Mr Ash’s next of kin last year, which outlined the progression of actions at that 
point.  

Further to  this,  NHS  England  has  contacted the  Trust  for any  further developments.  The 
Trust has stated that at the time of this incident, they did not have dedicated deep sedation 
lists for endoscopy. This has now changed, and it now offers deep sedation  only for these 
procedures. There are regular deep sedation lists which are in place since this incident. This 
is  provided  by  anaesthetists  who  have  the  required  expertise.  There  is  a  deep  sedation 
standard  operating  procedure  in  place  to  ensure  this  procedure  is  conducted  safely. 
Additionally, the consent process is more robust and learning from this incident was shared 
across the division. 

 
 
 
 
 
 
 Following  receipt  of  the  Prevention  of  Future  Deaths  report  for  Mr  Ash,  the  CQC  also 
contacted Barking Havering and Redbridge University Hospitals NHS Trust to follow up the 
concerns raised. The Trust provided an action plan which addressed 22 specific points. The 
majority  of  actions  related  to  improvements  in  clinical  governance,  such  as  policies  and 
processes,  and  these  have  been  completed.  There  are  some  actions  that  remain  in 
progress, and the CQC has, I understand asked the Trust for a further update.  

The  wider  questions  regarding  assurance  will  be  explored  through  the  CQC’s  ongoing 
engagement with the Trust and the CQC will continue to monitor their progress.  

I hope this response is helpful. Thank you for bringing these concerns to my attention.   

Yours sincerely, 

MINISTER OF STATE FOR HEALTH

10 July 2024 

Dear Miss Persaud, 

Re: Regulation 28: Report to Prevent Future Deaths in the matter of Mr Gary Ash 

Thank you for sending us a copy of your Regulation 28 Report regarding the sad death of Mr Gary Ash. We 
have jointly reviewed the information available to us in the report via our Safe Anaesthesia Liaison Group 
(SALG). SALG is a collaborative project between the Association of Anaesthetists, NHS England’s Patient 
Safety team and the Royal College of Anaesthetists. One of its core objectives is to analyse anaesthesia-
related serious incidents and to share the learning with the specialty across the UK. We have also reviewed 
the information available with the Faculty of Intensive Care Medicine (FICM). 

Your prevention of future death report raised concerns regarding the general medical knowledge regarding 
the recognition and treatment of neuroleptic malignant syndrome and serotonin syndrome. While both 
conditions are very rare, and anaesthetists may expect to go their entire career without treating either 
condition, we can confirm that anaesthetists and intensivists are taught about these conditions as part of their 
post-graduate training1,2,3. You specifically highlight knowledge of the “diagnosis of serotonin syndrome and 
the risk of it developing following the combined use of Fentanyl and Ondansetron as part of anaesthesia.” 
This combination of drugs is commonly used in anaesthetic practice and the very small risk of developing 
serotonin syndrome is clearly flagged in many electronic prescription programs, as well as being part of 
anaesthetic training. 

SALG publishes regular Patient Safety Updates, which are distributed to all members of the Association of 
Anaesthetists and Royal College of Anaesthetists. FICM publishes regular Safety Bulletins, which are distributed 
to all their members. We plan to use both publications to highlight the lessons to be learned from Mr Ash’s 
death, in particular highlighting educational material relating to the treatment of neuroleptic malignant 
syndrome and serotonin syndrome. 

We would be happy to respond to any questions that you might have. 

Yours Sincerely 

President,  
Royal College of Anaesthetists 

President 
Association of Anaesthetists 

Dean 
Faculty of Intensive Care Medicine

References 
1.  Bartakke, A. et al, Serotonin syndrome in the perioperative period, BJA Education, 20(1): 10e17 (2020) 

https://doi.org/10.1016/j.bjae.2019.10.003  

2.  Adnet, P. et al, Neuroleptic malignant syndrome, British Journal of Anaesthesia 85 (1): 129-35 (2000) 

https://doi.org/10.1093/bja/85.1.129 

3.  Baldo, B. and Rose, M., The anaesthetist, opioid analgesic drugs, and serotonin toxicity: a mechanistic 

and clinical review. British Journal of Anaesthesia, 124 (1): 44e62 (2020) 
https://doi.org/10.1016/j.bja.2019.08.010