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CRITICAL CARE
Organophosphorus nerve agent poisoning: managing the poisoned
patient
Elspeth J. Hulse
1
,
2
,
*
, James D. Haslam
3
, Stevan R. Emmett
4
and Tom Woolley
2
1
Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK,
2
Academic Department of Military
Anaesthesia and Critical Care, RCDM, Birmingham, UK,
3
Anaesthesia and Intensive Care Medicine, Salisbury NHS
Foundation Trust, Salisbury, UK and
4
Defence Science and Technology Laboratory, Wiltshire, UK
*Corresponding author. E-mail: e.hulse@nhs.net
Summary
Organophosphorus (OP) nerve agent poisoning made the headlines in 2018 with the nerve agent ‘Novichok’poisonings in
Salisbury, England. This event highlighted a gap in the knowledge of most clinicians in the UK. In response, this special
article aims to enlighten and signpost anaesthetists and intensivists towards the general management of OP nerve agent
poisoned patients. Drawing on a broad range of sources, we will discuss what OP nerve agents are, how they work, and
how to recognise and treat OP nerve agent poisoning. OP nerve agents primarily act by inhibiting the enzyme acetyl-
cholinesterase, causing an acute cholinergic crisis; death usually occurs through respiratory failure. The antimuscarinic
agent atropine, oximes (to reactivate acetylcholinesterase), neuroprotective drugs, and critical care remain the mainstays
of treatment. The risk to medical staff from OP poisoned patients appears low, especially if there is a thorough decon-
tamination of the poisoned patient and staff wear appropriate personal protective equipment. The events in Salisbury in
the past year were shocking, and the staff at Salisbury District General Hospital performed admirably in treating those
affected by Novichok nerve agent poisoning. We eagerly anticipate their future clinical publications so that the medical
community might learn from their valuable experiences.
Keywords: acetylcholinesterase; atropine; nerve agents; neurotoxin; organophosphate poisoning; Novichok; pralidoxime;
Sarin
For the average anaesthetist, tales of human nerve agent
poisoning are the subject of elaborate blockbuster movies or
something that happens elsewhere. That was until March 4,
2018, when a father and daughter were found slumped on a
bench in Salisbury, UK and taken to hospital with unexplained
symptoms. The poison responsible, Novichok, is a Soviet-
designed organophosphorus (OP) nerve agent and the criminal
case is ongoing.
1,2
Many healthcare professionals have since
been asking the following questions: What are nerve agents?
How do I recognisenerve agent poisoning? Howdo I treat it? And
what do I need to know about it to protect myself and my staff?
This review article aims to help answer some of these
questions and provide a handrail upon which to understand,
recognise, and treat nerve agent poisoning. Further references
Editor’s key points
Organophosphorus nerve agent poisoning remains rare,
but clinicians should ensure familiarity with toxidrome
recognition and treatments.
The mainstay of treatment for organophosphorus nerve
agent poisoning remains decontamination, atropine,
oximes, neuroprotection, and good quality critical care
(if required).
Lessons learned from the Salisbury Novichok
poisonings will help inform future guidelines on the
management of organophosphorus nerve agent
toxicity.
Editorial decision 05 April 2019; Accepted: 5 April 2019
Crown Copyright ©2019 Published by Elsevier Ltd on behalf of British Journal of Anaesthesia. All rights reserved.
For Permissions, please email: permissions@elsevier.com
457
British Journal of Anaesthesia, 123 (4): 457e463 (2019)
doi: 10.1016/j.bja.2019.04.061
Advance Access Publication Date: 24 June 2019
Review Article
are provided for those who wish to know more. When it comes
to human nerve agent poisoning, there are no well-designed
cohort studies of treatments and prospective randomised
controlled trials are ethically unacceptable. Much of our
knowledge has come from animal translational medicine
studies,
3
retrospective analysis of those exposed to these
substances through violence, accidental exposure, and a
number of micro-dosing studies in human volunteers.
4,5
Recently, there have been a number of articles relating to
nerve agent poisoning and the Salisbury incident in particular.
Only one group, Salisbury District General Hospital, and those
who assisted them, have the relevant, recent, and accurate
clinical information.
Background
It has been almost 20 yr since the previous (and still relevant)
specific clinical review of OP poisoning and anaesthesia. This
comprehensive paper by Karalliedde in 1999
6
was written
during a time when self-poisoning by drinking pesticide (much
of which contained OP chemicals) was more common,
particularly in the rural Asia Pacific region, in which 200,000
people died annually.
7
In contrast, deaths from nerve agent
poisoning during the same period have been rare. Saddam
Hussein used Sarin and Tabun in Iraq in the 1980s,
8
and the
Aum Shinrikyo doomsday cult in Japan used homemade Sarin
in two local attacks during the mid-1990s.
5
In the past 5 yr,
however, nerve agents have been used more frequently. In
Syria, weaponised Sarin (Sarin delivered by rockets) has
allegedly been used on multiple occasions, killing hundreds
through inhalational poisoning and
9,10
VX has allegedly been
used in an assassination attempt. Last year in Salisbury, UK,
six individuals were investigated for exposure to topical Nov-
ichok, which resulted in one death.
1
What are organophosphorus nerve agents?
Nerve agents are chemically related to OP insecticides and
include the G agents (GA [Tabun], GB [Sarin], GD [Soman], GF
[Cyclosarin]), the V agents (VX, methylphosphonothioic acid)
and the newer, less well understood agents including those
named ‘Novichok’, meaning ‘newcomer’in Russian.
How do organophosphorus nerve agents
work?
Nerve agents are usually systemically absorbed through the
inhalation or topical route and primarily act by inhibiting the
enzyme acetylcholinesterase (AChE), which is found in the
cholinergic synapses of the nervous system, neuromuscular
junction (NMJ), lung,
11
and red cell membrane. Many factors
also cause significant inhibition of other esterases including
butyrylcholinersterase (BuChE) found in the blood and tis-
sues.
5
Experience extrapolated from OP pesticide poisoning is
often limited to the ingestion route, and the efficacy of toxicity
is dependent on the physical properties of the agent, lipophilic
nature, method of exposure, and means of delivery.
The inhibited AChE cannot terminate normal neuronal/
neuromuscular transmissions by metabolising the acetylcho-
line in the synapse. This causes an increase in acetylcholine
(ACh) in the synapses with corresponding excess cholinergic
activity in the central, peripheral, and autonomic nervous
systems. The route of exposure and physical properties of the
agent will determine the speed of onset and the set of
symptoms experienced. Central effects include agitation, loss
of consciousness, loss of respiratory drive, and seizure activ-
ity. Autonomic muscarinic effects produce miosis, salivation,
bronchospasm, bronchorrhea, bradycardia, nausea, vomiting,
diarrhoea, and urination, although symptoms and signs vary
depending on the agent, route of exposure, and dose. Auto-
nomic nicotinic effects can produce tachycardia, hyperten-
sion, and sweating. Effects on the nicotinic receptors at the
NMJ can cause fasciculations and muscle weakness, and lead
to a depolarising block with flaccid paralysis.
12
Severe
poisoning, without medical intervention, produces death pri-
marily through respiratory failure via a combination of the
above mechanisms.
13
The OP compound binds to the serine residue (through
phosphorylation) of the AChE molecule. Oximes can reactivate
the AChE by catalysing the removal of the phosphoryl group.
The main therapeutic effect of this is to restore neuromuscular
transmission at the nicotinic synapses.
14
However, if the OP
compound is not removed through a process of spontaneous
or assisted (oxime) reactivation, an R-alkyl group will become
permanently removed and render the enzyme non-
reactivatable or ‘aged’. Time to ageing is dependent on the
specific OP nerve agent: Soman will cause demonstrable
ageing in 2 min, whereas Sarin and VX will take 5 and >40 h,
respectively.
15
Once an AChE molecule is ‘aged’, treatment
with oximes may not work; this is discussed below.
Recognition of organophosphorus nerve
agent poisoning
In the event of a large-scale chemical attack scenario, it is
likely that the majority of victims seeking medical attention
will self-present, with the most severely poisoned arriving by
ambulance. For example, of the 640 patients that presented to
the main receiving hospital after the Sarin poisonings in Japan,
541 self-presented with assistance from non-medical motor-
ists and 64 arrived by ambulance.
16
Similarly, the more severe
cases of suspected Novichok poisonings were brought in by
ambulance and the milder cases self-presented.
Lungs and eyes will absorb nerve agent rapidly, especially if
the agent has been aerosolised or is a vapour. Patients will
almost always present with miosis and some degree of auto-
nomic secretions. If the exposure dose is significant, then
systemic effects will occur. Nerve agents, such as Sarin, are
odourless, but are often mixed with other chemicals. For
example, the homemade Sarin in Japan had an ‘aromatic’or
‘unpleasant’odour.
16
Other clues that a toxic event has
occurred include unexplained dead animals at the scene and
people seeing ‘clouds’or ‘mists’of gas. Percutaneous exposure
may cause symptoms to be delayed, and casualties may pre-
sent with more systemic and ‘central’features first, poten-
tially with minimal, localised, respiratory tract features.
The moderately and severely poisoned patients will likely
present in a stupor, with reduced consciousness, pinpoint
pupils, and respiratory compromise. Clinicians might
initially suspect an opioid overdose. However, further clues
such as the circumstances in which the patient was found;
their dress; lack of drug-taking markings and paraphernalia;
and more than two or three patients with similar symptoms
might lead to a different conclusion. Where there is doubt,
initial management with naloxone is justified but with a
raised index of suspicion for OP nerve agent if high dose
opioid reversal is ineffective. Key to the effective
458
-
Hulse et al.
management of the chemical casualty is to follow the CBRN
(chemical, biological, radiological, and nuclear) ‘chain of
survival’with early toxidrome recognition, timely antidotes,
effective decontamination, and a swift transfer to hospital
for advanced medical care (Fig. 1).
Decontamination
The Organisation for the Prevention of Chemical Weapons
(OPCW) treatment handbook
8
draws on previous human poi-
sonings and the recent experiences from Sarin OP poisoning in
Syria. They stress the importance of decontamination to pre-
vent ongoing poisoning of the patient and to protect other
patients and staff members who are in close proximity to the
poisoned patient. The type and level of decontamination will
depend on the physical properties of the agent, if known, as
well as the route of exposure. If a patient has life-threatening
injuries such as airway compromise or life-threatening cata-
strophic haemorrhage, then this should be dealt with as a
priority in the ‘Hot Zone’(Fig. 2) before decontamination,
wearing appropriate personal protective equipment (PPE).
Liquid nerve agents have the potential to be absorbed
through the skin or will evaporate and subsequently be an
inhalational hazard to those around them (‘off-gassing’). In
contrast, inhaled nerve agents will be systemically absorbed,
metabolised, or naturally vented from the patient’s respiratory
system. Removal of clothing (‘disrobing’) will provide at least
80% of decontamination as clothes fibres can trap and hold
liquid nerve agents and vapours.
8
Liquid agents may also need
to be mopped up with material such as Fuller’s earth (a fine
adsorbent powder used by the military) or clinical paper
towels (‘blue rolls’) after disrobing, and then rinsed off with
soapy water at 35
C. The advice from Optimisation through
Research of Chemical Incident Decontamination Systems
(ORCHIDS) is that percutaneous OP nerve agents, such as VX,
are lipophilic and are therefore more easily removed through
use of adsorbents rather than a wet rinse and specialist advice
should always be sought. Standard UK military protocols
promote the use of dry decontamination followed by a wet
rinse to manage patients contaminated with liquid nerve
agent.
All clothing and jewellery should be removed and placed in
a double bag and sealed. The bag of contaminated clothing
must be safely removed and left in a cordoned and well-
ventilated area (ideally outside) to prevent accumulation of
any off-gassing agent.
As patients may be exhaling traces of agent, those who
need to be intubated or ventilated on ICU may contaminate
the ventilator and attached circuits. OP pesticides can pene-
trate rubber and plastics and may persist for some time.
18
It is
the view of the authors that designated machines should be
used for OP poisoned patients, but if required, the circuit and
rubber components of the machine should be replaced and the
machine washed before re-using on non-poisoned patients,
and specialist advice sought.
Treatment of organophosphorus nerve agent
poisoning
Treatment for OP nerve agent uses three types of therapies:
antimuscarinic, oxime, and anticonvulsant/neuroprotection.
The antimuscarinic drug atropine is a key component of
treatment and specific protocols vary. The UK military and
North Atlantic Treaty Organization (NATO)
19
treatment for
nerve agent protocol recommends an initial dose of 5e10 mg
intravenous (IV)/intraosseous (IO) atropine for severely
poisoned patients, titrated to effect every 5 min until atropi-
nisation (reversal of the ‘3Bs’dbradycardia, bronchospasm,
bronchorrhea [respiratory secretions]). This should be
administered with concurrent oxime and anticonvulsant
therapy (if required). Public Health England guidance recom-
mends 4e4.2 mg atropine as an initial dose in severe nerve
agent cases. In their report, Eddleston and colleagues
12
describe the treatment of moderate to severe OP insecticide
poisoning and recommends starting with a 1e3 mg bolus, then
doubling the dose every 5 min until atropinisation (systolic BP
>80 mm Hg, heart rate [HR] >80 beats min
1
, and drying of
pulmonary secretions), followed by an atropine infusion. This
latter treatment regime is echoed by the OPCW handbook and
is potentially more controlled compared with the operational
nerve agent protocols, and may be of more use in single
Fig 1. The chemical, biological, radiological, and nuclear (CBRN) chain of survival and sequence of events in the context of nerve agent
poisoning. The early spot decontamination through bagging of clothing and wiping off of liquid nerve agent with clinical towels (‘blue roll’)
or microfibre cloths will limit further internal/external contamination of the patient and staff. This spot decontamination can run
concurrently whilst assessing for catastrophic haemorrhage, airway, breathing, and circulation problems in the patient. Early toxidrome
recognition (e.g. miosis in nerve agent poisoning) will lead to early antidotes that will save lives. Further dry and then wet decontami-
nation are recommended in the case of liquid nerve agent poisoning. Image has been reproduced with kind permission of Calamai and
colleagues.
17
Managing patients with nerve agent poisoning
-
459
casualties rather than mass casualties. Those suffering from
severe nerve agent poisoning requiring intubation and venti-
lation after the Sarin incident on the Tokyo subway (n¼4)
required doses of atropine between 1.5 and 9 mg, that is less
than that required for similarly severe OP insecticide poisoned
patients with a mean initial atropine dose of 23 mg (i.e. 38 vials
of atropine [each 0.6 mg]).
20
In OP insecticide poisoning, mortality was not increased by
giving the atropine before oxygen. So, if access to oxygen is
limited, atropine should still be given to moderately and
severely poisoned patients.
21
In Syria, the use of bronchodi-
lators and steroids has been described
9
but does not currently
have an evidence base. Indeed, caution must be exercised
when using
b
2
agonists such as salbutamol as they may
cause tachyarrhythmias. In addition to atropine, other anti-
muscarinics may also be considered such as hyoscine
(scopolamine) and glycopyrrolate although the latter does not
cross the bloodebrain barrier.
Oximes can reactivate the AChE if given early enough,
before ageing and the dealkylation of the OP compound. There
are further nuances regarding oximes: the clinical response
will depend not only upon the type of nerve agent (discussed
above) but also on the oxime used.
15
The most commonly
available oxime in the UK is pralidoxime and is administered
as a 2 g IV/IO slow infusion over 5 min. Adults can be admin-
istered higher doses either divided or as an infusion, titrated to
clinical effect or reducing atropine requirement. Some nerve
agents respond better to different oximes,
8,22,23
but these data
come from in vitro and animal studies, or observation of hu-
man OP insecticide poisoning. Prolonged or high dose expo-
sure to some oximes (e.g. obidoxime) may lead to liver enzyme
dysfunction
24
so this should be balanced against the clinical
picture. Blood AChE is believed to be synthesised at a rate of
around 1% day
1
, but a return to full AChE activity is not
required for normal ventilation as OP insecticide poisoned
patients have been found to have normal muscle function
with only 30% red cell AChE activity.
12
Military and first responders may have access to combi-
nation therapy in the form of nerve agent antidote auto-
injectors. The combination of drugs varies between
autoinjectors and usually contains atropine and an oxime
with or without an anticonvulsant (e.g. avizafone). These have
a vital role in stabilising a patient in either a non-permissive
hazardous or operational environment (contaminated Hot
Zone) or before/during decontamination (Warm Zone). Anti-
dote is delivered as an intramuscular injection and is easier to
administer in PPE, although the IO route is now becoming a
preferred method of antidote administration in the semi-
permissive Warm Zone after disrobing.
Adjunct experimental treatments are designed to maxi-
mise the oximes’ ability to reactivate AChE by slowing down
ageing, or re-alkylation of aged AChE.
25
Other novel treat-
ments exist to scavenge OP in the blood or control the symp-
toms of OP poisoning and are discussed elsewhere.
26
Rodent models suggests that acute nerve agent exposure
leads to an increase in bloodebrain barrier permeability and
long-term damage,
27,28
so neuroprotection is an important
consideration and might consist of early use of benzodiaze-
pines and other agents such as propofol and even
ketamine.
29,30
The clinical course
The acute cholinergic effect of the OP nerve agent should
lessen after decontamination, metabolism of the OP, and
restoration of the body’s plasma BuChE and AChE. The
Fig 2. The ideal journey of the chemically exposed casualty through the ‘Hot Zone’at the point of exposure (PoE), Warm Zone for
decontamination ending in the Cold/Clean Zone at the hospital for advanced medical care. The red box describes the clinical interventions
permissible in the Hot Zone, the yellow box the clinical interventions available at the Warm Zone. A, advanced medical care; Cat Haem,
catastrophic haemorrhage; CCS, casualty clearing station; Decon, decontamination; F, first aid; (Fwd)CCP, forward casualty collection
point; L, life-saving interventions; PoE, point of exposure; T, triage point. Flow chart designed by SA Bland.
460
-
Hulse et al.
duration of intubation and ventilation will be determined by
the above, and the strength of the patient’s respiratory mus-
cles. If intubation is prolonged, tracheostomy formation may
prove useful on the ICU. One might assume that as OP nerve
agents inhibit both BuChE and AChE, their measurement
might be useful. However, their activity does not correlate well
with functional clinical severity.
12
That said, the enzyme ac-
tivity levels can be used to indicate OP exposure and trends in
recovery. For example, in Tokyo, most of the severely Sarin
poisoned patients requiring intubation had normal plasma
BuChE within hours (three out of four patients), but the red cell
AChE took between 13 and 72 days to return to normal.
16
In the most recent OPCW report from Syria, victims
exposed to Sarin were still reporting decreased visual acuity,
photophobia, tightness in the chest, and shortness of breath
for 15e25 days after exposure.
9
Other long-term sequelae have
also been reported after OP nerve agent exposuredfor
example CNS dysfunction,
31
peripheral neuropathies,
32
and
chronic lung changes.
33
In OP insecticide poisoning, there is a phenomenon called
‘intermediate syndrome’, which is a form of neuromuscular
dysfunction causing muscle weakness and can extend to
respiratory failure after 48 h of poisoning which is unrespon-
sive to atropine and oximes.
34
Conduct of anaesthesia
This topic causes the anaesthetist much consternation and
the knowledge is largely based on observations from OP
insecticide poisoning. The depolarising neuromuscular
blocking agent suxamethonium may have a longer onset (i.e. 2
min) and duration of action (up to 12 h) secondary to the OP
inhibition of BuChE. Caution should be exercised with non-
depolarising neuromuscular blocking agents for up to 2 yr
and lower doses used to avoid prolonged paralysis.
6
Caution
should also be exercised when using other BuChE metabolised
drugs such as ester local anaesthetics and mivacurium.
Deaths from organophosphorus nerve agent
poisoning
The chances of a patient dying (usually from respiratory fail-
ure) are related to the severity of exposure, in terms of time
and dose, and potency of OP compound with the numbers of
dead related to the mechanism of dispersal. The incident in
the Tokyo subway in Japan used poor-quality Sarin with an
inferior mechanism of dispersal, that is liquid on a train floor
left to evaporate. As the saturated vapour pressure of most OP
nerve agents is very low (e.g. Sarin 0.39 kPa
15
at 25
C,
compared with sevoflurane 26.3 kPa), little will evaporate.
Thus, of the 640 people that presented to the main hospital,
only two died, with 11 dying at the scene.
16
Calculating the
number of fatalities secondary to the use of Sarin delivered in
Syria is difficult, but estimated to be in the hundreds for the
deadly attack by rockets releasing Sarin into the atmosphere
in August 2013.
10
Should I worry about my staff?
With a combination of rapid recognition, appropriate donning
of PPE, and adequate patient decontamination, the risk to staff
will be substantially reduced. During the Japanese Sarin
poisoning, patients rushed to the main hospital and were not
decontaminated outside of the hospital, or even in the ED.
Some were washed on the ward and had their clothes placed
in bags on the ward by staff wearing normal surgical gloves
and masks. Staff members who completed a post-event
questionnaire (n¼472) revealed that the vast majority suf-
fered no symptoms, with no fatalities. However, 110 (23%) staff
experienced secondary poisoning including eye symptoms
(14%), headache (11%), throat pain (8%), shortness of breath
(5%), and nausea (3%).
31
Staff members in cave hospitals in
Syria exposed to Sarin and chlorine gas have also been
affected, with at least one death.
9
It is, therefore, important that all staff members under-
stand the hazards and necessary precautions. These include
early removal of clothing in a well-ventilated environment
before entering a medical facility. If further contamination is
suspected, staff members should wear appropriate PPE, which
may require level C: full or half face mask with air purifying
respirators, hooded chemical resistant clothing, chemical
resistant inner, and outer gloves and boots.
Once decontaminated, managing patients in well-
ventilated areas and simple, double-layer nitrile gloves with
disposable long-sleeve gowns are sufficient. Staff should also
know where the extra stockpiles of atropine (the Japanese
Sarin incident used 2800 [0.5 mg] ampules
31
of atropine in the
main receiving hospital), and oximes are located in their
hospital, city, and region. In the UK, further information and
advice can be sought from the National Poisons Information
Service (NPIS: https://www.npis.org).
Salisbury and Novichok nerve agent
poisoning
The ongoing criminal investigation means little can be said
about the recognition, treatment, and long-term effects of the
Novichok poisonings except that which has been reported in
the media. The facts made public to date suggest that at least
six patients may have had varying degrees of exposure, and
only one person has died. This is testament to the good and
timely clinical care that these patients have received. For this,
the physicians, critical care doctors, nurses, healthcare assis-
tants, laboratory staff, and all those involved at Salisbury
hospital must be congratulated.
There is less information in the public domain about the OP
nerve agent Novichok, which Russia still denies exists but
recent articles have offered commentary.
35,36
Some believe
that it is more difficult to treat compared with other OP nerve
agents, being less responsive to oximes.
37
An anecdotal story
by a dissident Soviet scientist details an accidental exposure
with Novichok that produced acute cholinergic poisoning with
long-term cognitive dysfunction.
38
A number of relevant re-
sources are available for those wishing further
information.
39e42
Conclusion
Although OP nerve agent poisoning has made headlines for
the past few years, the number of poisonings are very low
when compared with the global impact of self-harm with OP
insecticides. The mainstay of treatment remains atropine,
oximes, neuroprotection, and critical care support should ca-
sualties require ventilatory or other organ system support. The
Managing patients with nerve agent poisoning
-
461
fact that the Novichok poisonings in Salisbury have resulted in
only one death indicates that treatments have been success-
ful, but it has highlighted a gap in the medical knowledge and
training of most doctors and the wider clinical community. We
should take time to learn from this incident to refresh our
management of this toxicological emergency. The authors
look forward to the publication of the lessons learned from the
Salisbury OP nerve agent poisonings so that treatment guide-
lines can be optimised in the future.
Authors’contributions
Writing of the first draft: EH.
Contributed to the entirety of the manuscript: JH, SE, TW.
All authors reviewed and approved the manuscript in its final
form before submission.
Declaration of interest
EH is a Surgeon Commander in the Royal Navy UK and receives
grant funding from the Ministry of Defence to investigate the
effects of organophosphorus poisoning.
Acknowledgements
The authors thank Surgeon Commander Steve A Bland (Royal
Navy Defence Consultant Advisor for Chemical, Biological,
Radiological and Nuclear Medicine) for his input, use of a di-
agram, and advice on writing this manuscript.
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