Case Report

Novichok nerve agent poisoning

David Steindl, Wolfgang Boehmerle, Roland Körner, Damaris Praeger, Marcel Haug, Jens Nee, Adrian Schreiber, Franziska Scheibe,
Katharina Demin, Philipp Jacoby, Rudolf Tauber, Sven Hartwig, Matthias Endres, Kai-Uwe Eckardt

On Aug 20, 2020, a 44-year-old man who was previously brainstem reflexes, hyperactive deep tendon reflexes, and Published Online
healthy suddenly became confused and began to sweat pyramidal signs. Laboratory analyses showed substan­ December 22, 2020
https://doi.org/10.1016/
heavily on a domestic flight in Russia approximately tially decreased levels in plasma of butyrylcholinesterase S0140-6736(20)32644-1
10 min after departure; he vomited, collapsed, and lost (also called pseudocholinesterase) and increased levels of
See Online/Comment
consciousness. After an emergency landing, the man amylase, lipase, high-sensitivity troponin T, and sodium https://doi.org/10.1016/
was admitted to the toxicology unit of a local hospital in in plasma (appendix p 1). Based on clinical and laboratory S0140-6736(20)32749-5
Omsk, Russia, approximately 2 h after symptom onset. findings, severe cholinesterase inhibition was diagnosed Department of Nephrology
According to the discharge report, the patient presented and the patient was started on atropine and obidoxime and Medical Intensive Care
(D Steindl MD, R Körner MD,
comatose with hypersalivation and increased diaphoresis (250 mg bolus followed by continuous administration
J Nee MD, A Schreiber MD,
and was diagnosed to have respiratory failure, myoclonic of 750 mg per day). Cholinergic signs returned to normal Prof K-U Eckardt MD),
status, disturbed carbo­ hydrate metabolism, electrolyte within 1 h after the onset of this antidotal therapy. Analgo­ Department of Neurology
disorders, and metabolic encephalopathy. Therapeutic sedation with sufentanil and propofol was sup­plemented (W Boehmerle MD,
F Scheibe MD,
measures included intuba­tion, mechanical ventilation, with midazolam for neuroprotection.3
K Demin Dr rer medic,
and unspecified drugs for symptom control and Toxicological analysis and drug screening in blood and Prof M Endres MD), Department
neuroprotec­ tion. On Aug 22, 2020, the patient was urine samples obtained on admission to the intensive of Cardiology and Angiology
transferred by a German air ambulance to the Charité- care unit at Charité identified several drugs, including (D Praeger MD, M Haug MD),
Institute of Legal Medicine and
Universitätsmedizin Berlin at the request of his family. atropine, which we attributed to the previous treatment
Forensic Sciences
Severe poisoning with a cholinesterase inhibitor was the patient had received in the intensive care unit (S Hartwig MD), and Institute of
sub­sequently diagnosed. 2 weeks later, the German in Omsk before the medical transfer to Germany Laboratory Medicine, Clinical
Government announced that a laboratory of the (appendix p 2). Testing for cholinesterase status4 in a Chemistry and
Pathobiochemistry
German armed forces designated by the Organization for specialised external laboratory showed complete inhi­ (Prof R Tauber MD),
the Prohibition of Chemical Weapons (OPCW) had bition of acetylcholinesterase in red blood cells, thereby Charité-Universitätsmedizin
identified an organophosphorus nerve agent from the con­firming the exposure to a cho­lin­esterase inhibitor, Berlin, Berlin, Germany; Flight
novichok group in blood samples collected immediately and no evidence for reactivation by obidoxime or free Ambulance International,
Nürnberg, Germany
after the patient’s admission to Charité,1 a finding that unbound cholinesterase inhibitor in plasma (appendix (P Jacoby MD); Labor Berlin
was subsequently confirmed by the OPCW.2 Here, we p 3). Accordingly, obidoxime was stop­ped after 1 day.5 Charité Vivantes GmbH, Berlin,
report clinical details of this case. Atropine was continued for 10 days and titrated to Germany (Prof R Tauber)
suppress cholinergic symptoms (figure 1). On day 5, the Correspondence to:
Clinical course patient developed a fever that was treated with external Prof Kai-Uwe Eckardt,
Department of Nephrology and
Approximately 31 h after symptom onset, a doctor from the cooling for 9 days and subsequently with anti­ pyretic Medical Intensive Care,
German air ambulance crew had temporary access to the therapy using pethidine, metamizole, and para­cetamol. Charité-Universitätsmedizin
patient and recorded bradycardia (44 beats per min [bpm]), Intermittent myoclonic muscular contrac­tions, pre­domi­ Berlin, 10117 Berlin, Germany
hypothermia (34·4°C), wide pupils non-reactive to light, nately of the thoracic and abdominal muscles, responded nephro-intensiv@charite.de

and intermittent myoclonus under sedation with propofol, poorly to atropine and increased sedation and persisted See Online for appendix
the only obvious drug given at that time. Peripheral oxygen for up to 15 days.
saturation was 100% while the patient was on pressure- Cranial CT and MRI scans, analysis of cerebrospinal
regulated volume control ventilation with low positive end- fluid, short-latency somatosensory evoked potentials,
expiratory pressure and a fractional concentration of and plasma neuron-specific enolase concentration on
oxygen in inspired air (FiO2) of 30%. 16 h later, when the day 4 were all within normal ranges, and an electro­­­
patient was handed over to the German air ambulance encepha­lo­gram was consistent with sedation. Electrophys­
crew for transportation to Berlin, his condition had slightly io­
logical examinations showed the specific kind of
improved (pupils constricted, heart rate 59 bpm). Propofol dys­function of neuromuscular transmission that is
was again the only drug administered at that time. typical for cholinesterase inhibition. Repetitive responses
During subsequent airborne transport in an EpiShuttle were noted after a single supramaximal elec­ trical
isolation system (EpiGuard, Oslo, Norway), the patient stimulus (figure 2A). Repeated nerve stimulation showed
received propofol, fentanyl, and crystalloids and continued a decrement-increment response pattern at fre­quen­cies
to be ventilated with 30% FiO2. On arrival at an intensive of 10 Hz or greater, which was more pronounced at
care unit at Charité, approximately 55 h after symptom higher stimula­tion frequencies (figure 2B, 2C), con­sistent
onset, the patient was deeply comatose, with mild with blockade of neuromuscular transmission caused by
bradycardia (51 bpm, subsequently declining to 33 bpm), depolarisa­­tion.6 Stimulated single-fibre electro­myography
hypersalivation, hypothermia (33·5°C), increased diapho­ showed prolonged variation in the time between action
resis and small pupils not reactive to light, decreased potentials of the same motor unit, which is called jitter

www.thelancet.com Published online December 22, 2020 https://doi.org/10.1016/S0140-6736(20)32644-1 1

 Case Report

Day 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33

Ventilation Continuous ventilation Spontaneous breathing

Pyrexia

Myoclonus

Atropine ? ?

Antibiotics ? ?

8·0
Butyrylcholinesterase (kU/L) 4·0
0·0
400
C-reactive protein (mg/L) 200
0
400
γ glutamyl transferase (U/L) 200
0
40
Plasma albumin (g/L)
20
Dilatational tracheostomy Assisted spontaneous breathing
Decannulation Myoclonus
Spontaneous breaths ? Timing and duration of atropine application and antibiotic therapy before admission to ICU at Charité is
Spontaneous breathing trial uncertain
Administration of 6 units of fresh-frozen plasma

Figure 1: Schematic presentation of the clinical course

Figure shows selected clinical findings, treatment aspects, and laboratory values during the patient’s stay in intensive care (days 1–25) and on a regular hospital ward
(days 26–33). Symbol sizes provide a semiquantitative estimate. Trends of laboratory findings recorded at Charité are displayed as area charts; values are provided in
the appendix (p 4).

(figure 2D). These findings improved continuously and urine samples showed two different variants of
within the next 7 days (figure 2A, 2C, 2D). K pneumoniae. Based on these findings, we used
During the period in the intensive care unit at Charité, antibiotics very reluctantly. A urinary tract infection with
the patient temporarily showed signs of systemic inflam­ K pneumoniae was treated with co-trimoxazole, and
ma­tion and increases in liver enzymes (figure 1; appendix a possible bloodstream infection with Staphylococcus
p 4). Activity of butyrylcholinesterase in plasma started epidermidis was treated with a 4-day course of vanco­
to increase on day 4 but plateaued on day 6 at levels mycin. CT on admission and plain chest radiography on
below normal, which prompted us to administer 6 units days 3, 5, 9, 10, and 13 showed no clear signs of pulmonary
of fresh-frozen plasma; this transfusion led to a pro­ infiltration. Because of purulent bronchoalveolar fluid
nounced increase in activity with no subsequent decline, in conjunction with increased levels of C-reactive protein,
thus excluding consumption of butyryl­cholin­esterase by the patient received colistin inhalations for 9 days, sub­
unbound inhibitory nerve agent in blood, consistent with sequently tapered to prophylactic doses.
findings of in vitro testing (appendix p 3). On day 10, the During the patient’s stay in intensive care at Charité, gas
spontaneous increase in plasma butyrylcholinesterase exchange was never severely impaired. FiO2 was usually
activity resumed, and values within the normal range below 40%, except on day 9, when it was temporarily
were reached on day 20 (appendix p 4). By comparison, increased to 50%. We did a percutaneous dilatational
activity of acetylcholinesterase in red blood cells recov­ tracheostomy on day 13 in anticipation of complicated
ered more slowly and only partly until day 21 (appendix weaning. On day 12, the patient started to breathe spon­
p 3). The patient’s haemoglobin concentration dropped taneously (figure 1) and could subsequently be weaned
from 12·2 g/dL to 7·5 g/dL and recovered after intra­ from mechanical ventilation completely by day 24. He
venous iron and oral folate supplementation. gradually recovered from a delirium and was mobilised
In skin swabs obtained on admission to the intensive and transferred to a regular hospital ward on day 26. At
care unit at Charité, we noted colonisation with five discharge on day 33, a neurological examination showed
different multi­ drug-resistant bacteria: Staphylococcus enhanced physio­ logical tremor and hyperactive deep
aureus, Acinetobacter baumannii complex, Pseudomonas tendon reflexes but neither pyramidal signs nor evidence
aeruginosa, Escherichia coli, and Klebsiella pneumoniae. of polyneuropathy. Neuropsycholo­gical testing performed
Microbial characterisation of subsequent rectal swabs in Russian, the patient’s native language, showed subtle

2 www.thelancet.com Published online December 22, 2020 https://doi.org/10.1016/S0140-6736(20)32644-1

 Case Report

impairments in processing speed and verbal fluency,

A B
which had completely resolved 3 weeks later. At the last Day 5 Day 12 Day 55 10 Hz 20 Hz
follow-up visit on day 55 we found near-complete recovery 20
of neurological, neuro­ psychological, and neurophysi­ –10 000
ological findings without evidence of polyneuropathy. 15
–5000

CMAP (mV)
CMAP (μV)
Discussion 0 10
Novichoks are a group of nerve agents developed
in the former Soviet Union in the 1980s.7 Five recent 5
cases of novichok poisoning, including one fatal, have
been reported in the UK.7,8 However, up to now, no 0
clinical details have been published. 0 20 40 60 1 2 3 4 5 6 7 8 9 10
Time (ms) Stimulus number
Identification of an individual organophosphorus
com­pound is a complex and time-consuming process.9 C D
In fact, ascertaining the involvement of a novichok agent 3 Hz 10 Hz 20 Hz
and its biotransformation products in this case was only 30 Hz 50 Hz
40 200
achieved several days after establishing the diagnosis of
Change in CMAP impulse 1–5 (%)

cholin­ esterase inhibitor poisoning and did not affect 20

Jitter in abductor pollicis

150
therapeutic decisions.

brevis muscle (μs)

Organophosphorus nerve agents exert the same 0
100
mechanism of action as do organophosphorus pes­ ti­
–20
cides (ie, inhibition of acetylcholinesterase) and clinical
50
manage­ment is largely based on experience with organo­ –40
phosphorus pesticide poisonings, which still pose
–60 0
a major health burden in southeast Asia, with more Day 5 Day 8 Day 12 Day 5 Day 8
than 100 000 deaths per year.10 Clinical diagnosis of
organophosphorus poisoning should be straightforward. Figure 2: Selection of key electrophysiological findings in the abductor pollicis brevis muscle
(A) Repetitive responses were noted after a single supramaximal electrical stimulus, which disappeared at
The range of findings caused by overstimulation of follow-up. On day 55, normalised CMAP was seen. (B) Repetitive nerve stimulation of the median nerve on day 5
muscarinic and nicotinic receptors seen in our patient showed a decrement-increment pattern at frequencies ≥10 Hz, which was more pronounced at higher stimulation
was in line with published literature: miosis, conjunctival frequencies; (C) this finding continuously improved within the next 7 days. (D) Stimulated single-fibre
injection, hypersalivation, diaphoresis, bradycardia, and electromyography with concentric needles showed increased jitter; line shows median, boxes the IQR, and error
bars the range; dashed line represents upper limit of normal for individual jitter values. CMAP=compound motor
elevation of plasma lipase and amylase, which are action potential.
attributed to pancreatic and salivary gland stimulation,
hyperactive deep tendon reflexes, pyramidal signs, Additional findings with less clear pathophysiology
and prolonged muscular hyperactivity.11 Moreover, have previously been described in organophosphorus
we observed typical pathological changes in electro­ poisoning. Among these was a refractory disturbance
physio­logy and single-fibre electromyography studies.12,13 of thermoregulation with initial hypothermia followed
After normalisation of neuromuscular transmission, the by fever. Hypothermia during the early course might, in
patient started to breathe spontaneously on day 12. part, have been caused by increased diaphoresis, whereas
Tests for butyrylcholinesterase activity, which are side-effects of atropine, infectious complications, and
primarily used as a liver function test, are widely available unknown factors are considered to cause subsequent
in clinical routine practice and are usually the only fever.15 We also recorded a transient rise of troponin in
laboratory parameter to confirm a clinical diagnosis conjunction with repolarisation disturbances on electro­
of organophosphorus poisoning. The cholinesterase cardiogram in the presence of normal echocardiography,
status provides additional important information for consistent with cardiotoxicity of nerve agents.16 Signs
thera­peutic decisions, such as the presence of unbound of hepatic injury with increases of aminotransferases
acetyl­cholinesterase inhibitor in patient’s plasma and and γ glutamyl transferase have also previously been
the possibility to reactivate organophosphorus–acetylcho­ reported4,17 and, in part, been attributed to obidoxime,18
linesterase conjugates with a particular oxime (appendix which our patient received for less than 24 h. An
p 3).4 In fact, absence of inhibitory activity in our patient’s unexplained finding seen in this case was pronounced
plasma in conjunction with inability to reactivate transi­ent hypoalbuminaemia, which could not be attribu­
acetylcholinesterase in red blood cells prompted early ted to enteric or renal loss or impaired liver function.
termination of obidoxime. Consistent with findings Our patient had a very favourable outcome. Pre­
of experimental and clinical studies, suf ­fi cient muscle sumably, intubation and mech­­anical ventilation within
function enabling spontaneous breathing on day 21 2–3 h of symptom onset and absence of preceding
correlated with approximately 30% activity of acetylcho­ severe hypoxia were decisive. Onset and duration of
linesterase in red blood cells (figure 1; appendix p 3).14 atropine therapy during the first 2 days remain unclear.

www.thelancet.com Published online December 22, 2020 https://doi.org/10.1016/S0140-6736(20)32644-1 3

 Case Report

Fortunately, despite a high risk for aspiration during 5 Amend N, Langgartner J, Siegert M, et al. A case report of
the initial period of unconsciousness, and colonisation cholinesterase inhibitor poisoning: cholinesterase activities and
analytical methods for diagnosis and clinical decision making.
with several multidrug-resistant bacteria, the patient did Arch Toxicol 2020; 94: 2239–47.
not develop severe infection. His good health status 6 Maselli RA, Leung C. Analysis of neuromuscular transmission
before the poisoning probably favoured his recovery. failure induced by anticholinesterases. Ann N Y Acad Sci 1993;
681: 402–04.
Contributors 7 Vale JA, Marrs TC, Maynard RL. Novichok: a murderous nerve
DS and K-UE wrote the first draft of the report, coordinated internal agent attack in the UK. Clin Toxicol 2018; 56: 1093–97.
revision, and prepared the submitted version. All authors contributed to 8 OPCW Technical Secretariat. Summary of the report on activities
data collection, data analysis, and data interpretation. RK, DP, MH, JN, carried out in support of a request for technical assistance by the
AS and PJ were responsible for defined periods of treatment. WB, FS, United Kingdom of Great Britain and Northern Ireland (technical
and ME performed neurological and neurophysiological assessments. assistance visit TAV/03/18 and TAV/03B/18 “Amesbury incident”).
KD and ME did neuropsychological assessments. RT was responsible for Sept 4, 2018. https://www.opcw.org/sites/default/files/
clinical chemistry. SH did toxicological analyses. All authors vouch for documents/2018/09/s-1671-2018%28e%29.pdf (accessed Dec 3, 2020).
accuracy of the data. DS and K-UE had unlimited access to all clinical 9 John H, van der Schans MJ, Koller M, et al. Fatal sarin poisoning in
data and reports. Syria 2013: forensic verification within an international laboratory
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Declaration of interests 10 Mew EJ, Padmanathan P, Konradsen F, et al. The global burden of
We declare no competing interests. fatal self-poisoning with pesticides 2006–15: systematic review.
Acknowledgments J Affect Disord 2017; 219: 93–104.
This report was prepared using internal resources without specific 11 Grob D. The manifestations and treatment of poisoning due to
funding. We gratefully acknowledge the support from many colleagues nerve gas and other organic phosphate anticholinesterase
compounds. AMA Arch Intern Med 1956; 98: 221–39.
in the assessment and interdisciplinary management of this case,
including members of the Bundeswehr Institute of Pharmacology and 12 Besser R, Gutmann L, Dillmann U, Weilemann LS, Hopf HC.
End-plate dysfunction in acute organophosphate intoxication.
Toxicology in Munich, Germany, who did repetitive measurements of
Neurology 1989; 39: 561–67.
butyrylcholinesterase, acetylcholinesterase in red blood cells, and
13 Thiermann H, Zilker T, Eyer F, Felgenhauer N, Eyer P, Worek F.
cholinesterase status and gave toxicological advice.
Monitoring of neuromuscular transmission in organophosphate
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4 www.thelancet.com Published online December 22, 2020 https://doi.org/10.1016/S0140-6736(20)32644-1