Lancet case study on nerve agent poisoning – as Russia arrests the victim

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The current edition of The Lancet features an anonymous case study from a top Berlin hospital that is clearly based on the near-fatal poisoning of Russian opposition activist Alexei Navalny (44) last August, writes MedicalBrief. Navalny was arrested in Moscow at the weekend when he flew home from Germany, where he was treated for novichok nerve agent poisoning.

Last year the German government confirmed that Navalny had been victim of a novichok attack. Novichoks are nerve agents developed in the Soviet Union in the 1980s, reports The Lancet: “Five recent cases of novichok poisoning, including one fatal, have been reported in the United Kingdom. However, up to now, no clinical details have been published.”

Last August Navalny was emergency airlifted from Russia to Charité – Universitätsmedizin Berlin, which is one of Europe's largest university hospitals, affiliated with Humboldt University and Free University Berlin. There, his life was saved by expert treatment that is outlined in The Lancet.

BBC News reported that Navalny, a fierce critic of Russian President Vladimir Putin, had been detained after flying back to Moscow on Sunday 18 January 2021, accompanied by journalists. There were chaotic scenes at Vnukovo airport, where the plane was due to land, with Navalny supporters and police clashing.

At the last minute the plane was diverted for ‘technical reasons’ to Sheremetyevo airport, also in Moscow. Navalny, undoubtedly a brave man, was arrested on landing as expected. Several other activists were reportedly also detained.

Navalny has blamed Russian authorities for the attempt on his life, with his claims supported by reports from investigative journalists, according to BBC News. The Kremlin has denied any role.

The case report on “Novichok nerve agent poisoning” was first published online by The Lancet on 22 December 2020, and appears in its 16 January 2021 edition. It says that scientists at Charité – Universitätsmedizin Berlin report the clinical details of a Russian patient who was diagnosed with severe poisoning with a cholinesterase inhibitor.

According to the Case Report introduction, on 20 August 2020 a healthy 44-year-old man “suddenly became confused and began to sweat heavily on a domestic flight in Russia approximately 10 minutes after departure; he vomited, collapsed and lost consciousness.” After an emergency landing, around two hours after symptom onset, the man was admitted to the toxicology unit of a hospital in Omsk.

The Case Report introduction continues: “According to the discharge report, the patient presented comatose with hypersalivation and increased diaphoresis and was diagnosed to have respiratory failure, myoclonic status, disturbed carbohydrate metabolism, electrolyte disorders, and metabolic encephalopathy. Therapeutic measures included intubation, mechanical ventilation, and unspecified drugs for symptom control and neuroprotection.”

Two days later, following a family request, a German air ambulance transferred the patient to Charité-Universitätsmedizin Berlin. “Severe poisoning with a cholinesterase inhibitor was subsequently diagnosed,” says the Case Report.

“Two weeks later, the German government announced that a laboratory of the German armed forces designated by the Organisation for the Prohibition of Chemical Weapons (OPCW) had identified an organophosphorus nerve agent from the novichok group in blood samples collected immediately after the patient’s admission to Charité.”

Below is a slightly shortened version of the clinical details of the Case Report in The Lancet. Find the original, along with references and other information, in The Lancet via the link at the bottom.

 

Study details

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 and Kai-Uwe Eckardt

Published in The Lancet, 16 January 2021, Volume 397, Issue 10270.

 

Clinical course

Approximately 31 hours after symptom onset, a doctor from the German air ambulance crew had temporary access to the patient and recorded bradycardia (44 beats per minute), hypothermia (34·4°C), wide pupils non-reactive to light, and intermittent myoclonus under sedation with propofol, the only obvious drug given at that time.

Peripheral oxygen saturation was 100% while the patient was on pressure-regulated volume control ventilation with low positive end-expiratory pressure and a fractional concentration of oxygen in inspired air (FiO2) of 30%.

Sixteen hours later, when the patient was handed over to the German air ambulance crew, his condition had slightly improved (pupils constricted, heart rate 59 bpm). Propofol was again the only drug administered at that time.

During airborne transport “the patient received propofol, fentanyl and crystalloids and continued to be ventilated with 30% FiO2. On arrival at an intensive care unit at Charité, approximately 55 hours after symptom onset, the patient was deeply comatose, with mild bradycardia (51 bpm, subsequently declining to 33 bpm), hypersalivation, hypothermia (33·5°C), increased diaphoresis and small pupils not reactive to light, decreased brainstem reflexes, hyperactive deep tendon reflexes, and pyramidal signs,” says the Case Report.

Analyses showed substantially decreased levels in plasma of butyrylcholinesterase and increased levels of amylase, lipase, high-sensitivity troponin T, and sodium in plasma.

“Based on clinical and laboratory findings, severe cholinesterase inhibition was diagnosed and the patient was started on atropine and obidoxime (250 mg bolus followed by continuous administration of 750 mg per day). Cholinergic signs returned to normal within one hour after the onset of this antidotal therapy. Analgosedation with sufentanil and propofol was supplemented with midazolam for neuroprotection.”

Toxicological analysis and drug screening in blood and urine samples obtained on admission to Charité intensive care unit identified several drugs, including atropine, which the doctors attributed to treatment the patient had received in Omsk, the Case Report continues.

“Testing for cholinesterase status in a specialised external laboratory showed complete inhibition of acetylcholinesterase in red blood cells, thereby confirming the exposure to a cholinesterase inhibitor, and no evidence for reactivation by obidoxime or free unbound cholinesterase inhibitor in plasma. Accordingly, obidoxime was stopped after one day.

“Atropine was continued for 10 days and titrated to suppress cholinergic symptoms. On day five, the patient developed a fever that was treated with external cooling for nine days and subsequently with antipyretic therapy using pethidine, metamizole and paracetamol. Intermittent myoclonic muscular contractions, predominately of the thoracic and abdominal muscles, responded poorly to atropine and increased sedation and persisted for up to 15 days.”

“Cranial CT and MRI scans, analysis of cerebrospinal fluid, short-latency somatosensory evoked potentials, and plasma neuron-specific enolase concentration on day four were all within normal ranges, and an electro- encephalogram was consistent with sedation.

“Electrophysiological examinations showed the specific kind of dysfunction of neuromuscular transmission that is typical for cholinesterase inhibition. Repetitive responses were noted after a single supramaximal electrical stimulus.

“Repeated nerve stimulation showed a decrement-increment response pattern at frequencies of 10 Hz or greater, which was more pronounced at higher stimulation frequencies, consistent with blockade of neuromuscular transmission caused by depolarisation. Stimulated single-fibre electromyography showed prolonged variation in the time between action potentials of the same motor unit, which is called jitter.”

These findings improved over the next seven days, according to the Case Report, which continues: “During the period in the intensive care unit at Charité, the patient temporarily showed signs of systemic inflammation and increases in liver enzymes. Activity of butyrylcholinesterase in plasma started to increase on day four but plateaued on day six at levels below normal, which prompted us to administer six units of fresh-frozen plasma; this transfusion led to a pronounced increase in activity with no subsequent decline, thus excluding consumption of butyrylcholinesterase by unbound inhibitory nerve agent in blood, consistent with findings of in vitro testing.

“On day 10, the spontaneous increase in plasma butyrylcholinesterase activity resumed, and values within the normal range were reached on day 20. By comparison, activity of acetylcholinesterase in red blood cells recovered more slowly and only partly until day 21. The patient’s haemoglobin concentration dropped from 12·2 g/dL to 7·5 g/dL and recovered after intravenous iron and oral folate supplementation.”

In skin swabs obtained on admission, Charité doctors noted colonisation with five multidrug-resistant bacteria: Staphylococcus aureus, Acinetobacter baumannii complex, Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumoniae. Microbial characterisation of rectal swabs and urine samples showed two variants of K pneumoniae.

“Based on these findings, we used antibiotics very reluctantly. A urinary tract infection with K pneumoniae was treated with co-trimoxazole, and a possible bloodstream infection with Staphylococcus epidermidis was treated with a four-day course of vancomycin.”

“CT on admission and plain chest radiography on days three, five, 9, 10 and 13 showed no clear signs of pulmonary infiltration. Because of purulent bronchoalveolar fluid in conjunction with increased levels of C-reactive protein, the patient received colistin inhalations for nine days, subsequently tapered to prophylactic doses.”

During the patient’s stay at Charité, says the Case Report, gas exchange was never severely impaired. “FiO2 was usually below 40%, except on day nine, when it was temporarily increased to 50%. We did a percutaneous dilatational tracheostomy on day 13 in anticipation of complicated weaning. On day 12, the patient started to breathe spontaneously and could subsequently be weaned from mechanical ventilation completely by day 24.

“He gradually recovered from a delirium and was mobilised and transferred to a regular hospital ward on day 26. At discharge on day 33, a neurological examination showed enhanced physiological tremor and hyperactive deep tendon reflexes but neither pyramidal signs nor evidence of polyneuropathy.”

The report continues: “Neuropsychological testing performed in Russian, the patient’s native language, showed subtle impairments in processing speed and verbal fluency, which had completely resolved three weeks later. At the last follow-up visit on day 55 we found near-complete recovery of neurological, neuropsychological, and neurophysiological findings without evidence of polyneuropathy.”

Identification of an individual organophosphorus compound is complex and time-consuming, the Case Report points out. “In fact, ascertaining the involvement of a novichok agent and its biotransformation products in this case was only achieved several days after establishing the diagnosis of cholinesterase inhibitor poisoning and did not affect therapeutic decisions.

Organophosphorus nerve agents exert the same mechanism of action as do organophosphorus pesticides (ie, inhibition of acetylcholinesterase) and clinical management is largely based on experience with organophosphorus pesticide poisonings, which still pose a major health burden in southeast Asia, with more than 100,000 deaths per year.

The Case Report continues: “Our patient had a very favourable outcome. Presumably, intubation and mechanical ventilation within two to three hours of symptom onset and absence of preceding severe hypoxia were decisive. Onset and duration of atropine therapy during the first two days remain unclear.”

 

Russia Navalny: Poisoned opposition leader held after flying home

BBC News reported at the weekend that five months after the nerve agent attack, Alexei Navalny was detained at Sheremetyevo airport on his return home. “Thousands had gathered at a different Moscow airport to greet his flight from Berlin, but the plane was diverted,” it says.

After Navalny recovered from poisoning, he said he intended to return to Russia. On Sunday he boarded a Pobeda Airlines flight despite warnings that he would be arrested on landing. The plane was packed with journalists. Shortly before landing, the pilot announced that for ‘technical reasons’ the plane was being diverted from Vnukovo to Sheremetyevo airport.

“I know that I'm right. I fear nothing,” Navalny told supporters and the media upon landing, minutes before being detained. He is being held at a police station in Moscow.

Earlier on Sunday, BBC News reported, extra riot police had been deployed and metal barriers erected inside Vnukovo airport, where the plane was scheduled to land. “Russian media reported that a number of activists – including key Navalny ally Lyubov Sobol – had been detained.”

In a statement late on Sunday, Russia's prison service said Navalny had “been wanted since 29 December 2020 for repeated violations of the probation period”. The authorities accuse Navalny of violating conditions imposed after a conviction for embezzlement, for which he received a suspended sentence. He says the case was politically motivated.

“Separately, Russian prosecutors have launched a new criminal case against Navalny on fraud charges related to transfers of money to various charities, including his Anti-Corruption Foundation,” reports BBC News. The activist earlier argued that Putin was doing all he could to stop him from returning to Russia by fabricating new cases against him.

Russian authorities often claim Navalny is not popular and is no threat to Putin. However, BBC News points out, his return home sparked a major police operation. “In chaotic scenes, riot police pushed Navalny's supporters out of the arrivals hall of Vnukovo airport.”

The BBC News article continues: Last summer, Navalny was attacked in Siberia, “allegedly by an undercover hit squad of Russian security agents. His decision to return home is a direct challenge to Vladimir Putin – and creates a dilemma for the Kremlin.

“It risks turning him into a political martyr, a Nelson Mandela-like figure, and sparking more Western sanctions. Do nothing and the Kremlin's fiercest critic will almost certainly be a thorn in its side in an important election year.”

BBC News reports that Navalny had duped a security agent into revealing details of the operation against him, in a recorded phone conversation that he posted online. “The agent told him that the Novichok used to poison him had been placed in his underpants.”

 

Alexei Navalny: Two hours that saved Russian opposition leader's life

BBC Russian pieced together the story of how flight attendants and medics fought to save the life of opposition leader Alexei Navalny in the skies over Siberia, in an article published on 3 September 2020. “This is the dramatic two-hour timeline of that perilous journey,” it says.

Navalny started to feel unwell during the first half hour of the flight. There was a call for doctors on board – there was no response but a nurse stepped forward. “For the next hour she and the flight attendants focused on keeping Navalny conscious until the pilot could make an emergency landing,” writes BBC Russian.

The article, accessible via the link below, outlines how some passengers saw the events unfold and the medical responses of cabin crew and medical professionals.

 

The Lancet case report – Novichok nerve agent poisoning

 

BBC News report – Russia Navalny: Poisoned opposition leader held after flying home

 

BBC Russian report – Alexei Navalny: Two hours that saved Russian opposition leader's life

 

 


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