Author:  Anne Basil, DO, Emergency Medicine Resident, PGY I
Faculty:  Alexis Cates, DO, Medical Toxicology/Emergency Medicine Attending

The Case:

A 43-year-old male with no past medical history presents to the Emergency Department (ED) with three days of abdominal pain, vomiting, and profuse watery diarrhea. His symptoms have worsened by the time of his arrival. Patient is not forthcoming with any further history.  On exam, he is afebrile, his heart rate is 77 beats per minute, respiratory rate is 16 breaths per minute, blood pressure is 130/70, and his pulse oximetry is 100% on room air. He has dry mucus membranes and mild epigastric tenderness to palpation. The remainder of the exam is unremarkable. 

In the ED, his lab work shows a sight elevation in his BUN/Cr (33.6/1.14), a total bilirubin of 2.8 mg/dL. WBC of 21 x 10^9/L with a neutrophil predominance. All other labs are within normal limits at initial evaluation. The patient’s lab work and physical exam fit with his history of three days of gastrointestinal volume loss. The patient was admitted to the hospital for dehydration and symptom management. He was started on intravenous fluid repletion and ciprofloxacin 500mg every 12 hours to cover for bacterial etiology of gastroenteritis given the profuse nature of diarrhea.

Hospital course: 

Hospital day 2: WBC appears to be resolving with antibiotics, now 17. The patient’s acute renal injury resolved following judicious use of intravenous fluids.  Small drop in platelets  to 105 x10^9/L but otherwise, remainder of labs are unremarkable. ID following given continued diarrhea. 

Hospital day 5: stool sample positive for clostridium difficile toxin, general medical floor team attributes to cipro. When the c. diff diagnosis is discussed with the patient and his wife, he tells you that he is a former KGB agent and was admitted to the hospital under an alias. He tells you he defected to the West in 2000 and is concerned he may have been poisoned…

…You order P.O. metronidazole 400 mg TID. And maybe a psychiatry consult? Working diagnosis at this time is still clostridium difficile diarrhea associated with a possible underlying viral gastroenteritis. 

Hospital day 7: His platelets have continued to drop (now 63) and he is now neutropenic (1.1). His GI symptoms persist despite metronidazole. Differential diagnosis for cytopenia is documented as “viral gastroenteritis versus ciprofloxacin toxicity.” Two days go by and the patient is now febrile. His neutrophil count is < 0.5×10^9/L. He is empirically started on Piperacillin / Tazobactam and G-CSF to recover neutrophil count.

By day 11, the patient had severe mucositis and alopecia. Platelet count is now 2 x10^9/L. His bone marrow is acellular. Blood transfusions are started, and the patient is transferred to the hematology floor. Toxicology is consulted and a heavy metal screen sent. A standard Geiger counter, used for detecting and measuring ionizing radiation, is used but reveals only background values.

Over the next few days, his liver function begins deteriorating. On day 15, the heavy mental screen performed on urine samples comes back with mildly elevated thallium levels, though still under the toxic threshold. The patient does not exhibit peripheral neuropathy, a hallmark of thallium poisoning. Despite this, treatment with Prussian blue is started.

On day 16, the patient continues to be febrile despite broad-spectrum antibiotics. Amphotericin and acyclovir are added. His renal function starts to rapidly decline. Bilirubin is now 14. On hospital day 17, a rapid response is called due to a “heart rate irregularity.” EKG reveals t-wave inversions laterally but a normal troponin. Patient is upgraded to the intensive care unit (ICU) for closer monitoring. Repeat urine thallium levels are now within normal limits. An abdominal ultrasound is done and is normal.

The patient’s atypical clinical course of mucositis, alopecia and bone marrow failure prompt the ICU team to further consider poisoning with a radioactive material. 

Gamma ray spectrometry measurements on a urine sample showed a characteristic 803 keV photon emission, raising the possibility of polonium-210 poisoning. Confirmatory tests were immediately sent.

On the morning of hospital day 20, the patient acutely decompensated. He is acutely altered, now with a florid macular skin rash, hypothermic to 35.5 C, acidotic, anuric, and in cardiogenic shock per transesophageal echocardiogram (TEE).

Later that evening, the patient goes into pulseless electrical activity (PEA) cardiac arrest. Return of spontaneous circulation (ROSC) is achieved with escalating epinephrine. Two hours later, the patient goes into PEA arrests again. ROSC is subsequently achieved. Bedside echocardiogram done at that time reveals a severely reduced ejection fraction but no other abnormalities.

Over the next 16 hours, he remained unstable, requiring inotropic support, hemodialysis, and mechanical ventilation. Patient went into PEA arrest for a third time. The ICU team was not able to achieve ROSC and the patient was pronounced dead on hospital day 21.

Two hours later…results of send out tests became available, consistent with polonium poisoning.

Learning point 1: Polonium Toxicity 

Polonium is a very rare and highly volatile radioactive metal discovered by Marie Skłodowska-Curie in 1898. She named it after her beloved homeland, Poland. If ingested, it is lethal in extremely small doses. Once polonium-210 enters the bloodstream, its fatal effects are almost impossible to stop. 

Because most doctors are not known for their love of or expertise in physics, let’s review some basic concepts so we can better appreciate physiologically just how terrifying these toxic metals can be. 

Radioactivity is the emission of certain particles or electromagnetic waves caused by the breakdown of nuclei in atoms. Elements can vary so they have different numbers of neutrons within their nuclei; these are called isotopes. All of Polonium’s isotopes are radioactive. 

Radiation refers to the particles or energy released during radioactive decay. The radiation emitted may be in the form of particles, such as neutrons, alpha particles, and beta particles, or waves of pure energy, such as gamma and X-rays. The radiation released by polonium-210 is called an alpha particle. 

Alpha particles are a helium nucleus (two protons and two neutrons). Polonium-210 releases only a trivial amount of gamma radiation (the particles that easily travel through tissues and even lead). This means there is no real hazard with external contamination as it must be ingested or inhaled to cause toxicity. [As a spoiler to the case above, contact tracing determined Polonium was added to his tea while meeting with other “prior” KGB agents, causing him to ingest polonium-210 directly].

However, alpha particles are large and carry huge amounts of ionizing energy. Once ingested, the alpha particle pulls electrons out of other elements, ionizing them. In turn, the ionized elements are highly reactive and able to undergo reactions that would not normally occur in a human body. At the cellular level, “being struck by an alpha particle is like being hit by a falling piano.” The DNA and other cellular machinery experience significant damage.

Learning point 2: Clinical course

Because ingested polonium-210 causes whole-body exposure, the clinical manifestations are similar to acute radiation syndrome (which is more often caused by exposure to penetrating gamma radiation). Given the impact of ionizing radiation on the body described above, the clinical picture of patients with acute radiation syndrome makes sense. The body’s fastest growing cells are impacted first: Bone marrow (cytopenias), gastrointestinal (GI) tract (nausea, vomiting, diarrhea, mucositis), and follicular cells (alopecia). As demonstrated in this case, GI symptoms develop within the first 24 hours.  Several days later, the white blood cell count is likely to plummet.  This will progress to thrombocytopenia, bone marrow failure, and ultimately multi-organ failure. 

Due to the significant immunocompromised state, an exposed patient becomes at risk for significant bacterial infections with lack of ability to mount a meaningful immune response.  Damaged and friable intestinal mucosal allow for translocation of endogenous intestinal bacteria, which leads to an overwhelming sepsis which is likely fatal. 

Learning point 3: Diagnosis and Management

Early symptoms of polonium-210 poisoning are indistinguishable from those of a wide range of medical illnesses, infectious diseases, poisonings, and other toxicities, including those from toxic metals such as thallium. Hence, the diagnosis can be delayed and even missed without a high degree of suspicion. To make matters worse, alpha particles are not detected by body scanning with a Geiger counter, the standard instrument for detecting and measuring ionizing radiation. Thus, the standard detection equipment used by most emergency responders and hospitals would completely miss the presence of alpha radiation.  Essentially – polonium-210 is hard to detect! In this case, the diagnosis was ultimately made using gamma-ray spectroscopy of a urine sample. But at this point, you should already be consulting with experts at the Radiation Emergency Assistance Center, described below.

Management:

• Stabilization (ABCs) and decontamination with large volumes of tepid water should be your top priority when encountering these patients. 
• The Radiation Emergency Assistance Center/Training Site (REAC/TS) is part of the U.S. Department of Energy and provides 24/7 response capability for advice and consultation on radiological emergencies. Call them at 865-576-3131 for medical expertise. 
• Good supportive care is essential and should be directed at controlling symptoms, preventing and treating infections, and transfusion of blood and platelets as appropriate. G-CSF should also be given when appropriate. 
• Gastric aspiration or lavage may be useful if performed soon after ingestion. Chelation with Dimercaprol should be considered but it is likely to be increasingly less effective with time since exposure. 
• Once multiple organ dysfunction syndrome (MODS) develops, support organs appropriately (CRRT, mechanical ventilation, etc.). 
• There is currently no antidote.

Learning point 4: Notes for the Emergency Physician

While this case is believed to be the first documented human poisoning with Polonium, toxic radioactive substances have been and will continue to be fatal when accidental or intentional exposures occur. 

Around the world today, there is increasing concern about the possibility of the deliberate release of radioactive materials as a means of inciting economic and political instability. Polonium and other radioactive isotopes with the potential for use in nuclear terrorism as a “dirty bomb,” necessitate medical toxicologic expertise in radiation terrorism. Humans have always had malevolent tendencies. In this era of the dark web and cryptocurrency, it only takes a little imagination to appreciate the catastrophic degree of destruction that our malevolent tendencies could lead to at this point in human history. As we navigate how to approach these possibilities, let us draw on the wisdom of Dr. Marie Skłodowska-Curie, who said, “nothing in life is to be feared, it is only to be understood. Now is the time to understand more, so that we may fear less.”

The Case Concluded:

Two hours after the patient was pronounced dead on hospital day 21, results of send out tests became available and confirmed poisoning with polonium-210. Through meticulous contact tracing by the British government, it was determined that, on November 1, 2006, the patient, whose real name was Alexander Livenenko, was poisoned by two ‘former’ KGB operatives when they slipped polonium into his tea at the Millennium Hotel in London. Three days later, on November 3, 2006, Liveneko presented to the local emergency room under the name Edwin Carter.

Alexander Litvinenko (born 4 December 1962) was a former Russian operative who served in the Soviet KGB and its successor organization, the Russian FSB, from 1988-1998. After speaking out against Russian President Vladimir Putin and the Russian government, he fled retribution to the UK in 2000, where he was granted political asylum. In the UK up until his death, he remained a vocal critic of Putin, writing two books on corruption in the FSB, and worked for the British intelligence services and other European countries intelligence agencies. From his death bed shortly before he died, he delivered the following statement: “You may succeed in silencing me but that silence comes at a price. You have shown yourself to be as barbaric and ruthless as your most hostile critics have claimed. You have shown yourself to have no respect for life, liberty or any civilized value. You have shown yourself to be unworthy of your office, to be unworthy of the trust of civilized men and women. You may succeed in silencing one man but the howl of protest from around the world will reverberate, Mr. Putin, in your ears for the rest of your life. May God forgive you for what you have done, not only to me but to beloved Russia and its people.”

Had the results confirming polonium poisoning come back just a few hours earlier, would this have allowed Mr. Litvinenko to survive?

Unfortunately, an earlier diagnosis would have not changed his outcome as the high level of polonium absorbed and distributed to body organs within hours of intake would have resulted in rapid cell death and multiple organ failure regardless. It is unlikely that even if he had been correctly diagnosed on the day he first presented to the hospital, death could have been avoided. In the initial case report published in the Lancet, the authors concluded, “preparedness for such cases in the future would require a high level of clinical suspicion and investment in sensitive detection instrumentation by hospitals. However, such cases would remain untreatable without research into effective antidotes that reduce levels and biodistribution of polonium and limit the extent of organ damage.”

References:

Polonium-210 poisoning: a first-hand account. Nathwani, Amit C et al. The Lancet, Volume 388, Issue 10049, 1075 – 1080.

Gussow, Leon MD Five Things Every Toxicologist Should Know About Polonium, Emergency Medicine News: February 2007 – Volume 29 – Issue 2 – p 22 doi: 10.1097/01.EEM.0000264918.11267.01

What is polonium – and why is it so dangerous? – OpenLearn – Open University

Radiation Emergency Assistance Center/Training Site (REAC/TS).

Polonium • LITFL • CCC ToxicologyNemhauser JB. The polonium-210 public health assessment: the need for medical toxicology expertise in radiation terrorism events. J Med Toxicol. 2010;6(3):355-359. doi:10.1007/s13181-010-0090-x