Did the nerve agent VX kill Kim Jong Nam?

Last night Malaysian authorities announced that they identified the nerve agent VX taken off the face of Kim Jong Nam, who was murdered on February 13 at Kuala Lumpur International Airport.

As the History Channel video above indicates, nerve agents are potent acetylcholinesterase inhibitors that utilize the same mechanism as organophosphate insecticides such as parathion. Conceptually, the effect of VX exposure is simple: wherever in the body acetylcholine acts as a neurotransmitter, nerve agents cause unregulated, chaotic activity. There are generally 3 such sites:

  • muscarinic sites: connections between nerves and secretory glands and smooth muscle
  • nicotinic sites: neuromuscular junctions
  • central sites: in the cerebrum and brainstem

The effects of nerve agents on these sites are predictable:

  • muscarinic: massive respiratory secretions, bronchospasm, severe diaphoresis, vomiting, diarrhea, meiosis, and lacrimation
  • nicotinic: voluntary muscle fasciculation and spasm, followed by fatigue and flaccidity
  • central: seizures, central apnea

Victims exposed to nerve agents die of respiratory failure, due to a triple-whammy: airway obstruction and bronchospasm, dysfunction of voluntary muscles of respiration, and loss of central drive to breathe. With 3 separate types of effects, there are fittingly 3 antidotes:

Despite the announcement that VX was identified, there are still some puzzling details that don’t seem to fit. Video of Mr. Kim after he was exposed to the agent does not seem to show muscle weakness, fasciculation, or copious secretions. Also, given that VX is often called one of the deadliest substances on the planet, the attackers did not seem to suffer serious effects. (It is not clear if they were wearing gloves, and a recent report suggests that one of the young women seen on the video vomited.) There has also been speculation that a binary weapon was involved, in which two harmless chemicals might have been combined to produce VX.

[Addendum: 2/24/17  14:32 CST]

According to emedicine.com, after dermal exposure of V-series agents onset of symptoms may be delayed for hours. I remember from the time I taught in the Department of Defense Domestic Preparedness Program that Dr. Fred Sidell, one of the nation’s experts on chemical weapons, stated that symptoms might not develop until 18 (!) hours after skin exposure to VX. This would be consistent with what we know about the attack on Mr. Kim. However, if the agent got in his eye, I would expect meiosis to produce markedly decreased vision.

Note also that VX is quite viscous, having high persistence and  low volatility. Whereas the G-series nerve agents (tabun, soman, sarin) have approximately the consistency of water, VX is more like motor oil.

CORE EM: Vertebral Osteomyelitis

Originally published at CoreEM.net, who are dedicated to bringing Emergency Providers all things core content Emergency Medicine available to anyone, anywhere, anytime. Reposted with permission.

Follow Dr. Swaminathan and CORE EM on twitter at @EMSwami and @Core_EM

Written by: Latrice Triplett, MD // Edited By: Anand Swaminathan, MD

Definition

  • Inflammation of the vertebrae due to a pyogenic, fungal or mycobacterial organism.

    MRI Images - Vertebral Osteomyelitis (The Lancet)
    MRI Images – Vertebral Osteomyelitis (The Lancet)
  • Classified as either acute (days), subacute (weeks) or chronic (months)
  • Spondylodiscitis: a term encompassing osteomyelitis, spondylitis and discitis. Often used interchangeably with osteomyelitis.

Epidemiology

  • 1 to 2.4 cases per 100,000 people (Zimmerli 2010)
  • More common in males with M:F of 3:1
  • Rate is also increasing due to increased number of spinal procedures
  • Typically affects adults, with most cases occurring in patients over 50 years old.

Pathogenesis

  • Infection occurs by three routes:
    • Hematogenous spread – secondary to infections of the GU, skin, soft tissue and respiratory system, indwelling catheters or endocarditis
      • Due to the bifurcated structure of the arterial supply, generally presents as infection of 2 contiguous vertebrae and the intervertebral disc
    • Direct inoculation during trauma or spinal surgery
    • Spread from adjacent soft tissue infection
  • Organism
    • Most cases in the United States are pyogenic.
      • Most common organism is Staph Aureus (36-67% of cases) (Boody 2015).
      • Other pathogens include: E. Coli, Pseudomonas Aeruginosa and Group B and G hemolytic Strep
    • Other pathogens to consider:
      • Fungal – blastomycosis, coccidiomycosis, histoplasmosis, aspergillosis
      • Brucellosis
      • Mycobacterial
    • Location: lumbar (48%) most common, followed by thoracic (35%) and cervical (6.5%)

History and Physical

  • Risk Factors:
    • Diabetes Mellitus (most common)
    • Immunosuppression: HIV, Malignancy, chronic steroids or immunosuppressant medication use
    • Spinal fracture, trauma or recent procedure
    • Substance Abuse: Alcoholism and IVDU
    • Presence of an indwelling vascular device
    • Elderly
  •  Symptoms
    • Back pain – often described as dull, may be present for weeks to months
    • Neurologic symptoms (paresthesias, weakness or radiculopathy) present in approximately one-third of patients
    • Most patients lack systemic symptoms
  • Exam
    • Tenderness over affected vertebrae
    • Paraspinal tenderness or spams may be present which may mislead the clinician towards a musculoskeletal diagnoses

Diagnostics

  • Labs
    • Leukocytosis and Neutrophilia are poorly sensitive and highly non-specific (Gouliouris 2010). The degree of elevation does not predict disease severity.
    • ESR and CRP are sensitive, yet not specific.
      • CRP concentration rise and fall quicker than ESR, often used to guide treatment
    • Blood Cultures – an important element in management and treatment
      • Blood culture positivity often decides whether a patient will require a bone biopsy.
      • Cultured specimen narrows antibiotic coverage
    • Urinalysis/Urine Culture –UTI is a frequent missed source of bacteremia (especially in diabetic patients).
  • Imaging
    MRI Images (mghradrounds.org)

    MRI Images – mghradrounds.org

    • Gadolinium enhanced MRI – modality of choice, highly sensitive and specific (Mylona 2009).
      • Although MRI with and without contrast is preferred, a non-contrast MRI can evaluate for inflammatory processes.
      • If a patient requires premedication or has renal failure, obtain the non-contrast MRI first. A contrast MRI can be done later to delineate subtle findings.
      • Findings include: enhancement (hypointense on T1 and hyperintense on T2) of vertebral endplates and adjacent disc space (Image 1)
    • CT Scan with IV contrast – use only if MRI contraindicated
      • Inferior in evaluation of disc spaces and neural tissues
        • Less sensitive than MRI and may be falsely negative in early disease
        • Used primarily by surgeons for biopsy of spine
      • Findings include loss of end plate definition and narrowing of disc space (Image 2)
      • Previously used CT Myelogram now out of favor due to potential for intradural spread of infection.
    • Plain Radiographs – often done to evaluate other causes (masses, fracture) however not recommended for diagnosis
      • Poorly sensitive and findings typically present in advanced disease (10-14 days after onset), once significant bone demineralization has already occurred
    • Radionuclide studies – (including: Tech 99m Bone scan, Gallium -67)
    • Sensitive but not specific, long acquisition time and difficult to obtain in the emergent setting

Management

  • Pathogen directed therapy – Antibiotics tailored towards cultured organism
    • Given the dependence on blood culture results to guide therapy, current recommendations (IDSA 2015 Guidelines) suggest holding empiric antibiotics in medically stable patients (non-septic, hemodynamically stable, neurologically intact) until cultures grow out.
      • Note: this is a weak recommendation based on low quality evidence and patients should be managed on a case by case basis in conjunction with the inpatient treatment team
    • Empiric coverage:
      • Vancomycin 15-20 mg/kg/dose every 8-12 hrs PLUS
      • 3rd Generation Cephalosporin: Cefotaxime (2 g IV every 6 hrs), Ceftriaxone (1 to 2 g IV daily) or Ceftazidime (1 to 2 g IV every 8 -12 hrs)
      • Alternate: Cefepime 2 g IV every 12 hours
      • Duration: 6 weeks (occasionally 12 weeks if advanced disease) of IV antibiotics followed by 1-2 months of oral antibiotics
  • Surgical Consult – although most patients are successfully treated with antibiotics alone, some may require surgical intervention if there is concern for vertebral instability or spinal cord compromise.
    • Indications for surgical intervention include: associated abscess formation, spinal cord compression, progression of disease despite antimicrobial treatment
    • Obtain consult (Neurosurgery or Orthopedics) early, since patients may require bone biopsy for detection of organism

Take Home Points

  • Clinical presentation is very nonspecific; evaluate all patients presenting with back pain for infectious risk factors.
  • Baseline labs should not guide diagnosis, but may assist in later management.
  • MRI is key to diagnosis, obtain this imaging in all patients who raise clinical suspicion
  • Patients with hemodynamic instability and neurologic compromise warrant empiric antibiotics. The initiation of empiric antibiotics in hemodynamically stable, neurologically intact patients should be done on a case-by-case basis.

References

Berbari EF, Kanj SS, et al. Executive Summary: 2015 Infectious Disease Society of America (IDSA) Clinical Practice Guidelines for the Diagnosis and Treatment of Native Vertebral Osteomyelitis in Adults. Clin Infect Dis 2015 Sept 15;61(6):859-63. PMID: 26316526

Boody B, et al. Vertebral Osteomyelitis and Spinal Epidural Abscess: An Evidence-based Review. J Spinal Disord Tech. 2015 Jul;28(6):E316-27 PMID: 26079841

Chowdhury V, Gupta A, Khandelwal N. Diagnostic Radiology: Musculoskeletal and Breast Imaging. 3rd ed. New Delhi: JP Brothers Medical Ltd; 2012

Della-Guistina, D. Evaluation and Treatment of Acute Back Pain in the Emergency Department. Orthopedic Emergencies 2015 May; 33(2) 311-26. PMID: 25892724

Gouliouris T, et al. Spondylodiscitis: update on diagnosis and management. J Antimicrob Chemother. 2010 Nov;65 Suppl 3:iii 11-24 PMID: 20876624

Mylona E, et al. Pyogenic Vertebral Osteomyelitis: A Systematic Review of Clinical Characteristics. Semin Arthritis Rheum. 2009 Aug; 39(1):10-7. PMID: 18550153

Pruitt CR, Perron AD. Specific Disorders of the Spine. In: Sherman SC eds. Simon’s Emergency Orthopedics. 7th ed. New York, NY: McGraw-Hill; 2014

Winters ME, Kluetz P et al. Back Pain Emergencies. Med Clin North Am, 2006 May;90(3):505-23. PMID: 16473102

Zimmerli W. Vertebral Osteomyelitis. N Engl J Med 2010 Mar; 362(11)1022-9. PMID: 20237348

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Topical Toxicology: VX Gas and Kim Jong-nam

*Thanks to Dr. Clark Owyang for following this “case” with me!

 

On February 13, Kim Jong-un, son of Kim Jong-il and half-brother of current North Korean leader Kim Jong-un, was poisoned at Kuala Lumpur airport in Malaysia. He died shortly after. Yesterday, the Malaysian police reported that Kim Jong-nam died of exposure to VX gas.

 

Some background:

The UK first synthesized VX gas in 1952 in the UK, and then gave it to the U.S. for military development. It is an organic phosphorous compound, and the most potent nerve gas ever developed. The aerosolized dose causing mortality in 50% of humans (LD50) is only 10 mg/minute/m3. Because of its low volatility, it poses a higher risk for dermal exposure than respiratory exposure. Via this dermal route, death generally occurs within several hours.

 

Toxidrome:

VX is an acetylcholinesterase inhibitor, meaning that it prevents degradation of acetylcholine bound at the neuromuscular junction. It works at muscarinic, nicotinic, and central receptors. Muscarinic effects include the SLUDGE symptoms we all know: salivation, lacrimation, urination, defecation, GI cramping, and emesis. Nicotinic effects include muscle fasciculations, weakness, and paralysis. Centrally, this agent may cause seizures (prior to the flaccid paralysis caused by nicotinic activation) and respiratory depression.

 

In an aerosol exposure, the eyes are affected first. Symptoms include miosis (due to direct contact of nerve gas with the eye), blurring of vision, and ciliary spasm that causes eye pain. Next, the patient may experience rhinorrhea, increased airway secretions, and bronchial constrictions.

 

Treatment:

Self-protection is of the utmost importance. Don your own protective equipment before treating patients. The first treatment step is always decontamination. Clothing exposed to nerve gas may continue to release the toxic agent in fumes. Remove all the patient’s clothing and place it in an airtight receptacle. Next, the patient should be showered. Consider using a solution that releases chlorine, like household bleach or other alkaline substances. These substances hydrolyze and inactivate nerve gas. To make bleach application safe for skin, dilute household bleach in water to make a 1:10 solution. If bleach or an alkaline substance cannot be obtained rapidly, regular soap and water should be used.

 

Both the muscarinic and nicotinic effects of nerve gas must be addressed. Atropine is an anticholinergic, and should be used to reverse muscarinic symptoms. The standard dose determined by the military is 2mg, but severely poisoned adults should get a first dose of 5-6 mg. Titrate atropine to effect. The endpoint is drying of bronchial secretions. Tachycardia is expected. Do not stop administering atropine to a tachycardic patient who is still experiencing bronchial secretions.

 

Pralidoxime chloride (pyridine-2-aldoxime, or 2-PAM) reverses the nicotinic (i.e. neuromuscular) effects of nerve gas. It re-activates acetylcholinesterase. If “aging” (i.e. irreversible dealkylation) of the nerve gas-acetylcholinesterase has already occurred, 2-PAM won’t work. VX has an aging half-life of 48 hours.

 

References:

  1. Paddock RC, Sang-hun C. Kim Jong-nam was killed by VX nerve agent, Malaysians say. In: The New York Times. 23 February, 2017.
  2. Hoffman RS, Howland MA, Lewin NA, Nelson L, Goldfrank L. 132: Chemical weapons. In: Goldfrank’s Toxicologic Emergencies. 10th
  3. Joosen MJ, van den Berg RM, de Jong AL, et al. The impact of skin decontamination on the time window for effective treatment of percutaneous VX exposure. Chem Biol Interact. 2016;20009-2797(16):30030-8.
  4. Thiermann H, Worek F, Kehe K. Limitations and challenges in treatment of acute chemical warfare agent poisoning. Chem Biol Interact. 2013;206(3):435-43.

Pediatric Pneumonia

Community Acquired PneumoniaPediatric infectious diseases have been a common topic for the PedEMMorsels and rightfully so as kids love to collect numerous viral and bacterial infections (ex, Measles, Flu, Mumps, Omphalitis). With that being said, pneumonia is often the topic of conversation in the Peds ED and, thus, deserves special attention. We have discussed pneumonia several times previously (ex, Pneumonia Detective, Round Pneumonia, Penicillin for Pneumonia, and CAP), but recently our friends at the Section on Emergency Medicine at the AAP published a easy to follow guide to Community Acquired Pneumonia (displayed below). Let is take another moment to ensure we are up to date with current recommendations for Pediatric Pneumonia.

 

Pediatric Pneumonia: Basics

  • We see a lot of it – accounts for >500,000 ED visits annually!
  • Accounts for ~7% of pediatric admissions.
  • Streptococcus pneumoniae is the most common bacterial cause of community acquired pneumonia in kids.
    • Narrow spectrum beta-lactam antibiotics are still very effective against S. pneumoniae.
    • A significant amount of patients (even after published recommendations) continue to receive unnecessary broad spectrum antibiotics as initial therapy! [Ross, 2014]

 

Pediatric Pneumonia: Management Algorithm

AAP Pediatric Pneumonia Algorithm 2017

 

Moral of the Morsel

  • Penicillin works well! Most children, even ones who require hospitalization, will benefit from a narrow spectrum penicillin.
  • Look for an effusion! The presence of an effusion makes it a more complicated pneumonia and warrants more careful consideration.
  • No blood required! The mild and most of the moderate pneumonias will not benefit from extensive blood testing.

 

References

Queen MA1, Myers AL, Hall M, Shah SS, Williams DJ, Auger KA, Jerardi KE, Statile AM, Tieder JS. Comparative effectiveness of empiric antibiotics for community-acquired pneumonia. Pediatrics. 2014 Jan;133(1):e23-9. PMID: 24324001. [PubMed] [Read by QxMD]

Leyenaar JK1, Shieh MS, Lagu T, Pekow PS, Lindenauer PK. Comparative effectiveness of ceftriaxone in combination with a macrolide compared with ceftriaxone alone for pediatric patients hospitalized with community-acquired pneumonia. Pediatr Infect Dis J. 2014 Apr;33(4):387-92. PMID: 24168982. [PubMed] [Read by QxMD]

Ross RK1, Hersh AL, Kronman MP, Newland JG, Metjian TA, Localio AR, Zaoutis TE, Gerber JS. Impact of Infectious Diseases Society of America/Pediatric Infectious Diseases Society guidelines on treatment of community-acquired pneumonia in hospitalized children. Clin Infect Dis. 2014 Mar;58(6):834-8. PMID: 24399088. [PubMed] [Read by QxMD]

Bradley JS1, Byington CL, Shah SS, Alverson B, Carter ER, Harrison C, Kaplan SL, Mace SE, McCracken GH Jr, Moore MR, St Peter SD, Stockwell JA, Swanson JT; Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. Executive summary: the management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. Clin Infect Dis. 2011 Oct;53(7):617-30. PMID: 21890766. [PubMed] [Read by QxMD]

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