Acute cyanide exposure is an uncommon exposure the majority of which are unintentional but often results in cardiovascular embarrassment when it occurs. Various inorganic cyanide salts are used industries including metallurgy, photography, plastic manufacturing, and fumigation. Potassium and sodium cyanide salts are common laboratory reagents and chemists are frequent victims of accidental exposures. Organic compounds such as acetonitrile (methyl cyanide), found in artificial nail remover, have a cyano group bonded to alkyl moieties. Some plants, particularly pitted fruits from the Prunus species (apricots, cherry, peaches), contain the cyanogenic glycoside, amygdalin, which is converted to cyanide and other substances following ingestion. Concomitant cyanide poisoning may also occur in fire victims with smoke inhalation.
An otherwise healthy 35-year-old man was brought to the emergency department (ED) by sheriff deputies following development of depressed level of consciousness after he was booked into custody three hours prior. He was conscious when he was initially arrested by the police following a 2 hour standoff at his home. No other medical history was available. On arrival to the ED, his vital signs were: T 36.9 degrees Celsius rectally, BP 92/58, HR 130, RR 24, and oxygen saturation 100% on facemask with oxygen flow rate of 15 liters/min. On examination he was unconscious but did withdraw to painful stimuli in a extremities. There was no evidence of trauma and his pupils were equal and reactive to light and bedside glucose test was 231 mg/dL.The ED team decided to intubate the patient to protect his airway. Electrocardiogram demonstrated sinus tachycardia but was otherwise normal. Blood was obtained for analysis immediately following intubation and revealed arterial blood gas: pH 6.97, pCO2 37 mmHg, pO2 235 mmHg. Serum chemistry was significant for bicarbonate 7 mEq/L, glucose 226 mg/dL and an anion gap of 34. Measured serum osmolarity was 302 mOsm/kg and calculations yielded an osmol gap 2 (normal range -5 to 15). Initial plasma lactate 17.3 mmol/L (normal range 0 - 2.2 mmol/L). Transaminases and other measures of liver function were normal. Ethanol, acetaminophen, and salicylate concentrations were undetectable. Urine immunoassay drug of abuse screen was negative.
1) Under which clinical scenarios should cyanide poisoning be suspected?
2) Which laboratory tests may be helpful in the management of acute cyanide poisoning?
3) When utilizing antidotal therapy for cyanide poisoning, what potential problems associated with administration should the clinician consider before giving each agent ?
From 2007-2011, there 1,148 exposures to cyanide reported to the American Association of Poison Control Centers with the majority of cases being categorized as unintentional involving chemical laboratory personnel. Another study reported that 45% of cases were intentional and 25% of cases of ingestions. Of the ingestions, here were 8.3% deaths and 9% cardiac arrests or hypotension with the majority of these cases being intentional suicide.
Cyanide is a potent cellular asphyxiant inhibiting multiple enzyme systems but most importantly it inhibits cytochrome oxidase, an enzyme in the electron transport chain responsible for aerobic production of adenosine triphosphate (ATP). Because of this inhibition, ATP production is shifted to the much more inefficient anaerobic pathway and results in accumulation of lactate. Cyanide is also a potent neurotoxin with direct effects on the central nervous system (CNS) particularly in areas of the brain with the highest oxygen needs and metabolic activity. Interestingly, humans, animals, and plants have an endogenous enzyme, rhodanese (cyanide sulfuryl transferase), designed to detoxify cyanide, however, this mechanism is rapidly overwhelmed in the setting of acute poisoning. Along with the central nervous system, the cardiovascular system is also very sensitive to the insults of cyanide.
Because acute cyanide poisoning may impact multiple organ systems in addition the highly oxygen sensitive central nervous and cardiovascular systems, initial clinical signs may be nonspecific and vague such as headache, nausea, vomiting, anxiety, agitation, and confusion. With severe poisonings, lethargy, seizures and coma are potential manifestations of CNS toxicity. While terminal findings of hypotension and bradycardia, resulting in cyanosis are typical of severe cardiovascular toxicity, clinicians may briefly encounter tachycardia and hypertension due to catecholamine mediated reflex compensatory processes prior to hemodynamic embarrassment.
A definitive laboratory diagnosis of acute cyanide poisoning may be challenging for most hospitals in the United States because cyanide concentrations are not routine available in a timeframe to guide emergency medical care but both cyanide and thiocyanate levels may be used to confirm the diagnosis. Therefore, timely diagnosis and clinical management decisions are based solely on clinical manifestations and surrogate laboratory markers. Due to the inhibition of oxygen utilization, arterial blood may not unload oxygen and central venous blood may have a higher than expected oxygen saturation (>90%). This phenomenon is sometimes referred to as “arterialization” of venous blood. While the presence of this finding may be suggestive of acute cyanide poisoning, it may not be sufficiently specific for clinicians to completely rely on it to initiate potentially life-saving therapy for cyanide. Moreover, the finding may also be present in other medical conditions and poisonings in which oxygen utilization is impaired. Lastly, venous blood gases are not routinely sampled from central sites and application of the >90% oxygen saturation finding to peripherally obtained venous blood is not currently recommended.
Elevated lactate is another commonly used but nonspecific surrogate marker of acute cyanide poisoning. Several caveats should be considered in interpreting lactate because elevations may occur with ingestion of ethylene glycol antifreeze, propylene glycol antifreeze, or methanol but for different reasons in each case. The principal metabolite in the metabolism of ethylene glycol, glycolic acid, shares sufficient chemical structural homology to lactate. The presence of glycolic acid may cause interference in many analyzers and result in falsely elevated lactate measurements. Lactic acidosis has also been rarely described in cases of methanol poisoning and attributed to inhibition of oxidative phosphorylation by formate. Metabolism of propylene glycol produces both isomers of lactate. Because of the aforementioned, elevated lactate is not sufficient to diagnose cyanide poisoning or exclude any of the toxic alcohols mentioned. Additionally, metformin and severe acetaminophen poisonings have been described to cause lactic acidosis. The toxins mentioned above are not intended to be an exhaustive list of substances producing elevated lactate measurements but rather to illustrate pitfalls in the interpretation of the result.
Initial management of cyanide poisoning is largely supportive and includes supplemental oxygen as well as airway and ventilator support. Activated charcoal may be considered in conscious patients who present soon after ingestion. Although adsorption of cyanide to charcoal is poor, binding may be sufficient to avert severe toxicity in some case. Intravenous crystalloid should be administered initially to resuscitate hypotensive patients. Patients who are unresponsive of fluid administration should be given vasopressors. Sodium bicarbonate may be considered in severely acidemic patients that are refractory to other supportive measures.
For several decades that mainstay of antidotal treatment for suspected acute cyanide poisoning has been the administration of nitrite to induce methemoglobinemia and thiosulfate. Both nitrite and thiosulfate when given alone have been demonstrated to mitigate cyanide toxicity but greater benefit has been demonstrated when they are used together. While the administration of thiosulfate has few downsides, nitrites on the other hand may precipitate or exacerbate hypotension through its vasodilatory effects. Additionally nitrites lead to the production of methemoglobinemia, which may complicate concomitant carbon monoxide poisoning in fire victims.
Since the Food and Drug Administration approved its use for cyanide poisoning in 2006, hydroxocobalamin, a vitamin B12 precursor, has largely supplanted nitrite and thiosulfate as the first line antidote because of its ability to ameliorate toxicity as well as having a desirable safety profile. Acute allergic reactions and transient reddish discoloration of skin, mucous membranes, and urine may result from administration of hydroxocobalamin. While the reddish discoloration may be seemingly inconsequential, it may have important implications should the patient later require hemodialysis for severe acidemia, hyperkalemia, toxic alcohol intoxication, or renal insufficiency. During dialysis, blood normally passes on one side of a semi-permeable membrane and dialysate on the other. When hydroxocobalamin is present in the body, it not only discolors body fluids but will also discolor the dialysate as blood passes by the membrane. Most dialysis machines are equipped with photosensors intended to detect the undesired passage of red blood cells across the membrane and automatically shuts down the machine when a “blood leak” is detected. While it is possible to manually disable the sensor on some dialysis machines, disabling this safety mechanism is not advisable. When considering empiric administration of hydroxocobalamin, clinicians should also factor in the likelihood of the patient’s potential need for dialysis in the course of treatment. .
In conclusion, cyanide poisoning is rare and confirming the diagnosis in a timely manner is challenging. For these reasons, clinicians must be vigilant and consider this toxin in certain high-risk situations and initiate timely antidotal therapy.
Discussion of case questions
1) Under which clinical scenarios should cyanide poisoning be suspected?
Answer: (a) Sudden collapse of laboratory or industrial workers, (b) fire victim with coma or acidemia, (c) attempted suicide patient with unexplained coma or acidemia, (d) ingestion of acetonitrile containing artificial nail remover, (e) ingestion of fruits or plants containing cyanogenic glycosides (Prunus spp, Manihot spp, Linum spp. Sorgum spp, and Phaseolus spp).
2) When utilizing antidotal therapy for cyanide poisoning, what potential problems associated with administration should clinician consider before giving each agent?
Answer: Serum chemistry panel and blood gases may be helpful in establishing a presumptive diagnosis of cyanide poisoning when acidemia or elevated central venous oxygen saturation is demonstrated. These tests may also be helpful in monitoring response to therapy. While cyanide (whole blood) and thiocyanate (serum or urine) levels may be used to confirm cyanide exposure, neither test is typically available in a timely manner to guide clinical decisions.
3) How is cyanide best treated?
Answer: When administering nitrites, clinicians should be aware that the production of methemoglobinemia may impair blood oxygen carrying capacity and delivery to end organs particularly in fire victims with carbon monoxide poisoning. The clinician should also not be surprised if the patient becomes hypotensive following nitrite administration. Administration of thiosulfate alone has fewer downsides. For patients with severe acidemia who may require hemodialysis, the administration of hydroxocobalamin may cause some dialysis machines to initiate an auto-shutdown process due to a false “blood leak” detection across the dialysis membrane. A careful risk benefit analysis should be determined for use of cyanide antidotes when clinicians are faced with these situations
Consultation with a specialist in poison information or with a medical toxicologist can be obtained free of charge by calling the California Poison Control System at 1-800-222-1222.
This issue of CALL US... was written by Binh Ly, MD
Published on May 8, 2015
CALL US... is published by the California Poison Control System. Editorial Board: Executive Director, Stuart E. Heard, PharmD; CPCS Medical Directors: Timothy E. Albertson, MD, Richard F. Clark, MD, Richard Geller, MD, Kent R. Olson, MD; CPCS Managing Directors: Justin Lewis, PharmD, Thomas E. Kearney, PharmD, Lee Cantrell, PharmD; Editor:Binh T. Ly, MD; Assistant Editor: Alicia Minns, MD.
The California Poison Control System is operated by the School of Pharmacy, University of California, San Francisco (coadmin @calpoison.org)