Cyanide poisoning in patients with inhalation injury – the phantom menace

Introduction

Respiratory complications caused by smoke inhalation and associated major burns are a challenge for physicians taking care of these patients [1]. Inhalation injury comprises direct thermal injury, chemical irritation of lung parenchyma and the systemic effects of absorption of the toxic products of combustion. It is well known that fire generates various gases, some of them are very toxic, such as carbon monoxide (CO) and hydrogen cyanide (HCN), which can be lethal on inhalation [2]. There is increasing evidence that cyanide toxicity plays an important role in smoke inhalation injury and its associated mortality [3].

Cyanide refers to any substance that contains the cyano (CN) group. This includes inorganic cyanides with a negatively charged cyanide ion, such as sodium cyanide, and organic cyanides with a covalent CN group, such as methyl cyanide. Inorganic cyanides are salts of hydrocyanic acid, also known as hydrogen cyanide [4]. Cyanide compounds are widely used in the production of resins, adhesives, explosives, or rubber products. They are essential in the electrochemical industry. They are used for hardening steel, for extracting gold and silver from ore minerals or for plating. Cyanides are released into the air during the combustion of substances containing carbon and nitrogen (plastics, glass wool, wool, silk, nylon, foam or varnishes).

Cyanide's mechanism of action as a poison lies in its inhibition of numerous enzyme systems, including xanthine oxidase, carbonic anhydrase, glutamate decarboxylase, and cytochrome oxidase. Binding to the ferric iron of cytochrome a3, the last enzyme in the mitochondrial electron transport chain, is considered cyanide's most important effect [5,6]. This leads to shutting down cellular aerobic phosphorylation. Whole blood cyanide levels above 0.5–1.0 mg/L (19–40 μmol/L) are regarded as toxic [7]. Untreated levels above 2.5–3 mg/L (96–115 μmol/L) are potentially fatal [8].

We present two mini case reports of patients with burn trauma associated with inhalation injury and very probable cyanide intoxication. Due to the urgency of the situation, the diagnosis of intoxication was made on the basis of clinical and laboratory evidence, without confirmation by determining plasma cyanide levels.

Mini case report I

A 61-year-old woman was found in a burning house. The exact aetiology of the fire was unclear; the most probable version was burning a candle. The patient was intubated by the first responders, connected to mechanical ventilation and transferred to the Department of Burns and Plastic Surgery, University Hospital Brno.

The initial examination was performed in the operating theatre under general anaesthesia. A central venous catheter (CVC) and arterial line (AL) were inserted and the burn wounds were treated. The total extent of the burns was 26% total body surface area (TBSA). As a part of the complex diagnosis, fibreoptic bronchoscopy (FOB) was performed and revealed grade III inhalation injury.

After the primary treatment, the patient was hospitalised at the Intensive Care Unit (ICU) of our department. The individual fluid resuscitation was initiated, using continuously administered balanced crystalloid solutions. Catecholamine support was needed due to circulatory instability. Active and passive tetanus immunization was also performed on admission. Inhalation therapy was introduced according to the standard inhalation injury algorithm (mucolytics, unfractionated heparin, salbutamol). Metabolic acidosis (pH 7.31) and increased venous oxygen saturation (0.906) predominate in the initial laboratory findings. Due to the high suspicion of cyanide intoxication, Cyanokit (hydroxocobalamin for injection) 5 g was administered intravenously. Arterial and venous blood gas parameters began to normalise at an early stage after antidote use (Graph 1).

In view of the location of the full-thickness burns on the face and ventral side of the neck, and in view of the expected long-term mechanical ventilation, surgical tracheostomy was performed on 1st day postburn. Bronchoscopy was performed regularly with gradual improvement of the findings in the upper and lower airways. After the successful management of the initial burn shock, surgical treatment followed, including surgical necrectomy, wound bed preparation and wound closure using split-thickness skin grafts. The grafts healed without any complications. Only a residual defect of the frontal area with exposed frontal bone had to be covered with a serratus anterior free flap [9]. After 114 days of hospitalization at our department, the patient was transferred to the Department of Eye Treatments of the University Hospital Brno to resolve corneal defects.

Mini case report II

A 46-year-old man was found unconscious in a burning house, rescued by a fire brigade. An early ventricular fibrillation developed in the patient, for which cardiopulmonary resuscitation was initiated immediately. Blood circulation was successfully restored within 3 minutes. Then he was transported to our department under mechanical ventilation.

The initial examination was performed in the operating theatre under general anaesthesia. A CVC and AL were inserted and the local treatment was initiated. The total extent of the burns was 31% TBSA, most of them included full-thickness burns. FOB was also performed and revealed grade 3 inhalation injury. Bronchoalveolar lavage was performed.

After the primary treatment, the patient was hospitalised at ICU of our department. Despite the massive fluid resuscitation, the support the blood circulation with high doses of catecholamines was necessary. Inhalation therapy was introduced according to the standard inhalation injury algorithm. Signi­ficant metabolic acidosis (pH 6.96), lactate elevation (12.5 mmol/L) and venous blood arterialization (0.985) were detected in the laboratory analysis. Due to clear signs of cyanide intoxication, Cyanokit (hydroxocobalamin for injection) 5 g was administered immediately, followed by 10 mL natrium thiosulphate 10% administrated intravenously. At the same time, carbon monoxide intoxication was confirmed (COHb 0.179).

Despite all efforts, it was not possible to stabilise the patient's clinical condition as well as laboratory parameters (Graph 2). Gradually, symptoms of multiple organ dysfunction developed. The death caused by multiple organ failure was noted on 1st day postburn.

Discussion

Recognition of cyanide intoxication is more complicated than carbon mo­noxide intoxication. Clinical signs are non-specific and almost identical to carbon monoxide intoxication. Chronic low-dose exposure includes anxiety, dizziness, blurred vision, headache, nausea, hypertension, tachycardia, palpitations, or tachypnoea. In acute intoxication with higher doses, the main symptoms are somnolence to loss of consciousness, convulsions, bradycardia, hypotension, bradypnoea, development of pulmonary edema, cardiac arrhythmias, and circulatory instability [3]. However, patients with a history of burning in an enclosed space and with suspected inhalation injury are often intubated at the site of the accident already and connected to an artificial lung ventilation. Therefore, these clinical signs cannot always be reliably identified.

An increase in oxygen saturation of venous blood is typical for cyanide intoxication. This phenomenon is described as the arterialization of venous blood. On the other hand, arterial blood oxygen saturation is not reduced. Increased lactatemia along with an increase in the anion gap represents another laboratory sign of cyanide intoxication. We regularly find metabolic acidosis.

In contrast to the determination of carbonyl haemoglobin in carbon mo­noxide intoxication, the direct determination of plasma cyanide levels by atomic absorption spectrophotometry is almost unusable for routine clinical practice. This examination is performed in a few specialised laboratories only and usually takes several days. Therefore, it is necessary to start therapy even if poisoning is suspected, without definitive laboratory confirmation.

Cyanide intoxication therapy is based on supportive therapy in combination with the use of a specific antidote. Aggressive supportive care is critical to successful antidote use and survival in the cyanide-intoxicated patient. The goals of the treatment in the early stages of poisoning are to maintain adequate tissue perfusion and oxygenation while antidotal treatment and endogenous mechanisms reduce the availability of free cyanide at the sites of its toxic effects [10]. The therapy is based on high-flow oxygen. In more serious cases, airway management is required by endotracheal intubation, especially if intoxication is part of inhalation injury. The use of hyperbaric oxygen therapy is also advocated. However, the evidence for its efficacy in this situation is limited and inconsistent [11–13]. On the other hand, hyperbaric oxygen therapy is essential in carbon monoxide poisoning. We immediately start volumotherapy in case of hypotension development, using vasopressors, if necessary. We take care of metabolic aci­dosis. Performing the supportive the­rapy should not delay the administration of a specific antidote in any way.

The first group of cyanide antidotes are cobalt compounds. Hydroxocobalamin (Cyanokit) is a natural form of vitamin B12. It exchanges the hydroxy group for cyanide to form cyanocobalamin, a non-toxic substance that can be excreted by the kidneys [14]. Hydroxocobalamin has not been associated with clinically significant adverse effects with the exception of isolated allergic reactions, headache and transient, asymptomatic elevations in blood pressure [15]. It is also possible to observe skin and urine discolouration (Fig. 1). Dicobalt edetate (Kelocyanor) is the second antidote of this group. Dicobalt edetate chelates cya­nide as cobalticyanide. It is associated with several serious side effects, including vomiting, anaphylaxis, hypotension and cardiac arrhythmias [16]. These side effects may be even more pronounced if dicobalt edetate is administered in the absence of cyanide toxicity; therefore, it is generally recommended to use it only as an antidote in severe confirmed cases of cyanide toxicity [17]. This medicinal product is not approved by the State Institute for Drug Control in the Czech Republic.

Another group consists of sulphur donors. Endogenous thiosulphate forms part of the body's normal excretion mechanism of cyanide, by transferring sulphur to cyanide to form thiocyanate which is excreted by the kidneys, under the action of the catalyst rhodanese [3]. Natriumthiosulphate 10% is approved by the State Institute for Drug Control in the Czech Republic. Much of the evidence in the literature assesses the efficacy of sodium thiosulphate when given in conjunction with other antidotes [18]. Thiosulfate is contraindicated in patients with renal insufficiency because the thiocyanate formed may cause toxicity [19].

The last group is represented by met­haemoglobin inducers. Nitrites such as sodium nitrite or amyl nitrite oxidise iron in haemoglobin from ferrous to ferric iron, forming methaemoglobin. 4-dimethylaminopyridine (4-DMAP) works by a similar mechanism via methaemoglobin. This is usually facilitated by providing a large pool of ferric iron in the form of methaemoglobin to complex cya­nide. Cyanide preferentially competes with Fe3+ of methaemoglobin as compared with that of cytochrome oxidase and eventually binds with the former to form cyanmethaemoglobin. Thereby, the activity of inhibited cytochrome oxidase is restored [20]. The effectiveness of amyl nitrite inhalation as a first aid for cyanide poisoning is often disputed because of its inability to generate methaemoglobin more than 6%. Approximately 15% of methaemoglobin is required to challenge one LD50 of cyanide [19]. On the other hand, higher levels of methaemoglobin may have a side effect on the oxygen carrying capacity of blood. Therefore, they are not suit­able for patients with inhalation injury and concomitant carbon monoxide poisoning. In addition, nitrites cause vasodilation and consequently hypotension which can lead to circulation insta­bility, a side effect which could be particularly dangerous in patients with major burns [21]. Nowadays, only 4-DMAP is approved by the State Institute for Drug Control in the Czech Republic.

The definitive treatment of cyanide poisoning differs in various countries because of different medical practices and guidelines. The Cyanide Antidote Kit is widely used in the United States. The kit has been previously known as the Lily or Pasadena kit, and now the Taylor Cyanide Antidote Package. The current Taylor kit contains three medications: amyl nitrite, sodium nitrite, and sodium thiosulphate [10]. In contrast, cobalt compounds are preferred in most European countries and in developed Asian countries. The safety and efficacy of all the antidotes are still being debated, with no worldwide consensus for first choice antidote [20]. There are no randomised controlled human trials to evaluate the efficacy of cyanide antidotes in the literature, only animal models and case series. There are several factors to account for this, including the relative rarity of cyanide poisoning, the lack of a rapid test to confirm the presence of cyanide toxicity and ethical issues which would prevent the use of a placebo when cyanide toxicity is suspected. In the absence of controlled human studies, these animal models and case series become the only evidence on which we can base our practice [3].

Bebarta et al found that hydroxocobalamin with sodium thiosulphate led to a faster normalised mean arterial pressure compared with sodium nitrite with sodium thiosulphate. However, there was no difference between the antidote combinations in mortality, serum acidosis, or serum lactate [22]. The same author notes that sodium thiosulphate alone failed to reverse cyanide-induced hypotension and resulted in 100% mortality in the swine model of severe cyanide toxicity. The addition of sodium thiosulphate to hydroxocobalamin did not improve mortality, haemodynamic values, or biochemical markers such as lactic acidosis, acidaemia, or cyanide le­vels [23]. Moreover, if infused improperly, the combination may reduce hydroxocobalamin's effectiveness [24]. Due to its proven effect and minimal side effects, more and more authors are inclined to believe that hydroxocobalamin appears to be the most promising antidote for cyanide poisoning.

Role of authors: All authors have actively participated in the preparation, analysis and interpretation of the findings, enactment and processing of the article with the same contribution.

Disclosure: The authors have no conflicts of interest to disclose. The authors declare that this study has received no financial support. All procedures performed in this study involving human participants were in accordance with ethical standards of the institutional and/or national research committee and with the Helsinki declaration and its later amendments or comparable ethical standards.

Filip Raška, MD

Department of Burns and Plastic Surgery, University Hospital Brno,

Jihlavská 20

625 00 Brno

Czech Republic

e-mail: raska.filip123@gmail.com

Submitted: 15.7.2021

Accepted: 27.11.2021