Toxic inhalational injury

Abstract

A middle-aged patient presented with toxic inhalational injury, and was resuscitated prehospitally and treated in the emergency department for smoke inhalation, carbon monoxide (CO) exposure and cyanide poisoning with the use of antidotes. Due to the CO effects on spectrophotometry, an anaemia initially identified on blood gas analysis was thought to be artefactual, but was later confirmed by laboratory testing to be accurate. In addition, cyanide can confound haemoglobin testing due to its use in the analytical process and non-cyanide analysis is required when there is suspected exposure. Although no consensus exists on a first-line cyanide antidote choice, hydroxocobalamin is the only antidote without a serious side effect profile and/or deleterious cardiovascular effects. We propose prehospital enhanced care teams consider carrying hydroxocobalamin for early administration in toxic inhalational injury.

Background

Smoke inhalation is implicated in 75% of fire-related deaths in the USA,¹ and progresses to respiratory complications in 73% of cases, and acute respiratory distress syndrome in 20%.² Although carbon monoxide poisoning remains the most common cause of fatality from smoke inhalation, causing 80% of deaths,³ cyanide is present in the blood of 60% of fire-related fatalities⁴ and fire is the most common cause of cyanide poisoning.⁵ Incidences of cyanide poisoning are decreasing due to changing composition of domestic furnishings, but the above statistics and the paucity of data and case reports on the subject suggest it is still underdiagnosed. Despite this, many hospitals and prehospital providers do not have antidotes readily available.⁶

Confined-space fires, such as house fires, produce toxic smoke from incomplete combustion due to high temperatures and a limited availability of oxygen.⁷ This includes carbon monoxide and hydrogen cyanide (HCN) from combustion of materials containing carbon and nitrogen, such as rubber, wool, plastic and synthetic materials.¹ Carbon monoxide (CO) reduces tissue oxygen delivery by binding haemoglobin, forming carboxyhaemoglobin (COHb) which has a much higher affinity for oxygen. Cyanide binds to cobalt, ferric iron in methaemoglobin, cytochrome oxidase and ferrous iron in haemoglobin, due to its high affinity for metalloproteins.⁷ The non-competitive cytochrome inhibition causes cessation of oxidative phosphorylation and anaerobic respiration⁴ leading to a depletion of adenosine triphosphate (ATP) and lactic acidaemia.

The concentration of lactate produced due to cellular asphyxia can be used to assess the severity of cyanide poisoning (table 1). Cyanide is processed through two pathways in the body: by conversion into thiocyanate by rhodanese enzymes, which can be safely excreted by the kidneys, or by binding with hydroxocobalamin (vitamin B12) to form cyanocobalamin. These pathways are quickly overwhelmed by exhaustion of sulphur donors, resulting in an accumulation of mitochondrial cyanide resulting in histotoxic hypoxia.^{1 7}

Table 1.

Cyanide poisoning severity, lactate values and associated clinical features (adapted from TOXBASE)⁹

Severity	Lactate (mmol/L)	Features
Mild	<10	Nausea, dizziness, drowsiness, hyperventilation, anxiety
Moderate	10–15	Reduced Glasgow Coma Score, vomiting, convulsions, hypotension
Severe	>15	Coma, fixed dilated pupils, cardiovascular collapse, respiratory failure, cyanosis

Case presentation

A middle-aged patient was extricated, unconscious from a smoke filled room by the fire service in a rural part of the UK, a considerable distance from the receiving hospital. He was in asystolic cardiac arrest with agonal breathing. Advanced life support (ALS) resuscitation for 30 min resulted in return of spontaneous circulation (ROSC). No thermal injuries were evident externally but soot was present in the mouth and nares indicating possible smoke inhalation.

The helicopter emergency medical service (HEMS) team undertook a rapid sequence induction (RSI) with ketamine 40 mg and rocuronium 50 mg for airway protection. Post-ROSC care was instigated as per ALS guidance and epinephrine infused at 0.02 to 0.04 mcg/kg/min to maintain blood pressure. Following RSI, reassessment and blood gas analysis using the HEMS EPOC point of care machine demonstrated pH 6.5, pCO₂ 16.6 kPa, pO₂ 1.9 kPa, base excess −26.6 mEq/L and lactate >20 mmol/L (table 2). This prompted administration of 100 mL 8.4% sodium bicarbonate and 10 mL 10% calcium chloride to correct the acidosis.

Table 2.

Arterial blood gas trending values (white – normal, pink – abnormal, red – severely abnormal)

Values	13:59	14:40	15:47*	16:05	16:30
pH	6.93	7.04	6.93	6.84	6.90
Haemoglobin (g/L)	39	35	34	60	90
O2 saturation (%)	97.1	100.0	44.8	96.2	99.0
Oxyhaemoglobin (%)	73.7	84.7	41.2	78.1	93.2
Anion gap (mmol/L)	23.4	31.5	32.7	30.9	32.7
Lactate (mmol/L)	22.0	24.0	23.0	21.0	21.0
Standard BE (mmol/L)	−18.6	−18.8	−20.2	−22.7	−21.3
Bicarbonate (mmol/L)	10.1	9.9	8.7	7.2	8.0
pCO2 (kPa)	7.68	5.05	6.47	6.66	6.48
pO2 (kPa)	64.20	73.30	5.13	32.40	47.00
Carboxyhaemoglobin (g/L)	22.9	16.4	8.2	8.5	3.5

*Venous blood gas rather than arterial.

BE, Base excess.

Pre-departure, the patient’s BP decreased to 58/37, and remained low throughout transfer despite epinephrine infusion, an aliquot of 200 mcg epinephrine and 1000 mL 0.9% normal saline boluses (table 3). The HEMS team recognised the likelihood of cyanide poisoning and pre-alerted the emergency department (ED) team to prepare cyanide antidotes for their arrival. Transport was by air due to the distance and the severity of the patient’s condition.

Table 3.

Observations recorded at different time points during clinical care

Timing	GCS	BP (mm Hg)	HR	RR	O2 (%)	BM (mmol/L)	Temp (°C)
Post-ROSC	3	119/84	87	15	90	13.7	32.1
Post-RSI	3	153/88	87	27			32.0
Pre-departure	3	58/37	72	12			32.0
During transfer	3	70/40	76	25	82		32.2
Handover	3	53/27	89	20	93		35.7

Some values were not recorded during care.

BM, blood sugar; BP, blood pressure; GCS, Glasgow Coma Score; HR, heart rate; ROSC, return of spontaneous circulation; RR, respiratory rate; RSI, rapid sequence induction.

An arterial blood gas on arrival to the ED demonstrated a COHb of 22.9%, haemoglobin (Hb) of 39.0 g/L, profound acidaemia (table 2) and observations as stated in table 3. Sodium thiosulfate 12.5 g was administered immediately, the epinephrine infusion was increased to 0.4 mcg/kg/min, 1 L Hartmann’s infused and 50 mL 8.4% sodium bicarbonate repeated to address the severe acidaemia and associated haemodynamic instability, and the patient ventilated with 100% oxygen.

Despite an initial improvement in observations, the patient continued to deteriorate. The epinephrine infusion was increased to 0.6 mcg/kg/min and dicobalt edetate 300 mg administered due to worsening acidaemia likely due to severe un-resolving cyanide toxicity (table 2). After review by intensive care, 5 g hydroxocobalamin was administered intravenously.

Laboratory tests confirmed a severe microcytic anaemia, which was initially thought to be artefact due to the effects of carbon monoxide on spectrophotometry. The anaemia was corrected with four units packed red blood cells and two units fresh frozen plasma. The patient continued to deteriorate and eventually passed away 3 hours after admission.

Outcome and follow-up

Unfortunately it was not possible to follow this case up as sadly the patient passed away in ED.

Discussion

Patients who survive to hospital and receive appropriate treatment for cyanide toxicity have a survival rate of over 60%, and mild-to-moderate symptoms are associated with a good prognosis.⁸ However, severe cyanide poisoning and out-of-hospital cardiac arrest is associated with significant mortality.²

Blood cyanide concentration assays, as recommended to TOXBASE, take time and are only available in a small number of laboratories. Therefore the triad of lactate >7 mmol/L, elevated anion gap acidosis and reduced arterio-venous oxygen gradient can be used as both an indicator for cyanide toxicity and monitoring of treatment effect.⁹ A central venous oxygen saturation >90% that decreases on administration of antidote is specific for cyanide poisoning due to arteriolisation of venous blood following histotoxic hypoxia.⁴ This requires early central venous access prior to commencement of treatment, something that was not available in this case.

Cases of cyanide poisoning are decreasing due to regulation of materials that may produce cyanide in fires, yet many house fires still result in unrecognised cyanide toxicity.¹⁰ Recognising the potential for cyanide toxicity by the HEMS team on pre-alert gave us the crucial minutes needed to locate the hospital’s cyanide antidotes and review TOXBASE recommendations. A survey by the National Poisons Information Service in 2011 found 80% of hospital pharmacies do not stock cyanide antidotes and if the antidote is stocked, it is often kept in pharmacy, away from the ED and staff have neither the knowledge of its existence nor ability to access it.⁶ Our hospital did not have a Cyanokit available, resulting in administration of sodium thiosulfate and dicobalt edetate as first-line and second-line treatments, respectively.

There is a lack of consensus on which antidote should be used and when. The main antidotes currently in use are hydroxocobalamin, sodium thiosulfate and dicobalt edetate; sodium nitrite is less commonly used. A suggested treatment regime can be found in (table 4):

Table 4.

Treatment of cyanide poisoning as recommended by TOXBASE⁹

Severity	Treatment
Mild	12.5 g sodium thiosulfate IV over 10 min
Moderate	12.5 g sodium thiosulfate IV over 10 min OR 200 mL of 25 mg/mL hydroxocobalamin IV over 15 min OR 20 mL of 1.5% dicobalt edetate solution (300 mg) IV over 1 min followed immediately by 50 mL of 50% dextrose
Severe	20 mL of 1.5% dicobalt edetate solution (300 mg) IV over 1 min followed immediately by 50 mL of 50% dextrose. If only partial response or patient relapses after recovery, repeat dose OR 200 mL of 25 mg/mL hydroxocobalamin IV over 15 min. A second dose of 5 g can be given over 15 min to 2 hours depending on patient stability and poisoning severity OR If neither of the above available, give 10 mL of 3% sodium nitrite solution IV over 5–20 min AND 12.5 g of sodium thiosulfate IV over 10 min. A further dose of sodium thiosulfate can be given if necessary

IV, intravenous.

1. Hydroxocobalamin is the antidote of choice in many countries, where it has a widespread prehospital use.² It chelates cyanide ions to form cyanocobalamin, which can be safely renally excreted.⁷ Hydroxocobalamin is effective in treatment of severe cyanide poisoning with a rapid onset of action, effective reversal of severe cyanide-induced shock¹¹ and a good prognostic profile.⁸ Despite a favourable tolerability profile, facial rashes can occur, and rarely urticaria, facial oedema and dyspnoea.¹² It can also cause a red discolouration to skin/urine and may effect colorimetric measurements. Hydroxocobalamin precipitates an increase in blood pressure, partially by scavenging nitric oxide, independent of its action on cyanide poisoning.¹³ This increase in mean arterial pressure could prove supportive in cases of moderate or severe poisoning where vasopressors may be required, and may be contributory to the improved cardiovascular outcome with large doses of prehospital hydroxocobalamin.¹⁴ There is also evidence to suggest that earlier doses of hydroxocobalamin are associated with improved outcomes.^{2 14 15} However, the use of hydroxocobalamin in humans has only level 3 evidence of low quality.¹⁶

2. Sodium thiosulfate acts as a sulphur donor for rhodanase-mediated cyanide conversion to thiocyanate.⁷ Sodium thiosulfate does not interfere with oxygen delivery and has a very low toxicity,¹⁵ however it also has a delayed onset of action, a short half-life and poor penetration of mitochondria. It can also cause hypotension, increased bleeding time and vomiting.⁴ Sodium thiosulfate lacks human trials demonstrating efficacy as a sole treatment¹⁷ and has been found ineffective in animal models for severe cyanide poisoning. Opinions differ as to whether it has a role in the treatment of severe poisoning in conjunction with hydroxocobalamin,¹¹ and there are case reports of successful co-administration of sodium thiosulfate and hydroxocobalamin to treat cyanide poisoning, especially as a second-line treatment with hydroxocobalamin as the primary antidote.^{4 17}

3. Cyanide has a higher affinity for cobalt than cytochrome oxidase or iron, allowing cobalt containing compounds to be used as antidotes. Dicobalt edetate chelates cyanide ions to form cobalticyanide, and is a fast-acting and highly effective antidote in severe poisoning.¹⁸ However, it has deleterious cardiovascular side effects, and required co-administration with glucose to minimise these. It is poorly tolerated, with risks of angioedema, urticaria, seizures and anaphylaxis.⁵ Due to the high levels of free cobalt in the solution, it can also result in severe cobalt toxicity and cardiac arrest in the absence of cyanide poisoning.⁶

4. Sodium nitrite oxidises haemoglobin to methaemoglobin,¹ which has a greater affinity for the cyanide ion, chelating it to form cyanomethaemoglobin and removing it from the mitochondria. Cyanomethaemoglobin dissociates, enabling rhodanase facilitated conversion of the free cyanide to thiocyanate,⁷ which can be renally eliminated. Methaemoglobin has no oxygen transportation ability and therefore sodium nitrite will worsen histotoxic hypoxia and is not recommended for use in smoke inhalation. Nitrites also take time to work, cause vasodilatation, hypotension, syncope, arrhythmias, seizures and death. As such, nitrites are no longer the optimum antidote available.

The pre-existing microcytic anaemia in this patient most likely potentiated the effects of the carbon monoxide and cyanide toxicity and earlier administration of haemodynamically stable antidotes such as hydroxocobalamin, perhaps prehospitally, and earlier blood transfusion to enhance oxygen delivery may have been of benefit. However, it must be taken into consideration that laboratory analysis of haemoglobin measurement traditionally utilises cyanide ions in binding to haemoglobin molecules to stabilise them for colorimetry,¹⁹ although several accurate, non-cyanide methods exist. Therefore the presence of HCN in the blood may have already bound the haemoglobin, leading to more unbound reagent and therefore a spuriously low reading. This throws doubt on the question of whether our patient was truly so anaemic, and the benefit afforded by blood transfusion.

Learning points.

• Cyanide poisoning is present in a significant proportion of smoke inhalation patients and should always be considered in the acidotic patient rescued from a confined space fire.

• Hydroxocobalamin is an effective and safe treatment for severe cyanide poisoning and should be considered first-line treatment in the haemodynamically unstable patient.

• Prompt treatment can improve survival, as such, hospitals must have rapidly accessible Cyanokits and prehospital services should consider carrying hydroxocobalamin.