Evaluation of hydroxocobalamin use for the treatment of suspected cyanide toxicity secondary to smoke inhalation.

Hydroxocobalamin is used for cyanide toxicity after smoke inhalation, but diagnosis is challenging. Retrospective studies have associated hydroxocobalamin with acute kidney injury (AKI). This is a retrospective analysis of patients receiving hydroxocobalamin for suspected cyanide toxicity. The primary outcome was the proportion of patients meeting predefined appropriate use criteria defined as ≥1 of the following: serum lactate ≥8 mmol/L, systolic blood pressure (SBP) <90 mmHg, new-onset seizure, cardiac arrest, or respiratory arrest. Secondary outcomes included incidence of AKI, pneumonia, resolution of initial neurologic symptoms, and in-hospital mortality. Forty-six patients were included; 35 (76%) met the primary outcome. All met appropriate use criteria due to respiratory arrest, 15 (43%) for lactate, 14 (40%) for SBP, 12 (34%) for cardiac arrest. AKI, pneumonia, and resolution of neurologic symptoms occurred in 30%, 21%, and 49% of patients, respectively. In-hospital mortality was higher in patients meeting criteria, 49% vs. 9% (95% CI 0.16, 0.64). When appropriate use criteria were modified to exclude respiratory arrest in a post-hoc analysis, differences were maintained, suggesting respiratory arrest alone is not a critical component to determine hydroxocobalamin administration. Predefined appropriate use criteria identify severely ill smoke inhalation victims and provides hydroxocobalamin treatment guidance.

Cyanide Poisoning and Lactate in Smoke Inhalation.

House fires can lead to cyanide poisoning and an associated elevated serum lactate level. Because of delays in obtaining serum cyanide levels, clinical symptoms and serum lactate are often used to guide clinical decision making and antidote administration. However, as this case report identifies, lower levels of serum lactate may in fact correlate with higher levels of serum cyanide that could benefit from treatment with an antidote.

Protective Effect of Nebulized Heparin in the Animal Models of Smoke Inhalation Injury: A Meta-analysis and Systematic Review of Experimental Studies.

The pathophysiological mechanism of abnormal coagulation can result from smoke inhalation injury (SII). Heparin nebulization is a common treatment for lung disorders. This study aimed to use meta-analysis in animal models to examine the effectiveness of atomized heparin on SII. For our online searches, we used the Cochrane Central Register of Controlled Trials, PubMed, Web of Science, Chinese National Knowledge Infrastructure, Chinese BioMedical Literature Database, and Wanfang Database up to January 2022. Data for SII were retrieved and compared to control animals. The studies' findings were determined by combining standardized mean difference (SMD) analysis with 95% confidence intervals (CIs). The findings showed that as compared to the control group, the heparin-treated group had a lower death rate (relative risk 0.42; 95% CI 0.22, 0.80; p < .05). The meta-analysis demonstrated favorable changes in lung physiology, including PaO2/FiO2 (SMD 1.04; 95% CI 0.65, 1.44; p < .001), lung wet-to-dry weight ratio (SMD -1.83; 95% CI -2.47, -1.18; p < .001), and pulmonary shunt Qs/Qt (SMD -0.69; 95% CI -1.29, -0.08; p < .05) after heparin nebulization for lung injury. The present data indicated that pulmonary artery mean pressure in the heparin therapy group was significantly lowered after 24 and 48 hours of therapy, suggesting that the cardiovascular system could recover following heparin treatment. As a result, heparin nebulization appeared to be more effective against SII and improved cardiopulmonary function compared to the control group. Graphical Abstract.

Cost impact of hydroxocobalamin in the treatment of patients with known or suspected cyanide poisoning due to smoke inhalation from closed-space fires.

BACKGROUND & OBJECTIVES: Cyanide poisoning can occur due to exposure to smoke in closed-space fires. With no point of care cyanide test at the scene of a fire, first responders and clinicians base decisions to treat with cyanide antidote on patient history, clinical signs, and other indirect data points that have not been proven to correspond with actual systemic levels of cyanide. The aim of this exploratory study was to determine the economic implications of treating patients with known or suspected cyanide poisoning due to smoke inhalation with hydroxocobalamin. METHODS: A decision analysis model was developed from the US hospital perspective. Healthcare resource utilization was estimated from a retrospective evaluation of clinical outcomes in hydroxocobalamin-treated patients and in historical controls without hydroxocobalamin use (Nguyen, et al. 2017). Epidemiologic parameters and costs were estimated from the published literature, and publicly-available hospital charges were identified. Outcomes reported in the analysis included expected healthcare resource utilization in the US population and per-patient costs with and without the use of hydroxocobalamin. A cost-to-charge ratio was applied so that all costs would reflect hospital costs rather than hospital charges. Deterministic sensitivity analysis was performed to identify the most influential model parameters. All costs were reported in 2017 US dollars. RESULTS: Use of hydroxocobalamin reduces healthcare resource utilization and contributes to decreased per-patient hospital costs ($15,381 with hydroxocobalamin treatment versus $22,607 with no cyanide antidote). The most substantive cost-savings resulted from decreased hospital length of stay (i.e., intensive care unit [ICU] and non-ICU). Costs attributed to mechanical ventilation also decreased with use of hydroxocobalamin. A univariate sensitivity analysis demonstrated that the most impactful variables in the cost analysis were related to hospital length of stay (ICU followed by non-ICU stay), followed by the daily cost of ICU stay. CONCLUSIONS: Use of hydroxocobalamin in patients with known or suspected cyanide poisoning from closed-space fire smoke inhalation may decrease hospital costs and contribute to more efficient healthcare resource utilization.

Evaluation of prehospital hydroxocobalamin use in the setting of smoke inhalation.

BACKGROUND: The indications for prehospital hydroxocobalamin are not well defined. The aim of this study was to evaluate prehospital signs and symptoms in patients who received hydroxocobalamin to improve future use. METHODS: In this retrospective study, all patients who received prehospital Hydroxocobalamin at a tertiary care burn center from December 2012 to March 2018 were reviewed. Each case was evaluated for evidence of suspected cyanide toxicity: hypotension, syncope, CNS depression/altered mentation, seizures, respiratory or cardiac arrest. A determination was made whether or not hydroxocobalamin was indicated. RESULTS: In this study, EMS providers administered hydroxocobalamin to 42 patients between December 2012 and March 2018. The majority (71%) of suspected cyanide exposures were from house fires. The most common prehospital findings were coma or depressed CNS (36%), followed by hypotension (16%) and cardiac arrest (12%). Sixty percent of patients treated with hydroxocobalamin had none of the six clinical indicators for potential cyanide toxicity. Carboxyhemoglobin and serum lactate were significantly different in patients that had a clinical indication for hydroxocobalamin compared to those who did not. CONCLUSIONS: Prehospital hydroxocobalamin was used empirically however, indications are unclear. Using defined clinical indications may provide greater clarity for providers and reduce unnecessary use of hydroxocobalamin.

Edaravone combined with dexamethasone exhibits synergic effects on attenuating smoke-induced inhalation lung injury in rats.

Inhalational lung injury often leads to morbidity and mortality during fire disasters. In this study, we aimed to evaluate the protective effects of edaravone combined with dexamethasone on smoke-induced inhalational lung injury. Sprague-Dawley rats were divided into five groups, namely, the control, model (inhalation), and three treatment groups (edaravone, dexamethasone, and edaravone combined with dexamethasone). After drug intervention in the acute lung injury model, arterial blood gas, wet:dry weight ratio of the lung tissue, bronchoalveolar lavage fluid, and pulmonary histopathology were determined. The production of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), inflammatory cytokines, peroxidase and apoptosis were further analyzed to explore the underlying mechanisms. The results of blood gas and inflammatory cytokine analysis and the histopathological data demonstrated that edaravone combined with dexamethasone had obvious protective effects on smoke infiltration and tissue injury. Moreover, after the co-administration of edaravone and dexamethasone, malondialdehyde and myeloperoxidase levels in the lung tissue decreased, whereas those of glutathione peroxidase and superoxide dismutase were elevated. In addition, this drug combination could inhibit smoke-induced apoptosis in lung tissues by reducing the cleavage of caspase-3, caspase-9, and poly ADP-ribose polymerase (PARP), and also reverse smoke-mediated mitochondrial dysfunction, including ROS generation, loss of MMP, early release of cytochrome C, second mitochondrial activator of caspases, and apoptosis-inducing factor. In conclusion, edaravone combined with dexamethasone had a protective effect on smoke-induced inhalational lung injury in rats and can be further explored as an attractive therapeutic option for the treatment of smoke inhalation-induced pulmonary dysfunction.

High molecular weight sodium hyaluronate improves survival of syndecan-1-deficient septic mice by inhibiting neutrophil migration.

METHODS: Sepsis was induced by cotton smoke inhalation followed by intranasal administration of Pseudomonas aeruginosa in female (> 6 months) Balb/c and syndecan-1 knockout mice. Survival of mice, lung capillary endothelial glycocalyx integrity, lung water content, and vascular hyper-permeability were determined with or without HMW-SH treatment in these mice. Effects of HMW-SH on endothelial permeability and neutrophil migration were tested in in vitro setting. RESULTS: In septic wildtype mice, we found a severely damaged pulmonary microvascular endothelial glycocalyx and elevated levels of shed syndecan-1 in the circulation. These changes were associated with significantly increased pulmonary vascular permeability. In septic syndecan-1 knockout mice, extravascular lung water content was higher, and early death was observed. The administration of HMW-SH significantly reduced mortality and lung water content in septic syndecan-1 knockout mice, but not in septic wildtype mice. In in vitro setting, HMW-SH inhibited neutrophil migration and reduced cultured endothelial cell permeability increases. However, these effects were reversed by the addition of recombinant syndecan-1 ectodomain. CONCLUSIONS: HMW-SH reduced lung tissue damage and mortality in the absence of syndecan-1 protein, possibly by reducing vascular hyper-permeability and neutrophil migration. Our results further suggest that increased shed syndecan-1 protein levels are linked with the inefficiency of HMW-SH in septic wildtype mice.

Casticin Improves Respiratory Dysfunction and Attenuates Oxidative Stress and Inflammation via Inhibition of NF-ĸB in a Chronic Obstructive Pulmonary Disease Model of Chronic Cigarette Smoke-Exposed Rats.

OBJECTIVE: The present study was conducted to elucidate the protective effect of Casticin against chronic obstructive pulmonary disease (COPD) in rats. METHODS: The COPD in rats was induced by the controlled cigarette smoke, and CST (10, 20, and 30 mg/kg) was injected into the cigarette-smoke exposed rats. Blood was taken from the abdominal vein and centrifuged (1500×g, 4°C, 15min); plasma was collected and used for the determination of various biochemical parameters. RESULTS: The results of the study suggested that CST significantly improved the lung functions of the rats in a dose-dependent manner. It also causes a reduction of white blood cells, neutrophils, and macrophages in BALF of rats. The plasma level of leptin and C-reactive protein together with pro-inflammatory cytokines (TNF-α, IL-1ß, and IL-6) were also significantly restored to near to normal in CST-treated group. In Western blot analysis, CST causes significant inhibition of the NF-ĸB and iNOS pathway. CONCLUSION: Our study demonstrated that the CST protects lungs against COPD via improving lung functions and inhibition of oxidative stress and inflammation.

Effects of simvastatin on iNOS and caspase­3 levels and oxidative stress following smoke inhalation injury.

The overexpression of inducible nitric oxide synthase (iNOS) induces cell apoptosis through various signal transduction pathways and aggravates lung injury. Caspase­3 is an important protein in the apoptotic pathway and its activation can exacerbate apoptosis. Simvastatin, a hydroxymethyl glutaryl­A reductase inhibitor, protects against smoke inhalation injury by inhibiting the synthesis and release of inflammatory factors and decreasing cell apoptosis. Following the establishment of an animal model of smoke inhalation injury, lung tissue and serum were collected at different time points and the protein and mRNA expression of iNOS and caspase­3 in lung tissue by immunochemistry, western blot and reverse transcription­quantitative polymerase chain reaction, the malondialdehyde (MDA) content and superoxide dismutase (SOD) activity in lung tissue and serum were analyzed using thiobarbituric acid method and the WST­1 method. The results were statistically analyzed. The lung tissues of the rats in the saline group and the low­, middle­ and high­dose groups exhibited clear edema and hemorrhage, and had significantly higher pathological scores at the various time points compared with the rats in the control group (P<0.05). Furthermore, lung tissue and serum samples obtained from these four groups had significantly higher mRNA and protein expression levels of iNOS and caspase­3 (P<0.05), significantly lower SOD activity and higher MDA content (P<0.05). Compared with the saline group, the low­, middle­ and high­dose groups had significantly lower pathological scores (P<0.05), significantly lower mRNA and protein expression levels of iNOS, caspase­3 and MDA content in lung tissues (P<0.05) and significantly higher SOD activity in lung tissues and serum. The middle­ and high­dose groups had significantly lower pathological scores (P<0.05), significantly decreased iNOS and caspase­3 mRNA and protein expression in lung tissues, significantly higher SOD activity in lung tissues and serum and a significantly lower MDA content (P<0.05) compared with the low­dose group. With the exception of SOD activity in lung tissues at 24 and 72 h and MDA content in serum at 48 h, no significant differences were observed between the middle­ and high­dose groups. The present study demonstrated that there was an association between the therapeutic effect and dosage of simvastatin within a definitive range. In rats with smoke inhalation injury, simvastatin inhibited iNOS and caspase­3 expression in lung tissues and mitigated oxidative stress, thereby exerting a protective effect. In addition, the effect and dose were associated within a definitive range.

A comparative study of a preclinical survival model of smoke inhalation injury in mice and rats.

Smoke inhalation injury increases morbidity and mortality. Clinically relevant animal models are necessary for the continued investigation of the pathophysiology of inhalation injury and the development of therapeutics. The goal of our research was threefold: 1) to develop a reproducible survival model of smoke inhalation injury in rats that closely resembled our previous mouse model, 2) to validate the rat smoke inhalation injury model using a variety of laboratory techniques, and 3) to compare and contrast our rat model with both the well-established mouse model and previously published rat models to highlight our improvements on smoke delivery and lung injury. Mice and rats were anesthetized, intubated, and placed in custom-built smoke chambers to passively inhale woodchip-generated smoke. Bronchoalveolar lavage fluid (BALF) and lung tissue were collected for confirmatory tests. Lung sections were hematoxylin and eosin stained, lung edema was assessed with wet-to-dry (W/D) ratio, and inflammatory cell infiltration and cytokine elevation were evaluated using flow cytometry, immunohistochemistry, and ELISA. We confirmed that our mouse and rat models of smoke inhalation injury mimic the injury seen after human burn inhalation injury with evidence of pulmonary edema, neutrophil infiltration, and inflammatory cytokine elevation. Interestingly, rats mounted a more severe immunological response compared with mice. In summary, we successfully validated a reliable and clinically translatable survival model of lung injury and immune response in rats and mice and characterized the extent of this injury. These animal models allow for the continued study of smoke inhalation pathophysiology to ultimately develop a better therapeutic.

Superior Effects of Nebulized Epinephrine to Nebulized Albuterol and Phenylephrine in Burn and Smoke Inhalation-Induced Acute Lung Injury.

The severity of burn and smoke inhalation-induced acute lung injury (BSI-ALI) is associated with alveolar and interstitial edema, bronchospasm, and airway mucosal hyperemia. Previously, we have reported beneficial effects of epinephrine nebulization on BSI-ALI. However, the underlying mechanisms of salutary effects of nebulized epinephrine remain unclear. The present study compared the effects of epinephrine, phenylephrine, and albuterol on a model of BSI-ALI. We tested the hypothesis that both α1- and ß2-agonist effects are required for ameliorating more efficiently the BSI-ALI. Forty percent of total body surface area, 3rd-degree cutaneous burn, and 48-breaths of cotton smoke inhalation were induced to 46 female Merino sheep. Postinjury, sheep were mechanically ventilated and cardiopulmonary hemodynamics were monitored for 48 h. Sheep were allocated into groups: control, n = 17; epinephrine, n = 11; phenylephrine, n = 6; and albuterol, n = 12. The drug nebulization began 1 h postinjury and was repeated every 4 h thereafter. In the results, epinephrine group significantly improved oxygenation compared to other groups, and significantly reduced pulmonary vascular permeability index, lung wet-to-dry weight ratio, and lung tissue growth factor-ß1 level compared with albuterol and control groups. Epinephrine and phenylephrine groups significantly reduced trachea wet-to-dry weight ratio and lung vascular endothelial growth factor-A level compared with control group. Histopathologically, epinephrine group significantly reduced lung severity scores and preserved vascular endothelial-cadherin level in pulmonary arteries. In conclusion, the results of our studies suggest that nebulized epinephrine more effectively ameliorated the severity of BSI-ALI than albuterol or phenylephrine, possibly by its combined α1- and ß2-agonist properties.

Cutaneous burn diminishes beneficial effect of intravenously administered mesenchymal stem cells on acute lung injury induced by smoke inhalation in sheep.

OBJECTIVE: To investigate effects of intravenously administered allogeneic mesenchymal stem cells (MSCs) on burn/smoke-induced lung injury. METHODS: Sheep were subjected to 40%, third-degree flame skin burn and smoke inhalation under deep anesthesia and analgesia. One-hour after injury, PlasmaLite A (control) or 200 million MSCs (treatment) were intravenously administered. Pulmonary oxygenation index, PaO2/FiO2 ratio, lung-lymph flow, and bloodless lung wet-to-dry weight ratio were measured. Distribution of MSCs and stromal cell-derived factor-1 (Sdf-1) protein level were determined in lung and skin tissues. Effects of burn exudate on MSCs migration were characterized. RESULTS: MSCs did not attenuate pulmonary dysfunction. The number of MSCs was significantly higher in lungs of sheep with smoke inhalation compared with those with burn/smoke injury. In contrast, number of MSCs was significantly higher beneath burned skin in sheep with burn/smoke than in unburned skin of sheep with smoke inhalation only. Expression of Sdf-1 protein was increased in the burned skin compared to unburned skin. Effects of burn exudate on cultured MSCs proliferation differed depending on collection time. CONCLUSION: Skin burn diminishes beneficial effects of MSCs on smoke-induced lung injury, by promoting migration of MSCs from the pulmonary tissue to the injured skin area, possibly via expression of Sdf-1 protein.

Effects of the solid lipid nanoparticle of carvacrol on rodents with lung injury from smoke inhalation.

The aim of this present study was to evaluate the effect of solid lipid nanoparticles (SLN) containing carvacrol over the lung damage of airway smoke inhalation. The study was conducted with 30 rats subjected to smoke inhalation and divided into 5 groups such as, normal control, negative control, oxygen group, SLN alone, and SLN+CARV group. The animals were sacrificed 24 h after the induction of inhalation injury further, the tissues of larynx, trachea, and lungs were collected for the histological, hematological, myeloperoxidase, and malondialdehyde analysis. The obtained results showed that treatment with CARV+SLN minimized the inhalation injury, since it reduced malondialdehyde significantly, when compared to the negative control group and minimized the histological changes which proves the absence of pulmonary emphysema and exudate in laryngeal and tracheal lumen in the CARV+SLN-treated group. Meanwhile, the presence of lesion with chronic characteristics was observed in the negative control and oxygen groups. It is suggested that the SLN containing carvacrol minimized oxidative stress and histological damages generated from smoke inhalation in rodents.

Association between hydroxocobalamin administration and acute kidney injury after smoke inhalation: a multicenter retrospective study.

BACKGROUND: The use of hydroxocobalamin has long been advocated for treating suspected cyanide poisoning after smoke inhalation. Intravenous hydroxocobalamin has however been shown to cause oxalate nephropathy in a single-center study. The impact of hydroxocobalamin on the risk of acute kidney injury (AKI) and survival after smoke inhalation in a multicenter setting remains unexplored. METHODS: We conducted a multicenter retrospective study in 21 intensive care units (ICUs) in France. We included patients admitted to an ICU for smoke inhalation between January 2011 and December 2017. We excluded patients discharged at home alive within 24 h of admission. We assessed the risk of AKI (primary endpoint), severe AKI, major adverse kidney (MAKE) events, and survival (secondary endpoints) after administration of hydroxocobalamin using logistic regression models. RESULTS: Among 854 patients screened, 739 patients were included. Three hundred six and 386 (55.2%) patients received hydroxocobalamin. Mortality in ICU was 32.9% (n = 243). Two hundred eighty-eight (39%) patients developed AKI, including 186 (25.2%) who developed severe AKI during the first week. Patients who received hydroxocobalamin were more severe and had higher mortality (38.1% vs 27.2%, p = 0.0022). The adjusted odds ratio (95% confidence interval) of AKI after intravenous hydroxocobalamin was 1.597 (1.055, 2.419) and 1.772 (1.137, 2.762) for severe AKI; intravenous hydroxocobalamin was not associated with survival or MAKE with an adjusted odds ratio (95% confidence interval) of 1.114 (0.691, 1.797) and 0.784 (0.456, 1.349) respectively. CONCLUSION: Hydroxocobalamin was associated with an increased risk of AKI and severe AKI but was not associated with survival after smoke inhalation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03558646.

Is inhaled heparin a viable therapeutic option in inhalation injury?

Inhalation injury is a major cause of morbidity and mortality in patients with burns. Presence of airways injury adds to the need of fluid supplementation, increases risk of pulmonary complications. Due to many mechanisms involved in pathophysiology the treatment is complex. Among them the formation of fibrin casts inside airways constitutes a prominent element. The material residing in tracheobronchial tree causes ventilation-perfusion mismatch, complicates mechanical ventilation, provides a medium for bacterial growth. Many studies of animal models and single centre human studies investigated inhaled anticoagulation regimens employing heparin in management of inhalation injury. Simultaneously safety, especially in connection with possible bleeding risk, was the subject of research. The results suggest positive impact on treatment results, with low risk of side effects. This paper revise the available clinical data on inhaled heparin use in patients with burns.

Pharmacological treatment of inhalation injury after nuclear or radiological incidents: The Chinese and German approach.

Inhalation injury is often associated with burns and significantly increases morbidity and mortality. The main toxic components of fire smoke are carbon monoxide, hydrogen cyanide, and irritants. In the case of an incident at a nuclear power plant or recycling facility associated with fire, smoke may also contain radioactive material. Medical treatments may vary in different countries, and in this paper, we discuss the similarities and differences in the treatments between China and Germany. Carbon monoxide poisoning is treated by 100% oxygen administration and, if available, hyperbaric oxygenation in China as well as in Germany. In addition, antidotes binding the cyanide ions and relieving the respiratory chain are important. Methemoglobin-forming agents (e.g., nitrites, dimethylaminophenol) or hydroxocobalamin (Vitamin B12) are options. The metabolic elimination of cyanide may be enhanced by sodium thiosulfate. In China, sodium nitrite with sodium thiosulfate is the most common combination. The use of dimethylaminophenol instead of sodium nitrite is typical for Germany, and hydroxocobalamin is considered the antidote of choice if available in cases of cyanide intoxications by fire smoke inhalation as it does not further reduce oxygen transport capacity. Systematic prophylactic use of corticosteroids to prevent toxic pulmonary edema is not recommended in China or Germany. Stable iodine is indicated in the case of radioiodine exposure and must be administered within several hours to be effective. The decorporation of metal radionuclides is possible with Ca (DTPA) or Prussian blue that should be given as soon as possible. These medications are used in both countries, but it seems that Ca (DTPA) is administered at lower dosages in China. Although the details of the treatment of inhalation injury and radionuclide(s) decorporation may vary, the general therapeutic strategy is very similar in China and Germany.