Extracorporeal cardio-pulmonary resuscitation in a patient with missed diagnosis of sodium nitrite intoxication.

INTRODUCTION: Critical poisoning with sodium nitrite (NaNO2) can present challenges in promptly identifying and managing acute methemoglobinemia. CASE REPORT: We report the case of an overt self-intoxication by an initially unknown agent, leading to cardiac arrest. Despite prodromal signs of cyanosis, coma, desaturation, and hypotension, methemoglobinemia went unrecognized during extracorporeal cardiopulmonary resuscitation (ECPR) as the point-of-care test failed to provide methemoglobin levels, leading to untreated methemoglobinemia. The blood flowing through the oxygenator notably maintained the same brown colour. Return of spontaneous circulation was never achieved, and the patient was declared dead after 60 min of unsuccessful resuscitation. Cause of death by means of NaNO2 voluntary ingestion was later clarified and confirmed by postmortem finding of elevated nitrite and nitrate concentration. CONCLUSIONS: This case highlights the risk of failure of ECPR in the context of cardiac arrest due to methemoglobinemia, emphasizing the critical need for prompt recognition of the causative agent and early administration of antidotes.

Impact of chlorogenic acid on submandibular salivary gland and liver of albino rats exposed to sodium nitrite.

AIM: The aim of the present study is to show how sodium nitrite alters the histology of submandibular salivary glands and livers of Albino rats, as well as how chlorogenic acid may have therapeutic benefits. METHODS: A sample size of thirty male Sprague Dawley Albino rats weighing between 100 and 150 g (5-6 weeks old) was randomly allocated into 3 equal groups. Group I: rats were used as controls and were given phosphate buffer solution, whereas Group II: rats were given an 80 mg/kg sodium nitrites (SN) daily dissolved in distilled water. The rats in Group III were given a daily dose of 80 mg/kg SN dissolved in distilled water and after 6 hours each rat received 50 mg/mL freshly prepared chlorogenic acid (CGA) every other day. For 12 weeks, all treatment modalities will be administered orally, every day. After the experiment, all rats were euthanized. Samples from salivary glands and livers were processed and stained with H&E and interleukin 6 (IL 6). Malondialdehyde (MDA) and superoxide dismutase (SOD) enzymes were detected using an ELISA assay. RESULTS: Groups III had nearly comparable findings to Group I regarding histological pattern with normal submandibular glands and livers features. Group III salivary gland treated with CGA exhibited higher SOD levels (20.60±4.81 U/g) in comparison to the SN group, and lower MDA levels (111.58±28.28 nmol/mg) in comparison to the SN treated samples. In comparison to the SN group, CGA treatment significantly reduced MDA levels in liver samples (167.56±21.17 nmol/mg) and raised SOD (30.85±6.77 U/g). CONCLUSIONS: Chlorogenic acid has a protective effect against salivary gland and liver toxicity induced by SN in rats. This was mediated via the anti-inflammatory and antioxidative properties of CGA and the restoration of oxidant/antioxidant balance in rat salivary gland and liver.

The effect of Nano-liposomal sodium nitrite on smooth muscle cell growth in a tissue-engineered small-diameter vascular graft.

BACKGROUND: Nitric oxide is a chemical agent produced by endothelial cells in a healthy blood vessel, inhibiting the overgrowth of vascular smooth muscle cells and regulating vessel tone. Liposomes are biocompatible and biodegradable drug carriers with a similar structure to cell bilayer phospholipid membrane that can be used as useful nitric oxide carriers in vascular grafts. METHOD: Using a custom-designed apparatus, the sheep carotid arteries were decellularized while still maintaining important components of the vascular extracellular matrix (ECM), allowing them to be used as small-diameter vascular grafts. A chemical signal of sodium nitrite was applied to control smooth muscle cells' behavior under static and dynamic cell culture conditions. The thin film hydration approach was used to create nano-liposomes, which were then used as sodium nitrite carriers to control the drug release rate and enhance the amount of drug loaded into the liposomes. RESULTS: The ratio of 80:20:2 for DPPC: Cholesterol: PEG was determined as the optimum formulation of the liposome structure with high drug encapsulation efficiency (98%) and optimum drug release rate (the drug release rate was 40%, 65%, and 83% after 24, 48, and 72 h, respectively). MTT assay results showed an improvement in endothelial cell proliferation in the presence of nano-liposomal sodium nitrite (LNS) at the concentration of 0.5 µg/mL. Using a suitable concentration of liposomal sodium nitrite (0.5 µg/mL) put onto the constructed scaffold resulted in the controllable development of smooth muscle cells in the experiment. The culture of smooth muscle cells in a pulsatile perfusion bioreactor indicated that in the presence of synthesized liposomal sodium nitrite, the overgrowth of smooth muscle cells was inhibited in dynamic cell culture conditions. The mechanical properties of ECM graft were measured, and a multi-scale model with an accuracy of 83% was proposed to predict mechanical properties successfully. CONCLUSION: The liposomal drug-loaded small-diameter vascular graft can prevent the overgrowth of SMCs and the formation of intimal hyperplasia in the graft. Aside from that, the effect of LNS on endothelial has the potential to stimulate endothelial cell proliferation and re-endothelialization.

AB569, a nontoxic chemical tandem that kills major human pathogenic bacteria.

Antibiotic-resistant superbug bacteria represent a global health problem with no imminent solutions. Here we demonstrate that the combination (termed AB569) of acidified nitrite (A-NO2-) and Na2-EDTA (disodium ethylenediaminetetraacetic acid) inhibited all Gram-negative and Gram-positive bacteria tested. AB569 was also efficacious at killing the model organism Pseudomonas aeruginosa in biofilms and in a murine chronic lung infection model. AB569 was not toxic to human cell lines at bactericidal concentrations using a basic viability assay. RNA-Seq analyses upon treatment of P. aeruginosa with AB569 revealed a catastrophic loss of the ability to support core pathways encompassing DNA, RNA, protein, ATP biosynthesis, and iron metabolism. Electrochemical analyses elucidated that AB569 produced more stable SNO proteins, potentially explaining one mechanism of bacterial killing. Our data implicate that AB569 is a safe and effective means to kill pathogenic bacteria, suggesting that simple strategies could be applied with highly advantageous therapeutic/toxicity index ratios to pathogens associated with a myriad of periepithelial infections and related disease scenarios.

Optimizing transcardial perfusion of small molecules and biologics for brain penetration and biodistribution studies in rodents.

Efficiently removing blood from the brain vasculature is critical to evaluate accurately the brain penetration and biodistribution of drug candidates, especially for biologics as their blood concentrations are substantially higher than the brain concentrations. Transcardial perfusion has been used widely to remove residual blood in the brain; however, the perfusion conditions (such as the perfusion rate and time) reported in the literature are quite varied, and the performance of these methods on blood removal has not been investigated thoroughly. In this study, the effectiveness of the perfusion conditions was assessed by measuring brain hemoglobin levels. Sodium nitrite (NaNO2 ) as an additive in the perfusate was evaluated at different concentrations. Blood removal was significantly improved with 2% NaNO2 over a 20 min perfusion in mouse without disrupting the integrity of the blood-brain barrier (BBB). In mice, the optimized perfusion method significantly lowered the measured brain-to-plasma ratio (Kp,brain ) for monoclonal antibodies due to the removal of blood contamination and small molecules with a moderate-to-high BBB permeability and with a high brain-unbound-fraction (fu,brain ) presumably due to flux out of the brain during perfusion. Perfusion with or without NaNO2 clearly removed the residual blood in rat brain but with no difference observed in Kp,brain between the perfusion groups with or without 2% NaNO2 . In conclusion, a perfusion method was successfully developed to evaluate the brain penetration of small molecules and biologics in rodents for the first time. The transcardial perfusion with 2% NaNO2 effectively removed the residual blood in the brain and significantly improved the assessment of brain penetration of biologics. For small molecules, however, transcardial perfusion may not be performed, as small molecule compounds could be washed away from the brain by the perfusion procedure.

Sodium Nitrite Attenuates Reduced Activity of Vascular Matrix Metalloproteinase-2 and Vascular Hyper-Reactivity and Increased Systolic Blood Pressure Induced by the Placental Ischemia Model of Preeclampsia in Anesthetized Rats.

Preeclampsia is a maternal hypertension disorder associated with vascular dysfunction and fetal and placental growth restrictions. Placental ischemia is suggested as the primary trigger of preeclampsia-associated impairments of both endothelium-derived nitric oxide (NO) and the vascular activity of extracellular matrix metalloproteinase-2 (MMP-2). Reduced uteroplacental perfusion pressure (RUPP) is a placental ischemia model of preeclampsia. Reduction of sodium nitrite to NO may occur during ischemic conditions. However, sodium nitrite effects in the RUPP model of preeclampsia have not yet been investigated. Pregnant rats were divided into four groups: normotensive pregnant rats (Norm-Preg), pregnant rats treated with sodium nitrite (Preg + Nitrite), preeclamptic rats (RUPP), and preeclamptic rats treated with sodium nitrite (RUPP + Nitrite). Maternal blood pressure and fetal and placental parameters were recorded. Vascular function, circulating NO metabolites, and the gelatinolytic activity of vascular MMP-2 were also examined. Sodium nitrite attenuates increased blood pressure, prevents fetal and placental weight loss, counteracts vascular hyper-reactivity, and partially restores NO metabolites and MMP-2 activity. In conclusion, sodium nitrite reduction to NO may occur during RUPP-induced placental ischemia, thereby attenuating increased blood pressure, fetal and placental growth restriction, and vascular hyper-reactivity associated with preeclampsia and possibly restoring NO and MMP-2 activity, which underlie the blood pressure-lowering effects.

[Storage Stability of Nitrite in Nitrite Analysis of Meat Products].

For the analysis of nitrite ions in food, the stabilities of nitrite ions in meat products and their standard solutions were evaluated. Nitrite is easily oxidized or reduced; hence, products with standard solutions or colour retention agent must be carefully handled. To assess the stability and decreasing trend of nitrite, we examined the storage stability of standard solutions using calibration curves, the time course of nitrite in chopped meat products stored under different conditions, and the time course of nitrite in the sample solutions. Regarding calibration curves, the storage stability was determined for standard solutions that were prepared with ultrapure water at concentrations of 0.025 and 0.4 µg/mL and were stored at 5℃ for one year. The results revealed no changes in concentration of any solution over time, suggesting that no readjustments to the standard solution concentration were necessary before testing until one year after their preparation. Time course of nitrite in chopped meat products stored under different conditions showed a significant decrease in nitrite in refrigerated storage (5℃), whereas stability of nitrite was maintained for up to 1 day in frozen storage (-20℃) and for 14 days in frozen storage (-40℃). The time course of nitrite in the sample solutions showed that the quantitative values of nitrite in the extract remained unchanged within one week of extraction for the meat products tested in the study.

Suicidal sodium nitrite intoxication: a case report focusing on the postmortem findings and toxicological analyses-review of the literature.

Sodium nitrite (NaNO2) is an inorganic compound that is commonly used as a preservative (E250) in the fish and meat industry. When ingested, sodium nitrite will lead to methemoglobinemia, hypotension, and arrhythmias. An increasing trend in the use of sodium nitrite as a suicide agent has been reported. In Belgium however it remains a rare phenomenon. The ingestion of sodium nitrite is not always apparent from the death scene investigation, especially in cases of covert administration or accidental ingestion. Hence, the forensic pathologist must be aware of this trend and the postmortem changes related to the ingestion of sodium nitrite to effectively identify these cases and determine the cause and manner of death. We describe a case of fatal self-poisoning following the oral ingestion of sodium nitrite with suicidal intent. Postmortem investigations showed signs of methemoglobinemia, such as a gray-brown discoloration of lividity and a chocolate brown discoloration of the blood. Postmortem toxicological investigation revealed methemoglobinemia (35%) in cardiac blood, hypernatremia (159.6 mmol/L) in vitreous humor, and the presence of nitrite in gastric contents (1.15 g/L) and, for the first time in a forensic case, in serum (38 µg/mL). A review of the existing literature regarding cases of sodium nitrite intoxications was performed to correlate these findings.

Diazotization titrations in pharmacopoeial quality control of medicines and proposals for their revision in the European Pharmacopoeia.

Based on the data in the Ph. Eur., some other newer pharmacopoeias and published experimental papers propose to revise the text of Ph. Eur. 2.5.8. First, it is necessary to specify which of the electrometric methods should be used to indicate the endpoint of diazotization titrations in Ph. Eur. (preferable potentiometry with a platinum indicating electrode). The amount of potassium bromide in the titration solution may be reduced to 1 g, the cooling of the solution before titration may be omitted from the framework procedure, and it may be specified in individual monographs if necessary to obtain accurate and correct results for some medicines. Diazotization titration can be performed in Ph. Eur. and can also be used to determine the content of some other medicines.

Lewis acid-promoted direct synthesis of isoxazole derivatives.

Isoxazole derivatives were synthesized via a one-pot method utilizing 2-methylquinoline derivatives as template substrates, sodium nitrite as a nitrogen-oxygen source, and solely using aluminum trichloride as the additive. This approach circumvents the need for costly or highly toxic transition metals and presents a novel pathway for the synthesis of isoxazole derivatives.

Near-fatal pediatric methemoglobinemia secondary to intentional sodium nitrite ingestion.

Methemoglobinemia is the result of inappropriate oxidation of hemoglobin iron groups, leading to a failure of oxygen transport and delivery, resulting in a clinical state of refractory hypoxia. Methemoglobin levels above 70% are often considered fatal. Acquired methemoglobinemia can be caused by a variety of substances, including sodium nitrite, a commercially available food preservative and color fixative. This report describes a patient presenting with a methemoglobin level of 83% secondary to intentional sodium nitrite ingestion. The methemoglobin level recorded is amongst some of the highest found in surviving patients.

Increasing use of sodium nitrite in suicides-an emerging trend.

Sodium nitrite (NaNO2) is a compound with broad practical applications in food preservation, automotive maintenance, and animal control. Sodium nitrite is also potentially fatal when ingested, as it interferes with the ability of red blood cells to transport oxygen. While incidents of accidental consumption have been reported in the literature, case reports of sodium nitrite being used as a pharmacological suicide agent are becoming more frequent. Therefore, a study was undertaken to evaluate trends in sodium nitrite deaths in South Australia between 2000 and 2019. All cases of fatal sodium nitrite ingestion were identified in the Toxicology database and autopsy reports at Forensic Science SA (FSSA). Ten cases of fatal sodium nitrite ingestion were identified, with the rate of cases increasing significantly over the study period (p > .001). Of the ten deaths attributed to sodium nitrite toxicity, eight were male, and two were female. The age range of decedents was 22-74 years (mean 51.9, SD 21.1), 22-74 years for males (mean 58.4, SD 18.2) and 23-29 years for females (mean 26.0, SD 4.2). Males (80%) and those with a history of depression and/or suicidal ideation (70%) were over-represented within the study population. While autopsy findings were generally consistent with the literature, scene findings emphasized the accessibility of sodium nitrite to the general public. This study highlights both a significant increasing trend in the use of sodium nitrite in suicides and important analytical limitations in the evaluation of suspected cases.

Efficacy and safety of inhaled nebulized sodium nitrite in asthmatic patients.

BACKGROUND: Nitrite is a physiologic nitric oxide (NO) derivative that can be bioactivated to NO. NO has been shown to attenuate airway inflammation and enhance the anti-inflammatory effect of corticosteroids in the animal model of asthma. Here, we aimed to investigate the efficacy and safety of inhaled sodium nitrite as add-on therapy with inhaled corticosteroid (ICS) in adult patients with persistent asthma. METHODS: In protocol 1, 10 asthmatic patients were administered a single dose of nebulized 15-mg sodium nitrite to assess safety, effect on lung function, and pharmacokinetics of nitrite within 120 min. In protocol 2, 20 patients were randomly assigned to a nitrite (15 mg twice daily) group or a placebo group to assess the efficacy over 12 weeks. The primary outcome was the forced expiratory volume in 1 s (FEV1). The secondary outcomes were other lung function parameters, unplanned asthma-related visits at the emergency department (ED) or outpatient department (OPD), admission days, asthma control test (ACT), and safety. RESULTS: Nebulized sodium nitrite had neither acute adverse effect nor effect on lung function test within 120 min. No blood pressure change was seen. At week 12, FEV1 increased in the nitrite group, whereas there was no change in the placebo group. There were 5 events of asthma exacerbation, 4 ED visits, and one unplanned OPD visit in the placebo group, but none of these was noted in the nitrite group. There was no change in ACT scores in both groups. No adverse event was reported during 12 weeks in the nitrite group. There was no change in methemoglobin levels and sputum inflammatory markers. CONCLUSION: From our pilot trial, nebulized sodium nitrite is safe in asthmatic patients, and shows the potential to reduce asthma exacerbation compared with placebo.

Fatal Sodium Nitrite Poisoning: Key Considerations for Prehospital Providers.

Sodium nitrite is a powerful oxidizing agent that causes hypotension and limits oxygen transport and delivery in the body through the formation of methemoglobin. Clinical manifestations can include cyanosis, hypoxia, altered consciousness, dysrhythmias, and death. The majority of reports on sodium nitrite poisonings have been the result of unintentional exposures. We report a case of an intentional fatal overdose of sodium nitrite. A 17-year-old female reportedly drank approximately one tablespoon of sodium nitrite in a self-harm attempt. The patient was hypotensive and cyanotic upon EMS arrival. The patient decompensated rapidly into a bradycardic arrest during transport despite intubation, push-dose epinephrine, and intravenous fluid resuscitation. In the Emergency Department (ED), she received methylene blue and packed red cells but could not be resuscitated despite a prolonged effort. EMS professionals should consider sodium nitrite toxicity in patients with a suspected overdose who present with a cyanotic appearance, pulse oximetry that remains around 85% despite oxygen, and dark brown blood seen on venipuncture. Early prehospital contact with the Poison Control Center and ED prenotification in poisoned patients is encouraged.

Another suicide by sodium nitrite and multiple drugs: an alarming trend for "exit"?

This case report describes a fatal case of sodium nitrite and multiple drug consumption. A 37-year-old female was found in bed with a plastic bottle containing sodium nitrite and a bag containing multiple drugs and a suicide note. The results of the autopsy showed completely fixed grayish livor mortis, signs of asphyxia on the lips, and facial cyanosis. This represents the second case in just a few months and highlights how relatively easy it is to buy sodium nitrite to commit suicide, indicating that specific responses should focus on restricting its access, especially in large quantities. It was also evident that the number of web forums and shadow markets explaining how to use sodium nitrite for euthanasia (several times called the "exit") are increasing.

Investigating the Effects of Osmolytes and Environmental pH on Bacterial Persisters.

Bacterial persisters are phenotypic variants that temporarily demonstrate an extraordinary tolerance toward antibiotics. Persisters have been linked to the recalcitrance of biofilm-related infections; hence, a complete understanding of their physiology can lead to improvement of therapeutic strategies for such infections. Mechanisms pertaining to persister formation are thought to be associated with stress response pathways triggered by intra- or extracellular stress factors. Unfortunately, studies demonstrating the effects of osmolyte- and/or pH-induced stresses on bacterial persistence are largely missing. To fill this knowledge gap within the field, we studied the effects of various osmolytes and pH conditions on Escherichia coli persistence with the use of phenotype microarrays and antibiotic tolerance assays. Although we found that a number of chemicals and pH environments, including urea, sodium nitrite, and acidic pH, significantly reduced persister formation in E. coli compared to no-osmolyte/no-buffer controls, this reduction in persister levels was less pronounced in late-stationary-phase cultures. Our results further demonstrated a positive correlation between cell growth and persister formation, which challenges the general notion in the field that slow-growing cultures have more persister cells than fast-growing cultures.

Methanolic extract of Chlorella vulgaris protects against sodium nitrite-induced reproductive toxicity in male rats.

The current study aimed to investigate the protective potential of Chlorella Vulgaris (CV) extract against the reproductive dysfunction induced by sodium nitrite toxicity. Forty-five male Wistar albino rats were assigned into five groups (n = 9). Control group received normal saline orally for 3 months, CV-treated: administered CV extract (70 mg/kg.BW) orally for 3 months, sodium nitrite-treated: received sodium nitrite (80 mg/kg.BW) orally for 3 months, co-treated: simultaneously received CV along with sodium nitrite treatment, orally, daily for 3 months, and CV-pre-treated: pre-treated with CV extract for 4 weeks followed by simultaneous treatment with sodium nitrite and CV extract for additional 8 weeks. Treatment with sodium nitrite significantly decreased serum testosterone and follicle-stimulating hormone concentrations, sperm count, motility, and viability. Besides, it decreased testicular superoxide dismutase and glutathione peroxidase activities while increased malondialdehyde concentration. This effect of sodium nitrite was associated with degenerative, necrotic, vascular, and inflammatory changes in testicular tissues. Treatment of sodium nitrite-intoxicated rats with CV in co-treated and pre-treated groups significantly prevented sodium nitrite-induced alterations of sperm parameters, hormonal concentrations, testicular oxidative-antioxidant status, and histological architecture. This study indicates that CV extract ameliorates the reproductive dysfunction induced by sodium nitrite toxicity via improving reproductive hormonal levels and testicular antioxidant activities.

Severe Methemoglobinemia and Death From Intentional Sodium Nitrite Ingestions.

BACKGROUND: Sodium nitrite is known to induce methemoglobinemia and hypotension when ingested, but reports of intentional ingestion remain rare. CASE SERIES: We report five cases of severe methemoglobinemia secondary to large sodium nitrite ingestion that were reported to and managed by the California Poison Control System in 2019, resulting in three fatalities. The estimated doses ingested ranged from 15 grams to 113 grams, with one patient surviving after an ingestion of 60 grams. The highest documented methemoglobin level was 73%. The 2 patients who survived received methylene blue early in their clinical course. One patient required higher doses of methylene blue compared with other cases of nitrite-associated methemoglobinemia. In the patients who survived, all symptoms resolved within 24 h. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: These cases highlight the severe toxicity associated with intentional large sodium nitrite ingestion. In management, consideration should be given to administering higher initial or more frequent doses of methylene blue compared with standard practice. Given that sodium nitrite is readily accessible through online vendors, and is being circulated through various suicide forums, it has the potential to be more commonly encountered in the emergency department.

[Sodium nitrite in cooked meat during 2012-2015 in China].

OBJECTIVE: To investigate the contamination levels of sodium nitrite in cooked meat from parts of China during 2012-2015. METHODS: The samples were detected in accordance with the national standardization method, and were determined by the GB 2760-2014. RESULTS: The average sodium nitrite in cooked meat was 9. 7 mg/kg with the content range from not detected to 85. 3 mg/kg, and its exceeding standard rate was 4. 8%(922/19360). The average sodium nitrite in visceral products was 16. 6 mg/kg, which was the highest in all kinds of cooked meat. The exceeding standard rate of farmers' market was significantly higher than that of other sampling links. The exceeding standard rate of bulk samples was 5. 8 times of the stereotyped packaging. The exceeding standard rate was downgrade year by year. The main problem was the bulk sauce-stewed meat product in the farm product market which the exceeding standard rate was 9. 5%(327/3461). CONCLUSION: A four-year successive observation shows that the quality of cooked meat with sodium nitrite is improved. But the problem is focused on the bulk. The risk of nitrite in cooked meat is lower.