Methemoglobinemia in Hemodialysis Patients due to Acute Chlorine Intoxication: A Case Series Calling Attention on an Old Problem.

INTRODUCTION: Hemodialysis uses municipal water that must be strictly purified and sterilized to be used for that procedure. Large amounts of decontaminants are often used, such as chlorine, and if these compounds are not subsequently removed they can be transferred to the blood of patients causing complications including methemoglobinemia. METHODS: In this case series study, dialysis patients in one unit were evaluated. We reviewed clinical characteristics and laboratory findings obtained on the day when the water supply was disinfected with chlorine, with the aim to quantify methemoglobin concentrations. Our objective was to characterize the clinical presentation and management of patients who presented with methemoglobinemia on a specific index day. We also reviewed reported cases in the literature regarding this underreported complication. RESULTS: Eight patients who presented with chlorine intoxication were evaluated. The methemoglobin concentrations were between 1.3% and 7.9% (reference value 0-1%). We believe this to be caused by water containing 0.78 mg/L of total chlorine. Seven patients presented with cyanosis, 4 with dizziness, 6 with dark brown blood, 4 with dyspnea, and 4 with headache and hemolytic anemia. Subjects were treated with supplemental oxygen, methylene blue, intravenous vitamin C, blood transfusions, and increased doses of erythropoietin. No patient died, and all continued with their usual hemodialysis sessions. CONCLUSION: Acute chlorine intoxication transferred by the water used during hemodialysis sessions can present with methemoglobinemia accompanied by cyanosis, oxygen desaturation, and hemolytic anemia. Chlorine levels should be carefully monitored in the water used for hemodialysis treatment.

Inflammatory phenotype, clinicopathologic variables, and effects of long-term methylene blue in dogs with hereditary methemoglobinemia caused by cytochrome b5 reductase deficiency.

OBJECTIVE: To determine whether dogs with cytochrome b5 reductase (CYB5R) deficiency have a constitutive proinflammatory phenotype, characterize hematologic and serum chemistry results, and describe changes in methemoglobin (MetHb) levels and serum C-reactive protein (CRP) concentrations after long-term per os (PO) methylene blue (MB) therapy. ANIMALS: 21 client-owned dogs (CYB5R deficient, n = 10; healthy controls, 11). PROCEDURES: In this prospective, case-control study, methemoglobin levels were measured using a blood gas analyzer with co-oximetry. Plasma tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-10 (IL-10) concentrations were measured using a canine-specific multiplex bead-based assay. Serum CRP concentrations were measured with a canine-specific commercial ELISA kit. Serum CRP concentration and MetHb levels were measured in 6 dogs with CYB5R deficiency after ≥ 60 days of PO MB therapy. RESULTS: As expected, MetHb levels were higher in dogs with CYB5R deficiency compared to controls (P < .001). Plasma TNF-α, IL-6, IL-10, and serum CRP concentrations were no different between CYB5R-deficient and control dogs. Dogs with CYB5R deficiency had lower absolute lymphocyte (P = .005) and eosinophil counts (P = .04) and higher alanine transaminase (P = .04) and alkaline phosphatase activity (P = .02) than controls, but these changes were not clinically relevant. Methemoglobin levels decreased after PO MB therapy (P = .03). CLINICAL RELEVANCE: These results suggest that otherwise healthy dogs with CYB5R deficiency do not have a constitutive proinflammatory phenotype and clinically relevant abnormalities in hematologic and serum chemistry panels are not expected. Dogs with decreased quality of life attributed to methemoglobinemia from CYB5R deficiency might benefit from PO MB therapy.

Pharmacokinetic Profile, Safety, and Tolerability of Topical Berdazimer Gel, 10.3% in Patients With Molluscum Contagiosum.

BACKGROUND: Berdazimer (SB206), gel 10.3% is a novel, topical, nitric oxide–releasing agent intended for molluscum contagiosum (MC) treatment. METHODS: A 12-week, open-label, multicenter trial evaluated the safety, tolerability, and pharmacokinetic (PK) parameters of berdazimer gel, 10.3% applied topically once daily for the treatment of MC. Patients were aged ≥6 months with >20 molluscum lesions. The primary endpoint was the PK profile of the hydrolyzed N-methylaminopropyl-trimethoxysilane (hMAP3) monomer and nitrate during a 2-week period of once-daily berdazimer gel, 10.3% application (PK period) under maximal use conditions. Safety and tolerability were evaluated throughout the 12-week study period. RESULTS: Half of the 34 enrolled patients (17) were female and most (97.1% [33/34]) were white. Patients were 2 to 12 years old (mean, 5.3 years) with a mean of 50 MC lesions at baseline (mean time since MC awareness, 12.4 months). No patients had quantifiable plasma hMAP3 concentrations on day 1. On day 15, 2 patients had quantifiable plasma hMAP3 concentrations; however, the maximum concentration (33.9 ng/mL) was >10-fold lower than the no observed adverse effect level (NOAEL) in an animal toxicology study. Mean nitrate concentration–time profiles were similar on days 1 and 15 and remained flat for all patients throughout the 2-week PK period. The highest plasma methemoglobin level observed was 3.2%. Application-site pain (13/34 [38.2%]) and application-site erythema (6/34 [17.6%]) were the most frequent treatment-emergent adverse events (TEAEs), and most TEAEs were mild or moderate. CONCLUSIONS: Once-daily berdazimer gel, 10.3% was well-tolerated with minimal systemic absorption. J Drugs Dermatol. 2022;21(10):1104-1110. doi:10.36849/JDD.6938.

Effects of infusion of human methemoglobin solution following hydrogen sulfide poisoning.

RATIONALE: We have recently reported that infusion of a solution containing methemoglobin (MetHb) during exposure to hydrogen sulfide results in a rapid and large decrease in the concentration of the pool of soluble/diffusible H2S in the blood. However, since the pool of dissolved H2S disappears very quickly after H2S exposure, it is unclear if the ability of MetHb to "trap" sulfide in the blood has any clinical interest and relevance in the treatment of sulfide poisoning. METHODS: In anesthetized rats, repetition of short bouts of high level of H2S infusions was applied to allow the rapid development of an oxygen deficit. A solution containing MetHb (600 mg/kg) or its vehicle was administered 1 min and a half after the end of H2S intoxication. RESULTS: The injection of MetHb solution increased methemoglobinemia to about 6%, almost instantly, but was unable to affect the blood concentration of soluble H2S, which had already vanished at the time of infusion, or to increase combined H2S. In addition, H2S-induced O2 deficit and lactate production as well as the recovery of carotid blood flow and blood pressure were similar in treated and control animals. CONCLUSION: Our results do not support the view that administration of MetHb or drugs-induced methemoglobinemia during the recovery phase following severe H2S intoxication in sedated rats can restore cellular oxidative metabolism, as the pool of diffusible sulfide, accessible to MetHb, disappears rapidly from the blood after H2S exposure.

Cyanide poisoning: pathophysiology and treatment recommendations.

This paper aims to assess and compare currently available antidotes for cyanide poisoning. Such evaluation, however, is difficult. Thus, extrapolation from the results of animal studies has potential pitfalls, as significant inter-species differences in response may exist, and these experiments often involve administration of toxin and antidote almost simultaneously, rather than incorporating a more realistic time delay before initiation of treatment. Direct inference from human case reports is also problematic; either because of uncertainties over the exposure levels involved (and hence the likely outcome without treatment), or because of difficulties in identifying the specific contribution of a particular antidote within the overall treatment regimen. Certainly an effort to compare the relative efficacy of cyanide antidotes produces equivocal findings, with no single regimen clearly standing out. Indeed, factors such as the risks of antidote toxicity to various individuals and other practical issues, may be more important considerations. There is therefore no single treatment regimen which is best for all situations. Besides individual risk factors for antidote toxicity, the nature of the exposure and hence its likely severity, the evolving clinical features and the number of persons involved and their proximity to hospital facilities, all need to be considered. Clinically mild poisoning may be treated by rest, oxygen and amyl nitrite. Intravenous antidotes are indicated for moderate poisoning. Where the diagnosis is uncertain, sodium thiosulphate may be the first choice. With severe poisoning, an additional agent is required. Given the various risks with methaemoglobin formers or with unselective use of kelocyanor, hydroxocobalamin may be preferred from a purely risk-benefit perspective. However the former alternatives will likely remain important.

Multicomponent spectroscopic assay for hemoglobin and ferrihemoglobin species in methemoglobin treatment of cyanide poisoning.

Monitoring the concentrations of various hemoglobin and ferrihemoglobin species and their cyanide complexes is important in the study of the efficacy of methemoglobin-forming agents for the treatment of cyanide toxicity. In this study, the visible absorption spectra of three hemoglobin intermediates were experimentally determined and compared with computer-generated spectra. The data supported the assumption that the molar absorptivities of the intermediates are equivalent to the combined absorptivities of the component subunits. A multicomponent Fourier transform (FT)-aided full spectrum quantitation system (FSQ) to simultaneously measure hemoglobin (Hb), hemimethemoglobin (hemiMetHb), and the cyanide complex dicyanohemimethemoglobin (dicyhemiMetHb) was also evaluated. It was found that FSQ had satisfactory accuracy and precision to quantitate hemiMetHb and dicyhemiMetHb at concentrations from 2 to 20% of the total Hb, a range commonly encountered in the treatment of cyanide poisoning using methemoglobin-forming agents. The simplicity and rapid throughput of the method make it suitable for clinical evaluation studies and form the basis for the design of a portable instrument for field analysis of these species.

Development of neo red cells (NRC) with the enzymatic reduction system of methemoglobin.

To assess the oxygen transport capacity and safety of Neo Red Cells (NRC) with the enzymatic reduction system of methemoglobin in vitro and in experimental animals. Stroma free hemoglobin (SFH) prepared without damage of enzymes from outdated human red blood cells, together with inositol hexaphosphate as an allosteric effector, NAD as a coenzyme and glucose, adenine and inosine as a substrate was encapsulated within liposomes composed of hydrogenated soy phosphatidylcholine, cholesterol, myristic acid and alpha-tocopherol in the ratio of 7:7:2:0.28 respectively. NRC thus prepared with a mean diameter of 220 nm, encapsulation efficiency of 1.3 g-Hb:1 g-lipid and P50O2 of 50-60 mmHg were then coated with polyethylene glycol bound to hydrogenated soy phosphatidylethanolamine as a surface modifier to prevent aggregation of NRC in plasma. The methemoglobin formation of the NRC with enzymatic reduction system were evaluated by in-vitro examination and exchange transfusion with rats as in-vivo examination, then the methemoglobin formation was reduced from 1%/hr to 0.4%/hr by the addition of methemoglobin reduction system. The generation of the pyruvate and the lactate were observed within the NRC with enzymatic reduction system, then the activation of the Embden-Meyerhof pathway was confirmed. And we concerned about the availability of the NRC as a perfusate for the cardiopulmonary bypass during moderate or profound hypothermia, then we evaluated the oxygen transporting efficiency and capacity of the NRC under the using of the artificial lung system in vitro examination. The present investigation suggest that the effectiveness of the NRC with enzymatic reduction system, they restrained the formation of methemoglobin and they are efficient oxygen carriers as a perfusate of the artificial lung, and we suggest the new extracorporeal circulation system using of the NRC as a perfusate for the cardiopulmonary bypass.

Protective effect of stroma-free methemoglobin during cyanide poisoning in dogs.

BACKGROUND: During fire exposure, cyanide toxicity can block aerobic metabolism. Oxygen and sodium thiosulfate are accepted therapy. However, nitrite-induced methemoglobinemia, which avidly binds cyanide, decreases oxygen-carrying capacity that is already reduced by the presence of carboxyhemoglobin (inhalation of carbon monoxide in smoke). This study tested whether exogenous stroma-free methemoglobin (SFmetHb) can prevent depression of hemodynamics and metabolism during canine cyanide poisoning. METHODS: In 10 dogs (weighing 18.8 +/- 3.5 kg) anesthetized with chloralose-urethane and mechanically ventilated with air, baseline hemodynamic and metabolic measurements were made. Then, 137 +/- 31 ml of 12 g% SFmetHb was infused into five dogs (SFmetHb group). Finally, the SFmetHb group and the control group (n = 5, no SFmetHb) received an intravenous potassium cyanide infusion (0.072 mg.kg-1.min-1) for 20 min. Oxygen consumption (VO2) was measured with a Datex Deltatrac (Datex Instruments, Helsinki, Finland) metabolic monitor and cardiac output (QT) was measured by pulmonary artery thermodilution. RESULTS: From baseline to cyanide infusion in the control group, QT decreased significantly (p < 0.05) from 2.9 +/- 0.8 to 1.5 +/- 0.4 l/min, mixed venous PCO2 (PvCO2) tended to decrease from 35 +/- 4 to 23 +/- 2 mmHg, PvO2 increased from 43 +/- 4 to 62 +/- 8 mmHg, VO2 decreased from 93 +/- 8 to 64 +/- 19 ml/min, and lactate increased from 2.3 +/- 0.5 to 7.1 +/- 0.7 mM. In the SFmetHb group, cyanide infusion did not significantly change these variables. From baseline to infused cyanide, the increases in blood cyanide (4.8 +/- 1.0 to 452 +/- 97 microM) and plasma thiocyanate cyanide (18 +/- 5 to 65 +/- 22 microM) in the SFmetHb group were significantly greater than those increases in the control group. SFmetHb itself caused no physiologic changes, except small decreases in heart rate and PvO2. Peak SFmetHb reached 7.7 +/- 1.0% of total hemoglobin. CONCLUSIONS: Prophylactic intravenous SFmetHb preserved cardiovascular and metabolic function in dogs exposed to significant intravenous cyanide. Blood concentrations of cyanide, and its metabolite, thiocyanate, revealed that SFmetHb trapped significant cyanide in blood before tissue penetration.

[The experimental treatment of cyanide poisoning with a methemoglobin solution]. / Lechenie otravleniia tsianidami rastvorom metgemoglobina v éksperimente.

The stroma-free methemoglobin solution proved to be an effective antidote against acute cyanide poisoning in experiment. The poisoning was induced by intraperitoneal administration to rats of cyanide solutions in doses of 5, 10 and 15 mg/kg. Methemoglobin solutions were injected intravenously in doses of 2 and 4 g/kg. All the rats given methemoglobin solution after the administration of cyanide survived. Spectrophotometry of rat urine demonstrated rapid excretion of methemoglobin cyanide.

Stroma-free methemoglobin solution: an effective antidote for acute cyanide poisoning.

Several aspects of stroma-free methemoglobin solution (SFMS) as a cyanide antidote were investigated using a rat model. Stroma-free methemoglobin solution was more than 90% effective against multiples of the LD90 of cyanide up to and including four times the LD90 and approximately 50% effective against multiples up to and including eight times the LD90. Highly concentrated solutions of SFMS (33 g/dl) did not differ significantly from less concentrated solutions of SFMS (16 g/dl) when compared on the basis of efficacy. Administration of large doses of SFMS alone resulted in no apparent morbidity or mortality. It could be that SFMS is a safe and effective alternative antidote for the treatment of cyanide poisoning.

Comparison of nitrite treatment and stroma-free methemoglobin solution as antidotes for cyanide poisoning in a rat model.

The standard nitrite/thiosulfate regimen for cyanide poisoning was tested in our rat model. By modifying the treatment regimen and the nitrite solution an effective antidote against an LD90 of cyanide could be produced. However, this treatment was effective against two times the LD90 only when administered ten minutes prior to cyanide injection. These results are in marked contrast to our results with stroma-free methemoglobin solutions (SFMS) which showed SFMS to be a highly effective antidote against four times the LD90 when administered 30 seconds after an intravenous injection of cyanide. SFMS proved to be an effective antidote for two times the LD90 when administered up to sixty seconds after the cessation of respiration.

Stroma-free methemoglobin solution as an antidote for cyanide poisoning: a preliminary study.

Effective treatment of cyanide poisoning requires rapid diagnosis, good supportive treatment and the use of a specific antidote. The currently available antidotes offer demonstrated efficacy along with significant potential adverse side effects. We have investigated an alternate approach to antidote therapy for cyanide poisoning by using Stroma-Free Methemoglobin Solution ( SFMS ). Rats injected with an LD100 intravenous dose of cyanide were treated with SFMS equal to 1.5% of their total body hemoglobin. There was a highly significant increase in the survival rate of the treated group compared to saline controls. The potential advantages of SFMS over current antidotes include an immediate onset of action, rapid elimination of cyanide from the body and a mode of action that doesn't compromise any of the patients' oxygen carrying capacity. SFMS shows promise as a significant adjunct in the treatment of cyanide poisoning.