Indoxacarb poisoning causing methemoglobinemia treated with parenteral vitamin C: a case report.

INTRODUCTION: This case study reports on a suicide attempt involving indoxacarb and vitamin C. Indoxacarb is a neurotoxic insecticide used in agriculture and as a flea controller in pets. Cotton, vegetables, and fruits are treated with indoxacarb, an insecticide that can be applied both indoors and outdoors. It causes skin allergies, methemoglobinemia, and hemolytic anemia. It is also attributed to allergic reactions through ingestion, inhalation, physical contact, and translaminar action. This case report highlights use of vitamin C in methemoglobinemia caused by indoxacarb poisoning. Indoxacarb poisoning has the potential to be extremely serious and even lethal. In this instance, the patient initially had no symptoms after ingesting a substance containing indoxacarb in an attempt at suicide. However, further tests revealed methemoglobinemia and low oxygen levels. CASE PRESENTATION: A 28-year-old south-east Asian female patient ingested an insecticide containing 5.25% novaluron, 4.5% indoxacarb, and 25% thiamethoxam, and reported that she noticed muddy brown urine but presented with no active signs or symptoms of poisoning. Upon examination, the patient was fully conscious, alert, and hemodynamically stable, but had an oxygen saturation of 84%. Gastric lavage was performed, and blood investigations revealed a muddy-brown-colored blood sample and methemoglobin levels of 12%. The patient was treated with high-dose vitamin C and showed significant improvement, with a drop in methemoglobin levels to 1.2% and an increase in oxygen saturation to 97%. DISCUSSION: Indoxacarb poisoning can cause severe methemoglobinemia. Vitamin C may be a useful treatment option for methemoglobinemia caused by indoxacarb, particularly in cases in which traditional treatment with methylene blue is contraindicated or not tolerated. Hence high doses of ascorbic acid, that is, vitamin C, were administered to the patient, which lowered their methemoglobin levels and improved oxygen levels without much safety concerns. CONCLUSION: This example emphasizes the significance of early indoxacarb poisoning detection and treatment as well as the possible advantages of utilizing ascorbic acid in the management of methemoglobinemia, and highlights the use of vitamin C in the treatment of methemoglobinemia caused by indoxacarb poisoning. Therefore, it is important for healthcare professionals to be aware of the potential for indoxacarb to cause methemoglobinemia and to consider vitamin C as a treatment option.

Methemoglobin levels in malaria: a systematic review and meta-analysis of its association with Plasmodium falciparum and Plasmodium vivax infections and disease severity.

Reports indicate that Plasmodium infections influence methemoglobin levels. However, findings have been inconclusive or have varied across different geographic and demographic contexts. This systematic review and meta-analysis aimed to consolidate existing data regarding the association between Plasmodium infections and alterations in methemoglobin levels related to the severity of the infection. A comprehensive literature search of several databases, including Ovid, ProQuest, Embase, Scopus, MEDLINE, and PubMed, was conducted to identify relevant studies that examined methemoglobin levels in patients with malaria. Qualitative synthesis and meta-analysis of the pooled standardized mean difference were conducted to synthesize the differences in methemoglobin levels between: (1) patients with malaria and those without malaria and (2) patients with severe malaria and those with uncomplicated malaria based on various themes including publication year, study design, study area, Plasmodium species, age group, symptomatic status, severity status, and method of malaria detection. Of the 1846 studies that were initially identified from the main databases and additional searches on Google Scholar, 10 studies met the eligibility criteria and were selected for this review. The systematic review distinctly highlighted an association between malaria and elevated methemoglobin levels, an observation consistent across diverse geographical regions and various Plasmodium species. Furthermore, the meta-analysis confirmed this by demonstrating increased methemoglobin levels in patients with malaria compared to those without malaria (P < 0.001, Hedges' g 2.32, 95% CI 1.36-3.29, I2 97.27, 8 studies). Moreover, the meta-analysis found elevated methemoglobin levels in patients with severe malaria compared to those with uncomplicated malaria (P < 0.001, Hedges' g 2.20, 95% CI 0.82-3.58, I2 96.20, 5 studies). This systematic review and meta-analysis revealed increased methemoglobin levels in patients with P. falciparum and P. vivax infections, with a notable association between elevated methemoglobin levels and severe malaria. Future research should focus on elucidating the specific mechanisms by which changes in methemoglobin levels are related to infections by P. falciparum and P. vivax, particularly in terms of severity, and how these alterations could potentially impact patient management and treatment outcomes.

Detection of methaemoglobinaemia in a COVID-19 patient on dapsone.

Methaemoglobinaemia occurs when iron in haemoglobin is oxidised into a form that cannot transport oxygen. At low levels, it is asymptomatic, though at rising levels symptoms arise from impaired oxygenation, and it can ultimately be fatal. While uncommon, it is important to consider in hypoxaemic COVID-19 patients, especially if they are not clinically improving on standard treatments and workup for other causes does not explain the ongoing hypoxaemia. It is often diagnosed through a mismatch in peripheral and arterial oxygen, with the former typically less than the latter. We present the case of a COVID-19 patient who was found to have methaemoglobinaemia due to dapsone use for Pneumocystic jirovecii pneumonia (PJP) prophylaxis while on chemotherapy. Dapsone was stopped and supplemental high-flow nasal cannula was provided, and methaemoglobin levels improved over a 5-day period. She was discharged to follow-up with her haematologist in the clinic.

Elevated methemoglobin levels in patients treated with high-dose hydroxocobalamin.

OBJECTIVE: The aim of this study was to assess the impact of hydroxocobalamin (OHCbl) infusion on arterial blood gas and oximetry values in patients with vasoplegic syndrome. METHODS: Blood samples collected from 95 patients receiving OHCbl infusion were assayed using the ABL90 FLEX Plus blood gas analyzer for the concentration of methemoglobin (MetHb), total hemoglobin (tHb), carboxyhemoglobin (COHb), arterial oxygen saturation (SaO2), arterial oxygen partial pressure (PaO2), and arterial carbon dioxide partial pressure (PaCO2). Interference of OHCbl on these variables was evaluated using the measured difference between the preinfusion and postinfusion samples. RESULTS: Blood MetHb (%) measured after the infusion of OHCbl (5g) were significantly higher than the baseline levels, with a median of 4.8 (IQR, 3.0-6.5) versus 1.0 (IQR, 1.0-1.2) (P < .001). Blood COHb (%) increased from a median of 1.3 (IQR, 1.0-1.8) to 1.7 (IQR, 1.3-2.2) (P < .001) following the OHCbl infusion. No differences were seen in median levels of tHb, PaO2, PaCO2, and SaO2 between pre- and post-OHCbl treatment. CONCLUSION: The presence of OHCbl in blood clearly interfered with the oximetry measurements of the hemoglobin component fractions by falsely increasing the levels of MetHb and COHb. Blood levels of MetHb and COHb cannot be reliably determined by the co-oximetry when OHCbl is known or suspected.

A Pumpless Pediatric Artificial Lung Maintains Function for 72 h Without Systemic Anticoagulation Using the Nitric Oxide Surface Anticoagulation System.

BACKGROUND: Children with end-stage lung disease are commonly managed with extracorporeal life support (ECLS) as a bridge to lung transplantation. A pumpless artificial lung (MLung) is a portable alternative to ECLS and it allows for ambulation. Both ECLS and pumpless artificial lungs require systemic anticoagulation which is associated with hemorrhagic complications. We tested the MLung with a novel Nitric Oxide (NO) Surface Anticoagulation (NOSA) system, to provide local anticoagulation for 72 h of support in a pediatric-size ovine model. METHODS: Four mini sheep underwent thoracotomy and cannulation of the pulmonary artery (inflow) and left atrium (outflow), recovered and were monitored for 72hr. The circuit tubing and connectors were coated with the combination of an NO donor (diazeniumdiolated dibutylhexanediamine; DBHD-N2O2) and argatroban. The animals were connected to the MLung and 100 ppm of NO was added to the sweep gas. Systemic hemodynamics, blood chemistry, blood gases, and methemoglobin were collected. RESULTS: Mean device flow was 836 ± 121 mL/min. Device outlet saturation was 97 ± 4%. Pressure drop across the lung was 3.5 ± 1.5 mmHg and resistance was 4.3 ± 1.7 mmHg/L/min. Activated clotting time averaged 170 ± 45s. Methemoglobin was 2.9 ± 0.8%. Platelets declined from 590 ± 101 at baseline to 160 ± 90 at 72 h. NO flux (x10-10 mol/min/cm2) of the NOSA circuit averaged 2.8 ± 0.6 (before study) and 1.9 ± 0.1 (72 h) and across the MLung 18 ± 3 NO flux was delivered. CONCLUSION: The MLung is a more portable form of ECLS that demonstrates effective gas exchange for 72 h without hemodynamic changes. Additionally, the NOSA system successfully maintained local anticoagulation without evidence of systemic effects.

Erythroid anion Exchanger-1 (band 3) transports nitrite for nitric oxide metabolism.

Nitrite (NO2-) interacts with hemoglobin (Hb) in various ways to regulate blood flow. During hypoxic vasodilation, nitrite is reduced by deoxyHb to yield nitric oxide (NO). While NO, a hydrophobic gas, could freely diffuse across the cell membrane, how the reactant nitrite anion could permeate through the red blood cell (RBC) membrane remains unclear. We hypothesized that Cl-/HCO3- anion exchanger-1 (AE1; band 3) abundantly embedded in the RBC membrane could transport NO2-, as HCO3- and NO2- exhibit similar hydrated radii. Here, we monitored NO/N2O3 generated from NO2- inside human RBCs by DAF-FM fluorophore. NO2-, not NO3-, increased intraerythrocytic DAF-FM fluorescence. To test the involvement of AE1-mediated transport in intraerythrocytic NO/N2O3 production from nitrite, we lowered Cl- or HCO3- in the RBC-incubating buffer by 20 % and indeed observed slower rise of the DAF-FM fluorescence. Anti-extracellular AE1, but not anti-intracellular AE1 antibodies, reduced the rates of NO formation from nitrite. The AE1 blocker DIDS similarly reduced the rates of NO/N2O3 production from nitrite in a dose-dependent fashion, confirming that nitrite entered RBCs through AE1. Nitrite inside the RBCs reacted with both deoxyHb and oxyHb, as evidenced by 6.1 % decrease in deoxyHb, 14.7 % decrease in oxyHb, and 20.7 % increase in methemoglobin (metHb). Lowering Cl- in the milieu equally delayed metHb production from nitrite-oxyHb and nitrite-deoxyHb reactions. Thus, AE1-mediated NO2- transport facilitates NO2--Hb reactions inside the red cells, supporting NOx metabolism in circulation.

In vivo monitoring of hemoglobin derivatives in a rat thermal injury model using spectral diffuse reflectance imaging.

INTRODUCTION: To demonstrate the feasibility of our previously proposed Diffuse reflectance spectral imaging (DRSI) method for in vivo monitoring of oxygenated hemoglobin, deoxygenated hemoglobin, methemoglobin, tissue oxygen saturation, and methemoglobin saturation in a rat scald burn wound model and assess whether the method could be used for differentiating the burn depth groups in rats based on the hemoglobin parameters. METHODOLOGY: Superficial dermal burns (SDBs), deep dermal burns (DDBs), and deep burns (DBs) were induced in rat dorsal skin using a Walker-Mason method. An approach based on multiple regression analysis for spectral diffuse reflectance images aided by Monte Carlo simulations for light transport was used to quantify the hemoglobin parameters. Canonical discriminant analysis (CDA) was performed to discriminate SDB, DDB, and DB. RESULTS: CDA using the total hemoglobin concentration, tissue oxygen saturation, and methemoglobin saturation as the independent variables showed good performance for discriminating the SDB, DDB, and DB groups immediately after burn injury and the SDB group from the DDB and DB groups 24-72 h after burn injury. CONCLUSIONS: The DRSI method with multiple regression analysis for quantification of oxygenated hemoglobin, deoxygenated hemoglobin, and methemoglobin proved to be reliable for monitoring these hemoglobin derivatives in the rat experimental burn injury model. The parameters of tissue oxygen saturation, methemoglobin saturation, and total hemoglobin concentration are promising for the differentiating the degree of burn injury using CDA.

Elucidating the binding properties of methemoglobin in red blood cell to cyanide, hydrosulfide, and azide ions using artificial red blood cell.

Methemoglobin (metHb), the oxidized form of hemoglobin, lacks the ability of reversible oxygen binding; however, it has a high binding affinity to toxic substances such as cyanide, hydrosulfide, and azide. This innate property of metHb offers the clinical option to treat patients poisoned with these toxins, by oxidizing the endogenous hemoglobin in the red blood cells (RBCs). The binding properties of naked metHb (isolated from RBC) with these toxins has been studied; however, the binding behaviors of metHb under the intracellular conditions of RBC are unclear because of the difficulty in detecting metHb status changes in RBC. This study aimed to elucidate the binding properties of metHb in RBC under physiological and poisoned conditions using artificial RBC, which was hemoglobin encapsulated in a liposome. The mimic-circumstances of metHb in RBC (metHb-V) was prepared by oxidizing the hemoglobin in artificial RBC. Spectroscopic analysis indicated that the metHb in metHb-V exhibited a binding behavior different from that of naked metHb, depending on the toxic substance: When the pH decreased, (i) the cyanide binding affinity of metHb-V remained unchanged, but that of naked metHb decreased (ii) the hydrosulfide binding affinity was increased in metHb-V but was decreased in naked metHb. (iii) Azide binding was increased in metHb-V, which was similar to that in naked metHb, irrespective of the pH change. Thus, the binding behavior of intracellular metHb in the RBC with cyanide, hydrosulfide, and azide under physiological and pathological conditions were partly elucidated using the oxidized artificial RBC.

N-acetylcysteine: a novel approach to methaemoglobinaemia in normothermic liver machine perfusion.

Extended duration of normothermic machine perfusion (NMP) provides opportunities to resuscitate suboptimal donor livers. This intervention requires adequate oxygen delivery typically provided by a blood-based perfusion solution. Methaemoglobin (MetHb) results from the oxidation of iron within haemoglobin and represents a serious problem in perfusions lasting > 24 h. We explored the effects of anti-oxidant, N-acetylcysteine (NAC) on the accumulation of methaemoglobin. NMP was performed on nine human donor livers declined for transplantation: three were perfused without NAC (no-NAC group), and six organs perfused with an initial NAC bolus, followed by continuous infusion (NAC group), with hourly methaemoglobin perfusate measurements. In-vitro experiments examined the impact of NAC (3 mg) on red cells (30 ml) in the absence of liver tissue. The no-NAC group sustained perfusions for an average of 96 (range 87-102) h, universally developing methaemoglobinaemia (≥ 2%) observed after an average of 45 h, with subsequent steep rise. The NAC group was perfused for an average of 148 (range 90-184) h. Only 2 livers developed methaemoglobinaemia (peak MetHb of 6%), with an average onset of 116.5 h. Addition of NAC efficiently limits formation and accumulation of methaemoglobin during NMP, and allows the significant extension of perfusion duration.

Carboxyhemoglobin and Methemoglobin Levels and Hemolysis in Children Undergoing Cardiac Surgery With Cardiopulmonary Bypass.

Hemolysis is a complication of cardiopulmonary bypass (CPB). Carboxyhemoglobin (COHb) and methemoglobin (MetHb) were suggested as potential hemolysis biomarkers. This retrospective study was based on a prospective registry aimed to determine the association of COHb and MetHb levels with hemolysis in pediatric patients <4 years old who underwent cardiac surgery with CPB. Plasma-free hemoglobin (PFH), COHb, and MetHb levels were measured before CPB; every 30 minutes during CPB; and on postoperative days 1, 2, and 3. Patients were classified into hemolysis and nonhemolysis groups based on the maximum PFH levels during CPB. A total of 193 patients were included. No significant difference was observed in the maximum COHb levels during CPB (COHb CPB ) between the hemolysis and nonhemolysis groups (1.2% [interquartile range {IQR} 0.9-1.4%] vs. 1.1% [IQR: 0.9-1.4%]; p = 0.17). The maximum MetHb levels during CPB (MetHb CPB ) were significantly higher in the hemolysis group than in the nonhemolysis group (1.3% [IQR: 1.1-1.5%] vs. 1.2% [IQR: 1.0-1.4%]; p = 0.007). Areas under the receiver operating curves of COHb CPB and MetHb CPB were 0.557 (95% confidence interval: 0.475-0.640) and 0.615 (95% confidence interval: 0.535-0.695), respectively. Therefore, the predictive ability of both hemolysis biomarkers during CPB is limited.

Impact of methemoglobin on carboxyhemoglobin saturation measurement in fatal sodium nitrate and sodium nitrite cases.

An increase in suicide cases by sodium nitrate and sodium nitrite ingestion has been noted in the scientific literature. We report on the possible impact of nitrate/nitrite-caused methemoglobinemia on carboxyhemoglobin measurement by spectrophotometric methods. Elevated methemoglobin saturation may result in insufficient reducing agents to convert methemoglobin into deoxygenated hemoglobin, affecting the measured total hemoglobin and carboxyhemoglobin saturation. We highlight four cases where the cause of death was attributed to sodium nitrate or sodium nitrite ingestion. The possible impact of the nitrate/nitrite-caused methemoglobinemia on the carboxyhemoglobin saturation as measured by spectrophotometry is discussed. Further studies are needed to identify a causal relationship between nitrate/nitrite-caused methemoglobinemia and carboxyhemoglobin saturation as measured by spectrophotometric methods.

Pharmaceutical stability of methemoglobin-albumin cluster as an antidote for hydrogen sulfide poisoning after one-year storage in freeze-dried form.

Long-term stability during storage is an important requirement for pharmaceutical preparations. The methemoglobin (metHb)-albumin cluster, in which bovine metHb is covalently enveloped with an average of three human albumin molecules, is a promising antidote for hydrogen sulfide (H2S) poisoning. In this study, we investigated the pharmaceutical stability of metHb-albumin cluster after storage for one year in solution and as freeze-dried powder. The lyophilized powder of metHb-albumin cluster stored for one year was readily reconstituted in sterile water for injection, yielding a homogeneous brown solution. Physicochemical measurements revealed that the overall structure of the metHb-albumin cluster was still maintained after preservation. Results of the pharmacological study showed that 100 % of the H2S-poisoned mice survived after treatment with the reconstituted solution of metHb-albumin cluster powder. Furthermore, the solution did not cause any toxic reactions. The antidotal efficacy of metHb-albumin cluster for H2S poisoning was preserved in freeze-dried powder form for at least one year.

Exploring the Anti-Hypoxaemia Effect of Hydromethylthionine: A Prospective Study of Phase 3 Clinical Trial Participants.

Methylthioninium chloride (MTC) is a standard treatment for methaemoglobinaemia. A preparation of reduced MTC has been reported to increase blood oxygen saturation (SpO2) and lower respiratory rates in patients with severe COVID-19. We have developed a stable form of reduced methylthionine (hydromethylthionine-mesylate, HMTM) having a benign safety profile in two Phase 3 trials in Alzheimer's disease. The aim of this prospective study was to determine the effects of oral HMTM on SpO2 and methaemoglobin (metHb) levels in a cohort of patients with mild hypoxaemia not due to COVID-19. Eighteen participants randomised to a single dose of 4, 75, 100 or 125 mg doses of HMTM had SpO2 levels below 94% at baseline. Patients were routinely monitored by pulse oximetry after 4 h, and after 2 and 6 weeks of twice daily dosing. Significant ~3% increases in SpO2 occurred within 4 h and were sustained over 2 and 6 weeks with no dose differences. There were small dose-dependent increases (0.060-0.162%) in metHb levels over 2 to 6 weeks. Minimum-energy computational chemistry revealed that HMT can bind within 2.10 Å of heme iron by donating a pair of electrons from the central nitrogen of HMT to d orbitals of heme iron, but with lower affinity than oxygen. In conclusion, HMTM can increase SpO2 without reducing metHb by acting as a strong displaceable field ligand for heme iron. We hypothesise that this facilitates a transition from the low oxygen affinity T-state of heme to the higher affinity R-state. HMTM has potential as an adjunctive treatment for hypoxaemia.

Hemoglobin Derivatives in Beef Irradiated with Accelerated Electrons.

The efficiency of food irradiation depends on the accuracy of the irradiation dose range that is sufficient for inhibiting microbiological growth without causing an irreversible change to the physical and chemical properties of foods. This study suggests that the concentration of hemoglobin derivatives can be used as a criterion for establishing the limit for chilled beef irradiation at which irradiation-induced oxidation becomes irreversible. The express spectrophotometry method for estimating the hemoglobin derivative concentration shows a nonlinear increase in methemoglobin concentration from 15% to 50% in beef irradiated by accelerated electrons with the doses ranging from 250 Gy to 10,000 Gy. The monitoring of the hemoglobin derivative concentration for three days after irradiation shows nonmonotonous dependencies of methemoglobin concentration in beef in the storage time since the oxidation of hemoglobin occur as a result of irradiation and biochemical processes in beef during storage. The proposed method based on the quantitative analysis of the hemoglobin derivative concentration can be used to estimate the oxidation level for irradiation of foods containing red blood cells. The study proposes a model that describes the change in hemoglobin derivative concentration in beef after irradiation considering that oxidation of hemoglobin can be triggered by the direct ionization caused by accelerated electrons, biochemical processes as a result of bacterial activity, and reactive oxygen species appearing during irradiation and storage. This research throws light on the mechanisms behind food irradiation during storage that should be taken into account for selecting the optimal parameters of irradiation.

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.

Evaluation of methemoglobin as an intravascular contrast agent: T1 relaxation time effect in a rabbit model.

OBJECTIVE: Alternative contrast agents for MRI are needed for individuals who may respond adversely to gadolinium, and need an intravascular agent for specific indications. One potential contrast agent is intracellular methemoglobin, a paramagnetic molecule that is normally present in small amounts in red blood cells. An animal model was used to determine whether methemoglobin modulation with intravenous sodium nitrite transiently changes the T1 relaxation of blood. METHODS: Four adult New Zealand white rabbits were treated with 30 mg intravenous sodium nitrite. 3D TOF and 3D MPRAGE images were acquired before (baseline) and after methemoglobin modulation. T1 of blood was measured with 2D ss EPl acquisitions with inversion recovery preparation performed at two-minute intervals up to 30 min. T1 maps were calculated by fitting the signal recovery curve within major blood vessels. RESULTS: Baseline T1 was 1758 ± 53 ms in carotid arteries and 1716 ± 41 ms in jugular veins. Sodium nitrite significantly changed intravascular T1 relaxation. The mean minimum value of T1 was 1126 ± 28 ms in carotid arteries 8 to 10 min after the injection of sodium nitrite. The mean minimum value of T1 was 1171 ± 52 ms in jugular veins 10 to 14 min after the injection of sodium nitrite. Arterial and venous T1 recovered to baseline after a period of 30 min. CONCLUSION: Methemoglobin modulation produces intravascular contrast on T1-weighted MRI in vivo. Additional studies are needed to safely optimize methemoglobin modulation and sequence parameters for maximal tissue contrast.

Can We Estimate Late-Onset Sepsis by Serial Methemoglobin Levels? An Observational Study in Preterm Neonates.

Objective: To assess serial methemoglobin (MetHb) levels in preterm infants as a possible diagnostic method for late-onset sepsis (LOS). Methods: Preterm infants were assigned into two groups: those with culture-proven LOS and controls. Serial MetHb levels were measured. Results: The MetHb values of the LOS group were found to be significantly increased (p < 0.001). The cutoff value for the detection of LOS was calculated as MetHb > 1.75%, optimized for a sensitivity of 81.9% and specificity of 90%. After antimicrobial therapy, MetHb values were found to decrease significantly (p < 0.001). MetHb had an AUC of 0.810 for mortality using the calculated cutoff of >2% (p < 0.005). Conclusions: MetHb levels increase at the onset of LOS and decrease following treatment. MetHb can be added to other sepsis biomarkers as a rapid infectious process indicator for preterm neonates. MetHb > 2% is associated with LOS mortality.

Close relationship between high HbA1c levels and methemoglobin generation in human erythrocytes: The enhancement of oxidative stress in the process.

OBJECTIVE: This study aimed to investigate the effect of diabetic plasma on human red blood cells (RBCs) in order to highlight the amplification mechanisms of oxidative stress (OS) in relation to methemoglobin (metHb) production, a potential bio-indicator that could be related to diabetes disease. RESEARCH DESIGN AND METHODS: Normal RBCs were co-incubated with the diabetic plasma of 24 patients at different HbA1c levels, for 0, 24, and 48 h in order to assess cell turbidity and hemoglobin (Hb) stability. Hb and metHb production were quantified inside and outside RBCs. Malonaldehyde (MDA) level and cell morphology were concomitantly evaluated. RESULTS: The cell turbidity was significantly decreased in the group co-incubated with diabetic plasma at high HbA1c levels (0.074 ± 0.010 AU) compared to the control group (0.446 ± 0.019 AU). A significant decrease in intracellular Hb (0.390 ± 0.075 AU) and its stability (0.600 ± 0.001 AU) were revealed. Also, we found an important increase of metHb levels inside RBCs (0.186 ± 0.017 AU) and in its supernatant (0.086 ± 0.020 AU) after 48 h. Consequently, MDA absorbance increased significantly (0.320 ± 0.040 AU) in RBCs exposed to diabetic plasma with high HbA1c. CONCLUSION: These findings suggest that poor glycemic control in diabetes leads to metHb generation which is the main factor of the OS amplification.

Nitrite decreases sickle hemoglobin polymerization in vitro independently of methemoglobin formation.

The root cause of sickle cell disease (SCD) is the polymerization of sickle hemoglobin (HbS) leading to sickling of red blood cells (RBC). Earlier studies showed that in patients with SCD, high-dose nitrite inhibited sickling, an effect originally attributed to HbS oxidation to methemoglobin-S even though the anti-sickling effect did not correlate with methemoglobin-S levels. Here, we examined the effects of nitrite on HbS polymerization and on methemoglobin formation in a SCD mouse model. In vitro, at concentrations higher than physiologic (>1 µM), nitrite increased the delay time for polymerization of deoxygenated HbS independently of methemoglobin-S formation, which only occurred at much higher concentrations (>300 µM). In vitro, higher nitrite concentrations oxidized 100% of normal hemoglobin A (HbA), but only 70% of HbS. Dimethyl adipimidate, an anti-polymerization agent, increased the fraction of HbS oxidized by nitrite to 82%, suggesting that polymerized HbS partially contributed to the oxidation-resistant fraction of HbS. At low concentrations (10 µM-1 mM), nitrite did not increase the formation of reactive oxygen species but at high concentrations (10 mM) it decreased sickle RBC viability. In SCD mice, 4-week administration of nitrite yielded no significant changes in methemoglobin or nitrite levels in plasma and RBC, however, it further increased leukocytosis. Overall, these data suggest that nitrite at supra-physiologic concentrations has anti-polymerization properties in vitro and that leukocytosis is a potential nitrite toxicity in vivo. Therefore, to determine whether the anti-polymerization effect of nitrite observed in vitro underlies the decreases in sickling observed in patients with SCD, administration of higher nitrite doses is required.

Whole-blood ribonucleic acid sequencing analysis in methemoglobinemia: a case report.

INTRODUCTION: Methemoglobinemia is a condition in which methemoglobin is increased and the oxygen carrying capacity of tissues is decreased, causing a lack of oxygen to the whole body. RNA (ribonucleic acid) sequencing technologies have made it possible to systematically examine how the human transcriptome responds to invasive pathologies. To our knowledge, no previous studies have reported the results of RNA sequencing in a patient with methemoglobinemia. We describe the analysis of RNAs from the whole blood of a patient with methemoglobinemia. CASE PRESENTATION: A 31-year-old Japanese man was brought to our hospital with symptoms of dyspnea due to inhalation of gas from an acetic acid phosphonitrate storage tank at a factory. The nitrogen oxide concentration measured around the storage tank was over 2500 ppm, and he witnessed orange-brown smoke at that time. After entering the area and taking a few breaths, he suddenly became unwell, with dyspnea and numbness in his extremities. He was evacuated from the area within a few minutes, at which time he was suffering from whole-body cyanosis and was still aware of the above symptoms. On arrival at the hospital, his respiration rate was 18 breaths/minute, and his SpO2 ranged from 80% to 85% on 15 L/minute of oxygen by mask (2.5 hours postexposure). Arterial blood gas testing revealed a methemoglobin level of 23.1%. After the administration of methylene blue, the patient's methemoglobin level normalized and his symptoms improved. Chest X-ray and chest computed tomography showed no evidence of pulmonary edema or interstitial pneumonia, and no other abnormal findings were observed. RNA sequencing was performed on the blood samples obtained at the time of the visit, with the blood sample collected on day 5 used as a control. To our knowledge, the present study is the first to describe the analysis of RNAs from the whole blood of a patient with methemoglobinemia. The RNA sequencing analysis showed that an activated "hydrogen peroxide catabolic process" may be associated with the pathogenesis of methemoglobinemia. CONCLUSION: The results reported in the present study may explain the pathogenesis of methemoglobinemia.