Blood Methemoglobin Concentration Research Articles

Real-world safety and effectiveness of inhaled nitric oxide therapy for pulmonary hypertension during the perioperative period of cardiac surgery: a post-marketing study of 2817 patients in Japan

ObjectiveTo evaluate the real-world safety and effectiveness of inhaled nitric oxide (INOflo® for Inhalation 800 ppm) for perioperative pulmonary hypertension associated with cardiac surgery in Japan.MethodsThis was a prospective, non-interventional, all-case, post-marketing study of pediatric and adult patients who received perioperative INOflo with cardiac surgery from November 2015–December 2020. Safety and effectiveness were monitored from INOflo initiation to 48 h after treatment completion or withdrawal. Safety outcomes included adverse drug reactions, blood methemoglobin concentrations, and inspired nitrogen dioxide concentrations over time. Effectiveness outcomes included changes in central venous pressure among pediatrics, mean pulmonary arterial pressure among adults, and the partial pressure of arterial oxygen/fraction of inspired oxygen ratio (PaO2/FiO2) in both populations.ResultsThe safety analysis population included 2,817 Japanese patients registered from 253 clinical sites (pediatrics, n = 1375; adults, n = 1442). INOflo was generally well tolerated; 15 and 20 adverse drug reactions were reported in 14 pediatrics (1.0%) and 18 adults (1.2%), respectively. No clinically significant elevations in blood methemoglobin and inspired nitrogen dioxide concentrations were observed. INOflo treatment was associated with significant reductions in both central venous pressure among pediatrics and mean pulmonary arterial pressure among adults, and significant improvements in PaO2/FiO2 among pediatrics and adults with PaO2/FiO2 ≤ 200 at baseline.ConclusionsPerioperative INOflo treatment was a safe and effective strategy to improve hemodynamics and oxygenation in patients with pulmonary hypertension during cardiac surgery. These data support the use of INOflo for this indication in Japanese clinical practice.

Cases of a Spontaneous Increase in Methemoglobin Concentration in Fish Blood during the Annual Cycle

Cases of a Spontaneous Increase in Methemoglobin Concentration in Fish Blood during the Annual Cycle

Cases of Spontaneous Increase of Methemoglobin Concentration in Fish Blood during the Annual Cycle

The dynamics of the content of erythrocytes number and concentration of methemoglobin in the blood of the thermophilic mullet (Chelon auratus Risso, 1810) and the cold-loving flounder (Platichthys flesus L., 1758) during the annual cycle was studied. The degree of maturity of the circulating erythrocyte mass was judged on the basis of acid erythrograms construction. A pronounced negative relationship was found between the number of red blood cells and the concentration of methemoglobin in the blood of both types (r = –0.681; –0.778). It has been shown that the youngest generation of red blood cells appears in the peripheral bed of both species in the post–spawning period (1.5–2.0 months), which reflects the active production of erythrocytes by hematopoietic tissue. The rest of the time, there is a gradual aging of the circulating erythrocyte mass. This leads to a decrease in the number of red blood cells in the blood and is accompanied by an increase in the concentration of methemoglobin. The latter, apparently, determines the production of erythropoietins in the kidneys and activates the processes of erythropoiesis in hematopoietic tissue (pre-spawning period).

P1052ASUPPRESSION OF BLOOD COAGULATION ON THE SURFACE OF A DIALYSIS MEMBRANE USING A DIALYSATE CONTAINING 800 PPM OF NITRIC OXIDE

Abstract Background and Aims Activation of platelets and leukocytes when blood comes in contact with a dialysis membrane surface leads to increased oxidative stress and release of proinflammatory cytokines, which may result in complications in dialysis patients. Within the blood vessels, nitric oxide (NO) generated by nitric oxide synthase on the endothelial cells suppresses both aggregation/activation of platelets and migration/adhesion of leukocytes. We previously showed in a rat hemodialysis model that NO (800 ppm) gas added to the dialysate can suppress blood coagulation on the surface of a dialysis membrane. The aim of the present study was to determine, using a rat hemodialysis model, the appropriate concentration of NO that would most effectively prevent blood coagulation without causing any adverse effects. Method Male Sprague Dawley rats weighing 300 to 400 g were used for the experiments. After the rats were anesthetized (isoflurane, 1.5%-3.0%), extracorporeal circulation was established by removal of blood from the carotid artery and returning it to the tail vein. During the experiment, the blood flow rate was kept at 1.0 mL/min, and the dialysate flow rate at 3 mL/min. Heparin was administered by bolus injection (0.7 unit/g-mouse) at the start of the hemodialysis, and no further heparin was added during the 4-hour hemodialysis session. A cellulose triacetate membrane and polymethylpentene membrane were used for making the small dialyzer and gas exchanger, respectively (the prototype module was manufactured by NIPRO, Co., Japan). NO (200 ppm, 400 ppm, or 800 ppm) was added to the dialysate via the gas exchanger in the NO groups, and N2 gas was added to the dialysate in the control group. During the experiment, the arterial pressure, dialyzer inlet pressure, venous pressure, activated whole blood clotting time (ACT) and methemoglobin (met-Hb) concentration were measured. After circulation, the amount of coagulated blood was measured by the hemoglobin (Hb) content and lactate dehydrogenase (LDH) activity in the eluate from the residual blood clotting in the dialyzer. Results The 4-hour hemodialysis session achievement rate was highest in the NO-800 ppm group (control, 54%; NO-200 ppm, 66%; NO-400 ppm, 77%; NO-800 ppm, 85%). The blood met-Hb content was below 10% in all the NO groups. The Hb content and LDH activity in the eluate were significantly lower in the NO groups than in the control group. These results indicate that addition of higher concentrations of NO was associated with a lower likelihood of coagulation on the dialyzer and in the dialysis circuit and a higher likelihood of smooth and successful 4-hour dialysis sessions. Addition of NO was associated with little risk of adverse effects such as met-Hb accumulation and reduction of blood pressure. Therefore, 800 ppm is considered as the most appropriate concentration of NO to be added to the dialysate for effectively inhibiting blood coagulation without causing any adverse effects. Conclusion Our experiment in a rat hemodialysis model showed that 800 ppm was the most appropriate concentration of NO to be added to the dialysate to suppress blood coagulation on the surface of the dialysis membrane without causing any adverse effects.

Potential roles of nitrate and live yeast culture in suppressing methane emission and influencing ruminal fermentation, digestibility, and milk production in lactating Jersey cows

Concern over the carbon footprint of the dairy industry has led to various dietary approaches to mitigate enteric CH4 production. One approach is feeding the electron acceptor NO3-, thus outcompeting methanogens for aqueous H2. We hypothesized that a live yeast culture (LYC; Saccharomyces cerevisiae from Yea-Sacc 1026, Alltech Inc., Nicholasville, KY) would stimulate the complete reduction of NO3- to NH3 by selenomonads, thus decreasing the quantity of CH4 emissions per unit of energy-corrected milk production while decreasing blood methemoglobin concentration resulting from the absorbed intermediate, NO2-. Twelve lactating Jersey cows (8 multiparous and noncannulated; 4 primiparous and ruminally cannulated) were used in a replicated 4 × 4 Latin square design with a 2 × 2 factorial arrangement of treatments. Cattle were fed diets containing 1.5% NO3- (from calcium ammonium nitrate) or an isonitrogenous control diet (containing additional urea) and given a top-dress of ground corn without or with LYC, with the fourth week used for data collection. Noncannulated cows were spot measured for CH4 emission by mouth using GreenFeed (C-Lock Inc., Rapid City, SD). The main effect of NO3- decreased CH4 by 17% but decreased dry matter intake by 10% (from 19.8 to 17.8 kg/d) such that CH4:dry matter intake numerically decreased by 8% and CH4:milk net energy for lactation production was unaffected by treatment. Milk and milk fat production were not affected, but NO3- decreased milk protein from 758 to 689 g/d. Ruminal pH decreased more sharply after feeding for cows fed diets without NO3-. Acetate:propionate was greater for cows fed NO3-, particularly when combined with LYC (interaction effect). Blood methemoglobin was higher for cattle fed NO3- than for those fed the control diet but was low for both treatments (1.5 vs. 0.5%, respectively; only one measurement exceeded 5%), indicating minimal risk for NO2- accumulation at our feeding level of NO3-. Although neither apparent organic matter nor neutral detergent fiber digestibilities were affected, apparent N digestibility had an interaction for NO3- × LYC such that apparent N digestibility was numerically lowest for diets containing both NO3- and LYC compared with the other 3 diets. Under the conditions of this study, NO3- mitigated ruminal methanogenesis but also depressed dry matter intake and milk protein yield. Based on the fact that few interactions were detected, LYC had a minimal role in attenuating negative cow responses to NO3- supplementation.

Feasibility and preliminary safety of nitric oxide releasing solution as a treatment for bovine mastitis

Nitric oxide-releasing solution (NORS) is a liquid formulation that releases nitric oxide, a broad spectrum antimicrobial, single electron nitroxide radical. This solution was investigated as a potential antimicrobial treatment for bovine mastitis (BM). Three experiments were performed: a) NORS' effect on Staphylococcus aureus and Escherichia coli in an in vitro model; b) NORS' effect on milk obtained from dairy cows showing symptoms of clinical mastitis; and c) the consequences of administering NORS to healthy milking cattle using a dose-escalating in vivo study. Metabolite concentrations were estimated in their blood for methaemoglobin and nitrite; also, milk nitrite concentration and somatic cell count (SCC) were measured to study possible mammary gland inflammation following treatment. NORS lowered the bacterial concentration in all infected samples, in a time- and milk-diluted dependant fashion. Blood methemoglobin concentrations following treatment were all within the normal range for cattle. However, blood and milk nitrite concentrations increased initially but, during the next 24 h, returned to normal range, as did SCC, without any clinical signs of mammary gland inflammation. NORS, if shown to be effective, could be an alternative treatment for mastitis with a shorter clearance time.

The novel nitric oxide donor PDNO attenuates ovine ischemia-reperfusion induced renal failure

BackgroundRenal ischemia-reperfusion injury is a common cause of acute kidney injury in intensive care and surgery. Recently, novel organic mononitrites of 1,2-propanediol (PDNO) were synthesized and shown to rapidly and controllably deploy nitric oxide in the circulation when administered intravenously. We hypothesized that intravenous infusion of PDNO during renal ischemia reperfusion would improve post-ischemic renal function and microcirculation.MethodsSixteen sheep were anesthetized, mechanically ventilated, and surgically instrumented. The left renal artery was clamped for 90 min, and the effects of ischemia were studied for a total of 8 h. Fifteen minutes prior to the release of the clamp, intravenous infusions of PDNO (n = 8) or vehicle (1,2 propanediol + inorganic nitrite, n = 8) were initiated (180 nmol/kg/min for 30 min, thereafter 60 nmol/kg/min for the remainder of the experiment).ResultsRenal artery blood flow, cortical and medullary perfusion, and diuresis and creatinine clearance decreased in the left kidney post ischemia. However, in the sheep treated with PDNO, diuresis and creatinine clearance in the left kidney were significantly higher post ischemia compared to vehicle-treated animals (1.7 ± 0.5 vs 0.7 ± 0.3 ml/kg/h, p = 0.04 and 7.5 ± 2.1 vs 1.7 ± 0.6 ml/min, p = 0.02, respectively). Left renal medullary perfusion and oxygen uptake were higher in the PDNO group (73 ± 9 vs 37 ± 5% of baseline, p = 0.004 and 2.6 ± 0.4 vs 1.6 ± 0.3 ml/min, p = 0.02, respectively). PDNO significantly increased renal oxygen consumption and reduced the oxygen utilization for sodium reabsorption (p = 0.03 for both). Mean arterial blood pressure was significantly reduced by PDNO (83 ± 3 vs 94 ± 3 mmHg, p = 0.02) but was still within normal limits. Total renal blood flow was not affected, and there were no signs of increased blood methemoglobin concentrations or tachyphylaxis.ConclusionsThe novel nitric oxide donor PDNO improved renal function after ischemia. PDNO also prevented the persistent reduction in medullary perfusion during reperfusion and improved renal oxygen utilization without severe side effects.

ACUTE POISONING WITH SODIUM NITRATE IN NEUROLOGICAL PRACTICE

This article describes a clinical case of a patient with acute cerebrovascular accident, acute respiratory failure and acute coronary syndrome. The ischemic lesion was associated with sodium nitrate, poisoning and its metabolite nitrite which resulted in increased methemoglobin concentration in blood and manifested as reversible discirculatory encephalopathy, respiratory disorder and myocardial damage. The article shows figures, reflecting changes in the biochemical composition of blood and changes in the electrocardiogram. The purpose of this study is to demonstrate clinical features of acute poisoning with sodium nitrate.

Nitrate supplementation has marginal effects on enteric methane production from Bos indicus steers fed Flinders grass (Iseilema spp.) hay, but elevates blood methaemoglobin concentrations

This experiment has quantified the methane abatement potential of nitrate in the context of extensively managed cattle. The experimental protocol consisted of two, 4 × 4 Latin square design using eight rumen fistulated Bos indicus steers fed Flinders grass (Iseilema spp.) hay ad libitum. The treatments were Control (nil nitrogen supplement), urea (32.5 g/day urea) and two levels of calcium nitrate: CaN1 and CaN2 (to provide 4.6 g and 7.9 g NO3/kg DM equivalent to ~0.46% and 0.80% of DM, respectively). Complete supplement intake was ensured by dosing any supplement that had not been voluntarily consumed, through the rumen fistula, 1 h after feeding. Enteric methane production was measured using open circuit respiration chambers. Methane yield (g/kg DM intake) from the CaN2 treatment tended to be lower (P < 0.07) than either the Control or urea treatments. There were no significant differences in methane yield between Control, urea or CaN1 treatments. Mean blood methaemoglobin concentrations were significantly (P < 0.001) higher for CaN2 animals compared with the Control, urea or CaN1 treatments. In addition, a significant time effect after dosing (P < 0.001) and a significant interaction between treatment and time after dosing (P < 0.001) was apparent. Overall mean total volatile fatty acid concentration was 74.0 ± 1.53 mM with no significant treatment effect, but a significant effect for both time of sampling (3 h vs 6 h) within days and among 7 sampling days. The inclusion of calcium nitrate as a non-protein-N source significantly reduced the molar proportions of butyrate (P < 0.001), iso-butyrate (P < 0.05) and iso-valerate (P < 0.001) compared with the Control. The provision of nitrate supplements, providing both a NPN and an alternative sink for H that would otherwise support enteric methanogenesis, has some potential. In extensive grazing systems effective methane abatement strategies are required. The elevated concentration of MetHb using CaN2 suggests that the strategy of replacing urea with nitrate in supplements fed to extensively managed cattle in the northern rangelands may be inappropriate where supplement intake cannot be controlled on an individual animal basis and forage quality is seasonally variable.

Impact of adding nitrate or increasing the lipid content of two contrasting diets on blood methaemoglobin and performance of two breeds of finishing beef steers

Adding nitrate to the diet or increasing the concentration of dietary lipid are effective strategies for reducing enteric methane emissions. This study investigated their effect on health and performance of finishing beef cattle. The experiment was a two×two×three factorial design comprising two breeds (CHX, crossbred Charolais; LU, Luing); two basal diets consisting of (g/kg dry matter (DM), forage to concentrate ratios) 520 : 480 (Mixed) or 84 : 916 (Concentrate); and three treatments: (i) control with rapeseed meal as the main protein source replaced with either (ii) calcium nitrate (18 g nitrate/kg diet DM) or (iii) rapeseed cake (RSC, increasing acid hydrolysed ether extract from 25 to 48 g/kg diet DM). Steers (n=84) were allocated to each of the six basal diet×treatments in equal numbers of each breed with feed offered ad libitum. Blood methaemoglobin (MetHb) concentrations (marker for nitrate poisoning) were monitored throughout the study in steers receiving nitrate. After dietary adaptation over 28 days, individual animal intake, performance and feed efficiency were recorded for a test period of 56 days. Blood MetHb concentrations were low and similar up to 14 g nitrate/kg diet DM but increased when nitrate increased to 18 g nitrate/kg diet DM (P<0.001). An interaction between basal diet and day (P<0.001) indicated that MetHb% was consistently greater in Concentrate – than Mixed-fed steers at 18 g nitrate/kg diet DM. Maximum individual MetHb% was 15.4% (of total Hb), which is lower than considered clinically significant (30%). MetHb concentrations for individual steers remained consistent across time. Concentrate-fed steers were more efficient (lower residual feed intake (RFI) values) than Mixed-fed steers (P<0.01), with lower dry matter intake (DMI) (kg/day) (P<0.001) and similar average daily gain (ADG). CHX steers were more efficient (lower RFI; P<0.01) than LU steers with greater ADG (P<0.01), lower DMI (/kg BW; P<0.01) and lower fat depth (P<0.001). ADG, BW or DMI did not differ across dietary treatments (P>0.05). Neither basal diet nor treatment affected carcass quality (P>0.05), but CHX steers achieved a greater killing out proportion (P<0.001) than LU steers. Thus, adding nitrate to the diet or increasing the level of dietary lipid through the use of cold-pressed RSC, did not adversely affect health or performance of finishing beef steers when used within the diets studied.

A Case of Severe Methemoglobinemia with Shock and High Saturation Gap Following Suicidal Ingestion of Sodium Nitrite-Saved by Oral Methylene Blue

Here we report a case of sodium nitrite ingestion for suicidal attempt, presented in unconsciousness, shock and deeply cyanosed condition. He was pulseless and had no recordable BP with methemoglobin level of 77% and saturation gap of 20. He was put on ventilator in ICU and treated with ionotropes, oral methylene blue and parental ascorbic acid. He completely recovered after two days with normal methemoglobin level. Survival in a case of methemoglobinemia with extremely high level of methemoglobin, non recordable BP and deep cyanosis is rarely reported. We report this case for awareness about the severity of signs and symptoms depend on the methemoglobin concentration in blood, false results of pulse oximetry and high saturation gap in methemoglobinemia, and about the management of the lethal effect of poisoning.

The effect of incremental levels of dietary nitrate on methane emissions in Holstein steers and performance in Nelore bulls.

Two experiments were conducted to study effects of dietary nitrate on enteric methane production, blood methemoglobin concentration, and growth rate in cattle. In Exp. 1, 36 Holstein steers (288 ± 25 kg BW) were fed increasing levels of dietary nitrate (6 levels; 0 to 3.0% of feed DM) in corn silage-based total mixed rations. Nitrate was introduced gradually in a 25-d adaptation period before methane production was determined in environmentally controlled rooms. In the rooms, feed intake was restricted and similar among all treatments. Methane production (g/d) decreased linearly as dietary nitrate concentration increased (P < 0.01). The apparent efficiency (measured methane reduction divided by potential methane reduction) with which enteric methane was mitigated was 49%. Blood methemoglobin levels increased with increasing nitrate dose. In Exp. 2, 300 Nelore bulls (392 ± 28 kg) were fed increasing levels of nitrate (6 levels; 0 to 2.4% of feed DM) in high-concentrate total mixed rations offered ad libitum. Feed intake decreased linearly with increasing level of dietary nitrate (P < 0.01). However, ADG was not affected by nitrate dose (P = 0.54), resulting in a linear improvement in G:F (P = 0.03) as dietary nitrate level increased. Carcass dressing percentage showed a quadratic response to incremental dietary nitrate, reaching the highest value at 0.96% of NO3/kg DM (P = 0.04).

A Case of Tooth Extraction in a Patient with a History of Secondary Methemoglobinemia

We present a case of tooth extraction for a 25-year-old patient with a history of secondary methemoglobinemia at 6 months of age caused by Acetaminophen. The tooth extraction was performed under local anesthesia using 2% lidocaine with 1：80,000 epinephrine in an operating room equipped with respiratory support. As a result, the treatment was successfully completed and we found no significant signs of secondary methemoglobinemia such as cyanosis, dyspnea and rise in blood methemoglobin concentration.

Methemoglobinemia In Rhesus Monkeys Due To M-Hemoglobinopathy

M-hemoglobinopathies in humans are usually due to amino acid changes, which tend to stabilize the heme iron in ferric state and inaccessible to methemoglobin reductase. Consequently, blood methemoglobin concentrations are elevated despite normal methemoglobin reductase activity. No naturally-occurring animal models for M-hemoglobinopathies have been described. In contrast to humans where thousands of hereditary disorders and genetic predispositions to disease have been described, inborn errors of metabolism in non-human primates have been very rarely documented (e.g. globoid cell leukodystrophy). As part of an NIH-supported National Referral Center for Animal Models of Human Genetic Disease, which focuses on homologous hereditary diseases in dogs and cats, we present here the discovery and characterization of an M-hemogobinopathy in rhesus monkeys (Macaca mulatta). Adult rhesus monkeys of Chinese origin with persistent cyanotic mucous membranes and healthy controls were studied from two institutions. Despite the apparent cyanosis, these primates did clinically not show any other overt signs. Routine complete blood cell counts, chemistry screens and urinalyses as well as cardiopulmonary examinations did not reveal any abnormalities. Fresh EDTA blood samples were analyzed to determine the degree and cause of methemoglobinemia and results were compared to healthy rhesus monkeys from the same institutions. Blood methemoglobin concentrations were persistently increased to 15-30% in affected monkeys, while control animals had &lt;1% methemoglobin levels. Methemoglobin (cytochrome b5) reductase activities in erythrocytes were repeatedly measured in vitro and found to be normal compared to controls. Based upon the hemoglobin-oxygen dissociation curves and p50 values (14.8 mmHg; compared to 14.5 and 14.6 mmHg for controls) the oxygen transport function was normal. Both cation-exchange as well as reversed-phase and high performance liquid chromatography analyses revealed normal elution patterns of hemoglobin isotype and globin chains. DNA studies identified a disease-associated polymorphism in the alpha globin gene (CAC → CAA) in the affected animals. This change in the alpha globin protein was confirmed by mass spectrometry (α78 His → Gln). Our findings indicate an electrophoretically silent α-globin polymorphism is associated with methemoglobinemia in these rhesus monkeys. This is the first description of methemoglobinemia in a non-human primate and represents the first animal model of an M-hemoglobinopathy. While clinical signs were relatively mild in these rhesus monkeys, our findings represent one of the first inborn errors of metabolism described in non-human primates, thus emphasizing how unusual disorders caused by “experiments of nature” provide rare opportunities to gain a better understanding of both medicine and biology. Rhesus monkeys represent unique, valuable animal models for developing and testing new treatment options for hemoglobinopathies. Disclosures: No relevant conflicts of interest to declare.

Effect of intravenous or oral sodium chlorate administration on the fecal shedding of Escherichia coli in sheep1,2

The effect of gavage or intravenous (i.v.) administration of sodium chlorate salts on the fecal shedding of generic Escherichia coli in wether lambs was studied. To this end, 9 lambs (27 ± 2.5 kg) were administered 150 mg NaClO3/kg BW by gavage or i.v. infusion in a crossover design with saline-dosed controls. The crossover design allowed each animal to receive each treatment during 1 of 3 trial periods, resulting in 9 observations for each treatment. Immediately before and subsequent to dosing, jugular blood and rectal fecal samples were collected at 4, 8, 16, 24, and 36 h. Endpoints measured were fecal generic E. coli concentrations, blood packed cell volume (PCV), blood methemoglobin concentration, and serum and fecal sodium chlorate concentrations. Sodium chlorate had no effects (P > 0.05) on blood PVC or methemoglobin. Fecal generic E. coli concentrations were decreased (P < 0.05) approximately 2 log units (99%) relative to controls 16 and 24 h after sodium chlorate infusion and 24 h after sodium chlorate gavage. Within and across time and treatment, fecal chlorate concentrations were highly variable for both gavage and i.v. lambs. Average fecal sodium chlorate concentrations never exceeded 100 µg/g and were typically less than 60 µg/g from 4 to 24 h after dosing. Times of maximal average fecal sodium chlorate concentration did not correspond with times of lowered average generic E. coli concentrations. Within route of administration, serum sodium chlorate concentrations were greatest (P < 0.01) 4 h after dosing; at the same time point, serum chlorate was greater (P< 0.01) in i.v.-dosed lambs than gavaged lambs but not at 16 or 24 h (P > 0.05). At 8 h, serum chlorate concentrations of gavaged lambs were greater (P < 0.05) than in i.v.-dosed lambs. Serum chlorate data are consistent with earlier studies indicating very rapid transfer of orally dosed chlorate to systemic circulation, and fecal chlorate data are consistent with earlier data showing the excretion of low to marginal concentrations of sodium chlorate in orally dosed animals. Efficacy of sodium chlorate at reducing fecal E. coli concentrations after i.v. infusion suggests that low concentrations of chlorate in gastrointestinal contents, delivered by biliary excretion, intestinal cell sloughing, or simple diffusion, are effective at reducing fecal E. coli levels. Alternatively, chlorate could be eliciting systemic effects that influence fecal E. coli populations.

Two Cases of Methemoglobinemia Induced by the Exposure to Nitrobenzene and Aniline

ObjectiveTo report two cases of methemoglobinemia induced by inhaled nitrobenzene and dermally absorbed aniline.MethodsWe have evaluated a 37-year-old male worker exposed to nitrobenzene by inhalation while conducting maintenance job of mononitrobenzene pump and a 25-year-old male worker exposed dermally to aniline while unloading.ResultsThe first case is a 37-year-old male exposed to nitrobenzene. His blood methemoglobin concentration level was initially 19.8%, and chest X-ray was normal. After oxygen therapy, the blood methemoglobin concentration level decreased to 2.1%, and the symptoms were alleviated. The second case is a 25-year-old male exposed dermally to aniline. His chest X-ray was normal, but blood methemoglobin concentration level reached maximally 46.8%. He was treated with methylene blue due to relatively high blood methemoglobin level. Gradually after the treatment, his methemoglobin concentration level was normalized to 0.8% and simultaneously symptoms were resolved.ConclusionsAfter the thorough exposure investigations and medical evaluations, we have concluded that these cases were methemoglobinemia induced by occupational exposure to nitrobenzene and aniline. We suggest that businesses which handle methemoglobinemia-causing substances control the engineering process strictly, implement periodic screening, and establish emergency patient management system.

Methemoglobinemia in Postchemotherapy Stomatitis Topical Treatment

Methemoglobinemia is a rare congenital or acquired disease of increased blood methemoglobin concentration. We documented 2 cases of children suffering from neuroblastoma whose postchemotherapy anemia, leucopenia, and stomatitis were complicated by methemoglobinemia after using a formulary oral gel (7.5% benzocaine, doxycycline, nystatin, glycerin). The complication resulted in hospital treatment. Percutaneous oxygen saturation remained at 85% and 87% despite administration of 100% oxygen through a nonrebreather mask. Arterial blood gas analysis showed an oxygen saturation of 98% and 97%, respectively. Spectroscopic measurement showed methemoglobin concentration of 42% and 35.5%, respectively. After red blood cell transfusion and oral ascorbic acid in case 1 and methylene blue in case 2, the patients' condition improved. Although the benzocaine gel is not in use in several medical systems, it should be considered as a possible reason for methemoglobinemia.

Toluidine blue for the intraoperative staining of the ureters. Studies on the safe administration in rats

Acute cardiovascular events have repeatedly been reported to occur during the intraoperative presentation of the urinary tract with toluidine blue (TB). We here assessed the minimum TB dose required, and its safest and most suitable form of intravenous administration for the intraoperative staining of the ureters in rats. TB (0.13, 0.4, 1.3, or 4.0 mg/kg) was administered to anesthetized rats either by intravenous injection within 1 min or by infusion within 10 min. During the experiments,biomonitoring parameters such as electrocardiograms (ECGs)and mean arterial blood pressure (MAP) were recorded,blood gas analysis was performed, and methemoglobin measured. Tissue injury was assessed from released plasma enzyme activities and histopathologically. The intraoperative staining of the ureters was documented photographically,and total urinary excretion and final urine/plasma TB concentrations were determined. Parameters of blood gas analysis, methemoglobin concentrations, and markers of tissue injury were slightly affected by the two highest TB doses but not at all by the lower ones. At doses of ≥0.4 mg/kg, ureters were stained sufficiently. Staining was more intense, and urine excretion of TB higher on average when the dye was injected.The 1-min injection of ≥1.3 mg TB/kg strongly and temporarily decreased the MAP, while the infusions caused lesser effects. Mean ECG parameters were not affected by any TB administration, but one animal developed a temporary bundle branch block after the 1-min injection of 4.0 mg/kg. In rats, intravenous injection of 0.4 mg TB/kg was sufficient for the intraoperative staining of the urinary tract without the risk of severe cardiovascular and hemodynamic side effects. Provided our results are transferable to humans, the administration of low TB doses could allow its safer clinical use for the intraoperative visualization of the ureters.

Sub-chronic effects of nitrate in drinking water on red-legged partridge (Alectoris rufa): Oxidative stress and T-cell mediated immune function

In order to evaluate the effects of nitrates on birds, we have exposed captive red-legged partridges to nitrates concentrations of 0 (control), 100 (dwell water in farming areas) or 500 mg/l (fertirrigation level). The cellular immune response, plasma biochemistry, methemoglobin concentration (metHb), and oxidative stress biomarkers in blood and tissues were studied after two weeks of exposure. Several blood parameters such as aspartate aminotransferase, creatinine phosphokinase and lactate dehydrogenase activities and magnesium level decreased with nitrate exposure, whereas alkaline phosphatase activity and creatinine level increased. The oxidant effect of nitrates was evidenced by the increase in blood metHb, accompanied by the lipid peroxidation of red blood cells, the increased levels of oxidized glutathione (GSH) in liver, and the generation of oxidative DNA damage in plasma lymphocytes. GSH in erythrocytes was negatively correlated with blood metHb. The cellular immune function was slightly lower at partridges exposed to nitrates. These results suggest that adverse effects of nitrates on birds occur at concentrations potentially present in the field.

コ・オキシメータで測定される総ビリルビン濃度の評価

CO-oximeters provide an accurate evaluation of oxygenation of the patient. The ABL835 FLEX (ABL835, Radiometer A/S) is a blood gas analyzer with a CO-oximeter. The CO-oximeter measures total hemoglobin, hemoglobin derivatives and total bilirubin concentration (T-Bil). In this study, the T-Bil value measured in the CO-oximeter of ABL835 was compared with simultaneously obtained result from the dry chemistry multianalyzer FUJI DRY CHEM 3030 (FDC 3030, Fuji Photofilm Co., LTD.). As a result, the T-Bil values measured in whole blood by ABL835 were significantly well correlated with the obtained results from FDC 3030 (R=0.991, P<0.0001). However, the T-Bil values measured in whole blood by ABL835 were higher than the values of FDC 3030 with the average difference of 0.199mg/dL. In addition, this difference and the methemoglobin concentration in whole blood were significantly correlated (R=0.938, P<0.0001). In conclusion, it was found that the T-Bil measured in whole blood samples by ABL835 gives results that correlate well with those obtained using clinical chemistry method. However, the T-Bil value measured in whole blood by ABL835 may be higher under the influence of methemoglobin, so the T-Bil should be measured in plasma for a case of high methemoglobin concentration.