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Nitrous oxide (NO) is an inhalant that has become increasingly popular as a recreational drug. While it is presumed to be harmless, a number of adverse effects of NO have been described. We discuss the case of a 24-year-old man with no medical history, who initially presented to the emergency department with progressive polyneuropathy caused by vitamin B12 deficiency after NO abuse. Two days after being discharged with hydroxocobalamin supplementation, the patient returned with a severe headache, blurry vision and slurred speech. Imaging revealed cerebral venous sinus thrombosis. Hypercoagulability workup showed slightly elevated homocysteine and normalised vitamin B12 after supplementation. Genetic testing showed a heterozygous prothrombin G20210A mutation. He was treated with low-molecular-weight heparin followed by dabigatran. We hypothesise that NO use may increase the risk of developing cerebral venous thrombosis, especially in patients with multiple risk factors and elevated homocysteine levels.

Purpose Hydroxocobalamin has been observed to cause transient hypertension in healthy subjects, but rigorous studies examining its efficacy are lacking. Materials and methods Adults in shock who received hydroxocobalamin from 2017 to 2021 were analyzed retrospectively. Hourly hemodynamics from 24 h before and after treatment were collected, and the difference and hourly change of mean arterial pressure (MAP), systolic blood pressure (SBP), diastolic blood pressure (DBP), and norepinephrine-equivalent dose (NED) were examined in mixed-effects models. Results This study included 3992 hemodynamic data points from 35 patients and is the largest case series to date. In the mixed effects model, there was no difference in MAP 24-h after hydroxocobalamin administration (estimated fixed effect [EFE] −0.2 mmHg, p = 0.89). A two-piecewise mixed model found that the hourly change in MAP was not different from zero in either the pre-administration (EFE 0.0 mmHg/h, p = 0.80) or post-administration segments (EFE 0.0 mmHg/h, p = 0.55). Analysis of the SBP, DBP, and NED also found similar insignificant results. Conclusions Although hydroxocobalamin has been observed to cause hypertension in healthy subjects, our results suggest that in patients with shock, hydroxocobalamin may not be effective in improving hemodynamics at 24 h after administration.

Transcobalamin (TC) transports cobalamin (vitamin B12) from plasma into cells. Its congenital deficiency is a rare autosomal recessive disorder due to mutations in the TCN2 gene. It causes intracellular cobalamin depletion with early onset in the first months of life, failure to thrive with pallor due to megaloblastic anemia. It can be associated with pancytopenia, gastrointestinal symptoms with vomiting, diarrhea, and neurological complications with myelopathy. Aggressive vitamin B12 parenteral therapy must be instituted early and continuously. Retinopathy and maculopathy are rarely associated with this condition. We report the electrophysiological results of one TC-deficient patient diagnosed at the age of 4 months immediately and continuosly treated by hydroxocobalamin IM. Her visual function was followed by eight ophthalmological assessments, eight flash-ERG, six EOG, one mf-ERG, and seven P-ERG recordings over a 10-year period, between the age of 2y 9 m and 12y 6 m. Her ophthalmological assessment including visual acuity, fundi, optical coherent tomography (OCT), and retinal nerve fiber layer (RNFL) remained normal. From the age of 2y 9 m to 5y, dark-adapted and light-adapted flash-ERGs, EOGs and pattern-ERG were normal. From the age of 6y 4 m to 12y 6 m, dark-adapted flash-ERGs and EOGs remained normal. Cone a-wave amplitudes remained normal, whereas cone b-wave and flicker-response amplitudes were decreased. At the age of 12y 6 m, mf-ERG N1P1 amplitudes on the central 30° were decreased. From the age of 7y 4 m to 12y 6 m, P-ERG P50 amplitudes were decreased with no N95. While clinical and anatomical assessments remained normal over a 10-year period, patient’s electrophysiological results suggested the progressive onset of a subclinical retinopathy of inner-cone dystrophy type, and a subclinical maculopathy on the central 30° including the ganglion cell layer deficiency on the central 15°, despite continuous intramuscular treatment, RPE and scotopic system remaining normal. The origins of such subclinical retinopathy and maculopathy are unknown and independent of early disease identification and aggressive intramuscular hydroxocobalamin therapy.

BACKGROUND AND PURPOSE Nitrous oxide misuse is a recognized issue worldwide. Prolonged misuse inactivates vitamin B12, causing a myeloneuropathy. METHODS Twenty patients presenting between 2016 and 2020 to tertiary hospitals in Sydney with myeloneuropathy due to nitrous oxide misuse were reviewed. RESULTS The average age was 24 years, and mean canister consumption was 148 per day for 9 months. At presentation, paresthesias and gait unsteadiness were common, and seven patients were bedbound. Mean serum B12 was normal (258 pmol/L, normal range [NR] = 140-750) as was active B12 (87 pmol/L, normal > 35). In contrast, mean serum homocysteine was high (51 μmol/L, NR = 5-15). Spinal magnetic resonance imaging (MRI) showed characteristic dorsal column T2 hyperintensities in all 20 patients. Nerve conduction studies showed a predominantly axonal sensorimotor neuropathy (n = 5). Patients were treated with intramuscular vitamin B12, with variable functional recovery. Three of the seven patients who were bedbound at presentation were able to walk again with an aid at discharge. Of eight patients with follow-up data, most had persistent paresthesias and/or sensory ataxia. Mobility scores at admission and discharge were not significantly correlated with the serum total and active B12 levels or cumulative nitrous oxide use. There were no significant trends between serum active B12 level and cumulative nitrous oxide use (Spearman rho = -0.331, p = 0.195). CONCLUSIONS Nitrous oxide misuse can cause a severe but potentially reversible subacute myeloneuropathy. Serum and active B12 can be normal, while elevated homocysteine and dorsal column high T2 signal on MRI strongly suggest the diagnosis. Neurological deficits can improve with abstinence and B12 supplementation, even in the most severely affected patients.

Cyanide induces acute lethal poisoning resulting from inhibition of cytochrome c oxidase located in the complex IV (Complex IV) of mitochondria. However, current therapies for cyanide poisoning using hydroxocobalamin and nitrous acid compounds remain a clinical issue. Here, we show that liposome-encapsulated methemoglobin (metHb@Lipo), nanosized biomimetic red blood cells, replicate the antidotal mechanism of nitrous acid compounds against cyanide poisoning, achieving superior efficacy and fast action with no adverse effects. The structure of metHb@Lipo, which consists of concentrated methemoglobin in its aqueous core and a lipid membrane resembling the red blood cell membrane, provides favorable characteristics as a cyanide antidote, such as binding properties and membrane permeability. Upon cyanide exposure, metHb@Lipo maintained the mitochondrial function in PC12 cells, resulting in a cell viability comparable to treatment with nitrous acid compounds. In a mouse model of cyanide poisoning, metHb@Lipo treatment dramatically improved mortality with a rapid recovery from the symptoms of cyanide poisoning compared to treatment with nitrous acid compounds. Furthermore, metHb@Lipo also possesses satisfactory pharmacokinetic properties without long-term bioaccumulation and toxicity. Our findings showed a novel concept to develop drugs for cyanide poisoning and provide a promising possibility for biomimetic red blood cell preparations for pharmaceutical applications.

Vasoplegic syndrome is a rising problem affecting morbidity and mortality in patients undergoing cardiac surgery. Vasoplegia is a vasodilatory, shocklike syndrome characterized by decreased systemic vascular resistance, normal to high cardiac index, and hypotension refractory to fluid resuscitation and vasopressors. This review describes the presentation, physiology, risk factors, treatments, and implications of vasoplegia after cardiac surgery. No standardized methods for diagnosing and treating vasoplegia are available. Vasoplegia is caused by surgical trauma, systemic inflammation, and vascular dysregulation. Patients with comorbidities and those undergoing complex surgical procedures are at increased risk for vasoplegia. The use of β-blockers is protective. Vasoplegia is potentially reversible. Vasopressin is likely the most effective first-line vasopressor, and the use of methylene blue and/or hydroxocobalamin may restore vascular tone. Alternative therapies such as methylene blue and hydroxocobalamin show promise, but additional research and education are needed.

Amygdalin is originally a natural cyanogenic glycoside available as a dietary supplement used in the alternative treatment of cancer patients. Amygdalin hydroxylates to toxic cyanide in the body, which can cause life-threatening intoxication. The case report presents a 72-year-old patient with life-threatening cyanide poisoning after ingesting a dietary supplement containing amygdalin identified in prehospital care, which was successfully treated with hydroxocobalamin.

Pigmented urine in a hospitalized patient has a broad differential diagnosis including urinary tract infection or bacterial colonization, hemolysis, rhabdomyolysis, and drugs. We present a case of purple urine in a patient who received methylene blue and hydroxocobalamin for catecholamine-refractory vasodilatory shock. The patient's purple urinary discoloration is presumed to have resulted from a combination of the blue and red pigments of methylene blue and hydroxocobalamin, respectively. As these drugs are increasingly being used to treat vasoplegia in cardiopulmonary bypass, it is important for clinicians to be aware of this benign cause of urine discoloration.

Smoke inhalation from a structure fire is a common route of cyanide poisoning in the U.S. Cyanide inhibits cellular respiration, often leading to death. Its rapid distribution throughout the body can result in injuries to multiple organs, and cyanide victims were reported to experience myocardial infarction and other cardiac complications. However, molecular mechanisms of such complications are yet to be elucidated. While FDA-approved CN antidotes such as sodium thiosulfate and hydroxocobalamin are clinically used, they have foreseeable limitations during mass casualty situations because they require intravenous administration. To facilitate the development of better antidotes and therapeutic treatments, a global view of molecular changes induced by cyanide exposure is necessary. As an exploratory pursuit, we performed oligonucleotide microarrays to establish cardiac transcriptomes of an animal model of nose-only inhalation exposure to hydrogen cyanide (HCN), which is relevant to smoke inhalation. We also profiled cardiac transcriptomes after subcutaneous injection of potassium cyanide (KCN). Although the KCN injection model has often been used to evaluate medical countermeasures, this study demonstrated that cardiac transcriptomes are largely different from that of the HCN inhalation model at multiple time points within 24 h after exposure. Pathway analysis identified that HCN-induced transcriptomes were enriched with genes encoding mediators of pathways critical in modulation of cardiac complications and that a large number of such genes were significantly decreased in expression. We utilized the upstream regulatory analysis to propose drugs that can be potentially employed to treat cyanide-induced cardiac complications.

Background Transcobalamin deficiency is a rare autosomal recessive inborn error of cobalamin transport (prevalence: Case presentation We describe the case of a 31 years old woman who at the age of 30 days presented with the classical clinical and laboratory signs of an inborn error of vitamin B12 metabolism. Family history revealed a sister who died at the age of 3 months with a similar clinical syndrome and with pancytopenia. She was started on empirical intramuscular (IM) cobalamin supplements (injections of hydroxocobalamin 1 mg/day for 1 week and then 1 mg twice a week) and several transfusions of washed and concentrated red blood cells. With these treatments a clear improvement in symptoms was observed, with the disappearance of vomiting, diarrhea and normalization of the full blood count. At 8 years of age injections were stopped for about two and a half months causing the appearance of pancytopenia. IM hydroxocobalamin was then restarted sine die. The definitive diagnosis could only be established at 29 years of age when a genetic evaluation revealed the homozygous c.1115_1116delCA mutation of TCN2 gene (p.Q373GfsX38). Currently she is healthy and she is taking 1 mg of IM hydroxocobalamin once a week. Conclusions Our case report highlights that early detection of TC deficiency and early initiation of aggressive IM treatment is likely associated with disease control and an overall favorable outcome.

Detailed kinetic and mechanistic studies have been carried out on the reaction between aquacobalamin/hydroxocobalamin (CblOH2+/CblOH) and nitroxyl (HNO) generated by Piloty’s acid (PA, N-hydroxyben...

Management of refractory shock in the setting of overdose can be challenging. We describe a case of vasodilatory and cardiogenic shock after bupropion and citalopram overdose. Vasopressors and conv...

BackgroundImerslund-Gräsbeck syndrome is a rare genetic disease characterised by vitamin B12deficiency and proteinuria.Case presentationA 4-year old Sri Lankan boy presented with gradually worsening difficulty in walking for two weeks duration. He was previously diagnosed and managed as having non-transfusion-dependent α-thalassaemia based on the presence of hypochromic microcytic anaemia, haemoglobin H inclusion bodies in the blood film and compound heterozygous α-thalassaemia genotype with a gene deletion. However, his transfusion requirement increased over the past three months and he gradually lost his motor developmental milestones during two weeks before admission. The neurological examination revealed generalised hypotonia, exaggerated knee jerks and extensor plantar response. His complete blood count showed pancytopenia, and bone marrow biopsy revealed megaloblastic changes. Serum vitamin B12and red blood cell folate levels were low. MRI revealed sub-acute combined degeneration of the spinal cord with characteristic ‘inverted V sign’. Urine analysis showed non-nephrotic range proteinuria. The diagnosis of Imerslund-Gräsbeck syndrome was made due to the presence of non-nutritional vitamin B12deficiency and asymptomatic proteinuria. He showed a rapid haematological and neurological improvement to intramuscular hydroxocobalamin.ConclusionsThis case report presents a rare occurrence of severe vitamin B12deficiency due to Imerslund-Gräsbeck syndrome masked by co-existent α-thalassaemia, resulting in serious consequences. It highlights the need for a high index of suspicion in evaluating children with severe anaemia, especially in the presence of mixed pathologies.

Introduction Long-term outcome is postulated to be different in isolated methylmalonic aciduria caused by mutations in the MMAA gene (cblA type) compared with methylmalonyl-CoA mutase deficiency (mut), but case definition was previously difficult. Method Cross-sectional analysis of data from the European registry and network for intoxication type metabolic diseases (E-IMD, Chafea no. 2010 12 01). Results Data from 28 cblA and 95 mut patients, in most cases confirmed by mutation analysis (including 4 new mutations for cblA and 19 new mutations for mut). Metabolic crisis is the predominant symptom leading to diagnosis in both groups. Biochemical disturbances during the first crisis were similar in both groups, as well as the age at diagnosis. Z-scores of body height and body weight were similar in both groups at birth, but were significantly lower in the mut group at the time of last visit. Glomerular filtration rate was significantly higher in cblA; and as a consequence, chronic renal failure and related complications were significantly less frequent and renal function could be preserved even in older patients. Neurological complications were predominantly found in the mut subgroup. Methylmalonic acid (MMA) levels in urine and plasma were significantly lower in cblA. 27/28 cblA patients were reported to be responsive to cobalamin, only 86% of cblA patients were treated with i.m. hydroxocobalamin. 73% of cblA and 98% of mut patients followed a calculated diet with amino acid supplements in 27% (cblA) and 69% (mut). During the study interval 6 patients from the mut group died, while all cblA patients survived. Conclusion Although similar at first, cblA patients respond to hydroxocobalamin treatment, subsequently show significantly lower levels of MMA and a milder course than mut patients. This article is protected by copyright. All rights reserved.

We demonstrate evidence supporting the efficacy of hydroxocobalamin in reducing vasopressor requirements for LVAD patients with refractory vasoplegia. Further study is needed to substantiate these findings and determine its optimal use in practice.

The aim of this study was to investigate the antihypertensive properties of cis-[Ru(bpy)2ImN(NO)]3+ (FOR0811) in normotensive and in Nω–nitro-L-arginine methyl ester (L-NAME)-induced hypertensive rats. Vasorelaxant effects were analyzed by performing concentration response curve to FOR0811 in rat aortic rings in the absence or presence of 1H-[1,2,4]-oxadiazolo-[4,3,-a]quinoxalin-1-one (ODQ), L-cysteine or hydroxocobalamin. Normotensive and L-NAME-hypertensive rats were treated with FOR0811 and the effects in blood pressure and heart rate variability in the frequency domain (HRV) were followed. FOR0811 induced relaxation in rat aortic rings. Neither endothelium removal nor L-cysteine altered the FOR0811 effects. However, the incubation with ODQ and hydroxocobalamin completely blunted FOR0811 effects. FOR0811 administered intravenously by bolus infusion (0.01–1 mg/bolus) or chronically by using subcutaneous implanted osmotic pumps significantly reduced the mean arterial blood pressure. The effect was long lasting and did not induce reflex tachycardia. FOR0811 prevented both LF and VLF increases in L-NAME hypertensive rats and has antihypertensive properties. This new ruthenium complex compound might be a promising nitric oxide donor to treat cardiovascular diseases.

A high-performance liquid chromatographic method was developed for the separation and determination of 13 vitamin B compounds, including thiamin, riboflavin, riboflavin 5′-monophosphate, pyridoxine, hydroxocobalamin, cyanocobalamin, adenosylcobalamin, methylcobalamin, niacin, niacinamide, pantothenic acid, folic acid, and biotin. The method consisted of an ODS column, a gradient elution using pH 3.0 phosphate buffer–acetonitrile, ion-pairing reagent as mobile phase at 1.0 mL min−1, and UV detection at 210 nm. As a result, the 13 vitamin B compounds were separated in 60 min, and the specificity, linearity, range, limit of detection, limit of quantitation, intra- and inter-day precision, and recovery were satisfactory. The limit of detections ranged from 0.03 to 0.41 µg mL−1. Intra- and inter-day precision of peak area, expressed as RSD, were 0.542–5.144% and 0.216–6.367%, respectively. The method was used to evaluate vitamin B compounds in energy drinks and multivitamin pills. In case of energy drink analysis, the method identified and evaluated not only vitamin B compounds but also major ingredients, such as caffeine, vanillin, and benzoic acid. The vitamin B compounds in energy drinks and multivitamin pills were also quantitated and compared with values listed on each product label. Each quantitative value was close to the label values, suggesting high quantitative ability of the developed method.

Smoke inhalation injury is common in victims of domestic fires, among whom children are the most vulnerable. Cyanide poisoning may occur in addition to carbon monoxide poisoning and is challenging to diagnose. In France, the recommended antidotes are hydroxocobalamin for cyanide and hyperbaric oxygen for carbon monoxide. We managed a 26-month-old girl who sustained smoke inhalation injury with both carbon monoxide and cyanide poisoning during a house fire. Despite hydroxocobalamin and sodium thiosulfate therapy combined with hyperbaric oxygen, she had residual neurological impairments 3 months after the injury. The treatment challenges and detailed neurological follow-up data are described.

The industrial solvent trichloroethylene (TCE) and its two major metabolites trichloroethanol (TCE-OH) and trichloroacetic acid (TCA) cause formic aciduria in male F344 rats. Prior treatment of male F344 rats with 1-aminobenzotriazole a cytochrome P450 inhibitor, followed by TCE (16mk/kg, po), completely prevented formic aciduria, but had no effect on formic acid excretion produced by TCA (8 or 16 mg/kg, po), suggesting TCA may be the proximate metabolite producing this response. Dow and Green reported an increase in the concentration of 5-methyltetrahydrofolate (5-MTHF) in the plasma of rats treated with TCE-OH, suggesting a block in the cycling of 5-MTHF to tetrahydrofolate (THF). This pathway is under the control of the vitamin B12-dependent methionine salvage pathway. We therefore treated rats with three daily doses of methylcobalamin (CH3Cbl) or hydroxocobalamin (OHCbl), a cofactor for methionine synthase, or L-methionine, followed by TCE (16 mg/kg) to determine if they could alleviate the formic aciduria. These pretreatments only partially reduced the excretion of formic acid in the urine. Although prior treatment with S-adenosyl-L-methionine had no effect on formic acid excretion. Consistent with these findings, the activity of methionine synthase in the liver of TCE-treated rats was not inhibited. Transcriptomic analysis of the liver-identified nine differential expressed genes, of note, was downregulation of Lmbrd1 involved in the conversion of vitamin B12 into CH3Cbl, a cofactor for methionine synthase. Our findings indicate that the formic aciduria produced by TCE-OH and TCA may be the result of a block in the recycling of 5-MTHF to THF, the effect on the methionine salvage pathway being a secondary response following acute exposure.

Cobalamin C (cblC) deficiency is the most common inborn error of intracellular cobalamin metabolism caused by pathogenic variant(s) in MMACHC and manifests with methylmalonic acidemia, hyperhomocysteinemia, and hypomethioninemia with a variable age of presentation. Individuals with late‐onset cblC may be asymptomatic until manifesting neuropsychiatric symptoms, thromboembolic events, and renal disease. Although hydroxocobalamin provides a foundation for therapy, optimal dose regimen for adult patients has not been systematically evaluated. We report three adult siblings with late‐onset cblC disease, and their biochemical and clinical responses to high‐dose hydroxocobalamin. The 28‐year‐old proband presented with severe psychosis, progressive neurological deterioration, and deep venous thrombosis complicated by a pulmonary embolism. MRI studies identified lesions in the spinal cord, periventricular white matter, and basal ganglia. Serum homocysteine and methylmalonic acid levels were markedly elevated. Hydroxocobalamin at standard dose (1 mg/day) initially resulted in partial metabolic correction. A regimen of high‐dose hydroxocobalamin (25 mg/day) together with betaine and folic acid resulted in rapid and sustainable biochemical correction, resolution of psychosis, improvement of neurological functions, and amelioration of brain and spinal cord lesions. Two siblings who did not manifest neuropsychiatric symptoms or thromboembolism achieved a satisfactory metabolic control with the same high‐dose regimen. Hydroxocobalamin injection was then spaced out to 25 mg weekly with good and sustainable metabolic control. All three patients are compound heterozygotes for c.271dupA p.Arg91LysfsX14 and c.389A > G p.Tyr130Cys. This study highlights the importance of evaluating intracellular cobalamin metabolism in adults with neuropsychiatric manifestations and/or thromboembolic events, and demonstrates that high‐dose hydroxocobalamin achieves rapid and sustainable metabolic control and improvement in neuropsychiatric outcomes in adults with late‐onset cblC disease.

Pathogenic variants in MMAB cause cblB-type methylmalonic aciduria, an autosomal-recessive disorder of propionate metabolism. MMAB encodes ATP:cobalamin adenosyltransferase, using ATP and cob(I)alamin to create 5’-deoxyadenosylcobalamin (AdoCbl), the cofactor of methylmalonyl-CoA mutase (MMUT). We identified bi-allelic disease-causing variants in MMAB in 97 individuals with cblB-type methylmalonic aciduria, including 33 different and 16 novel variants. Missense changes accounted for the most frequent pathogenic alleles (p.(Arg186Trp), N = 57; p.(Arg191Trp), N = 19); while c.700C > T (p.(Arg234*)) was the most frequently identified truncating variant (N = 14). In fibroblasts from 76 affected individuals, the ratio of propionate incorporation in the presence and absence of hydroxocobalamin (PI ratio) was associated to clinical cobalamin responsiveness and later disease onset. We found p.(Arg234*) to be associated with cobalamin responsiveness in vitro, and clinically with later onset; p.(Arg186Trp) and p.(Arg191Trp) showed no clear cobalamin responsiveness and early onset. Mapping these and novel variants onto the MMAB structure revealed their potential to affect ATP and AdoCbl binding. Follow-up biochemical characterization of recombinant MMAB identified its three active sites to be equivalent for ATP binding, determined by fluorescence spectroscopy (Kd = 21 µM) and isothermal calorimetry (Kd = 14 µM), but function as two non-equivalent AdoCbl binding sites (Kd1 = 0.55 μM; Kd2 = 8.4 μM). Ejection of AdoCbl was activated by ATP (Ka = 24 µM), which was sensitized by the presence of MMUT (Ka = 13 µM). This study expands the landscape of pathogenic MMAB variants, provides association of in vitro and clinical responsiveness, and facilitates insight into MMAB function, enabling better disease understanding.

Vitamin B12, also known as the anti-pernicious anemia factor, is an essential micronutrient totally dependent on dietary sources that is commonly integrated with food supplements. Four vitamin B12 forms—cyanocobalamin, hydroxocobalamin, 5′-deoxyadenosylcobalamin, and methylcobalamin—are currently used for supplementation and, here, we provide an overview of their biochemical role, bioavailability, and efficacy in different dosage forms. Since the effective quantity of vitamin B12 depends on the stability of the different forms, we further provide a review of their main reactivity and stability under exposure to various environmental factors (e.g., temperature, pH, light) and the presence of some typical interacting compounds (oxidants, reductants, and other water-soluble vitamins). Further, we explore how the manufacturing process and storage affect B12 stability in foods, food supplements, and medicines and provide a summary of the data published to date on the content-related quality of vitamin B12 products on the market. We also provide an overview of the approaches toward their stabilization, including minimization of the destabilizing factors, addition of proper stabilizers, or application of some (innovative) technological processes that could be implemented and contribute to the production of high-quality vitamin B12 products.

Cobalt is a trace mineral important for normal metabolism. Elevated circulating cobalt concentrations may be seen after toxic ingestions, occupational exposure, and wear of metallic implants. We report a case of markedly elevated serum cobalt levels attributed to administration of hydroxocobalamin as a treatment for refractory hypotension. While excessive cobalt may be potentially toxic, the clinical significance of elevated serum cobalt associated with hydroxocobalamin administration remains to be elucidated. While hydroxocobalamin is an emerging therapy in a clinician's arsenal in treatment of vasodilatory shock, this case illustrates the need for a heightened level of awareness among clinicians for potential adverse effects and abnormal laboratory findings associated with this therapy.

Vasoplegic syndrome can occur after reperfusion in liver transplantation. Generally, vasopressor infusions along with volume resuscitation are used to combat this process. There are case reports of the use of hydroxocobalamin to improve vasoplegia in liver transplant and cardiac surgery. In this case report, we describe a patient who received hydroxocobalamin for a simultaneous liver-kidney transplant. Use of this medication facilitated a prompt decrease of very high-dose vasopressor infusions and allowed completion of the kidney transplantation portion of this case. To our knowledge, use in combined liver-kidney transplant has not been described. In light of the dearth of medications to improve vasoplegia outside of vasopressor infusions, the use of hydroxocobalamin as a therapeutic intervention may gain importance.

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

The first multiple stable isotope dilution assay method was developed for the simultaneous determination of four cobalamins, namely, hydroxocobalamin (OHCbl), adenosylcobalamin (AdoCbl), methylcobalamin (MeCbl), and cyanocobalamin (CNCbl), in their native forms. The sample preparation was optimized with enzyme treatment and immunoaffinity purification. The analysis was performed by LC-MS/MS using respective 15N-labeled cobalamins as internal standards. Method validation resulted in limits of detection ranging from 0.19 to 0.58 ng/g and limits of quantification ranging from 0.68 to 1.73 ng/g. Recoveries at three levels were between 82 and 121%. Intra-day and inter-day precisions were below 6% and 11% RSD, respectively. The analysis of a reference material resulted in a variance of

Background Vasoplegic syndrome (VPS) is defined as systemic hypotension due to profound vasodilatation and loss of systemic vascular resistance (SVR), despite normal or increased cardiac index, and characterized by inadequate response to standard doses of vasopressors, and increased morbidity and mortality. It occurs in 9%-44% of cardiac surgery patients after cardiopulmonary bypass (CPB). The underlying pathophysiology following CPB consists of resistance to vasopressors (inactivation of Ca2+ voltage gated channels) on the one hand and excessive activation of vasodilators (SIRS, iNOS, and low AVP) on the other. Use of angiotensin-converting enzyme inhibitor (ACE-I), calcium channel blockers, amiodarone, heparin, low cardiac reserve (EF 60-70 mmHg) are not achieved with nor-epinephrine and/or vasopressin. Aims The aims of this systematic review are to collect all the clinically relevant data to describe the VPS, its potential risk factors, pathophysiology after CPB, and to assess the efficacy, safety, and outcome of the therapeutic management with catecholamine and non-catecholamine vasopressors employed for refractory vasoplegia after cardiac surgery. Also, to elucidate the current and practical approach for management of VPS after cardiac surgery. Material and methods "PubMed," "Google," and "Medline" weresearched, and over 150 recent relevant articles including RCTs, clinical studies, meta-analysis, reviews, case reports, case series and Cochrane data were analyzed for this systematic review. The filter was applied specificallyusing key words like VPS after cardiac surgery, perioperative VPS following CPB, morbidity, and mortality in VPS after cardiac surgery, vasopressors for VPS that improve outcomes, VPS after valve surgery, VPS after CABG surgery, VPS following complex congenital cardiac anomalies corrective surgery, rescue therapy for VPS, adjuvant therapy for VPS, definition of VPS, outcome in VPS after cardiac surgery, etiopathology of VPS following CPB. This review did not require any ethical approval or consent from the patients. Results Despite the recent advances in therapy, the mortality remains as high as 30%-50%. NE has been recommended the most frequent used vasopressor for VPS. It restores and maintain the MAP and provides the outcome benefits. Vasopressin rescue therapy is an alternative approach, if catecholamines and fluid infusions fail to improve hemodynamics. It effectively increases vascular tone and lowers CO, and significantly decreases the 30 days mortality. Hence, suggested a first-line vasopressor agent in postcardiac surgery VPS. Terlipressin (1.3μg/kg/h), a longer acting and more specific vasoconstrictor prevents the development of VPS after CPB in patients treated with ACE-I. MB significantly reduces morbidity and mortality of VPS. The Preoperative MB (1%, 2mg/kg/30min, 1h before surgery) administration in high risk (on ACE-I) patients for VPS undergoing CABG surgery, provides 100% protection against VPS, and early of MB significantly reduces operative mortality, and recommended as a rescue therapy for VPS. Hydroxocobalamin (5 g) has been recommended as a rescue agent in VPS refractory to multiple vasopressors. A combination of ascorbic acid (6 g), hydrocortisone (200 mg/day), and thiamine (400 mg/day) as an adjuvant therapy significantly reduces the vasopressors requirement, and provides mortality and morbidity benefits. Conclusion Currently, the VPS is frequently encountered (9%-40%) in cardiac surgical patients with predisposing patient-specific risk factors and combined with inflammatory response to CPB. Multidrug therapy (NE, MB, AVP, ATII, terlipressin, hydroxocobalamin) targeting multiple receptor systems is recommended in refractory VPS. A combination of high dosage of ascorbic acid, hydrocortisone and thiamine has been used successfully as adjunctive therapyto restore the MAP. We also advocate for the early use of multiagent vasopressors therapy and catecholamine sparing adjunctive agents to restore the systemic perfusion pressure with a goal of preventing the progressive refractory VPS.

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

We discuss the case of a 22-year-old man who presented with paraesthesia, reduced sensation and weakness in his limbs. Examination was in keeping with a myeloneuropathy. Initial investigations including vitamin B12 were unremarkable but magnetic resonance imaging of the spinal cord showed subacute combined degeneration. The patient reported heavy recreational use of nitrous oxide, which can cause functional deficiency of vitamin B12 with neurological sequelae. A diagnosis of functional vitamin B12 deficiency was made and confirmed by an elevated methylmalonic acid level. The patient received intramuscular hydroxocobalamin and made a good recovery following rehabilitation. Nitrous oxide use is prevalent and can have significant health effects. Many adverse effects are mediated through inactivation of vitamin B12 and can be detected by elevated homocysteine and methylmalonic acid levels. Early identification and prompt treatment are important to support neurological recovery.

The Oceanographic Museum offers interesting exhibits of several marine lives for tourist sightseeing and entertainment. These sea water ornamental fish are all caught in the wild. However, its health can be affected by cyanide poisoning during human fishing. Depending on the level of cyanide poisoning, fish can die after one and two weeks that caused economic damages for the museum. The present study is concerned with results of cyanide detoxification by using direct injection into cinnamon clownfish or soak of hydroxocobalamin, sodium nitrite and sodium thiosulfate with the aim of improving the health, survival and life time for fish, contributing to increasing economic efficiency for the Oceanographic Museum.

Intracellular cobalamin metabolism (ICM) defects can be present as autosomal recessive or X-linked disorders. Parenteral hydroxocobalamin (P-OHCbl) is the mainstay of therapy, but the optimal dose has not been determined. Despite early treatment, long-term complications may develop. We have analyzed the biochemical and clinical responses in five patients with early onset of different types of ICM defects (cblC: patients 1-3; cblA: patient 4; cblX: patient 5) following daily P-OHCbl dose intensification (DI). In patient 4, P-OHCbl was started at age 10 years and in patient 5 at age 5 years. OHCbl was formulated at either, 5, 25, or 50 mg/mL. P-OHCbl was intravenously or subcutaneously (SQ) delivered, subsequently by placement of a SQ injection port except in patient 4. In all patients, homocysteine and methylmalonic acid levels, demonstrated an excellent response to various P-OHCbl doses. After age 36 months, patients 1-3 had a close to normal neurological examination with lower range developmental quotient. In patient 3, moderate visual impairment was present. Patient 4, at age 10 years, had normal renal, visual and cognitive function. In cblX patient 5, epilepsy was better controlled. In conclusion, P-OHCbl-DI caused an excellent control of metabolites in all patients. In the three cblC patients, comparison with patients, usually harboring identical genotype and similar metabolic profile, was suggestive of a positive effect, in favor of clinical efficacy. With P-OHCbl-DI, CblA patient has been placed into a lower risk to develop renal and optic impairment. In cblX patient, lower P-OHCbl doses were administrated to improve tolerability., SCOPUS: ar.k, info:eu-repo/semantics/published

Hydroxocobalamin (vitamin B12a) is an emerging treatment for vasoplegic syndrome (VS) associated with cardiopulmonary bypass (CPB). Given its cost and scarcity, an institutional guideline for its use as a rescue treatment in cases of suspected VS was developed. Hemodynamic variables and vasopressor requirements were reviewed for a series of 24 post-CPB patients who received B12a. Favorable changes in hemodynamic parameters and vasopressor requirements were seen after B12a administration although guideline criteria for VS were inconsistently met. These findings support the continued study of B12a in patients with CPB-associated VS.

Vasodilatory shock, as observed in postoperative states and sepsis, is hallmarked by low systemic vascular resistance and low blood pressure compensated by increased cardiac output. Gasotransmitters, such as nitric oxide and hydrogen sulfide, are implicated in the development and perpetuation of vasodilatory shock. Established therapies do not target these physiologic drivers of vasodilation. Due to their nontoxic and pleotropic effects, micronutrients are being used as rescue therapy in postoperative vasoplegia and septic shock. Here, we outline the pathophysiology of vasodilatory shock, describe the rationale for vitamin B12 (hydroxocobalamin) in vasodilatory shock, and identify literature evaluating its use in vasoplegic states.

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

Early, non-clinical studies support the use of hydroxocobalamin to treat sepsis-induced hypotension, but there is no translational, large animal model. The objective of this study was to compare survival in a sepsis model where large swine had endotoxaemia induced with lipopolysaccharide (LPS) and were treated with intravenous hydroxocobalamin (HOC), noradrenaline (NA), or saline. Thirty swine (45-55 kg) were anaesthetized, intubated, and instrumented with continuous femoral and pulmonary artery pressure monitoring. Hypotension, predefined as 50% of baseline, was induced with LPS. Animals then received HOC, NA, or saline and monitored for 3 hours. The main outcome was survival to the conclusion of the study. Using a power of 80% and an alpha of 0.05, 10 animals were used per group. Secondary outcomes included: mean arterial pressure (MAP), systemic vascular resistance (SVR) and cardiac output (CO) along with several markers of sepsis. No differences were detected between groups at baseline or after hypotension. The survival distributions of the three groups were significantly different with more HOC animals surviving (10/10) compared with NA (8/10) or Saline (5/10) (log-rank P

Objective To compare hydroxocobalamin and methylene blue for the treatment of vasopressor-refractory vasoplegic syndrome (VS) after adult cardiac surgery with cardiopulmonary bypass (CPB). Design A retrospective, propensity-matched, cohort study was performed. The primary endpoints were the percentage change in vasopressor use at 30, 60, and 120 minutes, characterized as both norepinephrine equivalents and vasoactive inotropic score. Eligible patients who received methylene blue were matched 3:1 with patients who received hydroxocobalamin based on sequential organ failure assessment score, preoperative mechanical circulatory support, CPB duration, and use of pre-CPB vasopressors, angiotensin-converting enzyme inhibitors, or beta-blockers. Setting A quaternary care academic medical center. Participants Adult patients who underwent cardiac surgery with CPB from July 2013 to June 2019. Interventions Patients were included who received either hydroxocobalamin (5,000 mg) or methylene blue (median 1.2 mg/kg) for VS in the operating room during the index surgery or in the intensive care unit up to 24 hours after CPB separation. Measurements and Main Results Of the 142 included patients, 120 received methylene blue and 22 received hydroxocobalamin. After matching, 66 patients in the methylene blue group were included in the analysis. Baseline demographics, surgical characteristics, and vasoactive medications were similar between groups. There were no significant between-group differences in percentage change in norepinephrine equivalents or vasoactive inotropic score at each timepoint. Conclusions In adult patients undergoing cardiothoracic surgery using CPB with VS, the ability to reduce vasopressor use was similar with hydroxocobalamin compared with methylene blue.

Injectable vitamin B12 (cobalamin) is traditionally used to prevent or treat vitamin B12 deficiencies in ruminants. Sheep and human studies have demonstrated the superiority of a single dose of hydroxocobalamin (OHB12) over cyanocobalamin (CNB12) in maintaining high levels of cobalamin in plasma and liver. However, limited data are available for cattle. The purpose of this study was to compare the pharmacokinetics of two forms of cobalamin—OHB12 and CNB12—as a single subcutaneous injection of 28 µg/kg BW at the same time of a trace mineral injection in six non‐cobalt/B12‐deficient Holstein‐Friesian steers. Plasma and liver samples were obtained to determine cobalamin concentration after treatment. Cyanocobalamin had lower retention in plasma and liver than OHB12 (p

Nitric oxide (NO) is a gaseous signaling molecule and a key endogenous mediator of vascular tone. Hydroxocobalamin (HCB) affects NO-mediated vasoplegia as (1) a direct inhibitor of nitric oxide synthase (NOS), thereby decreasing its production, and (2) by binding directly to NO and acting as a scavenger. HCB has been increasingly used in the treatment of refractory vasoplegia, particularly in cardiac surgery and liver transplant patients. Sepsis and septic shock are characterized by an increase in inducible NOS expression and activity with excessive NO production, resulting in endothelial dysfunction and profound systemic vasodilation. Therefore, a careful sustained reduction in NO burden represents a potential therapeutic target. Here, we present a case of refractory septic shock, which resolved after an extended duration infusion of high-dose HCB. We hope to foster further exploration regarding the safety, dosing, and efficacy of HCB when administered for vasopressor refractory septic shock.

espanolIntroduccion: la deficiencia de cobalamina C (Cbl C) es el defecto mas comun en el metabolismo intracelular de la cobalamina, asociado a acidemia metilmalonica y homocistinuria. Su presentacion clinica tardia es heterogenea y puede llevar a un retraso en el diagnostico. Caso clinico: presentamos el caso de un varon de 45 anos con 20 anos de evolucion de enfermedad renal cronica y paraparesia espastica de reciente diagnostico, ambos de origen desconocido. Los estudios metabolicos revelaron niveles elevados de homocisteina y acido metilmalonico en sangre y orina. El estudio genetico confirmo el deficit de cobalamina C. Se inicio tratamiento con hidroxocobalamina, betaina, carnitina y acido folico. El paciente pudo recibir un trasplante renal. Discusion: el establecimiento de un diagnostico precoz y un tratamiento adecuado mejora la evolucion clinica de los pacientes con deficit de Cbl C. La determinacion de homocisteina, acidos organicos y otros aminoacidos debe incluirse en el diagnostico diferencial de los pacientes con sintomas nefrologico-neurologicos sin una etiologia clara. EnglishIntroduction: cobalamin C (Cbl C) deficiency is the most common defect in intracellular cobalamin metabolism, associated with methylmalonic acidemia and homocystinuria. Its late clinical presentation is heterogeneous and may lead to a diagnostic delay. Case report: we report the case of a 45-year-old man with a 20-year history of chronic kidney disease and recently diagnosed spastic paraparesis, both of unknown origin. Metabolic studies revealed elevated levels of homocysteine and methylmalonic acid in the blood and urine. A genetic study confirmed cobalamin C deficiency. Treatment with hydroxocobalamin, betaine, carnitine, and folic acid was started. The patient eventually received a kidney transplant. Discussion: early diagnosis and appropriate treatment improve the clinical evolution of patients with Cbl C deficiency. Determination of homocysteine, organic acids, and other amino acids should be included in the differential diagnosis of patients with nephrological-neurological symptoms without a clear etiology.

In Southeast Asia, Mexico, and selected parts of Africa and America, nutritional deficiency of vitamin B12 and folic acid is the commonest cause of megaloblastic anemia. Vitamin B12 has vital biochemical roles like conversion of l-methyl malonyl CoA to succinyl CoA, conversion of homocysteine to methionine, and methyl-THFA to THFA. Deficiency of vitamin B12 leads to methyl malonyl aciduria, poor myelin formation leading to neuropathy, subacute combined degeneration of spinal cord, hyperhomocysteinemia, and megaloblastic anemia. Besides megaloblastic and pernicious anemia, vitamin B12 is also used to manage toxic amblyopia and cyanide poisoning. Folic acid, on the other hand, has multiple biochemical roles like conversion of homocysteine to methionine, serine to glycine and generation of one-carbon transfer compounds for purine and pyrimidine synthesis. Folic acid is commonly supplemented for pregnant women to avoid neural tube defects in the fetus. This chapter will review the pharmacology of vitamin B12 and folic acid.