Use of hydroxocobalamin to treat intraoperative vasoplegic syndrome refractory to vasopressors and methylene blue during liver transplantation.

INTRODUCTION: For patients with catecholamine-resistant vasoplegic syndrome (VS) during liver transplantation (LT), treatment with methylene blue (MB) and/or hydroxocobalamin (B12) has been an acceptable therapy. However, data on the effectiveness of B12 is limited to case reports and case series. METHODS: We retrospectively reviewed records of patients undergoing LT from January 2016 through March 2022. We identified patients with VS treated with vasopressors and MB, and abstracted hemodynamic parameters, vasopressor requirements, and B12 administration from the records. The primary aim was to describe the treatment efficacy of B12 for VS refractory to vasopressors and MB, measured as no vasopressor requirement at the conclusion of the surgery. RESULTS: One hundred one patients received intraoperative VS treatment. For the 35 (34.7%) patients with successful VS treatment, 14 received MB only and 21 received both MB and B12. Of the 21 patients with VS resolution after receiving both MB and B12, 17 (89.5%) showed immediate, but transient, hemodynamic improvements at the time of MB administration and later showed sustained response to B12. CONCLUSION: Immediate but transient hemodynamic response to MB in VS patients during LT supports the diagnosis of VS and should prompt B12 administration for sustained treatment response.

Kinetics of Cellular Cobalamin Uptake and Conversion: Comparison of Aquo/Hydroxocobalamin to Cyanocobalamin.

Cyanocobalamin (CNCbl) and aquo/hydroxocobalamin (HOCbl) are the forms of vitamin B12 that are most commonly used for supplementation. They are both converted to methylcobalamin (MeCbl) and 5'-deoxyadenosylcobalamin (AdoCbl), which metabolize homocysteine and methylmalonic acid, respectively. Here, we compare the kinetics of uptake and the intracellular transformations of radiolabeled CNCbl vs. HOCbl in HeLa cells. More HOCbl was accumulated over 4-48 h, but further extrapolation indicated similar uptake (>90%) for both vitamin forms. The initially synthesized coenzyme was MeCbl, which noticeably exceeded AdoCbl during 48 h. Yet, the synthesis of AdoCbl accelerated, and the predicted final levels of Cbls were MeCbl ≈ AdoCbl ≈ 40% and HOCbl ≈ 20%. The designed kinetic model revealed the same patterns of the uptake and turnover for CNCbl and HOCbl, apart from two steps. First, the "activating" intracellular processing of the internalized HOCbl was six-fold faster. Second, the detachment rates from the cell surface (when the "excessive" Cbl-molecules were refluxed into the external medium) related as 4:1 for CNCbl vs. HOCbl. This gave a two-fold faster cellular accumulation and processing of HOCbl vs. CNCbl. In medical terms, our data suggest (i) an earlier response to the treatment of Cbl-deficiency with HOCbl, and (ii) the manifestation of a successful treatment initially as a decrease in homocysteine.

A Potential Antidote for Both Azide and Cyanide Poisonings.

There do not appear to be any established therapeutics for treating azide poisoning at this time, and presently available antidotes to cyanide poisoning are far from ideal, being particularly impractical for use if multiple victims present. The cobalt (II/III) complex of the Schiff-base ligand trans-[14]-diene (5,7,7,12,14,14-hexamethyl-1,4,8,11-tetraazacyclotetradeca-4,11-diene (CoN4[14]) is shown to act as an effective antidote to both azide and cyanide toxicity in mice. Groups of animals challenged with an LD40 dose of NaCN (100 µmol/kg i.p.) exhibited significantly faster recovery from knockdown and fewer (zero) deaths if given CoN4[14] (50 µmol/kg i.p.) 2 minutes after the toxicant. Groups of animals challenged with an essentially lethal dose of NaCN (1.5 x LD50 = 150 µmol/kg i.p.) all survived if given the CoN4[14] (75 µmol/kg i.p.) 5 minutes before the toxicant dose. These data represent improved antidotal capability over the Food and Drug Administration-approved cobalt-based cyanide antidote hydroxocobalamin. Recovery of animals challenged sublethally with NaN3 (415 µmol/kg i.p.) was assessed employing a modified pole-climbing test. Mice given the CoN4[14] antidote (70 µg/kg i.p.) 5 minutes after the toxicant dose recovered twice as fast as the controls given no antidote. The interactions of cyanide and azide with CoN4[14] in vitro (buffered aqueous solutions) have been further investigated by a combination of spectroscopic approaches. The Co(II) form of the complex is able to bind two CN- anions while only binding a single N3 -, providing a reasonable explanation for the difference between their therapeutic abilities. SIGNIFICANCE STATEMENT: The Schiff-base complex CoN4[14] is shown to be an effective antidote to cyanide in mice, with improved therapeutic capabilities compared to the Food and Drug Administration-approved cobalt-containing hydroxocobalamin. CoN4[14] is also antidotal in mice toward azide poisoning, for which there is seemingly no approved therapy currently available. The activity toward cyanide involves a "redox-switching" mechanism that could be a common, but largely unrecognized, feature of all cobalt-based cyanide antidotes in use and under development.

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.

Treatment of refractory shock with vitamin B12 : A narrative review.

High-dose vitamin B12 is a potential treatment for patients with vasodilatory shock that is refractory to other therapies. Vasodilatory shock is characterized by low blood pressure and low systemic vascular resistance. Nitric oxide and hydrogen sulfide, two potential targets of high-dose vitamin B12 given as hydroxocobalamin, facilitate this syndrome. This review explores the relationship between high-dose vitamin B12 and hemodynamic outcomes in adults with vasodilatory shock and provides an update on the literature since a 2019 review on this topic. A literature search of studies published in the past 5 years was conducted in the CINAHL, PubMed, Cochrane, and EMBASE databases in May 2023. After assessing for eligibility, eight studies met this review's inclusion criteria. Seven of the eight studies reported decreased vasopressor requirements for part or all of the study samples after receiving a hydroxocobalamin infusion. However, not all patients responded to hydroxocobalamin. These findings are limited by patient selection and differences in the timing of vasopressor requirement and blood pressure outcome assessments. The current evidence is promising as to whether vitamin B12 , given as a hydroxocobalamin infusion, may improve hemodynamic outcomes in vasodilatory shock, but the evidence is of low quality. The use of hydroxocobalamin to treat refractory, vasodilatory shock remains investigative. Larger randomized controlled trials are required to elucidate the role of vitamin B12 in treating refractory, vasodilatory shock, including in conjunction with other alternative therapies such as methylene blue and corticosteroids.

Evaluation of hydroxocobalamin use for the treatment of suspected cyanide toxicity secondary to smoke inhalation.

Hydroxocobalamin is used for cyanide toxicity after smoke inhalation, but diagnosis is challenging. Retrospective studies have associated hydroxocobalamin with acute kidney injury (AKI). This is a retrospective analysis of patients receiving hydroxocobalamin for suspected cyanide toxicity. The primary outcome was the proportion of patients meeting predefined appropriate use criteria defined as ≥1 of the following: serum lactate ≥8 mmol/L, systolic blood pressure (SBP) <90 mmHg, new-onset seizure, cardiac arrest, or respiratory arrest. Secondary outcomes included incidence of AKI, pneumonia, resolution of initial neurologic symptoms, and in-hospital mortality. Forty-six patients were included; 35 (76%) met the primary outcome. All met appropriate use criteria due to respiratory arrest, 15 (43%) for lactate, 14 (40%) for SBP, 12 (34%) for cardiac arrest. AKI, pneumonia, and resolution of neurologic symptoms occurred in 30%, 21%, and 49% of patients, respectively. In-hospital mortality was higher in patients meeting criteria, 49% vs. 9% (95% CI 0.16, 0.64). When appropriate use criteria were modified to exclude respiratory arrest in a post-hoc analysis, differences were maintained, suggesting respiratory arrest alone is not a critical component to determine hydroxocobalamin administration. Predefined appropriate use criteria identify severely ill smoke inhalation victims and provides hydroxocobalamin treatment guidance.

[The Redox-Catalytic Properties of Cobalamins].

Vitamin B12, or cobalamin, is essential for normal body function and is used in the therapies of different diseases. Vitamin B12 has anti-inflammatory and antioxidant properties that can play an important role in the prevention of some diseases. On the other hand, it has been reported that vitamin B12 in combination with such reducing agents as ascorbate (vitamin C) and thiols showed prooxidant activity. This review provides information on the roles of vitamin B12 in diseases accompanied by inflammation and oxidative stress and the effects of vitamin B12 administrated alone and in combinations with different reducing agents such as ascorbate and thiols on oxidative stress. In addition, the mechanisms of prooxidant actions of combinations of vitamin B12 with these reducing agents depending on the form of vitamin B12 (hydroxocobalamin and cyanocobalamin) are discussed. Understanding the mechanisms of prooxidant action of vitamin B12 is necessary for developing strategies for therapeutic administration of vitamin B12.

Optimization of intravenous administration of hydroxocobalamin in pediatric emergencies - HYDROX-OPTIMIS study.

INTRODUCTION: Procedures to prepare and infuse intravenous drugs are poorly documented. OBJECTIVE: To determinate the optimal mode of hydroxocobalamin administration in children in emergency care. METHODS: We identified three modes of administration: (1) connect infusion tubing to the vial, start the infusion and interrupt it when the desired dose has been delivered; (2) remove from the vial the volume corresponding to the excessive dose and connect infusion tubing and (3) extract from the vial the required volume to be delivered and infuse directly. EXPERIMENTAL STUDY: 25 nurses performed each of these three procedures for children weighting 15 and 30 kg. Speed and precision were primary end-points; ease, safety and drug economy were secondary end-points. RESULTS: Mode 3 was the fastest (42[37-61] sec) followed by modes 1 and 2 (p < 0.05). Mode 3 was the most precise (100[100-100]%) followed by modes 1 and 2 (p = 0.001). Mode 3 was the easiest (10.0[9.0-10.0]) followed by modes 2 and 3 (p = 0.001). Modes 1 and 3 allowed administration of a second dose whereas mode 2 did not. CONCLUSION: Taking the required volume from the vial and infuse directly was the fastest, the most precise, the easiest and most economical mode of administration. It should be recommended.

Intraoperative Versus Postoperative Hydroxocobalamin for Vasoplegic Shock in Cardiothoracic Surgery.

OBJECTIVES: Hydroxocobalamin inhibits nitric oxide pathways contributing to vasoplegic shock in patients undergoing cardiopulmonary bypass (CPB). The objective of this study was to evaluate the effect of intraoperative versus postoperative application of hydroxocobalamin for vasoplegic shock in patients undergoing CPB. DESIGN: This was a historic cohort study. SETTING: The study was conducted at a quaternary academic cardiovascular surgery program. PARTICIPANTS: Adults undergoing cardiac surgery using CPB were participants in the study. INTERVENTIONS: Hydroxocobalamin (5 g) intravenously over 15 minutes. MEASUREMENTS AND MAIN RESULTS: The treatment groups were assigned based on the receipt location of hydroxocobalamin (ie, intensive care unit [ICU] versus operating room [OR]). The primary outcome was vasopressor-free days in the first 14 days after CPB. Of the 112 patients included, 37 patients received hydroxocobalamin in the OR and 75 in the ICU. Patients in the OR group were younger than those in the ICU group (57.5 v 63.9 years, p = 0.007), with statistically similar American Society of Anesthesiologists scores. The mean CPB duration was 3.4 hours in the OR group and 2.9 hours in the ICU group (p = 0.09). In both groups, the norepinephrine-equivalent dose of vasopressors at hydroxocobalamin was 0.27 µg/kg/min. Days alive and free of vasopressors were not different between the OR and ICU groups (estimated difference 0.48 [95% CI -1.76-2.72], p = 0.67). The odds of postoperative renal failure, mesenteric ischemia, ICU, hospital length of stay, and in-hospital mortality were also similar between groups. CONCLUSIONS: A difference in vasopressor-free days after CPB was not found between patients who received hydroxocobalamin intraoperatively versus postoperatively for vasoplegic shock.

Would, early, versus late hydroxocobalamin dose intensification treatment, prevent cognitive decline, macular degeneration and ocular disease, in 5 patients with early-onset cblC deficiency?

In early-onset (EO) cblC deficiency (MMACHC), hydroxocobalamin dose-intensification (OHCBL-DI) improved biochemical and clinical outcome. In mammals, Cobalamin is reduced, in a reaction mediated by MMACHC. Pathogenic variants in MMACHC disrupt the synthesis pathway of methyl-cobalamin (MetCbl) and 5'-deoxy-adenosyl-cobalamin (AdoCbl), cofactors for both methionine synthase (MS) and methyl-malonyl-CoA mutase (MCM) enzymes. In 5 patients (pts.), with EO cblC deficiency, biochemical and clinical responses were studied following OHCbl-DI (mean ± SD 6,5 ± 3,3 mg/kg/day), given early, before age 5 months (pts. 1, 2, 3 and 4) or lately, at age 5 years (pt. 5). In all pts., total homocysteine (tHcy), methyl-malonic acid (MMA) and Cob(III)alamin levels were measured. Follow-up was performed during 74/12 years (pts. 1, 2, 3), 33/12 years (pt. 4) and 34/12 years (pt. 5). OHCbl was delivered intravenously or subcutaneously. Mean ± SD serum Cob(III)alamin levels were 42,2 × 106 ± 28, 0 × 106 pg/ml (normal: 200-900 pg/ml). In all pts., biomarkers were well controlled. All pts., except pt. 5, who had poor vision, had central vision, mild to moderate nystagmus, and with peri-foveolar irregularity in pts. 1, 2 and 4, yet none had the classic bulls' eye maculopathy and retinal degeneration characteristic of pts. with EO cblC deficiency. Only pt. 5, had severe cognitive deficiency. Both visual and cognitive functions were better preserved with early than with late OHCBL-DI. OHCBL-DI is suggested to bypass MMACHC, subsequently to be rescued by methionine synthase reductase (MSR) and adenosyl-transferase (ATR) to obtain Cob(I)alamin resulting in improved cognitive and retinal function in pts. with EO cblC deficiency.

Hydroxocobalamin for Vasodilatory Hypotension in Shock: A Systematic Review With Meta-Analysis for Comparison to Methylene Blue.

Hydroxocobalamin inhibits nitric oxide-mediated vasodilation, and has been used in settings of refractory shock. However, its effectiveness and role in treating hypotension remain unclear. The authors systematically searched Ovid Medline, Embase, EBM Reviews, Scopus, and Web of Science Core Collection for clinical studies reporting on adult persons who received hydroxocobalamin for vasodilatory shock. A meta-analysis was performed with random-effects models comparing the hemodynamic effects of hydroxocobalamin to methylene blue. The Risk of Bias in Nonrandomized Studies of Interventions tool was used to assess the risk of bias. A total of 24 studies were identified and comprised mainly of case reports (n = 12), case series (n = 9), and 3 cohort studies. Hydroxocobalamin was applied mainly for cardiac surgery vasoplegia, but also was reported in the settings of liver transplantation, septic shock, drug-induced hypotension, and noncardiac postoperative vasoplegia. In the pooled analysis, hydroxocobalamin was associated with a higher mean arterial pressure (MAP) at 1 hour than methylene blue (mean difference 7.80, 95% CI 2.63-12.98). There were no significant differences in change in MAP (mean difference -4.57, 95% CI -16.05 to 6.91) or vasopressor dosage (mean difference -0.03, 95% CI -0.12 to 0.06) at 1 hour compared to baseline between hydroxocobalamin and methylene blue. Mortality was also similar (odds ratio 0.92, 95% CI 0.42-2.03). The evidence supporting the use of hydroxocobalamin for shock is limited to anecdotal reports and a few cohort studies. Hydroxocobalamin appears to positively affect hemodynamics in shock, albeit similar to methylene blue.

Comparison of hydroxocobalamin with other resuscitative fluids in volume-controlled and uncontrolled hemorrhage models in swine ( Sus-scrofa ).

BACKGROUND: Traumatic hemorrhage is the leading cause of preventable death in military environments. Treatment with resuscitative fluids and blood components is based on availability, thus, frequently unavailable in the prehospital setting, due to lack of resources and costs. Hydroxocobalamin (HOC), increases blood pressure via nitric oxide scavenging. We evaluated HOC as a resuscitation fluid, in two swine hemorrhage models. Our objectives were to (1) evaluate whether HOC treatment following hemorrhagic shock improves hemodynamic parameters and (2) determine whether those effects are comparable to whole blood (WB) and lactated ringers (LR). METHODS: Yorkshire swine (S us scrofa ) (n = 72) were used in models of controlled hemorrhage (CH) (n = 36) and uncontrolled hemorrhage (UH) (n = 36). Randomized animals received treatment with 500 mL of either WB, LR, HOC (150 mg/kg), followed by a six-hour observation (n = 6 each group). Survival, hemodynamics, blood gases (ABGs) and chemistries were collected. Data reported as mean ± standard error of the mean and statistical analysis by ANOVA ( p < 0.05). RESULTS: Blood loss for CH was 41% ± 0.02 versus 33% ± 0.07 for UH. For CH, HOC treatment maintained higher systolic blood pressure (sBP, mm Hg) compared with WB and LR (72 ± 1.1; 60 ± 0.8; 58 ± 1.6; respectively). Heart rate (HR), cardiac output (CO), Sp o2 and vascular resistance were comparable with WB and LR. The ABG values were comparable between HOC and WB. For UH, HOC treatment maintained sBP levels comparable to WB and higher than LR (70 ± 0.9; 73 ± 0.5; 56 ± 1.2). HR, CO, Sp o2 , and systemic vascular resistance were comparable between HOC and WB. Survival, hemodynamics, blood gases were comparable between HOC and WB. No survival differences were found between cohorts. CONCLUSION: Hydroxocobalamin treatment improved hemodynamic parameters and Ca 2+ levels compared with LR and equivalent to WB, in both models. Hydroxocobalamin may be a viable alternative when WB is not available.

Vitamin B12 status in infancy and the effect of a vitamin B12 injection in infants with subclinical vitamin B12 deficiency: study protocol for a register-based randomised controlled trial.

INTRODUCTION: Vitamin B12 (cobalamin) is crucial for optimal child development and growth, yet deficiency is common worldwide. The aim of this study is twofold; (1) to describe vitamin B12 status and the status of other micronutrients in Norwegian infants, and (2) in a randomised controlled trial (RCT), investigate the effect of vitamin B12 supplementation on neurodevelopment in infants with subclinical vitamin B12 deficiency. METHODS AND ANALYSIS: Infant blood samples, collected at public healthcare clinics, are analysed for plasma cobalamin levels. Infants with plasma cobalamin <148 pmol/L are immediately treated with hydroxocobalamin and excluded from the RCT. Remaining infants (cobalamin ≥148 pmol/L) are randomly assigned (in a 1:1 ratio) to either a screening or a control group. In the screening group, baseline samples are immediately analysed for total homocysteine (tHcy), while in the control group, the baseline samples will be analysed after 12 months. Screening group infants with plasma tHcy >6.5 µmol/L, are given an intramuscular injection of hydroxocobalamin (400 µg). The primary outcomes are cognitive, language and motor development assessed using the Bayley Scales of Infant and Toddler Development at 12 months of age. ETHICS AND DISSEMINATION: The study has been approved by the Regional Committee for Medical and Health Research Ethics (ref: 186505). Investigators who meet the Vancouver requirements will be eligible for authorship and be responsible for dissemination of study findings. Results will extend current knowledge on consequences of subclinical vitamin B12 deficiency during infancy and may inform future infant feeding recommendations. TRIAL REGISTRATION NUMBER: NCT05005897.