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Use of Artificial Intelligence to Detect Refractory Vasoplegic and Septic Shock when Hydroxocobalamin Used as a Rescue Therapy
, Arsha Anil Kumar1, Milan Muhammed2, Angela Thomas1, Divya Bahl3, Reeves Thomas George1, Christina Stella Timothy1, Mekha Mohan1
*Corresponding author: Prasamsa Preman, Department of Medicine, Tbilisi State Medical University, Tbilisi, Georgia. prashamsapreman15@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Preman P, Anil Kumar A, Muhammed M, Thomas A, Bahl D, George RT, et al. Use of Artificial Intelligence to Detect Refractory Vasoplegic and Septic Shock when Hydroxocobalamin Used as a Rescue Therapy. J Card Crit Care TSS. 2026;10:84-91. doi: 10.25259/JCCC_83_2025
Abstract
Hydroxocobalamin (HCB), which helps remove nitric oxide (NO) and hydrogen sulfide (H2S) from the body, is useful as a treatment option in severe cases of vasodilatory shock that do not respond to usual treatments. This includes situations such as sepsis, after heart-lung machine use, during liver transplants, and from certain drugs. This review examines its proposed mechanisms, emerging clinical applications, dosing approaches, safety profile, and comparison with agents such as methylene blue and angiotensin II. By binding excess NO/H2S and inhibiting inducible NO synthase and guanylate cyclase, it rapidly improves mean arterial pressure and reduces vasopressor dependence, often within hours. Small retrospective series report consistent hemodynamic rescue with mainly benign, transient side effects (e.g., chromaturia). Although encouraging, all current evidence is observational. To determine its function, ideal time, and dosage in critical care, randomized controlled trials are required.
Keywords
Hydroxocobalamin for septic shock
Hydroxocobalamin for shock
Hydroxocobalamin for vasoplegia
Hydroxocobalamin treatment
INTRODUCTION
Hydroxocobalamin (HCB) is a type of Vitamin B12 utilized for the treatment and prevention of Vitamin B12 insufficiency.[1] The active forms of Vitamin B12, methylcobalamin and adenosylcobalamin, are derived from HCB.[2]
However, its ability to act as a nitric oxide (NO) scavenger has led to its utilization in postoperative vasoplegia[3] and its approval as a medication for cyanide toxicity. In people with sepsis admitted to the intensive care unit (ICU), HCB infusions significantly increased mean arterial pressure (MAP) and decreased vasopressin needs. HCB mitigates catecholamine-resistant circulatory shock; however, it also removes, adheres to, and inhibits the production of NO and hydrogen sulfide (H2S), which can cause more blood vessels to widen and lower blood pressure. NO oxidizes HCB, which contains cobalt. This combination of cobalt and NO might move NO to hemoglobin, which can reduce the amount of NO present. Less amounts of NO and H2S might help keep capillary membranes healthy and bring back normal blood vessel function. [4]
H2S is produced by bacteria, and HCB was found to bind to it, reducing the amount of H2S in the blood.[3,5]
A type of distributive shock known as vasoplegic syndrome is defined by an arterial pressure average of <65 mmHg, which causes severe hypotension with normal-to-high cardiac output and is often resistant to inotropes, high intravenous vasopressor dosages, and fluid resuscitation. It frequently occurs after solid organ and heart transplant surgeries. Historically, vasoplegic shock has been treated with methylene blue (MB) to increase vascular tone and inhibit NO synthase (NOS).[1] When MB is ineffective in treating vasoplegic syndrome, HCB can be used both alone and in combination. Due to the product’s accessibility and the literature’s proof of its safety, it was chosen to address refractory vasoplegic syndrome. When MB is not available or is contraindicated, HCB can be used to treat vasoplegic syndrome that develops after cardiopulmonary bypass (CPB) that is resistant to other vasopressors. This will lower the demand for vasopressors and restore proper hemodynamic stability.[4]
In this literature review, we have primarily focused on the mechanism of HCB, its usage in types of shock such as vasoplegic, cpd, liver transplant, and drug-induced shock, its comparison to various vasopressors such as MB, and its adverse effects. More research, including randomized controlled trials, is required to determine the usefulness of HCB in critical care treatment.
MATERIAL AND METHODS
The entire evaluation process consisted of searching keywords like “hydroxocobalamin treatment,” “hydroxocobalamin for shock,” “hydroxocobalamin for vasoplegia,” and “hydroxocobalamin for septic shock” in literature search databases, including PubMed and Google Scholar. We reviewed and evaluated papers from the past 5 years before the study.
DISCUSSION
Brief pathophysiology of vasodilatory shock
Vasodilatory shock is characterized by the inability of blood vessels to constrict, leading to hypotension. The vessels become unresponsive to medications such as noradrenaline or adrenaline, subsequently causing poor blood flow to organs and eventually organ damage. The primary cause of this illness is the release of cytokines, including tumor necrosis factor-alpha, interleukin (IL)-1, and IL-6, which activate inductive NOS.[6]
NO relaxes blood vessels; not only does it increase cyclic guanosine monophosphate (cGMP) but also leads to an influx of potassium ions, thereby reducing the influx of calcium and preventing the muscle from contracting.[3] This, in turn, reduces the effectiveness of the vasopressors as the receptors become less responsive, the body’s own vasoactive hormones are depleted, and the smooth muscles remain in a constant state of relaxation.[7]
In addition, the condition is further worsened by factors such as chronic inflammation, tissue injury, hemolysis, and other endogenous vasodilators such as H2S. Therefore, therapies such as hydrocobalamin aid in moderately reducing NO levels without shutting it down completely and help to restore the vascular tone[5] [Figure 1].
- Pathophysiology of vasodilatory shock. IL-1: Interleukin-1, IL-6: Interleukin-6, TNF-α: Tumor necrosis factor-alpha, iNOS: Inducible nitric oxide synthase, NO: Nitric oxide, cGMP: Cyclic guanosine monophosphate, K+: Potassium ion, Ca2+: Calcium ion, NE: Norepinephrine, Epi: Epinephrine.
Mechanism of action of HCB
In the context of shock, NO signaling has become a desirable therapeutic target. NO produced by inducible NOS causes soluble guanylyl cyclase to indicate an increase in cGMP, which in turn causes vasodilation in sepsis.[8] In addition to targeting NO, HCB also addresses other vasodilators such as H2S, a gaseous mediator that aids in vasodilation and is linked to vasoplegia.[6]
HCB also improves the removal of vasodilators such as endothelium-hyperpolarizing factors and H2S, which helps to restore the equilibrium between vasoconstriction and vasodilator molecules[7] [Figure 2].
- Mechanism of action of hydroxocobalamin. cGMP: Cyclic guanosine monophosphate,, NOS: Nitric oxide synthase, H2S: Hydrogen sulfide.
Clinical evidence for HCB on shock
By addressing its mode of action and specific side effects, hydroxycobalamin has been instrumental in various types of shock [Table 1].[9-17]
| Clinical condition | Study type/Evidence level | Key findings and outcomes |
|---|---|---|
| Septic shock | Retrospective series,[3,6] Case reports,[6] Comparison study.[9] | Significant increase in MAP at 1, 6, and 24 h (+16.3 mmHg at 24 h). Significant drop in norepinephrine requirements at 6 and 24 h.[3] Better efficacy than methylene blue alone.[9] |
| Vasoplegic syndrome (post-cardiac surgery) | Case series,[10] Retrospective studies,[5,11] Meta-analysis.[12] | Sustained elevation in MAP and decreased vasopressor needs following cardiopulmonary bypass. Bolus dosing for acute severe vasoplegia; infusion for persistent cases.[9,11] |
| Catecholamine-resistant vasoplegia (liver transplant) | Recent series (44 patients), Review of published cases.[13] | 75% response rate (33/44 patients). Resulted in raised average MAP and decreased requirement for sympathetic drugs.[13] |
| ACE-inhibitor-induced vasoplegia | Case report (70-year-old male post-CABG).[14] | Hydroxocobalamin successfully treated refractory vasoplegia after standard pressors (Vasopressin, Adrenaline, Norepinephrine) failed.[14] |
| CCB-induced vasoplegia (nimodipine) | Case reports.[15,16] | Rapid increase in blood circulation and deactivation of all vasopressors within 15–70 min of HCB administration.[15,16] |
| Burn ICU/AKI risk | Clinical observation study.[17] | High incidence of AKI (42.8%) requiring CRRT in burn patients within 72 h of receiving HCB. Highlights need for further safety research.[17] |
CCB: Calcium channel blocker, AKI: Acute kidney injury, ICU: Intensive care unit, CABG: Coronary artery bypass graft, MAP: Mean arterial pressure, HCB: Hydroxocobalamin, CRRT: Continuous renal replacement therapy
Septic shock
A potentially lethal organ failure caused by an unregulated host reaction to infection is known as sepsis. Excessive NO generation and a sharp rise in the production and functioning of the induction of NOS are its hallmarks.[6] Clinical indicators of septic shock include the need for a vasopressor medication for maintaining an arterial pressure mean of 65 mmHg or higher and a blood lactate concentration more than 2 mmol/L following adequate volume replacement.[3]
By directly inhibiting NOS and lowering NO production, as well as by attaching directly to NO and acting as a removal agent, HCB affects NO-induced vasoplegia.[6] By oxidising the cobalt atom of HCB, NO can mechanistically generate a Co-NO complex, which can then transfer NO to glutathione or hemoglobin. It has been demonstrated that HCB binds to and lowers the circulating volume of H2S, which is produced by bacteria during septic shock and causes vasodilation.[3]
Certain evidence suggests that HCB may be a useful rescue medication for patients who are using large-dose blood thinners for acute septic shock. This therapy can deliver a long-lasting physiological advantage from HCB, giving medical professionals the crucial time to pursue conclusive actions such as source control.[6] Data shows that the average arterial pressure increased at 1, 6, and 24 h after HCB administration (+16.3, +14.3-, and +16.3-mmHg, in that order; P = 0.001), respectively. A substantial drop in the norepinephrine equivalents was noted at 6 and 24 h post dose (P = 0.001), despite the norepinephrine equivalents patients needed 1 h after HCB injection, remaining unchanged.[3] Better than MB alone, HCB may improve MAP and reduce the requirement for vasopressors.[9]
For instance, some research has shown that after an hour of B12 infusion, MAP increased, while NE equivalents remained the same, suggesting HCB’s utility in acute septic shock. Therefore, HCB may be a useful rescue treatment for patients suffering from acute septic shock, according to some research. However, more extensive research is necessary to evaluate HCB’s safety and effectiveness in the context of refractory septic shock.[6]
Vasoplegic syndrome
Vasoplegic syndrome is a frequent post-cardiac surgical problem that is characterized by extreme hypotension and a high need for vasopressors.[10]
It comprises 4.6% of all types of circulatory distress and has an incidence ranging from 5% to 44% following CPB.[12]In patients with persistent vasoplegic syndrome following heart surgery, high-dose intravenous HCB showed sustained elevations in MAP and decreased vasopressor needs.[11]
The pathophysiology is driven by a complicated interaction between inflammatory mediators and NO overproduction, which is fueled by iNOS activation. Independent of intracellular calcium levels, CPB causes a systemic inflammatory response that releases cytokines that increase iNOS and produce NO continuously. HCB is utilized off-label for refractory vasoplegic syndrome following CPB. By counteracting NO-mediated vasodilation through its mechanism of scavenging NO, inhibiting iNOS, and blocking guanylate cyclase, HCB helps to raise arterial pressure. Case series have documented its off-label usage for refractory vasoplegic syndrome following CPB, using different dosage approaches (bolus or prolonged infusion). The results suggest the possibility of customized dosing according to clinical presentation: Prolonged infusion for long-term control in persistent instances and bolus dosing for immediate, severe vasoplegia.[10]
Catecholamine-resistant vasoplegia
One life-threatening complication of liver transplantation is catecholamine-resistant vasoplegia. Although its etiology is most likely multifactorial, the incidence of vasoplegic syndrome in end-stage liver disease is not known. HCB has been studied as a treatment for refractory hypotension in this setting. In a recent series, 44 patients were administered HCB after the published cases were reviewed. Based on clinically significant increases in arterial pressure, the research team concluded that thirty-three participants (75%) were “responders” to the treatment. These findings indicate that HCB can effectively reduce refractory hypotension during liver transplantation, as its administration resulted in a raised average arterial blood pressure and a decreased requirement for sympathetic drugs. However, there are currently only a few case reports and a comparison study, the effectiveness of HCB in liver transplantation has not yet been thoroughly evaluated.[13]
ACE-inhibitor-induced vasoplegia
Vasoplegia is caused by ACE inhibitors because they raise bradykinin levels and lower angiotensin II concentrations, which lower blood pressure and vascular tone.[18] According to a case report, a 70-year-old man with several risk factors—including a 35% left ventricular ejection fraction-developed vasoplegia on the day of his elective coronary artery bypass graft (CABG) procedure after taking lisinopril. The patient’s condition required delaying the CABG despite initial vasopressor treatment. Vasopressin, adrenaline, norepinephrine, and hydrocortisone were used to stabilize the patient in the ICU, and HCB effectively treated his vasoplegia, resulting in notable clinical improvement.[14]
CCB-induced vasoplegia
CCB drugs, including nimodipine, are frequently administered to patients with aneurysmal subarachnoid hemorrhage to lessen the negative consequences of cerebral vasospasm. Nimodipine frequently causes mild hypotension, but in rare instances, it might worsen and result in refractory vasoplegia. Nonetheless, nimodipine-induced severe vasoplegia is still an uncommon and poorly understood side effect. Significant vasodilation may arise from nimodipine’s dysregulation of calcium signaling, which would raise NO release and activate cGMP. Clifford et al. described a case where IV HCB was administered to a patient who had experienced severe low blood pressure and was not responding to three vasopressors, following the first administration of nimodipine. This showed a rapid increase in blood circulation and the deactivation of vasopressors 70 min after nimodipine administration.[15]
In addition , an incident of nimodipine -associated vasoplegia that did not respond to norepinephrine, phenylephrine, or intravenous fluid boluses was identified. Despite the initial administration of MB, drug extravasation prevented any positive benefits. However, after receiving HCB as a rescue treatment, this individual was effectively taken off all vasopressors after 15 min.[16]
Comparison to other vasopressors
Vasopressors control vascular tone through a number of mechanisms, including the system of renin-angiotensin, the sympathetic nervous system, and vasopressin pathways. Synthetic angiotensin II binds to angiotensin II receptors of type I on the smooth muscle of the arteries to produce its vasoconstrictive effects. It is currently approved as a secondary vasopressor for the management of catecholamine-induced vasomotor shock in both the US and Europe. MB works by preventing excess NO generation and restores reduced cardiovascular tone by inhibiting soluble guanylate cyclase and inducible NOS.[19]
However, its vasoconstrictive impact is primarily limited to patients with increased NO signaling; individuals who do not overexpress NO may not respond.[20]
According to a recent meta-analysis, MB may dramatically raise MAP and lower lactate levels in individuals experiencing refractory hypotension brought on by vascular paralysis during vasodilatory shock.[21]
MB frequently causes negative side effects, such as elevated methemoglobin saturation and a green–blue tint of the urine. Severe methemoglobinemia or decreased splanchnic perfusion may occur when given in large dosages (>7 mg/kg) or by continuous infusion.[19]
HCB versus MB
HCB can be used in place of MB for treating vasoplegic syndrome, an illness that develops after the use of CPB and is resistant to other blood pressure medications. It can also be used to lower the demand for vasopressors and restore proper hemodynamic stability when MB is not available or contraindicated.[4] According to a case report, after receiving aggressive treatment for acute vasoplegic shock with several pressors, HCB, and MB, the patient’s hemodynamics significantly improved. The findings of this case suggest that the usage of HCB and MB in combination with catecholamine vasopressors may be linked to a quick rise in MAP and a decrease in the overall amount of norepinephrine equivalent vasopressors needed in patients with severe refractory vasoplegia.[22]
Both HCB and MB are effective in treating vasoplegic disorders; however, HCB has a better safety profile and improves hemodynamics rapidly.[9]
MB should not be used if a person has serotonin syndrome, and HCB is a viable substitute.[23]
Thus, there are certain instances, such as in individuals with neurologic disorders, G6PD deficiency, and those at risk of serotonin disorder, where hydroxycobalamin would be a better option when compared to MB[15] [Table 2].
| Feature | Hydroxocobalamin | Methylene blue |
|---|---|---|
| Primary mechanism | Scavenges NO and H2S; inhibits iNOS and guanylate cyclase. | Inhibits soluble guanylate cyclase and iNOS. |
| Onset of action | Rapid (15–70 min). | Variable; onset is less consistently defined in shock data. |
| Safety concerns | Chromaturia (red hue); lab/dialysis alarm interference; AKI concerns. | Elevated methemoglobin; risk of decreased splanchnic perfusion. |
| Contraindications | Cobalt hypersensitivity. | G6PD deficiency; Serotonin Syndrome risk. |
| Evidence level | Case series and retrospective studies. | Meta-analysis. |
NO: Nitric oxide, H2S: Hydrogen sulfide, iNOS: Inducible nitric oxide synthase, AKI: Acute kidney injury
Dosage and efficacy
The majority of reviewed literature used the dosage of HCB based on its original warning sign for poisoning by cyanide - 5–10 g IV infusion over 15 min with rapid reduction in MAP. In another study, a sole-center set of 20 cases involved administering medications that vary from 750 mg to 5 g for the management of catecholamine-resistant vasoplegia while on the process of liver transplantation.[11]The therapeutic environment may influence the dose strategy: Bolus dosing for rapid correction of acute hypotension and prolonged infusion for long-term control in less acute circumstances.[10]
High-dose HCB is a safe and efficient treatment for CPB-associated vasoplegia, according to small-scale retrospective studies.[5] Another study found that prophylactic HCB can successfully reduce the rate of vasoplegic syndrome, the overall vasopressor dose, and enhance perfusion of tissues in highly susceptible cardiac surgery patients.[24] The highest dose of intravenous HCB has an estimated half-life of 26–31 h and was delivered at a concentration that was 100 times greater than retained water-soluble concentrations detected in blood plasma. Further research is required, but lower doses might be adequate.[25]
Adverse effects and safety
Hypersensitivity reactions to cobalt or other injection-related substances are the primary source of additional effects.[16] Documented side effects consist of itching, vomiting, headaches, treatment area reactions, increased blood pressure, and the development of calcium oxalate crystals in urine. In addition, the drug’s intense red hue can cause chromaturia, which can interfere with certain chromatic tests in laboratories, and shading of hemodialysis ultrafiltrate particles, which could result in an inaccurate blood leakage signal in certain hemodialysis devices.[5]
Although HCB is typically regarded as safe and well-tolerated, case reports of crystalline nephropathy and interference with renal replacement therapy have raised concerns about the drug’s safety in recent years. A study found that within the first 72 h of being brought to the burn ICU, patients who received at least one dosage of HCB had acute kidney injury (AKI), with 42.8% of patients needing continuous renal replacement therapy during the initial resuscitation period. Additional research is necessary to determine how HCB delivery affects the development of AKI and in-hospital mortality[17] [Figure 3 and Table 3].
- Side effects of hydroxocobalamin.
| Category | Advantages | Disadvantages/Risks |
|---|---|---|
| Mechanistic | Scavenges NO, inhibits NOS, and blocks guanylate cyclase.[6] Also removes H2S and endothelium- hyperpolarizing factors.[7] | Optimal dosing is still not fully established; current practice often borrows doses from cyanide poisoning protocols.[11,25] |
| Clinical efficacy | Rapidly increases mean arterial pressure and decreases vasopressor requirements.[3,9,15,16] | Findings are largely based on case reports and small-scale studies; more extensive research is required.[6,13] |
| Safety and compatibility | Better safety profile than methylene blue.[9] Safe for patients with G6PD deficiency or risk of serotonin syndrome.[15,23] | Documented side effects: Itching, vomiting, headaches, and hypersensitivity to cobalt.[5,16] |
| Interference | Can be used as a rescue therapy when other vasopressors or methylene blue fail.[4,6,22] | Intense red hue interferes with chromatic lab tests and triggers false “blood leak” alarms in hemodialysis devices.[5] |
| Renal impact | Provides a “long-lasting physiological advantage,” buying time for source control.[6] | Potential for calcium oxalate crystals in urine[5] and concerns regarding acute kidney injury.[17] |
NO: Nitric oxide, H2S: Hydrogen sulfide, NOS: Nitric oxide synthase
Artificial intelligence (AI) in management of shock
AI is capable of bringing a revolution into the field of medical diagnosis, treatment, and patient results, particularly in terms of patient monitoring and imaging.[26] AI presents different techniques that can save the lives of patients by identifying and diagnosing septic shock in a timely manner.[27] The use of unstructured notes along with information in a structured data format allows the sepsis early risk assessment model to make accurate predictions regarding the presence of sepsis, providing a 12–48 h warning time before the onset of signs and symptoms.[26] AI offers the facility to design customized treatment plans based on the condition, history, and response to medication of the patient.[27] AI-aided mechanical ventilation techniques have also indicated positive results in the treatment of sepsis/shock. According to recent research studies, AI techniques can accurately predict the dose of norepinephrine for blood pressure management in sepsis/shock patients. As per a prospective study, if an AI model is employed in the first 24 h of ICU admission, the AI model is capable of 90% accurate prediction regarding the mortality rate in septic shock using 1st h vital sign data.
Ongoing studies seek to create even more sophisticated AI models, integrate AI with other health technologies in the care of patients, and address the ethical and practical challenges of using AI in the ICU.[26]
CONCLUSION
HCB serves as a vital rescue therapy for patients with vasodilatory states unresponsive to standard catecholamine treatment. By scavenging NO and H2S, it helps restore vascular tone and improve the average arterial pressure in conditions such as septic shock, post heart surgery, a liver transplant, and medication-induced hypotension. It is mostly favored because of its safety efficacy unlike MB which is contraindicated.
While the clinical signal for HCB is consistently positive across various shock etiologies, the current evidence base is primarily limited to case reports and small retrospective series. Larger randomized trials are necessary to confirm its efficacy and offer definitive protocols for treatment. In this regard, HCB should be considered an adjunct option for refractory vasoplegic and septic shock.
Authors’ contributions:
PP: Writing review & editing, conceptualization, methodology, validation, formal analysis, writing - original draft, supervision, project administration; AAK: Conceptualization, methodology, resources, writing - original draft, writing - review & editing, visualization, validation; MM: Formal analysis, writing - original draft, writing - review & editing, visualization, methodology, resources, conceptualization; AT: Methodology, formal analysis, resources, writing - original draft, writing - review & editing, visualization, conceptualization; DB: Conceptualization, methodology, validation, resources, writing - review & editing, visualization, writing - original draft; RTG: Conceptualization, methodology, validation, resources, writing - original draft, writing - review & editing, visualization; CST: Conceptualization, methodology, resources, writing - original draft, writing - review & editing, visualization, validation; MM: Conceptualization, methodology, validation, resources, writing - original draft, writing - review & editing, visualization.
Ethical approval:
Institutional Review Board approval is not required.
Declaration of patient consent:
Patient’s consent not required as there are no patients in this study.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
Financial support and sponsorship: Nil.
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