Hydroxocobalamin in Refractory Vasodilatory Shock: More Questions than Answers.

VASODILATORY SHOCK refractory to synthetic vasopressors portends a particularly poor prognosis, and has motivated investigation into multimodal rescue strategies, such as hydroxocobalamin.1Venkatesh B Khanna AK Cohen J. Less is more: Catecholamine-sparing strategies in septic shock.Intensive Care Med. 2019; 45: 1810-1812Crossref PubMed Scopus (10) Google Scholar In this issue of the Journal of Cardiothoracic and Vascular Anesthesia, Brokmeier et al. presented a systematic review of the use of hydroxocobalamin in vasodilatory hypotension.2Brokmeier HM, Seelhammer TG, Nei SD, et al., Hydroxocobalamin for vasodilatory hypotension in shock: A systematic review with meta analysis for the comparison to methylene blue [e-pub ahead of print]. J Cardiothorac Vasc Anesth, https://doi.org/10.1053/j.jvca.2023.04.006. Accessed April 7, 2023.Google Scholar The authors compiled 24 previously published manuscripts (12 case reports, 9 case series, and 3 retrospective cohort studies) encompassing 289 hydroxocobalamin recipients.2Brokmeier HM, Seelhammer TG, Nei SD, et al., Hydroxocobalamin for vasodilatory hypotension in shock: A systematic review with meta analysis for the comparison to methylene blue [e-pub ahead of print]. J Cardiothorac Vasc Anesth, https://doi.org/10.1053/j.jvca.2023.04.006. Accessed April 7, 2023.Google Scholar The authors also conducted a meta-analysis of the 3 cohort studies comparing the effect of hydroxocobalamin to methylene blue, another rescue agent used in refractory vasodilatory shock, on mean arterial pressure (MAP), vasopressor dosage, and mortality. The meta-analysis yielded that hydroxocobalamin was associated with a greater increase in MAP than methylene blue; however, neither agent significantly impacted change in MAP from baseline, vasopressor dosages after 1 hour after administration, or mortality compared with the other.2Brokmeier HM, Seelhammer TG, Nei SD, et al., Hydroxocobalamin for vasodilatory hypotension in shock: A systematic review with meta analysis for the comparison to methylene blue [e-pub ahead of print]. J Cardiothorac Vasc Anesth, https://doi.org/10.1053/j.jvca.2023.04.006. Accessed April 7, 2023.Google Scholar Hydroxocobalamin, also known as vitamin B12 or its tradename Cyanokit, received Food and Drug Administration approval in 2006 as an antidote for cyanide toxicity.3Shepherd G Velez LI. Role of hydroxocobalamin in acute cyanide poisoning.Ann Pharmacother. 2008; 42: 661-669Crossref PubMed Scopus (84) Google Scholar For this indication, it acts by swapping a hydroxyl group for a CN group to form a nontoxic compound, cyanocobalamin, which is then renally excreted.3Shepherd G Velez LI. Role of hydroxocobalamin in acute cyanide poisoning.Ann Pharmacother. 2008; 42: 661-669Crossref PubMed Scopus (84) Google Scholar Early observations of hydroxocobalamin administration noted increased blood pressure as a side effect, which has prompted interest in its potential in vasodilatory shock refractory to other agents.4Shapeton AD Mahmood F Ortoleva JP. Hydroxocobalamin for the treatment of vasoplegia: A review of current literature and considerations for use.J Cardiothorac Vasc Anesth. 2019; 33: 894-901Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar Hydroxocobalamin increases blood pressure by a pathway not targeted by the mainstay vasopressor therapies used in vasodilatory shock, inhibiting nitric oxide-mediated vasodilation, both directly through inhibition of nitric oxide and indirectly through inhibition of nitric oxide synthase.5Kruszyna H Magyar JS Rochelle LG et al.Spectroscopic studies of nitric oxide (NO) interactions with cobalamins: Reaction of NO with superoxocobalamin (III) likely accounts for cobalamin reversal of the biological effects of NO.J Pharmacol Exp Ther. 1998; 285: 665-671PubMed Google Scholar,6Weinberg JB Chen Y Jiang N et al.Inhibition of nitric oxide synthase by cobalamins and cobinamides.Free Radic Biol Med. 2009; 46: 1626-1632Crossref PubMed Scopus (56) Google Scholar Hydroxocobalamin also may raise blood pressure by increasing the elimination of the endogenous vasodilator hydrogen sulfide.7Jiang J Chan A Ali S et al.Hydrogen sulfide—mechanisms of toxicity and development of an antidote.Sci Rep. 2016; 6: 20831Crossref PubMed Scopus (158) Google Scholar Limited existing data to date on hydroxocobalamin in vasoplegic patients suggest it may be effective, but it should be noted that this medication causes chromaturia, slight interference with common laboratory measurements, including analysis of glucose, creatinine, and alkaline phosphatase levels, and false activation of dialysis blood leak alarms.4Shapeton AD Mahmood F Ortoleva JP. Hydroxocobalamin for the treatment of vasoplegia: A review of current literature and considerations for use.J Cardiothorac Vasc Anesth. 2019; 33: 894-901Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar Although there is consensus on the physiologic rationale of using hydroxocobalamin in vasodilatory shock, how this therapy can offer a tangible clinical benefit has yet to be determined. Brokmeier et al. can be commended for pooling much of the data that exists on this topic, and their systematic review has highlighted some key questions, the answers to which may help better deploy hydroxocobalamin in the operating room and intensive care unit. Notably, Brokmeier et al. did not analyze the reported effectiveness of hydroxocobalamin in the current literature. Such an analysis is challenging given that no established criteria define an “effective response” to rescue agents in vasodilatory shock. Current benchmarks include the effect on MAP, either by achieving a certain MAP goal (eg, >608Feih JT Rinka JR Zundel MT. Methylene blue monotherapy compared with combination therapy with hydroxocobalamin for the treatment of refractory vasoplegic syndrome: A Retrospective cohort study.J Cardiothorac Vasc Anesth. 2019; 33: 1301-1307Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar) and relative or absolute increase from baseline.9Sacco AJ Cunningham CA Kosiorek HE et al.Hydroxocobalamin in refractory septic shock: A retrospective case series.Crit Care Explor. 2021; 3: e0408Crossref PubMed Google Scholar Similarly, a case series of cardiac surgery patients by Shah et al. uniquely defined “responder” to hydroxocobalamin by the linear trajectory of MAP over 120 minutes after drug administration.10Shah PR Reynolds PS Pal N et al.Hydroxocobalamin for the treatment of cardiac surgery-associated vasoplegia: A case series.Can J Anaesth. 2018; 65: 560-568Crossref PubMed Scopus (44) Google Scholar Perhaps a better, more practical surrogate of effectiveness is a reduction in vasopressor requirements; hemodynamic improvements do not always translate to successful weaning of vasopressors, as shown by the meta-analysis of Brokmeier et al.2Brokmeier HM, Seelhammer TG, Nei SD, et al., Hydroxocobalamin for vasodilatory hypotension in shock: A systematic review with meta analysis for the comparison to methylene blue [e-pub ahead of print]. J Cardiothorac Vasc Anesth, https://doi.org/10.1053/j.jvca.2023.04.006. Accessed April 7, 2023.Google Scholar Future studies on the effectiveness of hydroxocobalamin should aim to convert vasopressor requirement to norepinephrine equivalents so as to provide a generalizable center-to-center measure of efficacy. The systematic review of Brokmeier et al. captured studies of hydroxocobalamin used in patients undergoing cardiac, noncardiac, and abdominal transplant surgery and those with septic shock and drug-induced vasoplegia.2Brokmeier HM, Seelhammer TG, Nei SD, et al., Hydroxocobalamin for vasodilatory hypotension in shock: A systematic review with meta analysis for the comparison to methylene blue [e-pub ahead of print]. J Cardiothorac Vasc Anesth, https://doi.org/10.1053/j.jvca.2023.04.006. Accessed April 7, 2023.Google Scholar However, the lion's share of the current hydroxocobalamin literature (13 reports of 198 patients) is in the cardiac surgery population, in which postbypass vasoplegia syndrome represents a significant issue.2Brokmeier HM, Seelhammer TG, Nei SD, et al., Hydroxocobalamin for vasodilatory hypotension in shock: A systematic review with meta analysis for the comparison to methylene blue [e-pub ahead of print]. J Cardiothorac Vasc Anesth, https://doi.org/10.1053/j.jvca.2023.04.006. Accessed April 7, 2023.Google Scholar,11Ortoleva J Shapeton A Vanneman M et al.Vasoplegia during cardiopulmonary bypass: Current literature and rescue therapy options.J Cardiothorac Vasc Anesth. 2020; 34: 2766-2775Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar Here, albeit largely per anecdotal reports, hydroxocobalamin appeared to produce some positive response in 2 out of 3 patients to whom the medication is given.2Brokmeier HM, Seelhammer TG, Nei SD, et al., Hydroxocobalamin for vasodilatory hypotension in shock: A systematic review with meta analysis for the comparison to methylene blue [e-pub ahead of print]. J Cardiothorac Vasc Anesth, https://doi.org/10.1053/j.jvca.2023.04.006. Accessed April 7, 2023.Google Scholar However, the current lack of a common definition for vasoplegia syndrome further confounds candidacy for hydroxocobalamin and any other agents, including methylene blue.11Ortoleva J Shapeton A Vanneman M et al.Vasoplegia during cardiopulmonary bypass: Current literature and rescue therapy options.J Cardiothorac Vasc Anesth. 2020; 34: 2766-2775Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar The development of treatment pathways will depend on consistent criteria for vasoplegia syndrome defined by MAP, systemic vascular resistance, and ongoing pressor requirements. The evidence for hydroxocobalamin in other etiologies of vasodilatory shock is much sparser. The second most represented etiology in the results of Brokmeier et al. was septic shock, from which the inpatient mortality of patients requiring a trial of hydroxocobalamin was more than twice that in the cardiac surgery population (26.8% v 71.4%).2Brokmeier HM, Seelhammer TG, Nei SD, et al., Hydroxocobalamin for vasodilatory hypotension in shock: A systematic review with meta analysis for the comparison to methylene blue [e-pub ahead of print]. J Cardiothorac Vasc Anesth, https://doi.org/10.1053/j.jvca.2023.04.006. Accessed April 7, 2023.Google Scholar Perhaps patients with sepsis are poorer substrates for hydroxocobalamin due to an ongoing vasodilation trigger (ie, active infection). Investigation into this hypothesis may help us further understand which etiologies of vasodilation hydroxocobalamin will most likely yield a positive treatment response. The optimal timing of hydroxocobalamin administration is unknown. Because no randomized controlled trials or large retrospective studies exist evaluating the efficacy of hydroxocobalamin in any population, hydroxocobalamin remains relegated to a role as a rescue agent, challenging the study of optimal timing of administration. The case report literature describes administrating hydroxocobalamin as a metaphorical Hail Mary, even after other rescue agents have been tried unsuccessfully; this may be too late. It has been hypothesized that patient responsiveness to hydroxocobalamin may be a function of patients’ baseline hemodynamic condition and whether it is given earlier versus later during decompensation.2Brokmeier HM, Seelhammer TG, Nei SD, et al., Hydroxocobalamin for vasodilatory hypotension in shock: A systematic review with meta analysis for the comparison to methylene blue [e-pub ahead of print]. J Cardiothorac Vasc Anesth, https://doi.org/10.1053/j.jvca.2023.04.006. Accessed April 7, 2023.Google Scholar The case series by Shah et al. demonstrated that patients with lower baseline MAPs before hydroxocobalamin was given were less likely to exhibit a blood pressure improvement to a MAP >65.10Shah PR Reynolds PS Pal N et al.Hydroxocobalamin for the treatment of cardiac surgery-associated vasoplegia: A case series.Can J Anaesth. 2018; 65: 560-568Crossref PubMed Scopus (44) Google Scholar This finding reinforced the premise that when refractory vasodilatory shock is prolonged, mortality risk is increased and chances of any therapy resulting in clinical improvement is lower. Rather than trialing hydroxocobalamin after a period of persistently high vasopressor requirements, it may be worth considering adding the medication upon arriving at a certain norepinephrine equivalent pressor requirement. When used in cases of cyanide toxicity, hydroxocobalamin is given in bolus doses of 5 g over 10 to 15 minutes.3Shepherd G Velez LI. Role of hydroxocobalamin in acute cyanide poisoning.Ann Pharmacother. 2008; 42: 661-669Crossref PubMed Scopus (84) Google Scholar The review from Brokmeier et al. has revealed that this dosing schema largely has been translated to the agent's use in vasodilatory shock, despite the separate molecular mechanisms targeted in these indications.2Brokmeier HM, Seelhammer TG, Nei SD, et al., Hydroxocobalamin for vasodilatory hypotension in shock: A systematic review with meta analysis for the comparison to methylene blue [e-pub ahead of print]. J Cardiothorac Vasc Anesth, https://doi.org/10.1053/j.jvca.2023.04.006. Accessed April 7, 2023.Google Scholar Though some reports gathered by their systematic review have demonstrated hydroxocobalamin used in smaller incremental boluses or as an infusion, there is no evidence advocating for any particular dosing schema.2Brokmeier HM, Seelhammer TG, Nei SD, et al., Hydroxocobalamin for vasodilatory hypotension in shock: A systematic review with meta analysis for the comparison to methylene blue [e-pub ahead of print]. J Cardiothorac Vasc Anesth, https://doi.org/10.1053/j.jvca.2023.04.006. Accessed April 7, 2023.Google Scholar Further, when considering hydroxocobalamin's half-life of 26 to 31 hours, there are currently no predictors for an expected duration of effect on blood pressure support nor risk factors for developing rebound hypotension once the vasoactive effect of hydroxocobalamin dissipates.3Shepherd G Velez LI. Role of hydroxocobalamin in acute cyanide poisoning.Ann Pharmacother. 2008; 42: 661-669Crossref PubMed Scopus (84) Google Scholar,10Shah PR Reynolds PS Pal N et al.Hydroxocobalamin for the treatment of cardiac surgery-associated vasoplegia: A case series.Can J Anaesth. 2018; 65: 560-568Crossref PubMed Scopus (44) Google Scholar Hydroxocobalamin is often described as used in combination therapy with methylene blue, with the latter being administered first.2Brokmeier HM, Seelhammer TG, Nei SD, et al., Hydroxocobalamin for vasodilatory hypotension in shock: A systematic review with meta analysis for the comparison to methylene blue [e-pub ahead of print]. J Cardiothorac Vasc Anesth, https://doi.org/10.1053/j.jvca.2023.04.006. Accessed April 7, 2023.Google Scholar When these 2 equally efficacious rescues are administered in series, the rationale of why hydroxocobalamin is the second line is cost. A 5-g vial of hydroxocobalamin has an average wholesale price of nearly $1,000, about 4 times the cost of a dose of methylene blue.12Furnish C Mueller SW Kiser TH et al.Hydroxocobalamin versus methylene blue for vasoplegic syndrome in cardiothoracic surgery: A retrospective cohort.J Cardiothorac Vasc Anesth. 2020; 34: 1763-1770Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar Regardless, there may be value in combination therapy. The cohort study by Feih et al. revealed that only combination therapy, not either agent as monotherapy, reduced vasopressor requirements at 1-hour post-administration.8Feih JT Rinka JR Zundel MT. Methylene blue monotherapy compared with combination therapy with hydroxocobalamin for the treatment of refractory vasoplegic syndrome: A Retrospective cohort study.J Cardiothorac Vasc Anesth. 2019; 33: 1301-1307Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar The choice in favor of hydroxocobalamin as first-line monotherapy may sometimes be informed by patient-specific factors that may preclude methylene blue. For instance, patients with glucose-6-phosphate dehydrogenase deficiency or receiving a higher burden of serotonergic medications are at risk for hemolytic anemia and serotonin syndrome, respectively, if given methylene blue.8Feih JT Rinka JR Zundel MT. Methylene blue monotherapy compared with combination therapy with hydroxocobalamin for the treatment of refractory vasoplegic syndrome: A Retrospective cohort study.J Cardiothorac Vasc Anesth. 2019; 33: 1301-1307Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar Thus, hydroxocobalamin would be favored in these patients. Hydroxocobalamin also should be preferred to methylene blue in patients with severe pulmonary hypertension, given the latter's elevating effect on pulmonary vascular resistance.13Clifton JI Leikin JB Methylene blue.Am J Ther. 2003; 10: 289-291Crossref PubMed Scopus (274) Google Scholar Additionally, while the current trials of hydroxocobalamin have an interest in comparison to methylene blue, there remains a perhaps more pressing question—what's the next step in managing vasoplegic patients who are refractory to both agents? In conclusion, the findings of Brokmeier et al. are useful in guiding further investigations into hydroxocobalamin but, unfortunately, did not yet answer the lingering questions clinicians have had. Ultimately, prospective multicentered or randomized controlled trials are needed to assess efficacy, establish treatment protocols, and verify optimal dosing. In the meantime, the existing literature supports using hydroxocobalamin as a rescue agent in refractory vasodilatory shock. None. Hydroxocobalamin for Vasodilatory Hypotension in Shock: A Systematic Review With Meta-Analysis for Comparison to Methylene BlueJournal of Cardiothoracic and Vascular AnesthesiaPreviewHydroxocobalamin 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. Full-Text PDF