Vasoplegic syndrome (VS), uncontrolled pathological vasodilation, is characterized by significant hypotension, normal or increased cardiac output, low systemic vascular resistance (SVR), and hyporesponsiveness to catecholamine vasopressors. Patients with severe sepsis have mortality >30%,1 whereas vasoplegic septic shock is often fatal. VS is also the common pathway of distributive shocks from different etiologies2 (eg, neurogenic, sepsis, cardiogenic, hemorrhage, and anaphylaxis). Pathophysiological processes of VS are likely to be multifactorial, including excessive production of nitric oxide (NO) leading to uncontrolled vascular smooth muscle relaxation.
Methylene blue (MB) has been used in treating septic shock with positive results.3,4 It is a selective inhibitor of soluble guanylate cyclase in the signaling of NO-mediated vasodilation. However, MB is short acting and contraindicated in patients taking serotonin reuptake inhibitors for the risk of serotonin syndrome. Alternative rescue agents for septic shock are currently under investigation. Hydroxocobalamin has shown efficacy in treating VS associated with cardiopulmonary bypass5,6 and liver transplantation.7,8 Unlike MB, it has no known contraindications. In this case report, we describe how a single dose of hydroxocobalamin (trade name: Cyanokit; Meridian Medical Technologies, Columbia, MD) facilitated the resolution of catecholamine-refractory septic shock in 2 patients: in the first case, septic shock in combination with demand myocardial ischemia; the second case, septic shock with oliguric renal failure.
Written consents were obtained from the patient (case 1) and the patient’s family (case 2) for use of medical histories in this case report.
A 55-year-old man with history of poorly controlled type 2 diabetes mellitus presented to the emergency department with shortness of breath and neck pain for 3 days. He started feeling ill 5 days before and became progressively dyspneic with worsening odynophagia and dysarthria. On examination, his heart rate was 138 beats/min, blood pressure (BP) 89/47 mm Hg, respiratory rate 22 breaths/min, temperature 37.4°C, and oxygen saturation 93% on ambient air. There was marked anterior neck fullness with erythema, firm to palpation. Otolaryngology specialists performed emergent laryngoscopy, which revealed extensive supraglottic edema. Subsequently, the patient had an urgent tracheostomy and neck abscess washout in the operating room on admission day. Postoperative laboratory results were as follows: white blood cell count 4900/mm3, hemoglobin 10.3 g/dL, hematocrit 29.3%, platelet count 137,000/mm3, international normalized ratio 1.99, prothrombin time 22 seconds, sodium 131 mmol/L, potassium 4.4 mmol/L, chloride 98 mmol/L, bicarbonate 19 mmol/L, blood urea nitrogen 57 mg/dL, creatinine 2.6 mg/dL, glucose 362 mg/dL, lactic acid 3.6 mmol/L, and troponin <0.03 ng/mL.
On postoperative day 1, the patient became increasingly unstable and required norepinephrine, vasopressin, and epinephrine infusions intravenously (IV) for BP support. Concurrently, the troponin I level was elevated and peaked at 37.98 ng/mL with new onset of inverted T waves in V1, V2, and V3 electrocardiography leads. The clinical diagnosis was septic shock from necrotizing fasciitis with multiple organ failure, including acute ischemic cardiac injury, acute respiratory failure, acute kidney injury, and coagulopathy. Later in the day, the norepinephrine infusion was increased to 0.31 µg/kg/min and the epinephrine infusion to 0.06 µg/kg/min. At this point, hydroxocobalamin 5 g IV was administered. Immediately, mean arterial pressure (MAP) increased to 76 mm Hg and remained >70 mm Hg while norepinephrine infusion was rapidly titrated downward. The rate stayed below 0.12 µg/kg/min during the following 12 hours (Figure 1). SVR remained >500 dynes·second·cm−5. The epinephrine drip was discontinued 4 hours after administration of hydroxocobalamin but was restarted at 0.01 µg/kg/min afterward.
Six days after admission, the patient no longer required vasopressor support. His remaining hospital course involved an acute ischemic stroke and 2 days of norepinephrine and dopamine support. Forty-three days after admission, patient was discharged to an acute care facility.
A 57-year-old man with hepatitis C cirrhosis and chronic bilateral lower extremity swelling presented to the emergency department with severe leg pain. He reported worsening left leg pain associated with low-grade fever, chills, and diaphoresis over the previous 2 days. His initial heart rate was 107 beats/min, BP 147/85 mm Hg, respiratory rate 24 breaths/min, temperature 36.9°C, and oxygen saturation 97% on ambient air. Laboratory results were as follows: white blood cell count 4200/mm3, platelet count 63,000/mm3, sodium 135 mmol/L, potassium 4 mmol/L, chloride 103 mmol/L, bicarbonate 16 mmol/L, blood urea nitrogen 40 mg/dL, creatinine 3.2 mg/dL, albumin 1.8 g/dL, total bilirubin 1.7 mg/dL, aspartate aminotransferase test 89 U/L, alanine aminotransferase test 25 U/L, international normalized ratio 1.5, lactate 7 mmol/L, and troponin 0.07 ng/mL. The working diagnosis was sepsis due to infection in left lower extremity.
Two days after admission, he was profoundly hypoten sive despite aggressive fluid resuscitation and a norepinephrine infusion up to 0.18 µg/kg/min. On physical examination, diffuse petechiae and purpura were noted in his left shin and medial thigh, and a large hemorrhagic bulla in posterior leg. Patient was subsequently taken to the operating room with his necrotizing soft tissue infection that required a left above knee amputation. Clinical diagnosis included septic shock from necrotizing fasciitis, pseudomonas bacteremia, and acute oliguric renal failure. Despite surgical management, he still required high-dose norepinephrine and vasopressin over the next 3 days. Furthermore, he had a positive 15 L fluid balance since admission and oxygenation was becoming more difficult because of refractory hypotension prohibiting fluid removal through continuous renal replacement therapy. At this point, hydroxocobalamin 5 g IV was administered. During the next 4 hours, norepinephrine was rapidly titrated downward to 0.05 µg/kg/min (Figure 2). One day after the treatment, he required only norepinephrine 0.02 µg/kg/min and vasopressin 0.04 U/min to keep MAP above 65 mm Hg and was able to tolerate continuous renal replacement therapy.
Ten days after admission, patient was off vasopressor support. Twenty-one days after admission, patient was transferred out the surgical intensive care to the burn unit. His remaining hospital course was complicated by recurrent sepsis, respiratory failure, hepatic failure, and renal failure. Thirty-five days after admission, the family decided on comfort care and he was pronounced dead in the next day.
VS is a well-known phenomenon in septic shock. Although no definitive hemodynamic parameters have been established, commonly accepted criteria for vasoplegia are SVR <800 dynes·second·cm−5, MAP <60 mm Hg, cardiac index >2.4 L/min/m2, and a requirement of ≥1 high-dose vasopressor (ie, >0.5 µg/kg/min norepinephrine-equivalent dose) after adequate fluid resuscitation.5,9 VS has complex pathophysiological processes and multiple potential causes. Three widely accepted mechanisms for the derangement of vascular tone homeostasis have been implicated: (1) unregulated excessive NO production by the inducible form of NO synthase in vascular smooth muscle cells; (2) activation of adenosine triphosphate-sensitive potassium channels in the plasma membrane of vascular smooth muscle cells prevents calcium entry for vasoconstriction; and (3) deficiency of endogenous vasoactive hormones, such as cortisol, vasopressin, and angiotensin II.9,10
Mortality rate of catecholamine-refractory septic shock is >75%.11 The standard management strategy of septic vasoplegia is correcting the underlying causes and fluid resuscitation before initiating first-line vasopressor norepinephrine. When this approach does not restore BP, second-line vasopressors such as vasopressin and epinephrine are added. Alternative rescue agents have been under study. Selepressin, a synthetic selective vasopressin V1a receptor agonist, is being investigated in clinical trials (NCT01000649, SEPSIS-ACT [Selepressin Evaluation Programme for Sepsis-Induced Shock - Adaptive Clinical Trial]). Angiotensin II significantly increased MAP in 70% of patients during the randomized double-blinded ATHOS-3 trial (Angiotensin II for the Treatment of High-Output Shock Phase 3).
MB has been used in treating catecholamine-refractory vasoplegia associated with septic shock.3,4 However, MB is a potent monoacid oxidase inhibitor and contraindicated in patients taking serotonin reuptake inhibitors for the risk of serotonin syndrome. It can also cause pulmonary hypertension and worsen oxygenation. Its vasopressor effect is short-lived and may require repeated dosing or continuous infusion. MB produces methemoglobin that may interfere pulse oximetry reading. MB should be used with caution in patients with severe renal failure and hepatic diseases because its extensive metabolism in liver and approximately 40% is excreted by the kidney.
While there have been several case reports of the efficacy of hydroxocobalamin in treating intraoperative vasoplegia during cardiopulmonary bypass5,6 and liver transplantation,7,8 very few cases reported its applications in septic shock.12 Hydroxocobalamin, a precursor of vitamin B12, was approved by the Food and Drug Administration in 1975 for the treatment of known or suspected cyanide poisoning. The vasopressor effect of hydroxocobalamin is likely related to the scavenging of NO, the inhibition on inducible form of NO synthase, and guanylate cyclase.13,14 Unlike MB, it has no known contraindications or risk of serotonin syndrome. The most common adverse reactions are chromaturia and increased BP. Elevation of BP was observed in 18% of healthy subjects receiving hydroxocobalamin 5 g IV.15 Treatment with hydroxocobalamin may falsely elevate red blood cell count in urine analysis and interfere with the hemodialysis sensors.
In this case report, we described high-dose hydroxocobalamin as a successful rescue agent in refractory septic shock state. In both cases, hydroxocobalamin rapidly raised arterial pressure while significantly reducing vasopressor requirement, making it the most likely cause for the resolution of the vasoplegia associated with sepsis. In contrast to MB, hydroxocobalamin had a lasting vasopressor effect, a second dose was not needed in either patient. Currently, there is paucity in the literature regarding dosing and effectiveness in patients with renal or hepatic impairments. The safety, dosing, and its impacts on mortality rate in septic shock will require further exploration.
Name: Yichun Lin, MD.
Contribution: This author helped collect the data, create the figures, and write the manuscript.
Name: Trung Q. Vu, MD.
Contribution: This author helped conceive the case report, and edit and revise the manuscript.
This manuscript was handled by: Raymond C. Roy, MD.
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