Unexpected Complication of Hydroxocobalamin Administration for Refractory Vasoplegia in Orthotopic Liver Transplant: A Case Report

Introduction

The following case is presented in an attempt to bring attention to an adverse interaction between hydroxocobalamin administration and intermittent hemodialysis (HD). There have been a handful of case reports describing the inability to perform HD after hydroxocobalamin administration for cyanide toxicity as well as vasoplegic syndrome.^1-3 These reports are primarily found in nephrology or toxicology literature, and there was no specific discussion as to the possibility of this complication arising intraoperatively. Given the frequency with which intermittent HD is utilized in orthotopic liver transplantation (OLT), ⁴ the likelihood of this interaction appearing intraoperatively in this group is not inconsequential. As such, transplant anesthesiologists should be aware of this possible problem. This complication impeded our attempts to maintain hemodynamic stability and almost prevented the ability to safely perform a subsequent kidney transplantation.

Hydroxocobalamin causes a red color change in the dialysate membrane, which registers as a “blood leak” within the dialysis machine. This alarm causes the machine to cease all flow in an effort to prevent exsanguination in the event of a true membrane leak. These false blood leak alarms can significantly delay or prevent the ability to perform urgent HD and have resulted in patient death in some case reports. ⁵ There are reportedly mechanisms to manually override the alarm, but this is often cumbersome and time consuming. ³ Additionally, overriding this alarm would mask a true blood leak, which, if undetected, could also be catastrophic for the patient.

This case report highlights the implications of this interaction in a patient who was scheduled to receive a simultaneous liver and kidney transplant. The inability to continue intraoperative HD significantly hindered our attempts to maintain hemodynamic stability. Kidney transplant in the setting of persistent hemodynamic instability is associated with poor graft function outcomes. ⁶ This adverse interaction presented a unique clinical decision-making challenge in this case.

Case Description

A 40-year-old male with alcoholic cirrhosis and end-stage renal disease received an offer for simultaneous liver and kidney transplant. The patient was receiving intermittent HD 3 days per week prior to transplant. On notice of available organs, he was admitted to the intensive care unit (ICU) and was dialyzed overnight prior to presenting to the operative room (OR) for transplantation. On arrival in the OR, general anesthesia was induced without incident. A right radial arterial line was placed followed by a left internal jugular central venous catheter and additional peripheral IVs. Intermittent HD was continued intraoperatively.

The dissection phase of the liver transplantation was well tolerated without significant transfusion requirements or vasopressor support. However, on clamping the inferior vena cava, the patient developed worsening hypotension requiring increasing amounts of vasoactive agents and additional blood product transfusion. When the inferior vena cava was unclamped, the patient experienced hemodynamically significant bradycardia that was treated with glycopyrrolate. The increase in chronotropy resulted in improvement in his overall hemodynamics. Shortly thereafter, he developed an increasingly widening QRS and progression to ventricular tachycardia. Initially, blood pressure remained stable, and amiodarone was administered. Amiodarone was ineffective, and he remained in ventricular tachycardia; he subsequently began to develop worsening hypotension. Since he was now becoming increasingly hemodynamically unstable, synchronized cardioversion was performed. He returned to sinus rhythm; however, he then developed what appeared to be a left bundle branch block. Despite the return to sinus rhythm, he remained hypotensive and on significant vasopressor support. Transesophageal echocardiography was emergently performed after return to sinus rhythm, which revealed good contractile function, no wall motion abnormalities, and no evidence of pulmonary embolus or pericardial effusion. This patient did not have a pulmonary artery catheter as it is not standard practice at our institution to routinely place these in patients without preoperative portopulmonary hypertension.

The patient continued to develop increasingly refractory hypotension despite escalating doses of norepinephrine, vasopressin, phenylephrine, as well as fluid and blood product administration. Methylene blue (100 mg) was administered without significant improvement. Hydroxocobalamin (5 g) was then administered for refractory vasoplegia, which improved hemodynamics, but resulted in persistent “blood leak” alarms on the HD machine. The “blood leak” alarm automatically stopped the dialysis machine from running, which required the dialysis technician to manually override the alarm and restart the machine. However, the alarm persisted and prevented the ability to adequately dialyze the patient. In an attempt to rectify the situation, we switched to a different HD machine but immediately encountered the same issue. Without the ability to continue HD, the patient developed worsening acidosis and hyperkalemia, which was treated with sodium bicarbonate and insulin as we continued to attempt dialysis. Of note, at our institution, we will only utilize intraoperative intermittent HD and we do not start continuous renal replacement therapy (CRRT) in the operating room, although this may be common practice at other institutions.

After a discussion with the surgical team, the decision was made to perform a staged operation and return the patient to the ICU to receive CRRT prior to attempting kidney transplantation. His laboratory abnormalities and hemodynamics improved after receiving CRRT overnight, and he was brought back the following morning to undergo kidney transplantation. The final cold ischemic time of the renal graft was 24.6 hours. Intraoperative HD was again attempted but the same “blood leak” alarm persisted preventing effective dialysis, although this was partially overcome by increasing the dialysate flow. The remainder of his operative course was uneventful. The patient’s vasopressor requirements remained stable, and he was extubated at the end of the case and returned to the ICU, where he remained for 3 days. Although his liver graft function improved, he did experience delayed renal graft function and continued to require HD until postoperative day 10. He was discharged on postoperative day 10 with a plan to follow-up as an outpatient. He continued to improve clinically as an outpatient and when seen 4 months posttransplant, he was noted to have excellent liver and kidney graft function.

Discussion

Hydroxocobalamin was originally identified as a treatment for cyanide toxicity, ⁷ and its administration was accompanied by an incidentally observed increase in blood pressure. This reaction is believed to occur due to the sequestration and depletion of endothelial nitric oxide. ⁸ Clinicians quickly realized the potential for hydroxocobalamin to be utilized in the treatment of vasoplegic syndrome. ⁸

Vasoplegic syndrome is most often described as systemic vascular resistance (SVR) less than 800 dyne * s/cm⁵, mean arterial pressure (MAP) less than 60, and cardiac index (CI) greater than 2.5 in the presence of at least one high-dose vasopressor infusion. ⁸ This syndrome is most commonly associated with cardiopulmonary bypass, although it has been described during OLT. ⁹ Vasoplegia resistant to catecholamine administration reportedly has a mortality rate up to 25%. ⁸ Methylene blue has previously been utilized as a treatment of choice for refractory vasoplegia, with hydroxocobalamin gaining acceptance as an alternative treatment for this phenomenon. ⁸

One of the few observed side effects from hydroxocobalamin administration is a discoloration of body fluids that can persist for weeks.^2,10 HD circuits separate blood from the dialysate solution with a semipermeable membrane. The distinct red color of hydroxocobalamin in the serum can penetrate this membrane, which is then erroneously interpreted by the machine as a blood leak. The integrity of the membrane is imperative to prevent exsanguination during dialysis. As a safety mechanism, modern HD machines are designed to cease all flow when blood is detected in the dialysate solution. While this is a reasonable fail-safe, it also means that medications that cause a color change within the dialysate may cause the machine to erroneously detect that color change as a blood leak, which will stop the process of hemofiltration. Notably, CRRT is not subject to the same interactions with hydroxocobalamin and will continue to function normally in its presence. It is likely that the different type of photodetector utilized by CRRT machines is the reason for its resistance to this interaction.^1,11,12 Also, the blood leak sensor is amenable to recalibration on CRRT machines, which will circumvent this issue. ¹¹

As mentioned, this interaction has been reported previously in case reports,^1-3 but there is no discussion of the implications of this occurring intraoperatively. The importance of knowing this interaction and the subsequent complications is exceedingly relevant for transplant anesthesiologists, as the likelihood of utilizing intraoperative HD is higher in liver transplant recipients than the general surgical population. ⁴ Agopian et al found that 14% of the patients receiving pretransplant renal replacement therapy went to the OR with planned intraoperative renal replacement therapy during OLT. An additional 5.8% of patients receiving pretransplant renal replacement therapy ended up requiring emergent dialysis intraoperatively, though this article did not specify whether intermittent HD or CRRT was utilized. ⁴ It is important to note that intraoperative dialysis use varies widely among transplant centers with some centers utilizing only intermittent HD, some preferring CRRT, and others not performing any intraoperative dialysis. Literature discussing the optimal strategy for intraoperative management of patients with preoperative renal failure who may require intraoperative renal replacement therapy is lacking. ⁴

Since the introduction of the MELD (Model for End-Stage Liver Disease) scoring system, we continue to see an increase in patients with preoperative renal failure who present for OLT. ¹³ End-stage liver disease patients with concomitant renal failure often have acid-base disturbances and electrolyte abnormalities, which can become problematic during the significant hemodynamic variability that is associated with OLT. ¹⁴ In liver transplantation, 2 major risk factors for postoperative complications include the development of postreperfusion syndrome ¹⁵ and intraoperative arrhythmias. ¹⁶ These have both been shown to increase the risk of poor allograft function, retransplantation, and mortality after OLT. ¹⁷ Patients with renal failure are particularly prone to these complications. ¹⁸ Intraoperative HD offers the opportunity to correct the severe acidosis, ¹⁹ hyperkalemia, ²⁰ and volume derangements ²¹ that often accompany the significant transfusion requirements that can occur in these unique cases.

As mentioned previously, CRRT is not subject to the same interference and will continue to function without issue. ¹¹ Hydroxocobalamin is increasingly being utilized intraoperatively as an emergency treatment for refractory vasoplegia. Awareness of the resulting false blood leak alarms is imperative to minimize the potential for morbidity and mortality from the inability to provide HD. The focus on allocating organs to patients with preoperative renal failure suggests that the number of patients undergoing OLT that require intraoperative HD will continue to increase. Given that there are few alternatives to hydroxocobalamin to treat refractory vasoplegic syndrome, this adverse interaction is likely to be seen again. Consideration of this potential interaction is suggested in the future; and although not a contraindication to intraoperative HD, it is suggested that CRRT machines be readily available if the patient develops vasoplegic syndrome that might require hydroxocobalamin.