Successful use of continuous renal replacement therapy after hydroxocobalamin administration

Abstract

Hydroxocobalamin was approved by the Food and Drug Administration in 2006 to treat known or suspected cyanide toxicity.1 Cyanide is a potent toxin that inhibits numerous metal-containing enzymes, including cytochrome oxidases, which leads to cellular hypoxia, cardiovascular collapse, and frequently death.2 Hydroxocobalamin is the naturally occurring form of vitamin B₁₂, and its therapeutic effects are believed to be from chelation of cyanide by the central cobalt atom and the subsequent formation of cyanocobalamin, which is then renally eliminated.3 It has been shown to be well tolerated in animal and human studies, with minimal adverse effects.4 One of the few known adverse effects from hydroxocobalamin is a dark red discoloration of skin and body fluids, which can lead to interference with several colorometric laboratory tests.5-8 There is one prior case report in the literature describing the inability to perform intermittent hemodialysis after administration of hydroxocobalamin due to the red pigment triggering the blood leak detector on the hemodialysis machine.9 In this article, we describe the first reported case of using continuous renal replacement therapy (CRRT) to overcome the hydroxocobalamin-related interference with hemodialysis.

A 33-year-old man was transported to the emergency department by paramedics after he was found unresponsive in a parking lot. The patient was unable to provide any history; however, there was no obvious sign of trauma. Upon arrival, the patient was placed on 100% oxygen by non-rebreather facemask and had the following vital signs: pulse 120 beats/min, blood pressure 189/95 mmHg, respiratory rate 35/min, and temperature 96.6°F. Physical examination revealed a depressed level of consciousness, rapid and deep respirations, normal-sized reactive pupils, absence of any external signs of trauma, and withdrawal to painful stimuli in all extremities. Finger stick glucose was 147 mg/dL. For airway protection the patient was endotracheally intubated by rapid sequence induction. An initial blood gas, ordered and reported as venous, but later determined to be arterial, revealed a pH of 6.92, pCO₂ of 41 mmHg, pO₂ of 198 mmHg, and carboxyhemoglobin of 0.5%.

Further lab tests revealed: sodium 139 mmol/L, potassium 5.0 mmol/L, chloride 100 mmol/L, bicarbonate 8 mmol/L, creatinine 1.31 mg/dL, blood urea nitrogen (BUN) 18 mg/dL, calcium 8.4 mg/dL, lactate 58.8 mg/dL (normal range 4.5–19.8 mg/dL), measured serum osmolarity 306 mOsm/kg, and calculated serum osmolarity 292 mOsm/kg (osmolar gap = 14). Liver enzymes were normal. Serum concentrations of acetaminophen, salicylate, and ethanol were not detectable. Microscopic analysis of the initial urine revealed hippuric acid crystals in a low amount. The toxicology service was consulted and recommended the immediate administration of intravenous fomepizole, thiamine, pyridoxine, and leucovorin, as well as nephrology consultation for emergency hemodialysis for suspected ethylene glycol or methanol poisoning.

The combination of lactic acidosis (which can occasionally occur in methanol poisoning and can be a false positive in ethylene glycol poisoning10), a significantly elevated pO₂ on reportedly a venous blood gas, and the inability to rapidly obtain confirmatory methanol or ethylene glycol concentrations led to consideration and treatment for cyanide poisoning. Five grams of hydroxocobalamin (Cyanokit) were administered intravenously for potential cyanide toxicity. Approximately 1 hour later intermittent hemodialysis was initiated on a Fresenius 2008k machine for treatment of overwhelming acidosis and progressive oliguria, and as an empiric treatment for toxic alcohol ingestion.

Within minutes of starting dialysis, the blood leak detector was triggered, and internal pre-set alarms did not allow hemodialysis to proceed. The effluent was markedly red, but cell counts demonstrated the absence of any red cells. The patient's urine had also developed a deep red discoloration. It was suspected that administration of hydroxocobalamin led to the red pigmentation of body fluids, triggering the blood leak detector on the hemodialysis machine, which could not be successfully disabled or recalibrated. Thus, given the inability to proceed with intermittent hemodialysis, CRRT was attempted using a Prismaflex machine, which has the ability to recalibrate the blood leak detector utilizing the pigmented effluent, and dialysis then proceeded without event (Figure 1). Cell counts were monitored at regular intervals from the red pigmented effluent fluid to ensure that no red blood cells were present. Initial blood flows were started at 100 mL/min, but on day 3 blood flow was increased to 200 mL/min with an ultrafiltration of 2 L/hr to improve clearance.

The patient required CRRT for 5 days until the effluent had become significantly less pigmented, and then he was transitioned to intermittent hemodialysis on the Fresenius 2008k machine without difficulty. Forty-eight hours after admission, an ethylene glycol concentration that was drawn at the time of admission was reported at 28 mg/dL (ARUP Labs, Salt Lake City, UT). Methanol level was undetectable. After 5 days, the patient was extubated. His mental status slowly cleared, and he admitted to drinking an unlabeled container of liquid he found in a parking lot, which he believed to be alcohol. Renal recovery occurred after nearly 3 weeks of intermittent hemodialysis. His creatinine continued to trend down to 2 mg/dL at the time of discharge.

The patient in this scenario experienced a rarely described and potentially serious complication of hydroxocobalamin administration. The red discoloration of body fluids as a result of its chromogenic properties, which in turn triggered the blood leak alarm and prevented intermittent hemodialysis, as was described previously in a case report with hydroxocobalamin, and was presumed to be a result of the drug's chromogenic effect.9 However, in that case report the patient did not ultimately require hemodialysis. The Fresenius 2008k dialysis machine contains a blood leak alarm consisting of a two-color light source transmitter and sensor that monitor the clarity of the dialysate effluent. The resolution is reported to alarm at >0.45 mL/min of blood (at a hematocrit of 25%).11 Presumably the presence of hydroxocobalamin altered the refractive properties of the effluent, which in turn activated the blood leak detector. In general, once the blood leak detector has been triggered, the blood and ultrafiltration pumps stop, and the venous clamp closes, bringing dialysis to a halt. An “override” button exists that provides a temporary solution, as it will allow the blood pump to continue to operate for 3 minutes while the problem is being addressed.

Proceeding with hemodialysis at this point is problematic, not only from a technical perspective but also in terms of patient safety. On the Fresenius 2008k, a technician is required to disable the blood leak detector as it is an internal alarm and not easily accessible. Not only can this process be time consuming, but the very concept of disabling the blood leak detector carries with it implicit risk to the patient in the event of an actual blood leak. Chromaturia due to hydroxocobalamin has been observed to persist for up to 5 weeks,4 which could potentially preclude intermittent hemodialysis as a mode of renal replacement for an extensive period of time. Therefore, in this case, alternate modalities of dialysis were considered. Given the availability and ease of administration of CRRT at our institution, this seemed to be the logical next step.

CRRT was initiated utilizing a Prismaflex machine. The Prismaflex blood leak detector is comprised of an infrared LED that transmits light at an angle such that it travels through the effluent line and reflects off mirrors sequentially three times before being detected by a phototransistor. Thus, the transmitted light passes through the effluent line a total of four times. The actual calibration of the blood leak detector occurs during the priming sequence, when the effluent line contains saline. At that time, the LED signal from the transmitter is calibrated such that the signal received by the phototransistor falls within a pre-defined acceptable range. Signals falling outside this range are sensed as a blood leak.12 With the aid of this information, the blood leak sensor was recalibrated against the patient's red effluent, instead of the routine saline flush. This process is referred to as “normalization.” This allowed CRRT to proceed even though the effluent remained red tinged. As a safety measure, cell counts from the effluent were monitored hourly throughout the treatment to evaluate for a true blood leak that might have been missed as a result of the recalibration. As the effluent fluid became progressively less red pigmented, intermittent hemodialysis was attempted again after 5 days of CRRT and was successful.

The patient who presents with an altered level of consciousness and a metabolic acidosis can be diagnostically challenging. The differential diagnosis can be vast, including toxicological, metabolic, and infectious etiologies. Confirmatory and diagnostic tests, such as methanol, ethylene glycol, or cyanide levels are often not immediately available, meaning physicians must frequently treat patients empirically for disease processes that require emergent interventions. In this case, the patient presented late after his ethylene glycol ingestion and hence had already metabolized much of the parent compound and manifested the toxicity of the metabolites, glycolic and oxalic acid. While ethylene glycol or methanol ingestion remained at the forefront of the differential diagnosis, confirmatory levels were not immediately available, and other possible causes of depressed mental status were considered. Cyanide toxicity can present with a depressed mental status and a lactic acidosis, although typically it presents with significant autonomic instability. Empiric treatment for possible cyanide toxicity with hydroxocobalamin led to an unexpected complication, namely, the inability to perform hemodialysis for what was eventually proven to be an ethylene glycol ingestion. In this case, the ingestion resulted in severe metabolic acidosis, mental obtundation, and renal failure. The prognosis would have been dismal without urgent renal replacement therapy. It is important for physicians to have an understanding of potential problems that can arise with the administration of hydroxocobalamin, and how these difficulties can be overcome with available resources in a safe and timely manner.