Faculty Bibliography

BACKGROUND: PCC (Kcentra(R)) is an Food and Drug Administration (FDA)-approved 4-factor PCC used for the treatment of warfarin-related coagulopathy (WRC), but it has also been used off-label to treat non-WRC. Three-factor PCC in the form of coagulation factor IX human (Bebulin(R)) has also been used for WRC and off-label to treat non-WRC. It is unclear whether the use of 3- or 4-factor PCCs is effective for the treatment of non-WRC,. OBJECTIVE: Our aim is to characterize the use of 3- and 4-factor PCCs for patients identified with a non-WRC. METHODS: A retrospective analysis of patients who received PCCs for both WRC and non-WRC between January 2012 and July 2015 was conducted. RESULTS: A total of 187 patients with elevated international normalized ratio (INR) who received PCCs were analyzed; 53.9% of patients in the WRC group and 27.7% in the non-WRC group corrected to an INR of 1.3 or less after 3- or 4-factor PCC administration. In those patients with non-WRC and who had underlying liver disease, 3- and 4-factor PCCs reduced mean INR by 0.98 and 1.43, respectively. CONCLUSION: Three and 4-factor PCCs can reduce INR in patients with WRC and in those with non-WRC secondary to liver disease.

Introduction: Overdoses of bupropion XL can result in severe morbidity and mortality. Prolonged toxicity may be related to slow drug release through a complex drug delivery system (DDS). Treatment of bupropion toxicity is largely supportive and includes activated charcoal (AC) and/or whole-bowel irrigation (WBI) with PEG-ELS. However, data are lacking on bupropion adsorption to AC, and the effects of PEG-ELS on drug release from the DDS and on AC adsorption. Aims: The primary aim of this study is to measure the in vitro effects of AC and PEG-ELS in a simulated human gastrointestinal model at therapeutic dosing and mimicking an overdose scenario. Methods: There were two main series; simulated gastric and simulated intestinal contents. Each series had five arms done in triplicate at a final volume of 500 ml at 37 degreeC, and repeated at two bupropion XL doses; 300mg and 3000 mg. Study arms were: (1) bupropion only; (2) bupropion plus 50 g AC added at 1 h (AC Only); (3) bupropion plus 250 ml PEG-ELS added at 1 h (PEG Only); (4) bupropion plus 50 g AC added at 1 h and 250 ml PEGELS added at 1.5 h; (5) bupropion plus 250 ml PEG-ELS added at 1 h and 50 g AC added at 1.5 h. Samples were collected at 0 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h to determine the bupropion concentration using HPLC. Areas under the isotherm curve at 8 h (AUC 8 h) were calculated and overall differences in mean AUC 8 h were tested using analysis of variance; post-hoc pairwise comparisons were performed using Tukey student t-tests. All analysis was stratified by initial bupropion concentration. Results: At the 300mg dose (Figure 1), compared to control, the study arms (AC, PEG or both) were all associated with differences in the AUC 8 h (p<.01) and not altered by fluid pH (p=.513). Also at this dose, all experimental arms had a lower AUC 8 h compared to control, though the effect size for the PEG Only arm was smaller (p=.02). At the 3000mg dose (Figure 2), the mean AUC 8 h was lowest in the AC Only group and highest in the PEG Only group. Compared to control, the AC Only group had the lowest AUC 8 h in both types of fluids (p<.01). The experimental arm with PEG added to AC lowered AUC 8 h in intestinal fluid (p<.01) but not in gastric fluid (p=.052). Both experimental arms that started with PEG were not significantly different compared to control (p>.05). Overall, AUC's were higher in gastric fluid compared to intestinal fluid (p<.01). Conclusions: In this in vitro model, AC adsorbs bupropion, though that adsorption appears to be affected by the specific media (gastric versus intestinal fluid). These results also suggest that PEG-ELS interferes with AC adsorption of bupropion. The clinical significance of this is unknown. This study was partially funded by a research grant from the American Academy of Clinical Toxicology

Background: Long-acting anticoagulant rodenticide (LAAR) poisoning can lead to a severe and prolonged coagulopathy. The ability to obtain LAAR concentrations and understand the toxicokinetics of LAARs could lead to individualized treatment plans and potentially decrease the intensive and prolonged treatment course following LAAR poisoning. We describe a single overdose case of the LAAR bromadiolone with serial blood concentrations and provide bromadiolone toxicokinetics. Case report: A 32-year-old woman presented to the emergency department (ED) after an acute ingestion of an unknown amount of 0.5% bromadiolone. Her husband called EMS immediately following the ingestion. On arrival to the ED, her vital signs were: BP, 120/80mmHg; HR, 87/min; RR, RR 14/min; SpO2 97%; T 36.9 degreeC. She was initially awake and tearful, but then became obtunded with tonic posturing. There was concern for seizure activity, so she was intubated for airway protection. A nasogastric tube was placed and bright pink tablet-like substance was removed in the gastric contents. The patient then received activated charcoal and was given 5mg of intravenous vitamin K1. Her initial coagulation studies were: INR, 1.0; PT, 12.0 s; PTT, 32.9 s. The day after admission, her mental status improved and she was extubated. A repeat laboratory analysis showed a rising INR on hospital day 1, at which point she was initiated on Vitamin K1 25mg by mouth every 6 h. Her INR peaked at 7.7 on hospital day 2, at which point her Vitamin K1 dose was increased to 50mg every 6 h. Her INR normalized by hospital day 5 on this dosing regimen. During her inpatient stay, the patient disclosed that her husband had coerced her into drinking the bromadiolone and other unknown substances. After discharge, the patient was monitored with weekly coagulation studies and slow tapering of her Vitamin K1 therapy. She took Vitamin K1 for a total of 8.5 weeks without recrudescence of a coagulopathy (Table 1). Serial bromadiolone concentrations were obtained from a laboratory outside of the United States after the patient completed treatment. Due to hemolysis of the samples, EDTA-tube specimens were analyzed using a new assay with a whole-bloodbased standard curve. Her initial whole blood bromadiolone concentration on arrival to the hospital was 1540 ng/ml. Case discussion: While most patients who ingest LAARs present to medical care already with a severe coagulopathy, our patient presented early following ingestion allowing us to obtain serial bromadiolone concentrations throughout her hospital stay and post-discharge. Our preliminary analysis suggests that bromadiolone toxicokinetics are consistent with a one-compartment model with first order kinetics and half-life of 76 h (Graph 1). Additionally, our patient's bromadiolone concentration was less than 2 (lower than the assay's detectable limit) by 35 d postingestion, but because these concentrations cannot be readily obtained, she continued Vitamin K1 therapy for an additional 24 d. Conclusion: Although bromadiolone concentrations are not currently available in the United States, real time bromadiolone concentrations may assist in determining improved therapeutic endpoints for Vitamin K1 therapy in patients with bromadiolone ingestions

Background: Apixaban is a factor Xa inhibitor indicated for treatment and prevention of multiple thromboembolic states. Significant bleeding from acute apixaban overdose seems to be uncommon however the safety and pharmacokinetics of apixaban in massive ingestions is underreported. We report a single case of a massive overdose of apixaban that was managed conservatively and without the occurrence of significant bleeding. Case report: A 76-year-old man with a past medical history of chronic heart failure, non-insulin dependent diabetes, atrial fibrillation and taking apixaban 5mg twice daily, presented to the emergency department (ED) 10 h after a reported ingestion of 60-70 of his home pills. His other medications include carvedilol, cetirizine, furosemide, glimepiride, hydralazine, isosorbide dinitrate, sitagliptin and tamsulosin. On initial presentation, he was alert and had a normal physical examination. His Initial vital signs were: BP, 112/97 mmH; HR, 68 beats/min, RR, 26 breaths/min; temperature, 97.4 degreeF; O2 Sat, 96% on room air; weight, 88.5 Kg. Initial blood tests demonstrated an INR of 12; platelets, 152, 000 cells/mm3; hemoglobin, 10 g/dl; creatinine, 1.77mg/dl; and antifactor Xa <0.2 IU/ml. Of note, the Antifactor Xa assay was calibrated for unfractionated heparin. The patient was given 60 g of activated charcoal and 4 units of fresh frozen plasma prophylactically. His initial apixaban blood concentration was 4000 ng/ml. Repeat apixaban concentrations were 3000 ng/ml and 2200 ng/ ml at 7 and 14 h, respectively (Figure 1). During the patient's hospital course, he did not develop any evidence of clinical bleeding nor had a decrease in hemoglobin concentration. Repeat INR at 7 hrs post admission was 7.9, and he was not given any additional fresh frozen plasma. On hospital day 3, he was medically cleared and transferred to psychiatry. Discussion: We report the case of a massive apixaban overdose that was managed conservatively. Consistent with prior case reports, our patient remained well and without evidence of bleeding despite a massive apixaban overdose documented with serial apixaban concentrations. The INR of this patient was elevated initially and consistent with one previous case report. Presumably, this is the reason the providers administered 4 units of FFP although the patient was not bleeding. While the administration of FFP may show a modest improvement in laboratory values, there is no evidence that FFP controls apixaban associated bleeding. The Antifactor Xa activity was not elevated likely due to its calibration for unfractionated heparin. Although there were a limited number of apixaban concentrations obtained, apixaban appears to follow first-order elimination kinetics with a half-life of 14 h. This apparent half-life is slightly longer than prior reports and may be due to impaired renal function in our patient. Conclusion: Despite a massive apixaban overdose documented with serial apixaban concentrations, apixaban was not associated with significant bleeding in this case report. Additional patient data are necessary to determine if overdoses of apixaban can be treated with supportive care alone

Background: Low molecular weight heparin (LMWH) overdoses are rarely described in the literature. While protamine is the treatment of choice for reversal of unfractionated heparin, its clinical efficacy in LMWH overdoses is less clear and reported with variable success. We report a single case of a massive enoxaparin overdose treated with small amounts of protamine. Case report: A 25-year-old man with a history of antiphospholipid antibody syndrome, pulmonary embolism, borderline personality disorder, presented to the emergency department after intentionally injecting himself with 31 vials of 80mg of enoxaparin (total of 2480 mg) in multiple areas of his body over the course of 1 h, and self-inflicted lacerations over his left forearm. His initial vital signs were notable for mild tachycardia of 107 bpm. Exam demonstrated multiple areas of ecchymosis over injection sites in his abdomen, calves and right inner thigh, as well as multiple superficial vertically oriented lacerations with blood oozing over the volar aspect of his left forearm. His initial laboratory findings were: hemoglobin of 16.6 g/dl, platelets of 168 per lL, creatinine 1.0 mg/dl, PT 14.8s, INR 1.33s, aPTT >120s, and an anti Xa 5.93 IU/ml (therapeutic range 0.5-1 IU/ml). Approximately 6.5 h post injection, 25mg of protamine was given for concern for compartment syndrome to left arm. Subsequent evaluation by hand surgery determined low suspicion for compartment syndrome. At 11 h post overdose, the aPTT rose to 206s prompting an additional 50mg of protamine. Fifteen minutes post protamine injection the aPTT decreased to 79s, then rose again at 21 h post overdose to 127s before decreasing. The anti-Xa levels peaked at 5.93 on arrival and plateaued for the first 21 h before decreasing. Kidney function remained unchanged, but patient's hemoglobin decreased by 6 g/dl without any obvious sources of bleeding besides superficial hematoma over injection sites and left forearm. Case discussion: Protamine binds to heparin and preventing the formation of a heparin-antithrombin III complex. LMWHs however are anti-Xa inhibitors with only modest anthrombin inhibition (a ratio of approximately 14:1 for enoxaparin). Additionally the reduction in sulfate charge of LMWHs may also minimize the neutralization by protamine sulfate. Protamine therefore may only partially reverse the anticoagulant effects of enoxaparin. Treatment options in enoxaparin overdoses range from observation to treating with doses of up to 250mg of protamine. Guidelines suggest protamine should be given a 1:1mg of enoxaparin with a max dose of 50mg as larger quantities protamine may worsen anticoagulation. Yet given the rarity of massive LMWH overdoses, there is still significant controversy in dosing of protamine. In this case, anti-Xa levels remained elevated for 21 h and were not affected by protamine administration. Furthermore, the aPTT decreased and rebounded hours later, consistent with previous reports. Conclusions: We present a case of a massive enoxaparin overdose treated with observation and small doses of protamine with a good outcome. The efficacy and optimal dose of protamine for LMWH overdoses needs further study