December 2016 FAQs

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What is the optimal dosing of 4-factor prothrombin complex concentrate in patients with warfarin-associated bleeding?

What is the optimal dosing of 4-factor prothrombin complex concentrate in patients with warfarin-associated bleeding?

The incidence of warfarin-associated major bleeding is approximately 1% to 3% each year.¹ Rapid reversal of warfarin is recommended when a patient experiences major bleeding regardless of international normalized ratio (INR) level. Generally, patients with warfarin-related bleeding are treated with fresh frozen plasma (FFP), recombinant factor VIIa, or one of the prothrombin complex concentrates (PCCs). Intravenous vitamin K is administered in conjunction with these agents in order to maintain sustained INR lowering. Although FFP, recombinant factor VIIa, and PCCs are all management options for warfarin-related bleeding, the American College of Chest Physicians recommends PCCs over FFP. Advantages of PCCs include a lower risk of infection transmission as well as reduced risk of fluid overload.

There are a variety of PCC formulations, including 3-factor PCC, 4-factor PCC, and 4-factor activated PCC. Kcentra, the 4-factor PCC available in the US, contains coagulation factors II, VII, IX, X, and proteins C and S, while 3-factor PCCs lack factor VII.¹ Kcentra is becoming one of the most frequently used agents for emergent warfarin reversal. Though the guidelines recommend PCCs as first-line agents for warfarin-associated bleeding, they do not provide guidance on dosage or administration of these agents.

Manufacturer-recommended dosing of Kcentra is based on patient-specific factors and is summarized in Table 1.² One of the main problems with these recommendations is that a baseline INR is required prior to administration.³ Additionally, it is thought that lower, fixed doses may be as effective at reversing a supratherapeutic INR, and potentially safer due to a theoretical lower risk of thrombosis. If lower, fixed doses of 4 factor-PCCs are indeed as safe and effective as higher, variable doses, then this could provide a more cost-effective way to manage patients who require reversal of anticoagulation. Therefore, some institutions have adopted protocols that instruct practitioners to administer fixed doses to patients requiring reversal of anticoagulation.

Table 1. Recommended Kcentra dosing.²

Pretreatment INR	2 to <4	4 to 6	>6
Dose (units of Factor IX/kg)	25	35	50
Maximum dose (units of Factor IX)	2500	3500	5000
Abbreviations: INR=international normalized ratio.

Fixed-dose evaluation

Fixed-dose 4-factor PCC has been evaluated in a variety of observational studies. In a 2015 systematic review of various PCC dosing strategies, 28 studies were identified, 6 of which included patients who received fixed-dose 4-factor PCC.³ All patients included in these studies received 4 factor-PCC to reverse vitamin K antagonists (VKA) for management of bleeding events or for emergent invasive procedures. Results of the included studies were variable, but fixed-dose 4-factor PCC seemed to be a safe and effective strategy for VKA reversal. In all but one study, fixed-dose 4-factor PCC was associated with high rates of rapid INR correction. Some studies also reported positive results for pre-specified clinical outcomes such as visual hemostasis, hemoglobin stabilization, blood pressure normalization, bleeding control, or hematoma enlargement. The administered dose of 4-factor PCC in the studies was quite variable, ranging from 200 IU to 1500 IU, with approximately 1000 IU most commonly used. In general, doses of 500 IU or less tended to be associated with less success than doses of at least 1000 IU. The details of these studies can be found in Table 2.

Additional studies not included in the systematic review have also been published. In a retrospective, observational study published in 2015, patients receiving a fixed 1500 IU dose of 4-factor PCC (Kcentra) per hospital protocol were assessed.⁴ Patients were included if they had pre- and post-dose INR levels available. The majority of patients (71.8%) required anticoagulant reversal due to an intracranial hemorrhage (ICH) or gastrointestinal (GI) hemorrhage (10.3%). Of the 39 included patients, 38 were taking chronic warfarin and 1 was receiving rivaroxaban. The median INR on presentation was 3.3, and the median INR after receipt of 4-factor PCC was 1.4. The median time between receiving 4-factor PCC and post-dose INR measurement was 51 minutes. Based on a target INR < 2.0 or INR < 1.5, success rates were 92.3% and 71.8%, respectively. No thrombotic events were noted in the 7 day follow-up period. The majority of patients also received IV vitamin K (92.3%) and 28.2% of patients received FFP. The authors also calculated the cost savings incurred by using a fixed-dose scheme rather than the manufacturer recommended dosage and estimated savings to be about $40,273 over the study period. Based on this study, a fixed dose of 1500 IU of 4-factor PCC seems to be safe and effective for anticoagulant reversal.

In a 2013 retrospective, single-center study, the efficacy of 4-factor PCC in patients with an elevated INR was assessed.⁵ There were a total of 142 consecutive patients who received 4-factor PCC, 76 on a VKA requiring an invasive procedure, 22 on a VKA with ICH, and 44 who were not on a VKA but had uncontrolled perioperative or traumatic bleeding. Mean INR prior to treatment was 4, which fell to 1.7 following treatment. Patients received a median fixed dose of 1200 IU. Of the 142 treated patients, 38% had INR remain ≥1.4. The efficacy of the PCC appeared to improve with higher doses – 42.6% of patients reached goal INR with a median dose of 1800 IU versus 29.3% with a dose of 1200 IU. Four-factor PCC seemed to be least effective amongst patients who received the medication for uncontrolled bleeding without VKA use. In the safety analysis of patients receiving 4-factor PCC, only 1 patient developed a deep vein thrombosis (DVT) episode 5 days after a dose of 1200 IU. This patient also had a history of prior DVT. Based on this study, the authors concluded that fixed doses of 4-factor PCC are effective, but higher doses may be needed to achieve a target INR <1.4.

Most recently, in April 2016, a retrospective study was published that assessed the efficacy of manufacturer-recommended variable doses of 4-factor PCC compared to fixed doses among ICH patients after a change in hospital protocol.⁶ The target INR in this study was ≤1.5. If the target INR was not achieved after administration of 1000 IU of 4-factor PCC, then another 500 IU was administered. A total of 53 patients were included in this study analysis, 25 in the variable-dose cohort and 28 in the fixed-dose group. The cause of ICH was spontaneous in 60% of patients. The remaining 40% had trauma–related ICH. Treatment success (reduction of INR to ≤1.5 after initial 4-factor PCC dose) was achieved in 96% of patients given a variable dose and 68% of patients given a fixed dose. As compared to patients in the fixed-dose group who received approximately 1000 IU 4-factor PCC, patients in the variable dosage group received a median initial dose of 1750 IU. Over 30% of patients in the fixed-dose group required an additional dose. Despite the hypothesis that a fixed dose of 4-factor PCC would shorten the delay in time-to-treatment, there was no significant difference between treatment groups in time to receipt of the drug. In contrast to the above 2 observational studies, this study does not support the use of fixed-dosed PCC over manufacturer-recommended variable dosing.

Discussion

The efficacy of variable 4-factor PCC dosing strategies based on INR and bodyweight has been demonstrated in prospective, randomized, multinational clinical trials. Generally, dosing 4-factor PCCs on baseline INR and patient weight is the most frequently used and well-studied dosing strategy when patients require rapid reversal of anticoagulation. However, fixed-dose strategies are being used more frequently due to the potential for decreased delay in administration of the drug, cost-savings, and potential safety benefits. Nevertheless, there have not been any well-designed randomized controlled trials (RCTs) evaluating these hypotheses. Therefore, the true safety and efficacy of a fixed-dose strategy is unknown.

Although most of the trials discussed above support the use of fixed-dose 4-factor PCC, there are some limitations that must be considered. The vast majority of trials are observational in nature, so they provide weak support for the use of fixed-dose 4-factor PCC. One open-label RCT was included in the systematic review by Khorsand et al.^3,10 This trial did not support the use of 500 IU fixed-dose 4-factor PCC when compared with individualized dosing due to significantly fewer patients reaching goal INR after administration of the drug. Furthermore, a fixed-dose of 4-factor PCC did not produce positive clinical outcomes in patients with ICH, even when INR was rapidly corrected. In patients who had non-ICH associated major bleeding, there seemed to be a trend toward better outcomes in patients who were treated with fixed-dose 4-factor PCC.

Conclusion

Based upon the available literature, use of a fixed-dose 4-factor PCC strategy may be useful when higher fixed doses (i.e., at least 1000 IU) are used. Caution should be exercised in patients with ICH as recent evidence indicates lower success rates with fixed dosing in these patients. More robust studies are needed to better determine the true place in therapy for fixed-dose 4-factor PCC.

Table 2. Summary of 4-factor PCC trials in systematic review.^3,7-12

Study

Population

Intervention

Results

Conclusion

Khorsand 2012⁷

Prospective, observational, 2-cohort, noninferiority

Major or clinically relevant, non-intracranial bleeding

Median INR=5.1 (fixed), 5.9 (variable)

N=240

1040 IU 4F-PCC (Cofact) vs. variable dose 4F-PCC

Goal INR (<2) reached in 92% and 95% of fixed and variable dose, respectively

Successful clinical outcome confirmed in 96% and 88% of fixed and variable dose, respectively

INR was rapidly corrected in the majority of fixed-dose patients, but less so than variable dose.

Fixed dosing was associated with a greater amount of positive clinical outcomes.

Dowlatshahi 2012⁸

Prospective, observational, multicenter

Anticoagulant-associated intracranial hemorrhage

Median INR= 2.6

N=141

1000 IU 4F-PCC (Octaplex)

INR correction to <1.5 within 1 hour: 71.8%

INR was rapidly corrected in the majority of patients with use of fixed-dose 4F-PCC.

Khorsand 2011⁹

Prospective (fixed) and retrospective (variable) cohort study

Major non-cranial bleed or emergency invasive procedure

Median INR= 4.7 (both cohorts)

N=67

1040 IU 4F-PCC for major bleeding or 520 IU for invasive procedure (Cofact) vs. variable dose 4F-PCC

Goal INR (<2) reached in 70% and 81% of fixed and variable dose, respectively (p=0.37)

Successful clinical outcome confirmed in 91% and 94% of fixed and variable dose, respectively (p=1.0)

Fixed-dose 4F-PCC may be an effective way to reverse VKA therapy.

van Aart 2006¹⁰

Open-label,

RCT

Major bleeding or urgent surgical intervention

Median INR= 3.4 (fixed), 3.6 (variable)

N= 93

500 IU 4F-PCC (Cofact) vs. variable dose 4F-PCC

Goal INR (≤2.1 for small surgeries or minor bleeding; ≤1.5 for major surgeries or major bleeding) was reached in 43% and 89% of fixed and variable dose, respectively (p<0.001) 15 minutes after administration

Similar results 1, 3, and 5 hours post-administration

Individualized dosing regimen is significantly more effective than a fixed 500 IU dose of 4F-PCC for VKA reversal.

Yasaka 2005¹¹

Prospective, observational

Major bleeding or emergency invasive procedure

Median INR= 3.3 (200 IU), 2.49 (500 IU), 2.33 (1000 IU or 1500 IU)

N=42

200 IU, 500 IU, 1000 IU, or 1500 IU 4F-PCC (PPSB-HT Nichiyaku)

Patients treated with 200 IU all (6/6) required additional 4F-PCC

One (1/30) patient who received 500 IU required additional 4F-PCC

No (0/6) patients who received 1000 IU or 1500 IU required additional 4F-PCC

In patients with baseline INR <5, 500 IU of 4F-PCC may be adequate; higher doses required for higher INRs.

Yasaka 2002¹²

Prospective, observational

Major bleeding

Median INR= 2.7 (PCC + VK), 6.2 (PCC alone)

N=17 (13 received 4F-PCC)

500 IU, 1000 IU, or 1500 IU 4F-PCC (PPSB-HT Nichiyaku)

Patients treated with 4F-PCC (500 IU in 9, 1000 IU in 1, 1500 IU in 1) and VK had a median INR reduction to 1.13, which was sustained at 12 and 24 hours

Patients treated with PCC alone had an INR reduction to 1.36, but INR increased to 2.07 12-24 hours later

Fixed-dose 4F-PCC is effective at rapidly correcting INR, but correction is better sustained when administered with VK.

Abbreviations: 4F-PCC=4-factor prothrombin complex concentrate; INR=international normalized ratio; IU=international unit; PCC=prothrombin complex concentrate; RCT=randomized controlled trial; VK=vitamin K; VKA=vitamin K antagonist.

References

Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e152S-e184S.
Kcentra [package insert]. Marburg, Germany: CSL Behring; 2014.
Khorsand N, Kooistra HA, Van hest RM, Veeger NJ, Meijer K. A systematic review of prothrombin complex concentrate dosing strategies to reverse vitamin K antagonist therapy. Thromb Res. 2015;135(1):9-19.
Klein L, Peters J, Miner J, Gorlin J. Evaluation of fixed dose 4-factor prothrombin complex concentrate for emergent warfarin reversal. Am J Emerg Med. 2015;33(9):1213-1218.
Leal-Noval SR, López-Irizo R, Bautista-Paloma J, et al. Efficacy of the prothrombin complex concentrate prothromplex in patients requiring urgent reversal of vitamin K antagonists or presenting with uncontrolled bleeding: a retrospective, single center study. Blood Coagul Fibrinolysis. 2013;24(8):862-868.
Abdoellakhan RA, Miah IP, Khorsand N, Meijer K, Jellema K. Fixed versus variable dosing of prothrombin complex concentrate in vitamin K antagonist-related intracranial hemorrhage: a retrospective analysis. Neurocrit Care. 2016 [epub ahead of print]. doi: 10.1007/s12028-016-0248-8.
Khorsand N, Veeger NJ, van Hest RM, Ypma PF, Heidt J, Meijer K. An observational, prospective, two-cohort comparison of a fixed versus variable dosing strategy of prothrombin complex concentrate to counteract vitamin K antagonists in 240 bleeding emergencies. Haematologica. 2012;97(10):1501-1506.
Dowlatshahi D, Butcher KS, Asdaghi N, et al. Poor prognosis in warfarin-associated intracranial hemorrhage despite anticoagulation reversal. Stroke. 2012;43(7):1812-1817.
Khorsand N, Veeger NJ, Muller M, et al. Fixed versus variable dose of prothrombin complex concentrate for counteracting vitamin K antagonist therapy. Transfus Med. 2011;21(2):116-123.
van Aart L, Eijkhout HW, Kamphuis JS, et al. Individualized dosing regimen for prothrombin complex concentrate more effective than standard treatment in the reversal of oral anticoagulant therapy: an open, prospective randomized controlled trial. Thromb Res. 2006;118(3):313-320.
Yasaka M, Sakata T, Naritomi H, Minematsu K. Optimal dose of prothrombin complex concentrate for acute reversal of oral anticoagulation. Thromb Res. 2005;115(6):455-459.
Yasaka M, Sakata T, Minematsu K, Naritomi H. Correction of INR by prothrombin complex concentrate and vitamin K in patients with warfarin related hemorrhagic complication. Thromb Res. 2002;108(1):25-30.

Prepared by:
Danielle Tompkins, PharmD
PGY1 Pharmacy Practice Resident
College of Pharmacy
University of Illinois at Chicago

December 2016

The information presented is current as October 15, 2016. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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Is there updated information on the off-label use of dexmedetomidine (Precedex®) for alcohol withdrawal syndrome?

Is there updated information on the off-label use of dexmedetomidine (Precedex^®) for alcohol withdrawal syndrome?

Introduction

Dexmedetomidine is a relatively selective alpha₂-adrenergic agonist indicated for sedation of initially intubated and mechanically ventilated patients in the intensive care unit (ICU) and sedation of non-intubated patients prior to and/or during surgical and other procedures.¹ In December 2013, the University of Illinois at Chicago Drug Information Group (UIC DIG) published an initial frequently asked question about the off-label use of dexmedetomidine for alcohol withdrawal syndrome (AWS; https://pharmacy.uic.edu/departments/pharmacy-practice/centers-and-sections/drug-information-group/2014/2013/december-2013-faqs#q3). Since posting of this document, the published data on the use of dexmedetomidine for AWS has expanded considerably, emphasizing the need for an updated overview of this topic.

As noted in the 2013 frequently asked question, chronic users of alcohol adapt to its central nervous system effects by enhancing the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), and inhibiting the major excitatory neurotransmitter, glutamate.² The abrupt withdrawal of chronic alcohol use results in overactivity of the central nervous system and a variety of mild (eg., insomnia, tremors, headache, palpitations, diaphoresis) and severe (eg, seizures, delirium tremens) effects. Intravenous benzodiazepines, such as diazepam and lorazepam, are most commonly used to manage severe effects of AWS in the inpatient setting usually using a symptom-triggered approach to management. If a patient experiences refractory delirium tremens despite high-dose benzodiazepine therapy, barbiturates (specifically phenobarbital), propofol, and dexmedetomidine may be administered although the quality of published evidence supporting their use varies.

Dexmedetomidine in Alcohol Withdrawal Syndrome

For patients with AWS, dexmedetomidine reduces autonomic hyperactivity and controls sympathetic symptoms (eg. tremor, hypertension, tachycardia) without resulting in respiratory depression.³ However, the drug lacks the GABA receptor activity necessary to combat withdrawal-related seizures.^3,4 Due to this absent pharmacologic effect, dexmedetomidine is inappropriate monotherapy for patients with severe AWS.⁴ As mentioned prior, the quantity of clinical data evaluating the efficacy and safety of dexmedetomidine for AWS continues to expand; however, the quality of the data is lacking. Retrospective cohorts and case series represent the majority of study designs used to evaluate dexmedetomidine in this off-label situation; case reports involving small numbers of patients are also available.^5-7 Only 2 prospective, randomized trials have been conducted.^8,9 A summary of published data is presented in Table 1.

Table 1. Dexmedetomidine for alcohol withdrawal syndrome.^8-19

Study design

Subjects

Interventions

Results

Beg et al 2016¹⁰

Retrospective cohort

n=67 ICU patients with severe AWS

Patients were administered either:

Dexmedetomidine with benzodiazepines (n=38); dexmedetomidine was titrated to a sedation target; no bolus dose given

Benzodiazepines alone (n=29)

Patients who received combination therapy were given significantly more benzodiazepines as compared to single therapy (100.5 vs. 37 lorazepam equivalent units; p<0.01)

Hospital (8.9 vs. 4.7 days) and ICU (2.9 vs. 1.4 days) LOS were also significantly longer in the combination therapy group (p<0.01 for both comparisons)

Mortality was not significantly different between the groups (2.6% combination vs. 6.9% single; p=0.56)

Initiation of dexmedetomidine was associated with significant improvements in Clinical Institute Withdrawal Assessment scores over the corresponding 24 hr intervals (14.5 vs. 8.5; p<0.01)

Benzodiazepine use decreased after initiation of dexmedetomidine

VanderWeide et al 2016¹¹

Retrospective cohort

n=20 patients admitted to the ICU for > 24 hrs for AWS

Dexmedetomidine (n=20) and controls matched by benzodiazepine dose densities (n=22)

Median time to dexmedetomidine initiation from hospital admission: 26.1 hrs

Median duration of treatment: 30.8 hrs

Mean dose: 0.46 mcg/kg/hr

Median ICU LOS: 86.6 hrs

Median hospital LOS: 152.7 hrs

Mean 12 hr pre-post benzodiazepine requirements were decreased to a larger extent in the dexmedetomidine group vs. the control group (-19.9 mg vs. -8.3 mg; p=0.0455)

Significantly more bradycardia was noted with dexmedetomidine vs. controls (35% vs. 0%; p<0.01)

Bielka et al 2015⁸

Prospective, randomized, controlled

n=72 ICU patients with AWS

Patients were randomly assigned to:

Dexmedetomidine (n=36): starting at a dose of 0.2 to 1.4 mcg/kg/hr and titrated to achieve the target sedation level of -2 to 0 on the Richmond Agitation Sedation Scale and a Clinical Institute Withdrawal Assessment score < 15

Loading doses of dexmedetomidine were not administered

Dosing and duration of the infusion was adjusted based on sedation assessment

Control (n=36): symptom-triggered diazepam protocol

Both groups were given diazepam every 30 minutes as needed to control symptoms of AWS

Median 24 hr diazepam consumption was significantly lower in the dexmedetomidine group as compared to control (20 vs. 40 mg; p<0.001)

Additionally, the median cumulative diazepam dose during the ICU stay was significantly reduced with dexmedetomidine (60 vs. 90 mg; p<0.001)

Patients in the dexmedetomidine group also experienced a higher median percentage of time in the target sedation range (90% vs. 64.5%; p<0.001)

Bradycardia occurred more commonly with dexmedetomidine (10 vs. 2 patients; p=0.03)

Ludtke et al 2015¹²

Retrospective cohort

n=32 critically ill patients with AWS

Patients were administered either:

Propofol and/or lorazepam continuous infusion (n=17)

Dexmedetomidine (n=15)

No standardized dexmedetomidine treatment protocol

Dexmedetomidine maximum infusion rate: 1.5 mcg/kg/hr

Loading dose not always administered; however, if given, usually administered at a reduced dose (< 1 mcg/kg) and/or over a longer period of time

As compared to propofol and/or lorazepam, dexmedetomidine was associated with less required intubation and mechanical ventilation (2 vs. 10 patients; p=0.006), ICU LOS (53 hrs vs. 114.9 hrs; p=0.016), and hospital LOS (135.8 hrs vs. 241.1 hrs; p=0.008)

No difference in the duration of mechanical ventilation was observed between the groups

Crispo et al 2014¹³

Retrospective cohort

n=61 nonintubated adults with severe AWS

Patients were administered either:

Benzodiazepine continuous infusion (lorazepam or midazolam; n=33)

Dexmedetomidine continuous infusion (n=28)

No standardized dexmedetomidine treatment protocol was used; no loading dose was given

Benzodiazepine vs. dexmedetomidine:

Mean duration of therapy: 55 hrs vs. 60.4 hrs

Mean total dose: 157 mg vs. 2512.5 mcg

Mean infusion rate: 3.5 mg/hr vs. 0.53 mcg/kg/hr

There was no difference between the groups in the composite endpoint of rate of respiratory distress requiring intubation or occurrence of withdrawal seizures (3 in the benzodiazepine group vs. 2 in the dexmedetomidine group)

Dexmedetomidine therapy was associated with more adverse events including hypotension and bradycardia

Benzodiazepine mean hospital LOS: 9.7 days

Dexmedetomidine mean hospital LOS: 10.2 days

Frazee et al 2014¹⁴

Case series

n=33 critically ill patients with a primary diagnosis of AWS

No standardized treatment protocol

An optional 0.5 to 1 mcg/kg loading dose of dexmedetomidine could be administered

Dose titration (0.1 to 0.3 mcg/kg/hr) could occur as frequently as every 15 minutes to a target Richmond Agitation and Sedation Scale score of 0 to -2

Median time to dexmedetomidine initiation: 11 hrs

Median duration of therapy: 25 hrs

Initial infusion rate: 0.15 to 1 mcg/kg/hr

Most patients received 0.7 mcg/kg/hr or less

Benzodiazepine use was reduced in the 12 hrs after dexmedetomidine initiation compared to the 12 hrs before (30 vs 8 mg; p<0.001))

Significant improvements in blood pressure and heart rate were noted

Median ICU LOS: 3.1 days

Median hospital LOS: 7 days

Lizotte et al 2014¹⁵

Retrospective cohort

n=41 patients with AWS

Patients were administered either:

Propofol (n=7)

Dexmedetomidine (n=34)

A standardized dexmedetomidine protocol was utilized but not described

Dexmedetomidine dose range: 0.4 to 1.2 mcg/kg/hr

24 hr pre-post lorazepam requirements decreased from 20.9 to 4.4 mg in the dexmedetomidine group vs. a reduction from 17.4 to 3.9 mg in the propofol group

Dexmedetomidine ICU LOS: 123.6 hrs vs. propofol ICU LOS: 156.5 hrs (p=0.125)

Dexmedetomidine therapy was associated with a reduction in rates of intubation (14.7% vs. 100%) and time of intubation (19.9 hrs vs. 97.6 hrs; p=0.002) as compared to propofol

Hypotension occurred more commonly in the propofol group (28.5%) as compared to the dexmedetomidine group (17.6%); bradycardia occurred more frequently with dexmedetomidine

Mueller et al 2013⁹

Prospective, randomized, double-blind, placebo-controlled

n=24 patients with a Clinical Institute Withdrawal Assessment score ³ 15 despite ³ 16 mg of lorazepam over a 4 hr period

Patients received treatment based on a symptom-triggered Clinical Institute Withdrawal Assessment protocol with lorazepam and were subsequently randomized to:

Dexmedetomidine 1.2 mcg/kg/hr (high dose; n=8)

Dexmedetomidine 0.4 mcg/kg/hr (low dose; n=8)

Placebo (n=8)

Therapy was administered for up to 5 days or resolution of withdrawal symptoms

24 hr pre-post lorazepam requirements were -8 mg in the placebo group vs. -62.1 mg in the low dose group and -45 mg in the high dose group (p=0.0037; dexmedetomidine vs. placebo)

Median ICU LOS:

5.5 days low dose

3.8 days high dose

4 days placebo

Median hospital LOS:

10.9 days low dose

8.6 days high dose

7.4 days placebo

Bradycardia occurred more frequently with dexmedetomidine as compared to placebo (25% vs. 0%; p=NS); most instances of bradycardia occurred in the high dose group

Tolonen et al 2013¹⁶

Prospective cohort

n=18 adult patient with AWS

No standardized treatment protocol

Mean maximal dexmedetomidine infusion rate: 1.5 mcg/kg/hr

Mean total duration of infusion: 23.9 hrs

Mean ICU LOS: 7.1 days

Mean hospital LOS: 12.1 days

Mean time to resolution of alcohol withdrawal delirium: 3.8 days

DeMuro et al 2012¹⁷

Case series

n=10 ICU patients with AWS

Dexmedetomidine and benzodiazepines were instituted at the discretion of the physician

Dexmedetomidine protocol for AWS was used starting at 0.1 mcg/kg/hr, titrating rapidly to a heart rate < 100 and a Ramsay scale of 2

No loading dose was administered

Dexmedetomidine mean dose: 0.63 mcg/kg/hr

Maximum dose administered: 1.2 mcg/kg/hr

Mean duration of therapy: 92.7 hrs

Average hospital LOS: 14.2 days (2 to 55 days)

Mean ICU LOS: 9.3 days (1 to 33 days)

Dexmedetomidine was associated with nonsignificant reductions in heart rate (-10.5%), mean arterial pressure (-2.8%), systolic blood pressure (-2.8%), and diastolic blood pressure (-2.7%) when comparing values pre-infusion to 4 hrs after drug initiation

Rayner et al 2012¹⁸

Retrospective cohort

n=20 ICU patients with benzodiazepine refractory AWS

No standardized treatment protocol

5 patients were administered a loading dose of dexmedetomidine

For the 19 nonintubated patients:

Mean dexmedetomidine dose: 0.53 mcg/kg/hr

Mean length of dexmedetomidine therapy: 49.1 hrs

Compared with the 24 hr period prior to dexmedetomidine initiation, in the 24 hrs after initiation, there was less benzodiazepine use (52.7 vs. 20.3 mg; 61.5% reduction), lower alcohol withdrawal scores, and reduced systolic blood pressure and heart rate

Mean ICU LOS: 98.5 hrs

Muzyk et al 2010¹⁹

Case series

n=5 ICU patients treated for AWS

No standardized treatment protocol

Dexmedetomidine was started after a mean of 1.6 days of treatment with benzodiazepines and were administered for a mean of 3 days

No loading dose was administered

Dexmedetomidine infusion rate ranged from 0.04 mcg/kg/hr to 0.7 mcg/kg/hr; mean dose: 0.22 mcg/kg/hr

Mean hospital LOS: 11.4 days

Mean ICU LOS: 4.8 days

In 4 of 5 patients, dexmedetomidine may have decreased the need for high-dose benzodiazepines, use of concomitant medications for agitation, Richmond Agitation Sedation Scale scores, and restraint use

Abbreviations: AWS=alcohol withdrawal syndrome; ICU=intensive care unit; LOS=length of stay; NS=nonsignificant.

Summary

Although dexmedetomidine is indicated for the sedation of initially intubated and mechanically ventilated patients in the ICU and non-intubated patients prior to and/or during surgical and other procedures, its off-label use for AWS is occurring more frequently. For patients with AWS, dexmedetomidine reduces autonomic hyperactivity and controls sympathetic symptoms without resulting in respiratory depression. The quality of the majority of clinical data evaluating the use of dexmedetomidine in AWA is low with most published information from retrospective cohorts or case series. Only a few prospective, randomized, controlled trials exist. Overall, dexmedetomidine is associated with a decrease in short-term benzodiazepine requirements and improvement in hemodynamic parameters and may be a useful adjunctive therapy in patients who do not respond appropriately to treatment with benzodiazepines.

References

1. Precedex [package insert]. Lake Forest, IL: Hospira, Inc.; 2016.

2. UpToDate [database online]. Waltham, MA: Wolters Kluwer; 2016. http://www.uptodate.com. Accessed November 2, 2016.

3. Dixit D, Endicott J, Burry L, et al. Management of acute alcohol withdrawal syndrome in critically ill patients. Pharmacotherapy. 2016;36(7):797-822.

4. Schmidt KJ, Doshi MR, Holzhausen JM, Natavio A, Cadiz M, Winegardner JE. Treatment of severe alcohol withdrawal. Ann Pharmacother. 2016;50(5):389-401.

5. Rovasalo A, Tohmo H, Aantaa R, Kettunen E, Palojoki R. Dexmedetomidine as an adjuvant in the treatment of alcohol withdrawal delirium: a case report. Gen Hosp Psychiatry. 2006;28(4):362-263.

6. Darrouj J, Puri N, Prince E, Lomonaco A, Spevetz A, Gerber DR. Dexmedetomidine infusion as adjunctive therapy to benzodiazepines for acute alcohol withdrawal. Ann Pharmacother. 2008;42(11):1703-1705.

7. Baddigam K, Russo P, Russo J, Tobias JD. Dexmedetomidine in the treatment of withdrawal syndromes in cardiothoracic surgery patients. J Intensive Care Med. 2005;20(2):118-123.

8. Bielka K, Kuchyn I, Glumcher F. Addition of dexmedetomidine to benzodiazepines for patients with alcohol withdrawal syndrome in the intensive care unit: a randomized controlled study. Ann Intensive Care. 2015 Dec;5(1):33. doi: 10.1186/s13613-015-0075-7. Epub 2015 Nov 2.

9. Mueller SW, Preslaski CR, Kiser TH, et al. A randomized, double-blind, placebo-controlled dose range study of dexmedetomidine as adjunctive therapy for alcohol withdrawal. Crit Care Med. 2014;42(5):1131-1139.

10. Beg M, Fisher S, Siu D, Rajan S, Troxell L, Liu VX. Treatment of alcohol withdrawal syndrome with and without dexmedetomidine. Perm J. 2016;20(2):49-53.

11. VanderWeide LA, Foster CJ, MacLaren R, Kiser TH, Fish DN, Mueller SW. Evaluation of early dexmedetomidine addition to the standard of care for severe withdrawal in the ICU: a retrospective controlled cohort study. J Intensive Care Med. 2016;31(3):198-204.

12. Ludtke KA, Stanley KS, Yount NL, Gerkin RD. Retrospective review of critically ill patients experiencing alcohol withdrawal: dexmedetomidine versus propofol and/or lorazepam continuous infusions. Hosp Pharm. 2015;50(3):208-213.

13. Crispo AL, Daley MJ, Pepin JL, Harford PH, Brown CVR. Comparison of clinical outcomes in nonintubated patients with severe alcohol withdrawal syndrome treated with continuous-infusion sedatives: dexmedetomidine versus benzodiazepines. Pharmacotherapy. 2014;34(9):910-917.

14. Frazee EN, Personett HA, Leung JG, Nelson S, Dierkhising RA, Bauer PR. Influence of dexmedetomidine therapy on the management of severe alcohol withdrawal syndrome in critically ill patients. J Crit Care. 2014;29(2):298-302.

15. Lizotte RJ, Kappes JA, Bartel BJ, Hayes KM, Lesselyoung VL. Evaluating the effects of dexmedetomidine compared to propofol as adjunctive therapy in patients with alcohol withdrawal. Clin Pharmacol. 2014;6:171-177.

16. Tolonen J, Rossinen J, Alho H, Harjola VP. Dexmedetomidine in addition to benzodiazepine-based sedation in patients with alcohol withdrawal delirium. Eur J Emerg Med. 2013;20(6):425-427.

17. DeMuro JP, Botros DG, Wirkowski E, Hanna AF. Use of dexmedetomidine for the treatment of alcohol withdrawal syndrome in critically ill patients: a retrospective case series. J Anesth. 2012;26(4):601-605.

18. Rayner SG, Weinert CR, Peng H, Jepsen S, Broccard AF. Dexmedetomidine as adjunct treatment for severe alcohol withdrawal in the ICU. Ann Intensive Care. 2012;2(1):12.

19. Muzyk AJ, Revollo JY, Rivelli SK. The use of dexmedetomidine in alcohol withdrawal. J Neuropsychiatry Clin Neurosci. 2012;24:E45-E46.

December 2016

The information presented is current as of November 2, 2016. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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What is the available evidence for the use of sodium thiosulfate for non-uremic calciphylaxis?

What is the available evidence for the use of sodium thiosulfate for non-uremic calciphylaxis?

Introduction

Calciphylaxis, also known as calcific uremic arteriolopathy, is characterized by calcification and occlusion of small blood vessels.^1,2 Most cases of calciphylaxis occur in the setting of chronic kidney disease and are the result of a disruption in calcium/phosphate hemostasis. However, due to detection of this condition in the setting of normal renal function (non-uremic calciphylaxis), it is now believed that the pathophysiology is much more complicated than solely precipitation of calcium and phosphate due to kidney disease. A multifactorial process involving reduced blood flow and perfusion, endothelial cell injury and dysfunction, remodeling of the extracellular matrix, differentiation of vascular smooth muscle cells, and adipose inflammation are believed to be some contributors to the calcification of arterioles and soft tissue and oxidative stress leading to subcutaneous (SC) ischemia and necrosis.² Painful skin lesions, SC nodules, and/or plaques typically develop on the lower limbs, abdomen, buttocks, breasts, and/or thighs.^1,2 Progression to painful deep ulcers, amputations, calcification of internal organs leading to organ failure, and sepsis are complications of calciphylaxis that contribute to significant morbidity and high mortality rates (60% to 80%).

A previous FAQ from the UIC Drug Information Group addressed the use of sodium thiosulfate for the treatment of calciphylaxis in patients with renal disease which is available here. The purpose of this review is to summarize the evidence available for the use of sodium thiosulfate for the treatment of non-uremic calciphylaxis. Table 1 provides a summary of published case reports of non-uremic calciphylaxis and the associated outcomes with use of sodium thiosulfate. Case reports in which either the outcome or the dose of sodium thiosulfate was not provided are not included in the table.

Table 1. Summary of case reports involving use of sodium thiosulfate for non-uremic calciphylaxis.^3-10

Case report	Patient demographics/ relevant medical history	Calciphylaxis signs/symptoms	Other treatments and associated outcomes	Sodium thiosulfate dose	Outcome
Ning et al³	30 years old Caucasian female history of alcohol abuse alcoholic hepatitis mild cirrhosis large pelvic hematoma s/p paracentesis prednisone therapy	Severe pain in thighs Indurated, well- defined red to violet colored plaques on both thighs Elevated phosphorus and low 1,25 di-hydroxyvitamin D levels, liver enzyme levels elevated	Wound care included hydrocolloid dressing and silver sulfadiazine	25 g IV every morning for 6 months	Increase in the number of erythematous patches during the first week of therapy No further disease progression and some healing occurred in subsequent weeks At 2 months, ulcers significantly reduced in size and pain was also lessened By 6 months, ulcers had completely healed
Smith et al⁴	58 years old Caucasian male HTN asthma daily corticosteroid use calcium supplementation laceration on leg 6 months prior Factor V Leiden mutation (activated protein C resistance)	2 necrotic, painful ulcers on lower leg at site of previous injury	Calcium supplement discontinued	25 g IV 3 times per week for several months	Signs of healing at 6 weeks and significant improvement at 3 months
Ong et al⁵	79 years old Caucasian female atrial fibrillation HTN osteoporosis chronic back pain warfarin therapy	Painful ulcer on calf for 2 months; pain refractory to high-dose opiates and other non-traditional analgesics	Warfarin switched to aspirin IV pamidronate plus compression bandaging (unsuccessful)	25 g IV 3 times per week for 2 weeks followed 2 months later by 25 g twice weekly for another 18 infusions	Treatment was stopped due to mild phlebitis, but ulcers had healed, and no relapse occurred within the 15-month follow up period.
Kalajian et al⁶	58 years old Caucasian female stage III endometrial cancer chronic pelvic abscess s/p surgery for cancer obesity HTN hypothyroidism anemia venous stasis DVT warfarin therapy	Painful ulceration and tender plaques on thighs and lower abdomen	Cinacalcet Sevelamer Ergocalciferol Local wound therapy and antibiotics These interventions stabilized disease but did not heal the ulcers	5 g IV daily for 5 months (initiated one month after other treatments for ulcer healing)	Signs of healing occurred within 2 weeks of sodium thiosulfate initiation Ulcer completely healed after 5 months of treatment with sodium thiosulfate and cinacalcet No recurrence of lesion with the 17-month follow-up period
Hackett et al⁷	44 years old female obese hypothyroidism hypoparathyroidism recurrent DVT warfarin therapy calcium and vitamin D supplementation	Painful subcutaneous nodules on lower abdomen and thighs with 2 deep, necrotic ulcers	Warfarin switched to heparin Calcium supplements discontinued Wound care with debridement IV pamidronate (unsuccessful)	25 g IV 3 times a week for 50 weeks	Significant reduction in analgesic requirement within 2 months of starting sodium thiosulfate Complete would healing after 29 weeks of sodium thiosulfate treatment
Maroz et al⁸	40 years old Caucasian female overweight chronic venous insufficiency recurrent Clostridium difficile colitis cellulitis	Painful wounds on thighs, calves and buttocks	Local wound care	25 g IV 3 times per week	No improvement in wound healing or pain
Maroz et al⁸	65 years old Caucasian female morbid obesity DM HTN venous insufficiency non-Hodgkin’s lymphoma warfarin therapy	Bilateral lower extremity with infection, necrotic wounds	Antibiotic therapy with no improvement Warfarin discontinued Debridement with Medihoney Multilayer legs compression Surgical debridement	25 g for 20 infusions	Significant improvement at discharge
Kwong et al⁹	65 years old Hispanic female IDDM rheumatoid arthritis atrial fibrillation warfarin therapy methotrexate therapy	Ulcer and purpura at site of skin biopsy conducted 30 days prior to evaluating the rash	Warfarin switched to rivaroxaban	25 g 3 times weekly for 8 weeks	Marked improvement and resolution of ulcer
Gee et al¹⁰	64 years old female DM calcium supplementation x 30 years	Painful retiform purpura on left calf Low PTH level	Local wound care with debridement and topical becaplermin gel initiated after sodium thiosulfate was discontinued Calcium supplement discontinued	20 g IV daily x 5 days	Sodium thiosulfate discontinued due to metabolic acidosis Ulcers healed and PTH level normalized 6 weeks after treatment
Abbreviations: DM=diabetes mellitus; DVT=deep vein thrombosis; HTN=hypertension; IDDM=insulin-dependent diabetes mellitus; IV=intravenous; PTH=parathyroid hormone.

Conclusion

In the 9 case reports summarized, patients who developed calciphylaxis were most commonly obese Caucasian females taking warfarin, calcium supplements and/or corticosteroids with multiple chronic conditions (e.g., diabetes, venous insufficiency) and some form of cutaneous trauma. These patient characteristics are consistent with known risk factors for non-uremic calciphylaxis. Additional risk factors including primary hyperparathyroidism, alcoholic liver disease, malignancy, protein C or S deficiency, and connective tissue disease were also identified in some of these cases. The use of sodium thiosulfate resulted in successful wound healing and pain reduction in all but one case. Adverse effects reported in these cases included phlebitis and metabolic acidosis. The most commonly used dose of sodium thiosulfate was 25 g IV 3 times per week. Duration of treatment was variable and was most likely driven by patient response. In all cases, additional interventions were required including discontinuation of precipitant medications (e.g., warfarin, calcium supplements), wound debridement and use of local wound healing agents such as silver sulfadiazine, Medihoney, and topical becaplermin.

Sodium thiosulfate is believed to have multiple effects on the pathways that cause calciphylaxis. Its antioxidant properties scavenge reactive oxygen species. Through activation of endothelial nitric oxide, it promotes vasodilation which is believed to aid in pain relief. As a chelating agent, sodium thiosulfate binds calcium to form a highly soluble salt, calcium thiosulfate which is then excreted renally.^1,5

Cases of non-uremic calciphylaxis are increasingly being reported in the literature in patients with similar characteristics. Based on limited reports, the use of sodium thiosulfate in conjunction with other interventions has demonstrated successful outcomes.

References

Vedvyas C, Winterfield LS, Vleugels RA. Calciphylaxis: a systematic review of existing and emerging therapies. J Am Acad Dermatol. 2012 ;67(6):e253-e260.
Oliveira TM, Frazão JM. Calciphylaxis: from the disease to the diseased. J Nephrol. 2015;28(5):531-540.
Ning MS, Dahir KM, Castellanos EH, McGirt LY. Sodium thiosulfate in the treatment of non-uremic calciphylaxis. J Dermatol. 2013;40(9):649-652.
Smith VM, Oliphant T, Shareef M, Merchant W, Wilkinson SM. Calciphylaxis with normal renal function: treated with intravenous sodium thiosulfate. Clin Exp Dermatol. 2012;37(8):874-878.
Ong S, Coulson IH. Normo-renal calciphylaxis: response to sodium thiosulfate. J Am Acad Dermatol. 2011;64(5):e82-e84.
Kalajian AH, Malhotra PS, Callen JP, Parker LP. Calciphylaxis with normal renal and parathyroid function: not as rare as previously believed. Arch Dermatol. 2009;145(4):451-458.
Hackett BC, McAleer MA, Sheehan G, Powell FC, O’Donnell BF. Calciphylaxis in a patient with normal renal function: response to treatment with sodium thiosulfate. Clin Exp Derm. 2009;34(1):39-42.
Maroz N, Mohandes S, Field H, Kabakov Z, Simman R. Calciphylaxis in patients with preserved kidney function. J Am Coll Clin Wound Spec. 2015;6(1-2):24-28.
Kwong AJ, Ebinger J, Hanna P, Spinelli M, Blanc PD. Calciphylaxis in a patient without renal failure. J Gen Intern Med. 2014;29:S327.
Gee S, Vleugels FR, Winterfield LS. A novel report of non-uremic calciphylaxis in the setting of excessive exogenous calcium intake. J Invest Dermatol. 2011;131:S140.

December 2016

The information presented is current as November 4, 2016. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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