Valproate, agitation & delirium prophylaxis, 섬망 동요 예방

 

<Valproate 국내 허가사항>

오르필 시럽	뇌전증[결신발작(소발작), 부분발작(초점발작), 정신운동성발작 및 혼합발작]과 뇌전증에 뒤따르는 성격·행동장애의 예방과 치료
바로인 주사	1. 뇌전증[결신발작(소발작), 부분발작(초점발작), 정신운동성발작 및 혼합발작]과 뇌전증에 뒤따르는 성격·행동장애의 예방과 치료 2. 수술후 및 외상후의 발작

 

• Valproate therapy was associated with a reduction in agitation, delirium, and concomitant psychoactive medication use within 48 hours of initiation.
• Median maintenance dose = 1500 mg/day(23 mg/kg/day)
• Valproate day 3, significantly decreased → incidence of agitation (96% vs 61%,P< .0001) and delirium (68% vs 49%,P= .012) 
• Hyperammonemia (19%) and thrombocytopenia (13%) were the most commonly observed adverse effects.

 

발프로산 섬망 예방 요법

Methods

Efficacy outcomes

• valproate 시작 2일 전~시작 후 7일간 또는 중단될 때까지(둘 중 빠른 날짜)까지 수집
• Richmond Agitation-Sedation Scale (RASS) scores ≥1: agitation day
• Sedation-Agitation Scale (SAS) scores ≥5: agitation day
• The Confusion Assessment Method for the ICU (CAM-ICU) at least 1 positive: delirium day

 

Safety outcomes

• Hepatotoxicity : Roussel Uclaf Causality Assessment Method (RUCAM)으로 평가
• ALT > 3 X (정상상한치) ;> 120 U/L
• ALP > 2 X (정상상한치) ;> 234 U/L
• Total bilirubin > 2 X (정상상한치) ;> 2 mg/dL

▶Hematologic toxicity

• leukocyte count < 4200 cells/mm³
• ANC(absolute neutrophil count) < 2400 cells/mm³
• PLT < 140,000 cells/mm³ or basal PLT의 50% 이하

▶Hyperammonemia

• > 60 μmol/L

▶Pancreatitis

• serum lipase > 3 X (정상상한치); > 189 IU/L & in the presence of clinical symptoms

 

Results

 

- Median maintenance dose = 1500 mg/day(23 mg/kg/day)

- Route of administration : IV & enteral

 

 

• The incidence of agitation increased from 73% on valproate day −2 to 80% on valproate day −1 and to 96% on valproate day 1. The incidence of agitation significantly decreased following the initiation of valproate to 61% on valproate day 3 ( P < .0001).
• The incidence of delirium exhibited a similar trend, occurring in 41% of patients on valproate day −2, 51% on valproate day −1, and 68% on valproate day 1. The incidence of delirium also decreased by valproate day 3 (49%, P = .012).

 

- opioid 투여받는 환자 비율이 valproate day1에 비해 day3 때 감소됨 (77% vs 65%. p=0.02)

- median daily fentanyl equivalents 감소됨. (1347 vs 800 mcg/day, p=0.04)

- dexmedetomidine과 qeutiapine 투여받는 환자 비율이 valproate day1에 비해 day3 때 감소됨 (각각 47% vs 24%, P = 0.004, 49% vs 35%, P = 0.04)

 

 

- 대부분의 환자(79%)는 valproate 치료 전/후로 간 기능 검사를 받음

- 한 환자에서 ALP 증가가 관찰되었으며 RUCAM score =4로 valpraote와의 상관성이 매우 높음

- 한 환자에서 total bilirubin의 상승이 관찰되었지만 RUCAM score =1로 valproate와의 상관성이 낮음

- 모든 환자가 valproate 치료 전/후로 CBC 모니터링을 받음

- 가장 흔한 혈액학적 부작용은 thrombocytopenia이며 그중 한명이 valpratoe 치료를 중단함

- 2명의 환자(5%)가 neutropenia가 발병하였지만 valpraote를 중단하지는 않음

- 32명의 환자(60%)가 암모니아 수치 모니터링을 받았고 그중 6명(19%)가 고암모니아혈증을 경험함. 그 중 4명의 환자가 복용을 중단하였음.

 

 

Discussion

Agitation 관리를 위한 적절한 용법용량

• Daily maintenance doses were slightly higher than those previously reported. (ex. 500 mg bid, 250 mg qid, 750 mg tid, 1000 mg qd 등)[1]
• The optimal dosing regimen for valproate in the ICU—and whether loading doses are beneficial—is not answered by our research and should be addressed in future studies.

모집단 별 valproate 효과

• traumatic brain injury : behevior disorder 치료 ⇒ the overall quality of data is low & TBI 이후 발작 예방을 위해 valpraote 사용은 오히려 mortality 증가(13.4% in the valproate group vs 7.2% in the phenytoin group; P = 0.07; relative risk, 2.0; 95% confidence interval, 0.9-4.1) 👉 limitation : the study was not powered to assess mortality
• dementia :  90,000 명 이상의 case-control study를 통해 valproate의 사용과 사망률과 관련이 없음을 발견, NICE guideline에 관련 권고사항임 ⇒ It should be emphasized that data dexcribing valproate use in these patient populations cannot be generalized to ICU patients. 

Dementia Assessment, management and support for people living with dementia and their carers, NICE guideline 2018

Hyperammonemia

• 환자의 19%에서 발생한 가장 흔한 부작용
• urea cycle interference by valproate & valproyl-CoA
• 고암모니아혈증과 valproate dose, serum concentration, duration of therapy와의 일관된 상관관계는 설명되지 않았음 

Thrombocytopenia

• 이 연구에서 환자의 13%가 경험한 흔한 부작용임
• valpratoe-treated psychiatric inpatient의 5-28%가 혈소판저하증 발생
• valproate induced thrombocytopenia는 dose dependent → bone marro suppression and/or autoantibody formation

Total serum valpratoe concentration

• A total valproate serum concentration of 50 to 125 mg/L is recommended by the American Psychiatric Association's guidelines for the treatment of patients with bipolar disorder, but this reference range has not been validated for ICU agitation 
• valpraote는 단백결합 비율이 높으므로(>90%) freaa fraction는 알부민 농도에 영향을 받음
• Future research should attempt to correlate clinical effect and toxicity with free and total serum valproate concentrations

 

reference : 

1) Bourgeois, James A., et al. "Adjunctive valproic acid for delirium and/or agitation on a consultation-liaison service: a report of six cases." The Journal of neuropsychiatry and clinical neurosciences 17.2 (2005): 232-238.

2) Gagnon, David J., et al. "Valproate for agitation in critically ill patients: a retrospective study." Journal of critical care 37 (2017): 119-125.