금단 현상: 외상 환자에서의 opioid/benzodiazepine withdrawal syndrom

중환자실에 내원하는 동안 기계 환기를 적용받는 대부분의 환자들이 opioid and/or 진정제(ex. benzodiazepine, propofol, dexmedetomidine)에 노출된다. 최근 지침을 통해 light sedation 등을 지향하며 진정제 노출 최소화를 위해 노력하지만 실제 임상에서 어려운 실정이다.

특히나 opioid나 BZD의 고선량/장기간 노출은 약물 내성(drug tolerance; 동일한 효과를 유지하기 위해 약물 복용량의 증가가 요구됨)과 약물 신체적 의존성(drug physical dependence; 급작스럽거나 성급한 약물 중단에 의해 불쾌한 신체적 증상 유발)을 야기할 수 있다.

 

 

일부 OWS 평가 도구는 소아 환자에게 제한적이며 해당 연구도 소아 환자를 대상으로 한 것이 많다.

Of note, there is no valid and reliable WS assessment tool available for the adult ICU population, although there are two tools for pediatrics.

Unlike in the PICU patient population, physical dependence during drug weaning of adult ICU patients exposed to prolonged doses of opioids and benzodiazepines has received little study. Indeed, there is a large discrepancy in the amount of literature regarding WS in the adult versus PICU populations.

 

진단도구

(1) Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)

이는 고선량/장기간 opioid 치료 중단 후 수 분에서 수 일 이후 나타나는 현상으로 dysphoric mood, nausea, vomiting, diarrhea, or fever 중 3가지 이상의 증상이 있다면 OWS(opioid withdrawal syndrome)으로 진단할 수 있다.

하지만 기계 환기를 받고 있는 환자에서는 증상 평가가 어려울 수 있으므로 이 기준을 적용하기 어렵다.

 

 

성인 중환자를 대상으로한 WS 연구(descriptive studies with retrospective chart review designs and small samples)

1. Adult ICU surgical-trauma patients: Cammarano, William B., et al. "Acute withdrawal syndrome related to the administration of analgesic and sedative medications in adult intensive care unit patients." Critical care medicine 26.4 (1998): 676-684.⇨ 표본의 32%(n = 28)가 WS가 발생했음을 발견
2. Burn ICU MV patients: Brown, Craig, et al. "Opioid and benzodiazepine withdrawal syndrome in adult burn patients/discussion." The American Surgeon 66.4 (2000): 367. ⇨ 7일 이상 opioid와 BZD를 투여 받은 모든 화상 & MV 환자(n = 11)가 WS 발생

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Therefore, the objectives of this exploratory study were to (1) identify risk factors associated with probable WS among adult TICU patients exposed to opioids and/or benzodiazepines; (2) explore clinical characteristics, signs and symptoms, and outcomes among patients who developed probable WS, questionable WS, and patients who did not develop WS.

 

 

Study Design

• Prospective exploratory observational study
• The Institutional Review Board of the University of Puerto Rico, Medical Sciences Campus approved this study, protocol number A5580416
• The study period was from September 2016 to May 2017

 

Setting and Patients

• 21세 이상
• 5일 이상 opioid and/or BZD에 노출될 거승로 예상되는 환자
• 두부 외상, 알코올 중독자는 제외

 

Instruments

• 성인의 WS를 평가하기 위한 검증된 도구가 없으며 증상/징후 역시 섬망, 통증 등의 다른 병인과 유사성이 있음
• 특히 CNS irritability와 항진된 신경계(빈맥, 빈호흡)가 특이도가 낮은 증상/징후임
• 명확하지는 않지만 일부 독특한 증상/징후를 보이기도 함(위장 기능 장애, 일부 신경계 활성화(하품, 발열, 눈물(lacrimation))

 

잠재적인 WS 평가를 위해 체크리스트

(참고: Diagnostic and Statistical Manual of Mental Disorders (DSM-5), the International Classification of Diseases, 10th Edition Classification of Mental and Behavioral Disorders, and previous WS research in adult ICU patients to develop the checklist)

Tachycardia and tachypnea were defined as more than 100 beats per minute and more than 30 breaths per minute, respectively, high blood pressure as a systolic pressure more than 150 mm Hg, and/or diastolic pressure more than 90 mm Hg. We used the Richmond Agitation-Sedation Scale (RASS) score to determine level of arousal (restlessness and agitation) and the Confusion Assessment Method-ICU (CAM-ICU) to determine delirium.

 

 

Withdrawal signs and symptoms may begin to appear within 6–12 hours for short-acting opioids (peak intensity 1–3 d) and 6–8 hours for benzodiazepine (peak in intensity 2 d)

 

 

“probable” WS	patients presenting with three or more sign/symptoms of opioid-WS and/or two or more sign/symptoms of benzodiazepine-WS that were not present at baseline (i.e., fourth day of opioid and/or benzodiazepine administration)
“no” WS	patients not presenting with the minimum sign/symptoms for opioid-WS and/or benzodiazepine-WS
“questionable” WS	patients presenting with the required number of sign/symptoms, but one or more of these were present during baseline evaluation. For example, tachycardia that was present at baseline evaluation was not counted as a probable withdrawal sign during weaning.

 

Differences in Demographics and Clinical Variables According to Patient Group

 

 

Adjusted Odds Ratios and 95% CIs for the Development of Probable Withdrawal Syndrome, According to Potential Predictors

본 연구에서 젊은 참가자에서 WS 확률이 높았다.(Model No.4) 뿐만 아니라 다른 연구(Cammarano et al)에서도 젊은 참가자의 WS 발생률이 상당히 높았다.(mean age of 34.9 ± 4.6 vs 50.9 yr ± 4.0; p = 0.017)

Opioid을 weaning하기 전의 누적 opioid dose가 WS 발생과 관련있음을 보여준다.(Model No. 6) 

The final model (Model No. 6) also showed that cumulative opioid dose amounts prior to weaning were associated with development of WS, although the number of days that patients received opioids was protective. 

예상대로 opioid 사용 기간과 누적 opioid dose는 강한 상관관계를 보여주었다.  (Spearman correlation coefficient = 0.78, not shown in the tables)

즉 동일한 누적 opioid dose에서 opioid 지속 시간이 긴(낮은 일일 선량) 환자는 WS의 발병 확률이 낮았다.

이러한 결과는 WS의 전구체인 opioid receptor에서 차이를 일으킬 수 있는 여러 요인이 존재함을 시사한다. 

Another explanation for this finding is that there are several factors that can cause differences in opioid tolerance, the precursor to WS, at the opioid receptor level. 
Cumulative doses may affect the opioid receptor differently than length of time receiving opioids. 
In addition, genetic differences in opioid receptor synthesis and variable opioid receptor affinity, the difference in type of opioid administered, and the use of continuous versus intermittent administration may be influential factors. Use of multimodal analgesia may help to counteract development of WS through reduction of opioid amounts administered to the patient. However, further research is warranted on time versus amount differences in opioids and their risk for WS.

 

 

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결론:

In our study, we identified probable WS in a sample of TICU patients through observation of several associated signs and symptoms. We identified certain factors that were associated with WS such as increased agitation, previous drug user, and greater cumulative doses of opioids prior to the weaning process. We also found that patients who developed probable WS spent more time on MV and had increased lengths of time in both ICU and hospital. They also had associated agitation/restlessness and delirium as assessed by valid, reliable, feasible tools frequently used in the ICU, the RASS and the CAM-ICU. Further research should focus on the validation of the opioid and benzodiazepine WS checklist in larger samples of ICU patients at risk for WS. Prospective studies are warranted on methods to promote analgesia and sedation while preventing WS. Finally, exploring the occurrence of WS after patient discharge may emphasize the importance of identifying and treating WS in ICU patients.

 

 

reference:

1) Arroyo-Novoa, Carmen Mabel, et al. "Opioid and benzodiazepine withdrawal syndromes in trauma ICU patients: a prospective exploratory study." Critical care explorations 2.4 (2020).

2) Freye, E., and L. Latasch. "Development of opioid tolerance--molecular mechanisms and clinical consequences." Anasthesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie: AINS 38.1 (2003): 14-26.