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Jain RP, Gosek K, Johnston M. Reduction of iatrogenic withdrawal syndrome in high-risk critically ill patients with acute respiratory distress syndrome. Anaesth Intensive Care 2025:310057X241233604. [PMID: 40404590 DOI: 10.1177/0310057x241233604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/24/2025]
Abstract
Limited data suggest a subset of patients with acute respiratory distress syndrome receive high-dose and prolonged opioid and sedative infusions. With prolonged use, patients may be at risk for developing iatrogenic withdrawal syndrome after discontinuation or tapering of these agents. Iatrogenic withdrawal syndrome is well described in paediatric patients; however, limited guidance exists in adult intensive care unit patients regarding risk factors and ideal management strategies. This article discusses several weaning strategies for high-risk patients to minimise withdrawal symptoms and safely reduce or discontinue opioid and sedative infusions. Ideal weaning strategies are lacking, but several options exist. These include a gradual reduction of the agent, changing the route of delivery by switching to an enteral or parenteral longer-acting agent from the same class, and substitution to an alternative agent to help mitigate potential withdrawal symptoms. This should be accomplished through a multidisciplinary approach by involving experts from relevant specialties while closely observing for withdrawal symptoms.
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Affiliation(s)
- Ruchi P Jain
- Hackensack University Medical Center, Department of Pharmacy, Hackensack, NJ
| | | | - Madeline Johnston
- HonorHealth John C. Lincoln Medical Center, Department of Pharmacy Services, Phoenix, AZ
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Schuler A, Yoon CH, Caffarini E, Heine A, Meester A, Murray D, Harding A. Alpha2 Agonist Use in Critically Ill Adults: A Focus on Sedation and Withdrawal Prevention. J Pharm Pract 2025; 38:155-167. [PMID: 38907529 DOI: 10.1177/08971900241263171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/24/2024]
Abstract
The management of sedation in critically ill adults poses a unique challenge to clinicians. Dexmedetomidine, an α2 agonist, has a unique mechanism and favorable pharmacokinetics, making it an attractive intravenous option for sedation and delirium in the intensive care unit. However, patients may be at risk for withdrawal with prolonged use, adding to the complexity of sedation and agitation management in this patient population. Enteral α2 agents have the benefit of cost savings and ease of administration, thus playing a role in the ability to decrease intravenous sedative use and prevent dexmedetomidine withdrawal. Clonidine and guanfacine are the two most common enteral α2 agents utilized for this purpose, however, there is a paucity of evidence regarding the comparative benefit between the two agents. The decision to use one vs the other agent should be determined based on their differing pharmacology, pharmacokinetics, and side effect profile. The most effective dosing strategy for these agents is also unknown. Ultimately, more robust literature is required to determine enteral α2 agonists place in therapy. This narrative review evaluates the currently available literature on the use of α2 agonists in critically ill adults with an emphasis on sedation, delirium, and withdrawal.
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Affiliation(s)
- Ashley Schuler
- Department of Pharmacy, Ohio Health Riverside Methodist Hospital, Columbus, OH, USA
| | - Connie H Yoon
- Department of Pharmacy, Ohio Health Riverside Methodist Hospital, Columbus, OH, USA
| | - Erica Caffarini
- Department of Pharmacy, Ohio Health Riverside Methodist Hospital, Columbus, OH, USA
| | - Alexander Heine
- Department of Pharmacy, Ohio Health Riverside Methodist Hospital, Columbus, OH, USA
| | - Alyssa Meester
- Department of Pharmacy, Ohio Health Riverside Methodist Hospital, Columbus, OH, USA
| | - Danielle Murray
- Department of Pharmacy, Ohio Health Riverside Methodist Hospital, Columbus, OH, USA
| | - Angela Harding
- Department of Pharmacy, Ohio Health Riverside Methodist Hospital, Columbus, OH, USA
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Rajendraprasad S, Wheeler M, Wieruszewski E, Gottwald J, Wallace LA, Gerberi D, Wieruszewski PM, Smischney NJ. Clonidine use during dexmedetomidine weaning: A systematic review. World J Crit Care Med 2023; 12:18-28. [PMID: 36683967 PMCID: PMC9846870 DOI: 10.5492/wjccm.v12.i1.18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 11/15/2022] [Accepted: 11/30/2022] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Dexmedetomidine is a centrally acting alpha-2A adrenergic agonist that is commonly used as a sedative and anxiolytic in the intensive care unit (ICU), with prolonged use increasing risk of withdrawal symptoms upon sudden discontinuation. As clonidine is an enterally available alpha-2A adrenergic agonist, it may be a suitable agent to taper off dexmedetomidine and reduce withdrawal syndromes. The appropriate dosing and conversion strategies for using enteral clonidine in this context are not known. The objective of this systematic review is to summarize the evidence of enteral clonidine application during dexmedetomidine weaning for prevention of withdrawal symptoms.
AIM To systematically review the practice, dosing schema, and outcomes of enteral clonidine use during dexmedetomidine weaning in critically ill adults.
METHODS This was a systematic review of enteral clonidine used during dexmedetomidine weaning in critically ill adults (≥ 18 years). Randomized controlled trials, prospective cohorts, and retrospective cohorts evaluating the use of clonidine to wean patients from dexmedetomidine in the critically ill were included. The primary outcomes of interest were dosing and titration schema of enteral clonidine and dexmedetomidine and risk factors for dexmedetomidine withdrawal. Other secondary outcomes included prevalence of adverse events associated with enteral clonidine use, re-initiation of dexmedetomidine, duration of mechanical ventilation, and ICU length of stay.
RESULTS A total of 3427 studies were screened for inclusion with three meeting inclusion criteria with a total of 88 patients. All three studies were observational, two being prospective and one retrospective. In all included studies, the choice to start enteral clonidine to wean off dexmedetomidine was made at the discretion of the physician. Weaning time ranged from 13 to 167 h on average. Enteral clonidine was started in the prospective studies in a similar protocolized method, with 0.3 mg every 6 h. After starting clonidine, patients remained on dexmedetomidine for a median of 1-28 h. Following the termination of dexmedetomidine, two trials tapered enteral clonidine by increasing the interval every 24 h from 6 h to 8h, 12h, and 24 h, followed by clonidine discontinuation. For indicators of enteral clonidine withdrawal, the previously tolerable dosage was reinstated for several days before resuming the taper on the same protocol. The adverse events associated with enteral clonidine use were higher than patients on dexmedetomidine taper alone with increased agitation. The re-initiation of dexmedetomidine was not documented in any study. Only 17 (37%) patients were mechanically ventilated with median duration of 3.5 d for 13 patients in one of the 2 studies. ICU lengths of stay were similar.
CONCLUSION Enteral clonidine is a strategy to wean critically ill patients from dexmedetomidine. There is an association of increased withdrawal symptoms and agitation with the use of a clonidine taper.
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Affiliation(s)
- Sanu Rajendraprasad
- Department of Pulmonary & Critical Care, Mayo Clinic, Rochester, MN 55905, United States
| | - Molly Wheeler
- Department of Pharmacy, Mayo Clinic, Rochester, MN 55905, United States
| | - Erin Wieruszewski
- Department of Pharmacy, Mayo Clinic, Rochester, MN 55905, United States
| | - Joseph Gottwald
- Department of Anesthesiology & Perioperative Medicine, Mayo Clinic, Rochester, MN 55905, United States
| | - Lindsey A. Wallace
- Critical Care Medicine Independent Multidisciplinary Program, Mayo Clinic, Rochester, MN 55905, United States
| | - Danielle Gerberi
- Mayo Medical Libraries, Mayo Clinic, Rochester, MN 55905, United States
| | | | - Nathan J Smischney
- Department of Anesthesiology & Perioperative Medicine, Mayo Clinic, Rochester, MN 55905, United States
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Abstract
UNLABELLED Describe the efficacy and safety of guanfacine for dexmedetomidine weaning in critically ill patients. DESIGN Retrospective descriptive analysis. SETTING Six hundred thirteen-bed academic medical center from October 2020 to October 2021. PATIENT/SUBJECTS All Adult patients on IV dexmedetomidine who received at least one dose of guanfacine for sedation or agitation were included. INTERVENTIONS Enteral guanfacine. MEASUREMENTS AND MAIN RESULTS The primary outcome was discontinuation of dexmedetomidine therapy within 48 hours after guanfacine initiation. Secondary outcomes assessed included adjunctive medication use, rate of dexmedetomidine reinitiation, and safety outcomes. One hundred five patients were included in the analysis. Median age was 59 years old, 66% were male, and median daily dose of guanfacine was 1.5 mg. Dexmedetomidine was discontinued within 48 hours in 58% of patients (n = 61) and within 72 hours in 71% of patients (n = 75). Fifty-five percent of patients (n = 58) required rescue medications for poorly controlled agitation, sedation, or pain while on guanfacine. Dexmedetomidine withdrawal occurred in 2% of patients (n = 2) while on guanfacine. Adverse effects attributed to guanfacine occurred in 8% of patients (n = 8), all experiencing hypotension leading to medication discontinuation. CONCLUSION Dexmedetomidine was successfully weaned within 48 hours of guanfacine initiation in 58% of patients with minimal withdrawal or adverse effects. Guanfacine may be an effective and safe enteral option for dexmedetomidine weaning in critically ill patients.
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Root-Bernstein R. Biased, Bitopic, Opioid-Adrenergic Tethered Compounds May Improve Specificity, Lower Dosage and Enhance Agonist or Antagonist Function with Reduced Risk of Tolerance and Addiction. Pharmaceuticals (Basel) 2022; 15:214. [PMID: 35215326 PMCID: PMC8876737 DOI: 10.3390/ph15020214] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 02/02/2022] [Accepted: 02/07/2022] [Indexed: 01/03/2023] Open
Abstract
This paper proposes the design of combination opioid-adrenergic tethered compounds to enhance efficacy and specificity, lower dosage, increase duration of activity, decrease side effects, and reduce risk of developing tolerance and/or addiction. Combinations of adrenergic and opioid drugs are sometimes used to improve analgesia, decrease opioid doses required to achieve analgesia, and to prolong the duration of analgesia. Recent mechanistic research suggests that these enhanced functions result from an allosteric adrenergic binding site on opioid receptors and, conversely, an allosteric opioid binding site on adrenergic receptors. Dual occupancy of the receptors maintains the receptors in their high affinity, most active states; drops the concentration of ligand required for full activity; and prevents downregulation and internalization of the receptors, thus inhibiting tolerance to the drugs. Activation of both opioid and adrenergic receptors also enhances heterodimerization of the receptors, additionally improving each drug's efficacy. Tethering adrenergic drugs to opioids could produce new drug candidates with highly desirable features. Constraints-such as the locations of the opioid binding sites on adrenergic receptors and adrenergic binding sites on opioid receptors, length of tethers that must govern the design of such novel compounds, and types of tethers-are described and examples of possible structures provided.
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Butt AK, Patel J, Shirwany H, Mirza Q, Hoover J, Khouzam RN. Beneficial Extracardiac Effects of Cardiovascular Medications. Curr Cardiol Rev 2022; 18:e151021197270. [PMID: 34779371 PMCID: PMC9413730 DOI: 10.2174/1573403x17666211015145132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 08/10/2021] [Accepted: 08/25/2021] [Indexed: 11/22/2022] Open
Abstract
Cardiovascular diseases are the most common cause of death worldwide, with cardiovascular medications being amongst the most common medications prescribed. These medications have diverse effects on the heart, vascular system, as well as other tissues and organ systems. The extra cardiovascular effects have been found to be of use in the treatment of non-cardiovascular diseases and pathologies. Minoxidil is used to manage systemic hypertension with its well-known side effect of hirsutism used to treat alopecia and baldness. Sildenafil was originally investigated as a treatment option for systemic hypertension; however, its side effect of penile erection led to it being widely used for erectile dysfunction. Alpha-1 blockers such as terazosin are indicated to treat systemic hypertension but are more commonly used for benign prostatic hyperplasia and post-traumatic stress disorder. Beta blockers are the mainstay treatment for congestive heart failure and systemic hypertension but have been found useful to help in patients with intention tremors as well as prophylaxis of migraines. Similarly, calcium channel blockers are indicated in medical expulsion therapy for ureteric calculi in addition to their cardiovascular indications. Thiazides are commonly used for treating systemic hypertension and as diuretics. Thiazides can cause hypocalciuria and hypercalcemia. This side effect has led to thiazides being used to treat idiopathic hypercalciuria and associated nephrolithiasis. Spironolactone is commonly utilized in treating heart failure and as a diuretic for edema. It's well described anti-androgen side effects have been used for acne vulgaris and hirsutism in polycystic ovarian syndrome. This review article discusses how the various extracardiovascular effects of commonly used cardiovascular medications are put to use in managing non-cardiovascular conditions.
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Affiliation(s)
- Asra K. Butt
- Department of Internal Medicine, Veteran Affairs Medical Center, Memphis, TN 38104, USA
| | - Jay Patel
- Department of Internal Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Hamid Shirwany
- University of Tennessee Health Science Center, College of Medicine, Memphis, TN 38163, USA
| | - Qasim Mirza
- Department of Medicine, Division of Pulmonary, Critical Care & Sleep Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Jonathan Hoover
- Department of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Rami N. Khouzam
- Department of Medicine, Division of Cardiovascular Diseases, University of Tennessee Health Science Center, Memphis, TN 38163, USA
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Ego A, Halenarova K, Creteur J, Taccone FS. How to Manage Withdrawal of Sedation and Analgesia in Mechanically Ventilated COVID-19 Patients? J Clin Med 2021; 10:4917. [PMID: 34768436 PMCID: PMC8584278 DOI: 10.3390/jcm10214917] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Revised: 10/12/2021] [Accepted: 10/22/2021] [Indexed: 01/06/2023] Open
Abstract
COVID-19 patients suffering from severe acute respiratory distress syndrome (ARDS) require mechanical ventilation (MV) for respiratory failure. To achieve these ventilatory goals, it has been observed that COVID-19 patients in particular require high regimens and prolonged use of sedatives, analgesics and neuromuscular blocking agents (NMBA). Withdrawal from analgo-sedation may induce a "drug withdrawal syndrome" (DWS), i.e., clinical symptoms of anxiety, tremor, agitation, hallucinations and vomiting, as a result of adrenergic activation and hyperalgesia. We describe the epidemiology, mechanisms leading to this syndrome and our strategies to prevent and treat it.
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Affiliation(s)
- Amédée Ego
- Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium; (K.H.); (J.C.); (F.S.T.)
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