The practice of critical care cardiology relies on the use of invasive hemodynamics, mechanical ventilation, mechanical circulatory support, and other advanced techniques to help our patients recover from critical cardiac illnesses. To facilitate these interventions, it is essential to have a broad understanding of how sedation and analgesia keep our patients comfortable and safe throughout their time in the CICU. In this episode, series co-chair, Dr. Yoav Karpenshif, and CardioNerds co-founder, Dr. Daniel Ambinder, are joined by Dr. Natalie Tapaskar, cardiology fellow and CardioNerds FIT Ambassador from Stanford, and faculty expert, Dr. Chris Domenico, to discuss sedation in the cardiac ICU.

We discuss the use of analgesics and sedative medications in the cardiac ICU. We dissect three cases of VT storm, heart failure associated cardiogenic shock, and cardiac arrest. We assess the hemodynamic, arrhythmic, and metabolic effects of opioids and sedatives and delve into the altered pharmacokinetics of these drugs during targeted temperature management. Most importantly, we highlight the use of structured pain and sedation scoring systems and discuss the recognition and management of ICU delirium both from a pharmacologic and non-pharmacologic standpoint.

Notes were drafted by Dr. Natalie Tapaskar and episode audio was edited by student Dr. Anusha Gandhi.

The CardioNerds Cardiac Critical Care Series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Mark Belkin, Dr. Eunice Dugan, Dr. Karan Desai, and Dr. Yoav Karpenshif.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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1. Think about analgesia and sedation as separate entities with management of analgesia first and sedation second. Frequent re-assessment of needs should be performed to reduce ICU delirium and improve long-term outcomes.
   
2. Fentanyl is generally a good starting point for analgesia in the ICU since it is fast on/fast off, but can stick around for a long time the longer it is used. The choice of bolus or continuous infusion opioids depends on the clinical scenario and personal/institutional preference. Remember to administer bolus doses that are 50-100% of the hourly continuous infusion dose to reach steady state faster.
   
3. When managing refractory VT storm with sedative agents (propofol, benzodiazepines and/or dexmedetomidine), you should target the deepest level of sedation necessary to suppress sympathetic drive.
   
4. For cardiogenic shock patients, the choice of sedative agent is a nuanced decision. Think about etomidate first for intubation as it has the least cardiovascular and hemodynamic impact. And remember the propofol trifecta: negative inotropy, direct vasodilation, and bradycardia!
   
5. Pharmacokinetics are disrupted during targeted temperature management, thus be weary of overly sedating patients due to reduced drug clearance.
   

• How do we initiate analgesics and sedatives?
  
  • Analgesia first and sedation second!
    
  
  
• Analgesia: think about how to reduce a patient’s pain
  
  • Everyone has a different pain tolerance and critically ill patients can have moderate to severe pain at baseline.
    
  • Metrics to assess pain include self-reported scales, behavioral scales, facial expressions, extremity movement, compliance with the ventilator, tachycardia, tachypnea, and hypertension.
    
  
  
• Sedation: think about how to reduce a patient’s agitation or anxiety
  
  • The target depth of sedation depends on the clinical scenario.
    
    • For example, a patient with a femoral balloon pump may need more sedation if agitation is causing excessive lower extremity movement and thus a higher risk of device dislodgement.
      
    
    
  • Use the Richmond Agitation and Sedation Scale (RASS) for titrating sedation leve.
    
    • -5 – Unarousable. No response to voice or physical stimuli
      
    • -4 – Deep sedation. No response to voice, but movement or eye opening to physical stimulation
      
    • -3 – Moderate sedation. Movement or eye-opening to voice
      
    • -2 – Light sedation. Briefly awakens to voice
      
    • -1 – Drowsy. Not fully alert, but has sustained awakening to voice
      
    • 0 – Alert and calm
      
    • +1 – Restless. Anxious, apprehensive, but not aggressive
      
    • +2 – Agitated. Frequent non-purposeful movement, fights vent
      
    • +3 – Very agitated. Pulls or removes tubes/catheters
      
    • +4 – Combative. Violent, immediate danger to staff
      
    
    
  
  

• What are the different opioid options and when should we use them?
  
  • Break down opioids into 3 groups (as per Dr. Domenico):
    
    • Group 1 (morphine, hydromorphone, fentanyl) for pain management in the ICU.
      
      • Onset of action: Fentanyl is the quickest on/off (30 seconds-2 minutes), but is highly lipophilic, redistributing in fatty tissues after ~30 minutes. The longer you use fentanyl, the longer it will stick around – i.e. “context-sensitive half-time.” Morphine and Hydromorphone have an onset from 5-15 minutes.
        
      • Half-life: All 3 are similar at 2-4 hours. (Fentanyl can be even higher the longer it is used).
        
      • Metabolism: Morphine is metabolized by the liver, but has active metabolites that are renally cleared; thus, be cautious with high doses in renal impairment. Fentanyl is metabolized by the CYP system thus it accumulates in hepatic dysfunction.
        
      
      
    • Group 2 (remifentanil and sufentanil) generally for use in the operating room.
      
      • Onset of action: Both are very quick on/off ranging from 1-3 minutes.
        
      • Half-life: Remifentanil’s is 3-10 minutes, whereas sufentanil’s is 2-3 hours.
        
      • Metabolism: Remifentanil demonstrates no accumulation in hepatic or renal impairment, thus is a good choice in these scenarios. Beware of the rare possibility of serotonin syndrome with both these agents.
        
      
      
    • Group 3 (methadone) as a bridge to wean off from long term infusions of other opioids.
      
      • Onset of action: 1-20 minutes when given intravenously, but 3-5 days when given orally.
        
      • Half-life: Ranges from 8-60 hours.
        
      • Metabolism: Hepatic, exercise caution with dysfunction. Also monitor for QT prolongation.
        
      
      
    
    
  
  

• Should we administer opioids as boluses or continuous infusions?
  
  • There is no strong data to guide bolus versus continuous infusion dosing of opioids and the choice is often left up to personal/institutional preference. Small studies in emergency department patients suggest there is less ICU delirium post-intubation with bolus dosing over continuous infusions of opioids.
    
  • Generally, think about starting with bolus dosing to assess a patient’s true needs, but patients may require continuous infusions if they are receiving frequent boluses.
    
  • When increasing the rate of a continuous infusion, one can reach steady state faster by administering bolus doses at 50-100% of the hourly dose of the infusion.
    
  
  

• How should we use analgesics and sedatives for management of arrhythmias, specifically VT storm?
  
  • The main goal in refractory VT storm is to sedate the patient as deeply as necessary to suppress their sympathetic drive. Generally, the choice of sedative agent is less important than the level of sedation achieved.
    
    • Propofol, benzodiazepines, and dexmedetomidine can all decrease sympathetic drive.
      
    • Propofol has some anti-arrhythmic effects via autonomic nervous system modulation.
      
    • Dexmedetomidine may increase the arrhythmogenic threshold.
      
    • Benzodiazepines have no direct effect on the conduction system.
      
    
    
  • Opioids have GABA agonist properties and thus have some anti-arrhythmic properties. However, opioids alone are rarely effective in managing malignant arrhythmias unless pain is the main trigger for the arrhythmia. 
    
  • In some animal studies, fentanyl and morphine are thought to increase the ventricular fibrillation threshold, but this is not validated with hard outcomes in clinical trials.
    
  
  

• What sedatives are safe to use for intubation in cardiogenic shock?
  
  • Induction: Etomidate, ketamine, and propofol are common agents used for induction of sedation peri-intubation.
    
    • Etomidate – has minimal cardiovascular/hemodynamic effects and should be considered first for induction in cardiogenic shock. Can lead to adrenal insufficiency. 
      
    • Ketamine – is a direct vasoconstrictor (including coronary arteries) and results in hypertension and tachycardia. It should be avoided in patients with ACS. It may have a direct myocardial depressant effect, so its use is avoided in prolonged shock states.
      
    • Propofol – has a plethora of properties-sedative, hypnotic, amnestic, antiemetic, and anticonvulsant, but importantly has NO ANALGESIC properties. Remember its hemodynamic trifecta: negative inotropy, direct vasodilation, and bradycardia. It is also highly lipophilic, with a long half-life with extended infusions- i.e. “context-sensitive half-time”. Don’t forget to check triglyceride levels at baseline and at regular intervals while on a continuous infusion.
      
    
    
  • Maintenance: Propofol, benzodiazepines, and dexmedetomidine can be used for maintenance of sedation post-intubation.
    
    • Benzodiazepines
      
      • Also have a plethora of properties- sedative, amnestic, anticonvulsant, anxiolytic, and hypnotic but NO ANALGESIC properties.
        
      • Midazolam is quicker on/off (2-5 minutes) compared to lorazepam. Midazolam can accumulate in renal dysfunction. Think about polyethylene toxicity when patients on lorazepam at high doses for extended periods of time develop metabolic acidosis.
        
      • In general, benzodiazepines use is associated with increased ventilator time, ICU delirium, and ICU length of stay.
        
      
      
    • Dexmedetomidine
      
      • Is an alpha 2 agonist and thus monitor for hypotension and bradycardia with ongoing use. It does not cause respiratory depression. It generally does not result in deep sedation (less than -2) and is not very effective for acute management of agitation. Consider its use for patients that require mild sedation during extubation.
        
      
      
    
    
  
  

• What are general principles of analgesia and sedation during targeted temperature management?
  
  • Always assess baseline pain and RASS prior to medication initiation. Once the need for analgesia and sedation is established, these medications should be started prior to initiating cooling protocols.
    
  • Consider using the lowest effective doses of medications to increase the ability to perform accurate neuro-prognostication.
    
  • Pharmacokinetics are disrupted during TTM, including absorption, distribution, metabolism, and excretion. These properties may vary among drugs of the same class.
    
    • In hypothermia, there is a general decrease in global drug perfusion as there is shunting of blood away from non-vital organs and intra-vascular volume of distribution is reduced. Drug clearance may be reduced, thus be cautious of over-sedation.
      
    • Serum creatinine may not be a reliable indicator of renal function during TTM as there is a decrease in creatinine synthesis and secretion.
      
    
    
  • Remember that hypothermia can cause hypomagnesemia, check and replete often!
    
  
  

• How should we manage shivering?
  
  • Shivering increases baseline metabolic activity and is associated with decreased brain tissue oxygenation and can lead to worsening hypoxic brain injury.
    
  • Assess shivering using the bedside shivering assessment scale (BSAS).
    
  • Use the Columbia anti-shivering protocol to achieve shiver control with the least sedating regimen.
    
  • There is limited data on opioids versus neuromuscular blockade for shivering, both strategies may be effective. Generally, neuromuscular blockade is considered after other strategies have failed.
    
  
  

• How do we assess and treat ICU delirium?
  
  • Delirium should be assessed frequently using metrics such as the Confusion Assessment Method (CAM-ICU) or the Intensive Care Delirium Screening checklist (ICDSC).
    
    • CAM-ICU assesses for acute changes or fluctuation in mental status, inattention, altered level of consciousness, and disorganized thinking.
      
    
    
  • There is not a lot of data on the use of antipsychotics to treat ICU delirium.
    
    • Haloperidol is most often used even though data is limited.
      
    • Quetiapine has some positive data in small studies. Try to start with 15 mg q12 hours and titrate up to reach a target dose of 200 mg q12 hours as needed. Be cautious of hypertension and QT prolongation.
      
    • Very few patients will require antipsychotics once they leave the hospital, unless they have a pre-existing indication.
      
    
    
  • Non-pharmacologic methods should always be used such as sleep hygiene, freedom from lines/catheters, early mobilization, avoidance of constipation, and providing glasses/hearing aids as needed.
    
  
  

• What strategies can be used to limit analgesia and sedation and why is that important?
  
  • Constant re-evaluation of the need for analgesia and sedation is paramount to reducing ventilator time, ICU delirium, and ICU and hospital length of stay.
    
  • Ask yourself if the RASS goal is the same today as it was yesterday. Re-evaluate often.
    
  • Take sedation vacations! Spontaneous breathing and spontaneous awakening trials should be performed at least daily if it is safe for the patient.
    
  • Consider re-introduction of home medications when appropriate, such as gabapentin for neuropathic pain or prior psychiatric medications.
    
  
  

1. Riker RR, Gagnon DJ, May T, Seder DB, Fraser GL. Analgesia, sedation, and neuromuscular blockade during targeted temperature management after cardiac arrest. Best Practice & Research Clinical Anaesthesiology. 2015;29(4):435-450. doi:10.1016/j.bpa.2015.09.006
   
2. Zakaria S, Kwong HJ, Sevransky JE, Williams MS, Chandra-Strobos N. Editor’s Choice-The cardiovascular implications of sedatives in the cardiac intensive care unit. European Heart Journal: Acute Cardiovascular Care. 2018;7(7):671-683. doi:10.1177/2048872617695231
   
3. Schenone A, Chen K, Andress K, Militello M, Cho L. Editor’s Choice- Sedation in the coronary intensive care unit: An adapted algorithm for critically ill cardiovascular patient. European Heart Journal: Acute Cardiovascular Care. 2019;8(2):167-175. doi:10.1177/2048872617753797
   
4. Van Diepen S, Katz JN, Albert NM, et al. Contemporary Management of Cardiogenic Shock: A Scientific Statement from the American Heart Association. Circulation. 2017;136(16):e232-e268. doi:10.1161/CIR.0000000000000525