Oct 202017


Treating Pain in Mechanically Ventilated Patients

Adult patients in the intensive care unit (ICU) frequently experience pain, resulting from acute and chronic illness as well the positioning and interventions standard to ICU care.1,2 Besides being ethical and humane, adequately treating pain prevents agitation and delirium in mechanically ventilated patients. There are also many physiologic responses to acute pain that can impact patient care in the ICU, including tachycardia, hypertension, increased work of breathing, increased cortisol release, and increased risk of infection.3 The incidence of pain is thought to be 50% or greater in ICU patients, and the inability to communicate due to mechanical ventilation dose not negate the possibility that the patient is experiencing pain.1

According to clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit (PAD guidelines), behavioral pain scoring tools, such as the Critical-Care Pain Observation Tool (CCPOT) or Behavioral Pain Scale (BPS), should be used in the ICU to improve pain management.1 When integrated into a protocol, these tools have been linked to a reduction in use of analgesic medications, shorter duration of mechanical ventilation, and decreased ICU length of stay.

Intravenous (IV) opioids are first line for non-neuropathic pain, and all IV opioids are equally efficacious in regards to treatment of pain. In practice, fentanyl is typically preferred as it does not have problematic metabolites and causes less hypotension than other agents. In contrast, morphine has metabolites that could potentially accumulate to a harmful level in renal or hepatic impairment. For the treatment of neuropathic pain, gabapentin is a reasonable option. In order to decrease the amount of opioids administered or potentially eliminate the need for opioids altogether, agents such as acetaminophen, ketorolac, or ketamine could be considered.1


Agitation and Sedation in Mechanically Ventilated Patients

Agitation is one of the most common issues that critically ill patients experience, occurring in 59-71% of patients who are admitted to the ICU.4,5 Agitation can result from unmanaged co-morbidities, pain, medications, or psychological response to the environment or internal stimuli. Determining the cause of agitation can be difficult and may not always be possible, especially in patients with a reduced level of consciousness. Different approaches to manage agitation may be chosen based on the most likely perceived cause.

Sedation Scales & Monitoring

Guidelines suggest the Richmond Agitation-Sedation Scale (RASS) as a valid and reliable sedation assessment tool for measuring quality and depth of sedation in adult ICU patients.6 Sedation should be titrated to a RASS score of 0 to -2 for most mechanically ventilated patients. Patients experiencing ventilator dysynchrony or requiring aggressive ventilator settings (e.g. ARDS) may require RASS -3 or -4.

When using neuromuscular blocking agents, the bispectral index (BIS) might be helpful in ensuring deep sedation and amnesia. (Others have concluded using the BIS isn't reliable, though.)


The PAD guidelines suggest that analgesia-first sedation (e.g. fentanyl) be used in mechanically ventilated adult ICU patients (+2B ) and that sedation strategies using nonben­zodiazepine sedatives (either propofol or dexme­detomidine) may be preferred over sedation with benzodiazepines (either midazolam or lorazepam) to improve clinical outcomes (+2B).


  • Propofol reduces time to extubation compared to benzodiazepines, according to multiple randomized trials.
  • Propofol causes hypotension especially with bolus dosing, but this may be minimal or clinically unharmful in volume-replete patients.
  • Monitor triglycerides 1-2 times / week and advise nutrition (since propofol contributes 1.1 kcal/mL) while a patient is receiving a propofol infusion.
  • Propofol infusion syndrome (cardiac failure from sudden bradycardia, metabolic acidosis, hyperkalemia, rhabdomyolysis) appears quite rare in adults receiving usual doses (4-5 mg/kg/hr or less); consider checking pH, lactate, creatine kinase when using propofol for long periods or at high doses.7


  • Dexmedetomidine is an alpha-2 agonist similar to the antihypertensive clonidine, but preferentially binds a subset of receptors causing sedation.
  • Dexmedetomidine does not have respiratory depressant effects unlike most other sedatives, and likely also causes less delirium than benzodiazepines but did cause hypotension and bradycardia in higher doses during clinical trials.8,9,10
  • A randomized trial in JAMA 2012 demonstrated dexmedetomidine given for longer periods (days) likely reduces time to extubation compared to midazolam and propofol. A withdrawal syndrome after ending longer infusions can include hypotension, tachycardia, and agitation.


  • Midazolam (Versed) and lorazepam (Ativan) are the most commonly used benzodiazepine sedatives, although in randomized trials benzodiazepines result in longer time to extubation and discharge.
  • Benzos are lipophilic and accumulate in fat, prolonging sedation in obese patients after continuous infusions. Midazolam's active metabolites are renally cleared and accumulate during kidney failure, prolonging sedation. Lorazepam is preferred for patients with impaired renal function; its metabolites are not active.
  • Lorazepam is as effective at achieving sedation and is more cost effective than midazolam, according to one randomized trial. IV lorazepam is dissolved in a propylene glycol diluent which can cause an anion gap metabolic acidosis with prolonged IV drip use. Osmolar gaps should be monitored on patients with lorazepam drips.
  • Benzodiazepines suppress respiratory drive, in a shallow-breathing pattern (as opposed to the "deep and slow" respiratory depression from opioids). Benzodiazepines are believed to frequently cause delirium when used for patients in the ICU, especially elderly patients, although the evidence for this is weak.
  • Benzodiazepine withdrawal is a risk of abrupt discontinuation of infusions after long periods.


  • Clonidine is an alpha-2 partial agonist that has been studied for the treatment of agitation in critically ill patients. Clonidine’s sedative properties offer advantages over other agents, as it does not produce respiratory depression, decreases the dose requirements of other sedatives, facilitates opiate withdrawal, and can be administered enterally.
  • The use of clonidine as an agent to reduce agitation and delirium has been extrapolated from the trials of dexmedetomidine and much of the recent literature addresses the transition from dexmedetomidine to enteral clonidine.
  • Clonidine appears to be a safe and effective option for sedation and treatment of agitation in the ICU, especially as an adjunct agent to help with weaning IV sedatives.11

Sedation Vacations

The PAD guidelines recommend either daily sedation interruption or a light target level of sedation be routinely used (+1B).  Interrupt sedation completely on a daily basis whenever possible (sedation vacation). Restart the dose at half the previous rate, if the patient becomes agitated. Sedation vacations have been shown to reduce ventilator days and length of ICU stays. Pair the daily sedation interruption with a spontaneous breathing trial, when possible. This led to reduced ventilator days and 1 year mortality in a randomized trial.

Daily sedation vacations don't seem to result in psychological harm; in fact, sedation vacations may reduce the incidence of post-traumatic stress disorder after critical illness.

A whole-team interdisciplinary strategy with buy-in from nursing, physical therapists, pharmacists, etc is required to ensure an ICU sedation strategy is applied consistently across shifts, staff, and patients. Nurses are ultimately in control of the sedation on an hour-by-hour basis; nursing-driven protocols have reduced sedation doses and improved outcomes in numerous studies.


Delirium in the Mechanically Ventilated Patient

Delirium is common in critically ill patients, and is associated with a variety of worse outcomes such as decreased respiratory and functional status, quality of life, and mortality in both the short and long term. In fact, it is estimated that up to 60% of mechanically ventilated ICU patients experience delirium at some point during their ICU stay.12 Other common risk factors for the development of delirium include increased age, history of alcohol abuse, immobility, hearing or vision impairment, and high severity of illness.

Incidence of delirium can be reduced by nonpharmacologic measures such as reorientation, enhancing the conditions for sleep, and reducing exposure to benzodiazepines, anticholinergics, and other delirium-causing medicines. Early mobilization, daily sedation interruptions, and daily spontaneous breathing trials have reduced delirium in mechanically ventilated patients in randomized trials.

The best validated tool for assessing delirium, CAM-ICU, is recommended for routine use in the PAD guidelines, as well as the ICDSC. Identifying and treating delirium can reduce mortality, length of stay, and risk of long-term cognitive impairment.

Antipsychotics for ICU Delirium

Antipsychotic drugs, such as haloperidol, are commonly used to treat agitation believed to be due to ICU delirium; however evidence is lacking for the benefits of antipsychotics in the treatment of ICU delirium. No high quality randomized trials have been done to confirm the benefit of antipsychotics for ICU delirium.

retrospective study did show lower mortality in haloperidol-treated patients receiving mechanical ventilation, and a randomized trial testing haloperidol against olanzapine showed reductions in delirium in both groups. Neither medication was superior; however 6 of 45 patients treated with haloperidol developed extrapyramidal side effects, compared to none in the olanzepine group.

Most antipsychotics can lengthen QT intervals, but haloperidol is most strongly linked to torsades de pointes. Due to its tendency to prolong QT intervals and induce torsades de pointes, haloperidol has carried an FDA black-box warning. Still, the PAD guidelines recommend haloperidol for treatment of ICU delirium (C).


Alyssa D. Rabon, PharmD; Melanie N. Smith, PharmD, BCPS



  1. Devlin JW, et al. Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. Crit Care Med. 2018;46(9):e825.
  2. Puntillo KA, Max A, Timsit JF, et al. Determinants of procedural pain intensity in the intensive care unit. The Europain study. Am J Respir Crit Care Med. 2014;189(1): 39-47.
  3. Rosenquist RW, Vrooman BM. Chapter 47. Chronic Pain Management. In: Butterworth JF, IV, Mackey DC, Wasnick JD. eds. Morgan & Mikhail's Clinical Anesthesiology, 5e. New York, NY: McGraw-Hill; 2013. http://accessmedicine.mhmedical.com/content.aspx?bookid= 564&Sectionid=42800580. Accessed January 05, 2017.
  4. Burk RS, Grap MJ, Munro CL, et al. Agitation onset, frequency, and associated temporal factors in critically ill adults. Am J Crit Care.2014;23(4):269-304.
  5. Fraser GL, Prato BS, Riker RR, et al. Frequency, severity, and treatment of agitation in young adults versus elderly patients in the ICU. Pharmacotherapy. 2000;20(1):75-82.
  6. Sessler CN, Gosnell MS, Grap MJ, et al. The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med. 2002;166(10):1338-1344.
  7. Mirrakhimov AE, Voore P, Halytskyy O, Khan M, Ali AM. Propofol infusion syndrome in adults: a clinical update. Crit Care Res Pract. 2015;2015:260385.
  8. Riker RR, Shehabi Y, Bokesch PM, et al; SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study Group: Dexmedetomidine vs midazolam for sedation of critically ill patients: A randomized trial. JAMA 2009; 301:489–499.
  9. Pandharipande PP, Pun BT, Herr DL, et al: Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: The MENDS randomized con­trolled trial. JAMA 2007; 298:2644–2653.
  10. Ruokonen E, Parviainen I, Jakob SM, et al; “Dexmedetomidine for Continuous Sedation” Investigators: Dexmedetomidine versus pro­pofol/midazolam for long-term sedation during mechanical ventila­tion. Intensive Care Med 2009; 35:282–290.
  11. Yeo QM, Wiley TL, Smith MN, Hammond DA. Oral agents for the management of agitation and agitated delirium in critically ill patients. Crit Care Nurs Q. 2017 Oct/Dec;40(4):344-362.
  12. Brummel NE, Girard TD. Delirium in the Intensive Care Unit. In: Hall JB, Schmidt GA, Kress JP. eds. Principles of Critical Care, 4e. New York, NY: McGraw-Hill; 2015. http://accessmedicine.mhmedical.com/content.aspx?bookid=1340&Sectionid=80035891. Accessed January 04, 2017.

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Pain Control and Sedation in Mechanically Ventilated Patients: Review