Pain control and sedation in mechanically ventilated patients (Review, AJRCCM)

Providing appropriate sedation and analgesia to mechanically ventilated patients is of paramount importance in the ICU. John P. Kress changed clinical practice for the better by showing that daily sedation interruptions (sedation vacations or sedation holidays) reduce ventilator days and mortality. He and Shruti Patel of the University of Chicago provide a fresh update on the topic for the March 1 AJRCCM.

Treating Pain in Mechanically Ventilated Patients

Untreated pain equates to unnecessary suffering, and treating pain prevents agitation and delirium in mechanically ventilated patients. Thus, ensuring good pain control is of paramount importance. The problem is figuring out who is in pain, when most patients can’t communicate. Many physicians treat all intubated patients for pain with an opioid infusion, but pain is only present in 40% of the severely critically ill during their ICU stays, some studies show, and excessive opioids can prolong mechanical ventilation and ICU stays.

Kress & Patel recommend using validated tools such as the Numeric Rating Scale, for patients who can at least point, and the Behavioral Pain Scale, the Critical Care Pain Observation Tool or the Nonverbal Pain Scale for patients who can’t communicate. These tools are each limited and flawed, but have been validated in some contexts and are better than not formally assessing pain.

Fentanyl and remifentanyl are the preferred analgesics, as they and their metabolites don’t accumulate harmfully in renal failure (unlike morphine and hydromorphone/Dilaudid). The ultra-short acting remifentanyl is metabolized by enzymes in the blood (unlike fentanyl which can accumulate during hepatic failure), but remifentanyl can also rarely result in a strange, paradoxical increased sensitivity to pain (hyperalgesia), and can also wear off quickly, leaving the patient with no analgesia.

Anecodtal analgesic strategies also include:

• When a patient is believed to be in pain, use high bolus doses of opioids preferentially to achieve analgesia (e.g., repeated doses of 100 mcg of fentanyl), while making only small increases (e.g., < 25%) in the basal infusion rate as infrequently as possible.
• Check the infusion rate on your patient every morning, and after the patient returns from procedures, to see if other professionals have increased the basal infusion rate to reduce movement or agitation. Reduce the opioid continuous infusion rate as much as possible on a daily basis, preferably as part of a sedation interruption protocol.

Sedation in Mechanically Ventilated Patients

Avoid sedation agents and their side effects entirely if possible; analgesics (e.g. fentanyl) may be sufficient to ensure comfort, especially if pain is causing the observed agitation.

BENZODIAZEPINES

• Benzodiazepines midazolam (Versed) and lorazepam (Ativan) are the most commonly used sedatives, likely due to their lower per-unit cost, although in randomized trials benzodiazepines result in longer time to extubation and discharge, potentially increasing costs overall.
• 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. Versed has a faster onset than Ativan.
• 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 measured association is actually quite weak.
• Benzodiazepine withdrawal is believed to be a risk of abrupt discontinuation of infusions after long periods (although the only series cited is of 9 patients at one center).

 

PROPOFOL

• Propofol reduces time to extubation compared to benzodiazepines, according to multiple randomized trials.
• Propofol causes hypotension especially with bolus dosing, but authors argue the effect is minimal in volume-resuscitated patients.
• Monitor triglycerides 1-2 times / week and include the 1.1 kcal/mL in the nutrition plan while a patient is receiving a lipid-rich 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.

 

DEXMEDETOMIDINE (Precedex)

• Precedex 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.
• Because Precedex caused hypotension and bradycardia in higher doses during clinical trials, its FDA approval has thus far been limited to sedation for <24 hours duration.
• However, a randomized trial in JAMA 2012 (funded by the patent holder) 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.

The AnaConDa, a new closed-circuit system for delivering inhalational anesthetics to mechanically ventilated patients (without intoxicating everyone else in the room), shows promising early results in postoperative patients, suggesting reduced time to extubation and improved outcomes compared to infusion sedation agents.

When using neuromuscular blocking agents/paralytics (hopefully infrequently), Kress & Patel think the bispectral index might be helpful in ensuring deep sedation and amnesia. (Avidan et al in NEJM 2008 concluded using the bispectral index isn’t reliable, though.)

 

Sedation Scales, Sedation Vacations & Strategy

The Richmond Agitation-Sedation Scale (RASS) is the most-validated and most widely-used tool to assess depth of sedation. Titrate almost all patients to a RASS score of -2 or less; very ill or agitated patients (e.g., severe ARDS) may “rarely” require RASS -3 or -4 (according to these authors).

Interrupt sedation completely on a daily basis in all mechanically ventilated patients whenever possible (sedation vacation or sedation holiday). Restart the dose at half the previous rate, if the patient becomes agitated. As Kress et al showed, sedation holidays 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 (Girard, Kress et al Lancet 2008).

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

A whole-team interdisciplinary strategy with buy-in from nursing, physical therapists, 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 (as they should be); 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 (decreased respiratory and functional status, quality of life, and mortality in both the short and long term). However, it is not clear whether delirium causes poor outcomes, or is simply a marker of severe illness. It is also unclear whether interventions that treat or prevent delirium likewise improve outcomes.

For this reason, it’s likewise unclear whether devoting resources (mainly nursing) to systematically screen for delirium repeatedly on every patient is justified or beneficial. Measures like early mobilization that improve delirium also improve other outcomes like ventilator days, contaminating any potential benefit from reduction of delirium per se.

Despite the dearth of evidence, reducing delirium seems a worthy goal; authors cite modest evidence that nonpharmacologic measures (reorientation, enhancing the conditions for sleep, reducing benzodiazepines, anticholinergics, and other delirium-causing medicines) can reduce delirium outside the ICU; possibly they work for patients in the ICU as well. 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, has a high specificity but had only 50% sensitivity when tested in a real-world setting. The ICDSC requires more effort and reportedly had higher sensitivity than CAM-ICU in one comparison (But what is the gold standard for validating a test for delirium in critically ill, intubated, noncommunicative patients?)

ANTIPSYCHOTICS FOR ICU DELIRIUM

Antipsychotic drugs are commonly used to treat agitation believed to be due to ICU delirium; Haldol (haloperidol) is probably the most often-used drug. However, Kress & Patel point out ”[t]here is no convincing evidence for the use of antipsychotics in the treatment of ICU delirium.” Simply put, no good-quality, prospective or placebo-controlled randomized trials have been done to confirm the benefit of Haldol or other antipsychotics for ICU delirium.

Authors suggest the practice is nevertheless defensible: A retrospective study showed lower mortality in haloperidol-treated patients receiving mechanical ventilation, and a randomized trial testing Haldol against Zyprexa (olanzapine) showed reductions in delirium in both groups (neither was superior, there was no placebo arm, and 6 of 45 Haldol-treated patients developed extrapyramidal side effects, compared to none in the olanzepine group).

Due to its tendency to prolong QT intervals and induce torsades de pointes in a tiny fraction of patients, Haldol has carried an FDA black-box warning since 2007. A 1998 retrospective case control study (including 8 cases of TdP) suggested that critically ill patients are at risk for TdP from haloperidol. All antipsychotics can lengthen QT intervals, but Haldol (and thioridazine and droperidol) is most strongly linked to torsades de pointes (28+ cases as of 2007). Still, the Society of Critical Care Medicine recommends haloperidol for treatment of ICU delirium, based on “level C” (the weakest).

 

Parting Points

1. Pain (requiring analgesia), agitation or anxiety (justifying sedation), and delirium (justifying antipsychotics) are often not reliably distinguishable in mechanically ventilated patients, even by experienced physicians and nurses.
2. The sicker the patient, the greater may be the difficulty in ascertaining the cause of distress (and, often, the higher the doses of drugs required).
3. Pain comes first in the “hierarchy of agitation causes,” and carries a moral imperative to treat it; always seek to dentify and treat any pain that’s present.
4. Continually strive to reduce pharmacotherapy to the minimum required in each class, and especially for sedating medications; evidence says this will result in shorter ICU stays, faster and fuller recoveries for critically ill patients.

Patel SB, Kress JP. Sedation and Analgesia in the Mechanically Ventilated Patient. Concise clinical review. Am J Respir Crit Care Med 2012;185:486-497.

Jacobi J et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med 2002;30:119-141. 

Puntillo K et al. Evaluation of pain in ICU patients. Chest 2009;135:1069-1074. 

Vanderbilt University Medical Center, icudelirium.org