Introduction
Patient comfort in an intensive care unit (ICU), from both a mental and physical health perspective, is of utmost importance for patient safety and recovery. Proper management of analgesia and sedation is especially important in patients admitted to the neurocritical care unit (NCCU), because these patients have significant comorbidities and often management goals (e.g., sedation vs. need to evaluate consciousness or neurologic function) are opposing. In addition, health care providers have to be cognizant of the anxiety experienced by family members and understand how to alleviate it. Family anxiety in the ICU is beyond the scope of this chapter and is discussed elsewhere. This chapter provides an overview of analgesia and sedation in the critically ill and how to monitor its proper use. The reader also is referred to recent reviews and guidelines on analgesia, sedation, and delirium in the ICU. Most research has been on patients in medical or surgical ICUs with far less specific information available for patients in the NCCU. The following topics are discussed:
- 1.
Indications for the use of analgesia and sedation in the ICU
- 2.
Potential complications of analgesic and sedative medications, with a focus on the role of these medications in delirium of critical illness
- 3.
Strategies to optimize the delivery of analgesia and sedation
- 4.
Selection of analgesia and sedation for the critically ill
- 5.
Management of delirium
Indications for Analgesia and Sedation
Comfort and safety are the two main indications for analgesia and sedation in the ICU, and both analgesia and sedation may be administered for prolonged periods, particularly when a patient is mechanically ventilated. In addition, in the NCCU analgesia and sedation are used to treat intracranial pressure (ICP) and can help improve brain oxygen.
Pain or discomfort is treated by analgesics. The ICU patient often has multiple sources of discomfort that arise from primary disease, invasive monitoring, endotracheal intubation, phlebotomy, and procedures performed while in the ICU. Inadequately treated discomfort and pain may cause an increased stress response manifested by tachycardia, increased oxygen consumption, hypercoagulability, immunosuppression, hypermetabolism, increased endogenous catecholamine activity, and, in patients with acute brain injury, an increase in ICP. Insufficient pain relief also can lead to sleep deficiency, disorientation, and anxiety. Oxygen consumption can be decreased by about 15% from baseline when adequate analgesia is provided, thus reversing some of these unwanted effects. In addition, a blood pressure increase that can contribute to intracranial bleeding after a craniotomy can be attenuated by effective pain control rather than antihypertensives in some patients.
Critically ill patients often experience anxiety that can be alleviated by judicious sedation. Apart from anxiolysis, sedatives also can produce amnesia, an effect that should be sought only when neuromuscular blocking agents are administered. There are also potentially unwanted mental health effects from how sedation is used in the ICU. Unpleasant memories of an ICU stay have been associated with post-traumatic stress disorder (PTSD) symptoms in survivors. However, some studies suggest that the occurrence of PTSD may be more specifically related to whether the memories retained are delusional, and that factual memories, even if unpleasant, are less likely to cause PTSD. In addition there are some emerging concerns that some drugs themselves may produce cognitive dysfunction post ICU.
The use of analgesia and sedation in the ICU can be a double-edged sword. Both are inherently necessary but both can have unwanted consequences. The administration of analgesia and sedation therefore should account for patient heterogeneity, including severity and prognosis, to develop a tailored, optimized approach for each individual. There are many approaches to the same patient, and these often are influenced by unexpected factors such as resources, technology, and culture. Given the potential deleterious effects of mismanagement, the Society of Critical Care Medicine (SCCM) guidelines provide recommendations for appropriate use of sedative and analgesic medications and outline specific monitoring to be used when these medications are administered to ICU patients. Adherence to these guidelines can help ensure that the medications are used properly and side effects are minimized.
Complications of Sedative Administration
Drug pharmacokinetics and pharmacodynamics can be unpredictable in ICU patients because of their disease, drug interactions, organ dysfunction, irregular absorption, and variable protein binding. Each of these parameters can contribute to complications, including need for mechanical ventilation, infection, delirium, and chronic illness among survivors. Structured multidisciplinary approaches, including protocols and algorithms can help reduce these adverse effects associated with sedation and analgesia in the ICU. Sedation and analgesia algorithms should include identification of goals and specific targets, use of valid and reliable tools to assess analgesia, agitation, and sedation, and incorporation of logical medication selection.
Respiratory Depression
Overuse of opiates and sedatives in the conscious patient can cause respiratory depression. It therefore is important to individualize doses of opiates and sedatives to achieve levels of analgesia and anxiolysis that are appropriate without needing to establish an artificial airway.
Prolonged Mechanical Ventilation
Deep sedation, especially when administered through continuous infusions without daily interruption, can be associated with prolongation of mechanical ventilation and ICU length of stay. The inability to perform adequate daily patient assessments and neurologic examinations then may result in increased need to evaluate the neurologic status with imaging or electrophysiologic studies. This contributes to increased costs of care and potential complications associated with transport of a critically ill patient. On the other hand, inadequate sedation and analgesia in an intubated patient can contribute to coughing or compromise ventilation (i.e., patient optimization arises from conflicting therapeutic priorities).
Critical Illness Polyneuromyopathy
Patients who survive critical illness often have long-lasting physical, neuropsychiatric, and quality of life impairments. Prolonged bed rest and stay in the ICU can be associated with persistent functional debilitation and reduced quality of life, even after ICU discharge. This functional debilitation often manifests as a polyneuropathy or an associated myopathy. Although the two conditions are physiologically distinct from each another, they frequently coexist and are recognized as critical illness polyneuropathy and myopathy (CIPNM), critical illness neuromuscular abnormalities (CINMA), or critical illness polyneuromyopathy (CIPM).
CIPM manifests itself physically as a generalized, symmetrical muscle weakness that spares facial muscles. Although some suggest that physical examination and history may be sufficient for the diagnosis, nerve conduction studies, electromyography, and possibly even muscle biopsy increase the sensitivity to identify this entity. Additional potential risk factors include steroid use, age, hyperglycemia, and the presence of systemic inflammatory response syndrome (SIRS). None are definitive, but the association with prolonged immobilization makes it reasonable that reduction of sedation may improve the ability to mobilize critically ill patients early, thus minimizing the occurrence or the severity of CIPM.
Neuro-Specific Complications
Analgesics and sedatives often are administered in continuous drips and have variable accumulation in critically ill patients; this can predispose patients to experience a withdrawal syndrome on discontinuation. In addition, many psychological conditions have been studied in relation to prolonged analgesia and sedation, particularly depression and PTSD, with symptoms that appear directly related to the number of days receiving such medications. There is also some suggestion that not being able to recall specifics of their ICU stay may have negative effects on patients’ long-term cognitive abilities compared with those who have specific recall. ICU survivors also may recall pain, anxiety, fear, and inability to sleep during their ICU stay when questioned later. These are important aspects for the intensivist to keep in mind because they are effects that are unlikely to be manifested in the ICU but have significant impact on the patient as an individual.
Delirium
Delirium is defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM IV ) as a disturbance of consciousness with inattention, accompanied by a change in cognition or perceptual disturbance that develops over a short period (hours to days) and fluctuates over time. Delirium occurs in between 20% and 80% of mechanically ventilated medical, trauma, and surgical ICU patients. However, the majority of the cases are not recognized ; this creates a delay in diagnosis, or the symptoms are attributed to another cause.
One approach to classify delirium is to group patients according to their level of alertness (hyperactive, hypoactive, or mixed). Peterson et al. found the distribution of the delirium subtypes among ICU patients to be 1.6% hyperactive, 43.5% hypoactive, and 54.1% a mixed type. Hyperactive delirium is assigned to patients with characteristics of agitation, restlessness, attempts to remove catheters or tubes, violent behaviors, and emotional lability and has an overall better prognosis compared with hypoactive delirium, which is manifested by flat affect, withdrawal, apathy, lethargy, and decreased responsiveness. Given its subtle appearance in a population that may be subject to polypharmacy, it is not surprising that hypoactive delirium remains unrecognized in 66% to 74% of patients in a variety of settings. Use of a validated monitoring system can help guard against the failure to recognize this type of delirium.
Recognition of delirium in ICU patients is important because its development is associated with longer time on mechanical ventilation, ICU length of stay, higher costs, increased likelihood of discharge to a nursing home, an increased in-hospital mortality, and long-term cognitive impairment in survivors. Indeed, patients who develop delirium during their ICU stay have a two- to threefold increase risk of death after adjustment for covariates such as age, presence of sepsis or acute respiratory distress syndrome (ARDS) and Acute Physiology and Chronic Health Evaluation (APACHE) II scores. In addition, a delay in initiating treatment for delirium and a longer duration of delirium are strong predictors of increased mortality in the ICU.
The delirium research field continues to expand, and multiple potential mechanisms of delirium have been proposed including imbalances in the synthesis, release, and inactivation of neurotransmitters ; inflammatory abnormalities induced by endotoxins and cytokines ; impaired oxidative metabolism ; a relative cholinergic deficiency secondary to this impaired oxidative metabolism ; and variations in levels of neurotransmitter precursor amino acids.
Who is at risk for developing delirium in the ICU population? Baseline characteristics including genetic factors, dementia, chronic illness, advanced age, and depression are associated with an increased risk of developing delirium. Although many of these risk factors are not modifiable, there are iatrogenic factors to which clinicians can pay close attention to help reduce the risk of delirium. These factors include hypoxia, metabolic and electrolyte imbalances, substance withdrawal syndromes, infection, dehydration, hyperthermia, vascular disorders, and sleep deprivation. In addition neurologic insults such as seizures, head trauma, and intracranial space–occupying lesions have been suggested to have a role in delirium.
Benzodiazepines and opiates are implicated in the development of delirium in non-ICU and in ICU patients (including the postsurgical population). This often puts the clinician in a paradoxical situation because these medications may be necessary and are established as standard practice in clinical practice guidelines by the SCCM to provide analgesia and anxiolysis to patients who undergo procedures or are on mechanical ventilation. Hence the need for sedation and analgesia must be balanced against its associated complications.
Although benzodiazepines have been shown to be risk factors for delirium, the data that implicate fentanyl and morphine are less convincing. For example, Morrison et al. in a prospective cohort study showed that inadequate analgesia may predispose patients to delirium, with patients who receive lower doses of parenteral morphine after hip fracture to be at higher risk for developing delirium. This may also depend in part on other medications (e.g., some anesthesiologists often comment that premedication with scopolamine makes patients who arouse in pain more likely to suffer delirium).
Delirium Scales
Screening tools and guidelines allow the clinician to approach the patient at risk for delirium in a systematic fashion. Two scales ( Fig. 11.1 and Table 11.1 ), the Confusion Assessment Method for the ICU (CAM-ICU) and the Intensive Care Delirium Screening Checklist (ICDSC) have been validated to diagnose delirium in mechanically ventilated patients. Delirium monitoring was included in the 2002 SCCM practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. The management guidelines for pain, agitation, and sedation were under revision in 2012. A separate diagnostic instrument to diagnose pediatric delirium in critically ill children, the Pediatric Confusion Assessment Method for Intensive Care Unit (pCAM-ICU), has been validated. Importantly, unlike bedside pain assessment tools that have been validated in critically ill patients with neurologic disorders, delirium and sedation tools have had less rigorous research in NCCU patients.
| Patient Evaluation | |
|---|---|
| Altered level of consciousness (A-E) * | |
| Inattention | Difficulty in following a conversation or instructions. Easily distracted by external stimuli. Difficulty in shifting focuses. Any of these scores 1 point. |
| Disorientation | Any obvious mistake in time, place, or person scores 1 point. |
| Hallucinations-delusion-psychosis | The unequivocal clinical manifestation of hallucination or of behavior probably due to hallucination or delusion. Gross impairment in reality testing. Any of these scores 1 point. |
| Psychomotor agitation or retardation | Hyperactivity requiring the use of additional sedative drugs or restraints in order to control potential danger to oneself or others. Hypoactivity or clinically noticeable psychomotor slowing. |
| Inappropriate speech or mood | Inappropriate, disorganized, or incoherent speech. Inappropriate display of emotion related to events or situation. Any of these scores 1 point. |
| Sleep-wake cycle disturbance | Sleeping less than 4 hours or waking frequently at night (do not consider wakefulness initiated by medical staff or loud environment). Sleeping during most of the day. Any of these scores 1 point. |
| Symptom fluctuation | Fluctuation of the manifestation of any item or symptom over 24 hours scores 1 point. |
| Total score (0-8) | Score of 4 or more is consistent with diagnosis of delirium |
Sedation Scales
The diagnosis of delirium first requires the assessment of arousal level, followed by an assessment for delirium. Examples of sedation scales include the Ramsay Sedation (RS) scale, the Riker Sedation-Agitation Scale (SAS), and the Richmond Agitation-Sedation Scale (RASS). Although any of these can be used to assess agitation, this chapter focuses on the RASS ( Table 11.2 ) because it has excellent interrater reliability and can be used to detect changes over consecutive days. The RASS is a 10-point scale that ranges from +4 to –5. A score of 0 signifies a calm and alert patient. Positive RASS scores denote levels of aggressive behavior, and negative RASS scores denote less responsiveness, and differentiate between response to verbal (–1 to –3) and physical stimuli (–4 and –5). Patients with a RASS score of –3 and higher (lighter levels of sedation) can further be assessed for delirium.
| Score | Term | Description |
|---|---|---|
| +4 | Combative | Overtly combative, violent, immediate danger to staff |
| +3 | Very agitated | Pulls or removes tube(s) or catheter(s); aggressive |
| +2 | Agitated | Frequent nonpurposeful movement, fights ventilator |
| +1 | Restless | Anxious but movements not aggressive or vigorous |
| 0 | Alert and calm | |
| −1 | Drowsy * | Not fully alert, but has sustained awakening (eye opening/eye contact) to voice (≥10 seconds) |
| −2 | Light sedation * | Briefly awakens with eye contact to voice (<10 seconds) |
| −3 | Moderate sedation † | Movement or eye opening to voice (but no eye contact) |
| −4 | Deep sedation † | No response to voice, but movement or eye opening to physical stimulation |
| −5 | Unarousable | No response to voice or physical stimulation |
Confusion Assessment Method for Intensive Care Unit
The CAM-ICU is a scale that assesses delirium, that can be done in approximately 60 to 90 seconds. It has high specificity and interrater reliability but may not always help detect early delirium. In addition, the CAM-ICU allows for delirium assessment in the face of sedative medication. This then may be a potential limitation in the NCCU, where it is important to determine if there is neurologic deterioration as well. The CAM-ICU assesses four features: acute change or fluctuation in mental status (feature 1), inattention (feature 2), disorganized thinking (feature 3), or an altered level of consciousness (feature 4) (see Fig. 11.1 ). The diagnosis of delirium using the combination of the RASS and the CAM-ICU requires:
- 1.
RASS score of –3 or higher and
- 2.
Feature 1 of CAM-ICU (acute change or fluctuation in mental status) and
- 3.
Feature 2 of CAM-ICU (inattention) and
- 4.
One of the following:
- ▪
Feature 3 (disorganized thinking)
- ▪
Feature 4 (altered level of consciousness)
- ▪
Intensive Care Delirium Screening Checklist
The ICDSC has eight diagnostic features (see Table 11.1 ). To be diagnosed with delirium, a patient should have four or more features from the checklist during the evaluation period. Patients who demonstrate some features from the ICDSC but do not meet all the criteria for delirium are considered to have subsyndromal delirium. Work by Ouimet et al. has shown that subsyndromal delirium is part of the spectrum of acute brain dysfunction between normal and full-feature delirium and is associated with worse outcomes than in patients with normal cognition, though better than in those with delirium.
Strategies to Optimize the Delivery of Analgesia and Sedation
Systematic ICU management protocols including rating scales are important for analgesia, sedation, and delirium, and their use likely improves outcome including in ventilated ICU patients. Studies that evaluate the efficacy of sedation protocols and target-based sedation all show benefits such as shorter time on mechanical ventilation and less time in the ICU and hospitals. However, subjective sedation scales that depend on patient behavior and clinical examination may be insensitive during deep sedation. This is evident from a study that showed that almost 40% of patients admitted to a medical ICU had episodes of burst suppression on their electroencephalogram (EEG), despite being managed by the use of targeted sedation with sedation scales. In addition, burst suppression was associated with an increased in-hospital and 6-month mortality after adjusting for severity of illness and presence of sepsis. The bispectral analysis of the EEG with a Bispectral Index (BIS) monitor can be measured easily in the ICU setting. A frontal temporal sensor is attached to the patient; this derives a signal from several EEG components that can be visualized but also numerically graded on a scale from 100 (completely awake) to 0 (deep sedation). The visualization of potential burst suppression allows the clinician to recognize the presence of a drug-induced coma, and the graded scale allows the clinician to otherwise titrate sedative medications to their desired effect. This is particularly helpful in the case of the paralyzed patient, in whom the depth of sedation and amnesia is difficult to determine. However, even in the nonparalyzed patient, the BIS monitor may provide further information to better titrate sedation.
The BIS and the SAS or RASS have been compared in mechanically ventilated patients and appear comparable (i.e., BIS can differentiate inadequate from adequate sedation). Similarly Riker et al. studied 39 ICU patients sedated after cardiac surgery and observed significant agreement between BIS and SAS. In addition, the authors described significant changes in the BIS values as patients became more arousable. In trauma patients the BIS wave form appears to coincide with propofol on/off during daily spontaneous awakening trials (SATs). However, the role of the BIS to guide the titration of sedation in ICU remains unclear, and in one study use of a BIS monitor to support clinical sedation management decisions in ventilated patients did not reduce the amount of sedation used, the length of mechanical ventilation (MV), or the length of ICU stay. In addition, the interpretation of BIS findings in traumatic brain injury (TBI) patients can be subjective. Further studies on the applicability of neurologic monitoring beyond sedation scales are under way. However, in the interim, sedation protocols and scales need to be implemented to prevent unnecessary administration of sedatives and analgesics to critically ill patients.
One method used in ICUs to assess sedation is the “daily wake-up.” The role of daily interruptions of continuous sedative infusions in critically ill patients has been evaluated in several studies. Patients managed with sedation cessation had a significant reduction in the duration of MV, shorter ICU and hospital length of stay, and fewer neuroradiologic procedures and tracheostomies. Importantly there was no increase in long-term mental health sequelae associated with the daily “wake-ups.” Girard et al. in a multicenter randomized clinical trial, the Awakening Breathing Controlled trial, examined the efficacy and safety of a linked sedation and ventilator weaning protocol for mechanically ventilated ICU patients. Patients were managed by a “targeted-sedation” strategy and control group patients received daily spontaneous breathing trials (SBTs). In the treatment group patients had a mandatory SAT as step A (total cessation of sedation long enough to wake to verbal stimulus or tolerate for 4 hours), followed by the SBT as step B. The “wake-up and breathe” intervention was associated with a 3-day reduction of MV, 1 day less in coma, 4 days less in the ICU and hospital, and a 14% absolute reduction in the risk of death within 1 year ( Fig. 11.2 ). Whether the daily wake-up is beneficial in the NCCU or the ideal method to detect neurologic deterioration in a sedated patient is still to be fully elucidated.
Selection of Analgesia and Sedation for Critically Ill Patients
The selection of an opioid traditionally has depended on the likely duration of analgesic infusion and the pharmacology of the specific opioid. There is little evidence that one sedative agent is better than another for control of ICP or cerebral perfusion pressure in adults with severe brain injury. Morphine and hydromorphone because of their longer duration of action are used typically for cases of prolonged infusions. Hydromorphone has several advantages over morphine including a lack of histamine release and lack of a clinically active metabolite. This may result in less vasodilation and hypotension and less prolonged sedation in patients with renal insufficiency. Fentanyl’s rapid onset and short duration of action make it better suited for shorter periods of infusion. Its ease of titration and lack of histamine release also make it better suited to the hemodynamically unstable patient.
Remifentanil is one of the newest µ agonists with a rapid onset and offset of action. Its lack of accumulation makes it a useful drug for continuous infusion in the ICU, especially the NCCU. Dahaba et al. conducted a randomized double blind study on ventilated patients receiving remifentanil or morphine. Those in the remifentanil group had more optimal sedation and a shorter duration of mechanical ventilation. Muellejans et al. compared remifentanil with fentanyl in ICU patients; the efficacy of sedation was similar but more propofol was required in the fentanyl group. The time to extubation was similar. However, the percentage of patients who experienced pain after extubation was greater in the remifentanil group, suggesting the need for proactive pain management when weaning remifentanil. This is important in patients with neurologic compromise because increased pain and the potential for withdrawal may contribute to hypertension and tachycardia that may be detrimental to the patient. Other studies suggest that fentanyl and remifentanil provide similar amounts of analgesia.
The safety and efficacy of analgesia-based sedation with remifentanil have been compared with conventional sedation with hypnotic-based regimens for patients with brain injury who require prolonged sedation for MV. Neurologic assessment times and time to extubation were shorter for patients who received remifentanil than those who received propofol or midazolam supplemented with morphine or fentanyl. Breen et al., in another randomized controlled trial that compared remifentanil-based sedation with a midazolam-based regimen, observed that the duration of mechanical ventilation and duration of weaning were shorter in patients who received remifentanil. There also was a trend toward shortened ICU stay.
There are several comparative trials between hypnotic sedative regimens. Barr et al. used a pharmacologic model to compare lorazepam and midazolam infusions for ICU sedation. Lorazepam was found to have twice the sedative potency and four times the amnestic potency of midazolam. The emergence times for light and deep sedation were longer for lorazepam than midazolam. In a prospective randomized controlled study in trauma patients in which infusions of lorazepam, midazolam, and propofol were compared, McCollam et al. observed that oversedation occurred most frequently with lorazepam, and the greatest number of dosage adjustments was required by the lorazepam group. Cost was greatest, and undersedation occurred most often with propofol. The results suggest that midazolam is the most titratable drug with the least amount of oversedation or undersedation and that lorazepam was the most cost-effective agent for sedation.
Propofol has been compared to individual benzodiazepines in several studies, including in randomized controlled trials (RCTs). Carson et al. conducted a randomized trial that compared intermittent lorazepam boluses to propofol infusion with daily interruption of sedatives in both groups. Patients in the propofol group had fewer mechanical ventilation days, with a trend toward greater number of ventilator-free survival days. In an economic evaluation of propofol and lorazepam, overall propofol was less costly per patient than lorazepam despite the considerably lower pharmacy unit cost of lorazepam. The lower costs likely were associated with the greater number of ventilator-free days in the propofol group. Compared with midazolam infusion, patients sedated by propofol infusion have faster and more reliable wake-up times, have equal efficacy of achieving sedation goals, spend a larger percentage of time at their target sedation goal, and have more rapid extubation, although this does not always mean earlier ICU discharge. However, propofol appears to require more frequent dose adjustments, has a lower nurse-rated quality of sedation, and may cause more cardiovascular depression and less amnesia than midazolam, with higher costs. Average time to sedation and change in oxygen consumption is similar in patients who receive propofol or midazolam. Walder et al. performed a systematic review of trials that compared sedation with propofol or midazolam in 2001. The duration of adequate sedation was greater with propofol, independent of the length of sedation, and weaning times were shorter with propofol, but this was only significant in patients sedated for less than 36 hours. Together these various data suggest that propofol is associated with better outcomes when compared with benzodiazepines and appears to be particularly useful in neurologic patients in whom evaluation of the neurologic status is important. In addition when compared with morphine, use of propofol may reduce the need for other interventions to control ICP in patients with TBI.
Dexmedetomidine, an alpha-2 agonist, provides an alternative to gamma-aminobutyric acid (GABA)–agonist sedative medications. There are several potential advantages to its use: “arousable sedation,” suppression of delirium, and preserved ventilatory drive. In 2007, Pandharipande et al. compared dexmedetomidine to lorazepam in mechanically ventilated ICU patients in an RCT, and found that sedation with dexmedetomidine resulted in more days alive without delirium or coma, a lower prevalence of coma, greater achievement of target sedation, and an important trend toward reduction in mortality (27% in lorazepam and 17% in dexmedetomidine group). Studies in ICU patients comparing dexmedetomidine to midazolam have shown superior outcomes with dexmedetomidine, including time on mechanical ventilation and lower probability of delirium. Propofol and dexmedetomidine use is associated with similar outcomes in critically ill patients. After coronary artery bypass surgery, sedation with dexmedetomidine has similar times to weaning and extubation as propofol but there is a significant reduction in narcotic, β-blocker, antiemetic, nonsteroidal anti-inflammatory drug, epinephrine, and diuretic use in patients who receive dexmedetomidine. Observational data suggest patients with neurologic disorders in the ICU may require higher doses of dexmedetomidine to achieve desired sedation levels. It does not seem that higher doses are associated with more adverse side effects.
Sedation paradigms have changed in the ICU; there is less benzodiazepine exposure and unnecessary deep sedation. However, with use has also come identification of disorders such as propofol infusion syndrome, propylene glycol toxicity from lorazepam (see Chapter 22 ), and lipid accumulation with very prolonged emergence with high doses. In addition, risks can be associated with off-label use of attractive sedatives (e.g., unexpected deaths were observed when etomidate was tried off label) and there have been some propofol deaths related to infusion syndrome. Postmarketing discoveries of new risks associated with off-label use of dexmedetomidine and remifentanil may still arise before it can be concluded that the change in sedation paradigm is an independent factor associated with improved patient outcomes especially in the NCCU.
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