Khuram Ameen MDOregon Lung Specialists

Critically ill patients frequently require invasive monitoring and other support that can lead to anxiety, agitation, and pain

Use of sedation is essential for the comfort and safety

More than 50 percent of patients received one or more sedatives by intravenous infusion.

The most common agent was propofol (82 percent), followed by benzodiazepines (31 percent), and dexmedetomidine (4 percent).

Opiates were commonly combined with benzodiazepines.

Heavy sedation may increase mortality and morbidity has led to a new model in which the emphasis is on maximizing the comfort of these patients while they remain interactive, oriented,and able to follow instruction

To determine whether the use of continuous i.v. sedation is associated with prolongation of the duration of mechanical ventilation

Prospective observational cohort study The primary outcome measure was the

duration of mechanical ventilation. Secondary outcome measures included ICU

and hospital lengths of stay, hospital mortality, and acquired organ system derangements

The duration of mechanical ventilation was significantly longer for patients receiving continuous i.v. sedation compared with patients not receiving continuous i.v. sedation (185+/-190 h vs 55.6+/-75.6 h; p

Approaches to removal of sedation and mechanical ventilation for critically ill patients vary widely. Our aim was to assess a protocol that paired spontaneous awakening trials (SATs)-ie, daily interruption of sedatives-with spontaneous breathing trials (SBTs)

336 mechanically ventilated patients were randomized

Patients in the intervention group spent more days breathing without assistance during the 28-day study period than did those in the control group (14.7 days vs 11.6 days; mean difference 3.1 days)

They were discharged from intensive care (median time in intensive care 9.1 days vs12.9 days; p=0.01) and the hospital earlier (median time in the hospital 14.9 days vs 19.2 days; p=0.04

More patients in the intervention group self-extubated than in the control group (16 patients vs six patients; 6.0% difference, 95% CI 0.6% to 11.8%; p=0.03), but the number of patients who required reintubation after self-extubation was similar (five patients vs three patients; 1.2% difference)

Our results suggest that a wake up and breathe protocol that pairs daily spontaneous awakening trials (ie, interruption of sedatives) with daily spontaneous breathing trials results in better outcomes for mechanically ventilated patients in intensive care than current standard approaches and should become routine practice.

Open-label, randomized, prospective, phase IV clinical trial

Patients were randomized to receive midazolamor propofol sedation was titrated to achieve synchronization with mechanical ventilation

All patients received 0.5 mg/kg/24 hrs of morphine chloride

When the patient was ready for weaning according to defined criteria, sedation was interrupted abruptly and the time from interruption of sedation to the first T-bridge trial and to extubation was measured

Duration of sedation was 141.7 ± 89.4 hrs and 139.7 ± 84.7 hrs, and cost (US dollars) attributed to sedation was $378 ±342 and $1,047 ±794 (p =.0001) for the midazolam and propofol groups, respectively.

In the midazolam group, time from discontinuation of the drug infusion to extubation was 97.9 ± 54.6, In the propofolgroup, time from discontinuation of the drug infusion to extubation was 34.8 ±29.4 hrs

Cost per patient in the midazolam group (including ICU therapy and sedation with midazolam) was $10,828 ± 5,734. Cost per patient in the propofol group was $9,466 ±5,820, $1,362 less than in the midazolam group.

To compare the effectiveness, characteristics, duration of action, hemodynamic and biochemical effects, and side effects of propofol and midazolam used for continuous intravenous sedation of ventilated critically ill patients

Multicenter, prospective, randomized, nonblinded study.

Supported, in part, by a grant from Zeneca Pharmaceuticals

Propofol or midazolam was used for induction and maintenance of continuous intravenous sedation for a maximum of 5 days

The effectiveness of those two regimens was assessed according to their effects on ventilatory management and the presence of agitation

The mean duration of sedation was 81 ±25 hrs and 88 ± 27 hrs for the propofol and midazolam groups, respectively

There was no difference regarding the opiate and muscle relaxant requirements between the two groups.

Sedation with propofol was more effective in achieving patient-ventilator synchrony than that with midazolam after the first hour of treatment

Patients sedated with propofol awoke more rapidly and with less variability than those patients sedated with midazolam (23 ± 16 mins vs. 137 ± 185 mins,

Prospective,randomized study evaluate the efficacy of continuous infusions

of lorazepam vs. midazolam for sedation in the intensive care unit

Patients were randomized to Receive either lorazepam or midazolam. The infusion rate was adjusted by the nurse to maintain sedation at Ramsay’s 2 or 3

Mean time to return to baseline mental status was 216 minutes for lorazepam and 815 minutes for midazolam

Average fluid used to infuse the lorazepam was 1.2 liters and 1.3 liters for midazolam

Time to wake up was occasionally delayed for 24 hours

Nine open label, randomized trials comparing long term sedation: Most compared propofol with midazolam

▪ “Propofol consistently provided faster awakening [and extubation] than midazolam with statistical and probable clinical significance.”

Midazolam vs. lorazepam▪ Double-blind study of long-term sedation

▪ No statistical difference in awakening time however, awakening time with lorazepam was more predictable and cost-effective.

Jacobi J, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med2002; 30(1): 119-142.

GABA Receptor agonist medications are the most commonly used sedatives for intensive care unit (ICU) patients, yet preliminary evidence indicates that the 2 agonist dexmedetomidine may have distinct advantages

Prospective, double-blind, randomized trial conducted in 68 centers in 5 countries between March 2005 and August 2007

Percentage of time within target RASS range. Prevalence and duration of delirium, Use of fentanyl and open-label midazolam,

and nursing assessments. Duration of mechanical ventilation, ICU

length of stay, and adverse events

There was no difference in percentage of time within the target RASS range (77.3% for dexmedetomidine group vs 75.1% for midazolam group

The prevalence of delirium during treatment was 54% (n = 132/244) in dexmedetomidine-treated patients vs 76.6% (n = 93/122) in midazolam-treated patients (difference, 22.6%

Median time to extubation was 1.9 days shorter in dexmedetomidine-treated patients

ICU length of stay was similar (5.9 days) Dexmedetomidine-treated patients were

more likely to develop bradycardia (42.2% [103/244] vs 18.9%),but had a lower likelihoodof tachycardia (25.4% vs 44.3%) or hypertension requiring treatment (18.9% vs 29.5%)

many questions remain unanswered. Because benzodiazepines have shown the greatest association with delirium, and guidelines recommend midazolam only for short-term use due to “unpredictable awakening and time to extubation” with longer use, it is perhaps not surprising that infusion of midazolam for multiple days resulted in longer time to extubation

It remains unclear whether dexmedetomidinewould produce the same decrease in delirium and improvement in time to extubation if it were compared with another medication such as propofol

Whether benzodiazepines given as bolus rather than infusion may have reduced delirium and length of mechanical ventilation in the midazolam group also remains an important question

Delirium is defined as an acute change or fluctuation in mental status plus inattention, and either disorganized thinking or an altered level of consciousness at the time of the evaluation

Several studies have now confirmed that delirium occurs in 60% to 80% of mechanically ventilated patients

Increased incidence in ventilated patients

Incidence in critically ill patients range from 35-60%.

Up to 81.7% of mechanically ventilated pts developed delirium at some point during Vanderbilt study.

Underdiagnosed condition

Delirium goes undiagnosed in >66% of patients

- Ely EW et al. Delirium as a predictor of mortality in mechanically ventilated patients in the ICU. JAMA 2004; 291: 1753-62- Ely EW et al. The impact of delirium in the intensive care unit on hospital length of stay. Intensive Care Med 2001; 27: 1892-1900- Inouye SK et al. Nurses’ recognition of delirium and its symptoms. Arch Intern Med. 2001; 161: 2467-2473.

Eli EW et al. Delirium as a predictor of mortality in mechanically ventilated patients in the ICU. JAMA 2004; 291: 1753-62Milbrandt EB et al. Costs Associated with Delirium in Mechanically Ventilated Patients. Crit Care Med 2004; 32: 955-962, 2004

Independent predictor of mortality (3-fold increase) and increased length of stay in ventilated pts.

After adjusting for confounders, delirium was also associated with a 39% increase in ICU costs.

Term ICU psychosis is “old-fashioned, inaccurate and not appropriate”

Hyperactive - paranoid, agitated

Readily recognized, best prognosis

Purely hyperactive: 1.6% of delirium episodes

Hypoactive - withdrawn, quiet, paranoid

“Quiet delirium”

Often not well recognized, misdiagnosed

Purely hypoactive episodes 43.5%

Mixed - combination

Most common in ICU patients 54.9%

Worst prognosis

Peterson JF, et al. Delirium and Its Motoric Subtypes: A Study of 614 Critically Ill Patients. J Am Geriatr Soc 54: 479-484, 2006.

Richmond Agitation Sedation Scale (RASS)

Evidence of acute change from baseline?Fluctuating RASS, GCS or other assessment?

Attention Screening Exam: Auditory or Visual

Questions: Will a stone float on water?Are there fish in the sea?Does one pound weight more than two pounds?Can you use a hammer to pound on a nail?

Confusion Assessment Method for ICU (CAM)

Richmond Agitation Sedation Scale (RASS)

Neurobiology of attention Cortical vs subcortical mechanisms Neurotransmitter mechanisms

Acetylcholine plays a key role in pathogenesis

▪ Anticholinergic drugs caused delirium in healthy volunteers, reserved by cholinesterase inhibitors

▪ Serum anticholinergic activity correlated with severity of delirium

Mach, JR, Dysken, MW, Kuskowski, M, et al. Serum anticholinergic activity in hospitalized older persons with delirium: A preliminary study. J Am Geriatr Soc 1995; 43:491.

Haloperidol is agent of choice*

▪ Best antipsychotic, few anticholinergic side-effects▪ Unlikely to cause sedation and hypotension

▪ Typical starting dose: 1-2 mg IV every 2-4 hours▪ Adjust for elderly and degree of agitation

▪ Can double dose every 20-30 minutes if uncontrolled --> continuous drip 5-10 mg/hr

▪ QT prolongation▪ Cardiac monitoring at higher doses, measure K+ and Mg2+

▪ Discontinue if QTc>450ms or extrapyramidal symptoms develop

American Psychiatric Association. Practice Guidelines for Treatment of Patients with Delirium. 1999.UK Clinical Pharmacy Association. Detection, Prevention and Treatment of Delirium in Critically Ill Patients. June 2006.

Role for benzodiazepines

Specifically indicated for EtOH or BZD withdrawal delirium

If possible, avoid use

▪ Contribute to development of delirium

▪ Ineffective in treating delirium

In ventilated patients, sedation with benzodiazepines is often necessary

No published data in critical care literature Antipsychotics may still play a role

Treat like hyperactive delirium

Stimulants such as methylphenidate may be used

American Psychiatric Association. Practice Guidelines for Treatment of Patients with Delirium. 1999.UK Clinical Pharmacy Association. Detection, Prevention and Treatment of Delirium in Critically Ill Patients. June 2006.