Sedation Administration Timing: Intermittent Dosing Reduces Time to Extubation

Background:

Sedation is a significant component in the comprehensive treatment of a critically ill
patient. The presence of anxiety and pain can often be left unexpressed, particularly in
patients on mechanical ventilation. Opioids are primarily used for the treatment of acute
pain and sedative agents (i.e. benzodiazepines, propofol) are used to achieve sedation.
Sedation is required in mechanically ventilated patients, yet the optimal strategy for its
management is unclear. Daily interruptions of continuous intravenous (IV) sedation (i.e.
sedation holiday) have shown to result in a shorter duration of time on mechanical
ventilation and intensive care unit (ICU) stay. However, sedative agents have the potential
to accumulate despite daily interruptions, leading to drug redistribution from the tissues
into the circulation. This may delay mental status recovery and cause abrupt agitation
despite decreased or discontinued sedatives. Therefore, daily sedation holidays do not always
result in awakened and communicative patients. Optimal management for sedation is necessary
to avoid accumulation of drug and prevent sedation-induced delirium.

According to the guidelines on the sustained use of sedatives and analgesics in the
critically ill adult, published by the Society of Critical Care Medicine, maintenance of
sedation with intermittent or "as needed" doses of diazepam, lorazepam, or midazolam may be
adequate to accomplish the goal of sedation. Continuous infusions must be used cautiously due
to accumulation of the parent drug and inadvertent over-sedation.

There are two main clinical trials that studied the use of continuous sedation compared to
intermittent sedation in the critical care setting. In one study, a prospective, randomized,
multicenter, open-labeled trial compared intermittent IV lorazepam with continuous infusion
midazolam. The investigators concluded that intermittent lorazepam and continuous midazolam
had similar levels of sedation and anxiolysis as measured by objective hemodynamic and
laboratory data, along with patient and nurse scoring systems. However, it was determined
that higher doses of continuous infusion midazolam were required to obtain adequate sedation
and anxiolysis. In another prospective, cohort study, mechanically ventilated patients
received either continuous or intermittent doses of sedation using a targeted Ramsay Scale of
3. Patients in the intermittent group required less hours on mechanical ventilation compared
to the continuous IV sedation group, p<0.001. The authors of this trial concluded that
continuous sedation may be associated with prolongation of mechanical ventilation. These two
clinical trials conclude that the use of intermittent sedation may provide additional benefit
to sedated patients in decreasing the days on mechanical ventilation and cumulative doses of
sedative agents.

Using these studies as a starting point, the investigators conducted a prospective pilot
study demonstrating that the use of intermittent sedation in medical intensive care unit
patients significantly decreased amount of sedatives used, the hospital length of stay, and
most importantly reduced duration of mechanical ventilation. In this study it was shown that
intermittent sedation administered within twenty-four hours of mechanical ventilation reduced
ventilation time by twenty-four hours (p<0.001). However, much like the studies that formed
the basis of this pilot, this study suffered from some lack of control as well as small
sample size. More importantly, this study analyzed only medically critically ill patients in
whom large doses of narcotics are often not routinely employed. In surgical patients
narcotics are often used concomitantly with a sedative in order to achieve anxiolysis and
pain control while ventilated.

The investigators have already demonstrated in a small cohort that the use of intermittent
sedation protocol is not only non-inferior but significantly reduces mechanical ventilation
time in medical intensive care patients. The investigators hypothesize that an intermittent
administration of both sedative and narcotic medications will reduce mechanical ventilation
time in multiple critically ill patient populations requiring ventilation.

Purpose:

This prospective, randomized cohort study is designed to compare continuous infusions to
intermittent boluses of sedative agents (i.e. opioids, benzodiazepines) and narcotic agents
(i.e. fentanyl, dilaudid) for sedation and pain control in mechanically ventilated patients
in the surgical trauma unit and neurologic intensive care unit (STU, NCC).

The primary end point measured will be the number of hours on mechanical ventilation.
Secondary end points will include length of ICU stay, length of overall hospital stay,
cumulative amount of sedative agents used per day, and time within target sedation levels.

Methods:

At the investigators institution, there are two critical care units that serve the majority
of surgical, traumatic, and neurovascular critically ill patients (The surgical trauma unit
and neurologic intensive care unit). These two units work in tandem and their patient
populations are distributed throughout both units (hereafter referred to as the ICU).
Patients requiring mechanical ventilation will be randomized into a control arm or trial arm
of the study. The following demographic data will be collected: patient age, gender, race,
indication for mechanical ventilation, APACHE II score, injury severity score (if patient is
a trauma patient), and serum creatinine. All data will be recorded without patient
identifiers to maintain confidentiality. Specific methods are detailed below.

Study Design: The S.A.T.I.R.E. trial will be a two year, randomized control trial performed
on intubated patients in the ICU (surgical and neurovascular patients). The control group
will consist of intubated patients that will be sedated and given pain control with using
current practice: continuous infusions of a narcotic and sedative. The trial group will
consist of intubated patients that will be sedated and given pain control with an
investigational timing of dosing: Q1 hour bolus dosing given in a sliding scale fashion. The
target levels of sedation and pain control will not differ between the two arms of the study.
Upon admission to the ICU the surgical resident on call (hereafter referred to as ICU
resident) is required to assess a patient. During that time, if the patient is intubated and
does not fall into exclusion criteria, the ICU resident will then assign the patient to the
control arm of the study or the trial arm of the study randomly as described below. The ICU
residents will use designated order sets with specific protocols for each arm of the study
which are described in more detail below. Each day during the week the clinical pharmacist on
staff will record patient demographics (age, gender, race, indication for mechanical
ventilation, serum creatinine, APACHE II, injury severity score if trauma) and MRN#, as well
as time of intubation and time of extubation if applicable. During the weekend the ICU
resident will record new patients enrolled into the study (MRN only); on Monday, the
investigators or clinical pharmacist will review the weekend data and retrospectively record
demographics, time of intubation, and time of extubation from patients admitted to the ICU
over the weekend. This Monday data collection will be assigned on a rotating weekly schedule
to the investigators. Data will be collected for approximately two years; aggregate data will
be analyzed every six months.

Randomization: Patients will be randomized upon admission to the ICU based on birth year.
Patients with a birth year ending in an even number will be randomized to the control arm and
patients with a birth year ending in an odd number will be randomized to the trial arm. This
randomization will occur during placement of initial sedation/pain medication orders and will
be done via an order-set with two initial options (even birth year vs. odd birth year) which
will open up to have sub-orders containing the medications dosed in either a continuous or
intermittent fashion, respectively.

Study Medications: The control and trial arms will use the same medications. These will be
ordered using a specified order set detailed below. Study participants will be evaluated
daily by the resident, surgical critical care attending, and clinical pharmacist (weekdays
only for clinical pharmacy) for appropriateness and adjustment for patient specific
requirements.

If the patient's birth year ends in an even number, the order set will open the control arm.
Here, the ICU resident will be able to order a midazolam continuous infusion using existing
orders, and a fentanyl infusion. The midazolam infusion order is standardly dosed at 1 mg/hr
and titrated to RASS -1. This order can be found under "MIDAZOLAM Infusion 50 mg/50 mL 0.9%
sodium chloride". Fentanyl is standardly dosed at 25 mcg/hr and will be titrated to the CPOT
for pain control per nursing protocol. This order can be found under "Fentanyl Infusion Order
Set". This differs slightly from current practice with the addition of the CPOT scale in that
previously nursing had titrated both sedative and narcotic to RASS and now fentanyl will be
titrated specifically to pain; however, this is a change being adopted hospital wide and will
be the current practice for the institution at the time of the study or shortly after launch
of the study. Additionally, current practice is for nursing to administer infusions and
titrate to RASS at their discretion by either increasing/decreasing the rate, bolus/pushing
additional medication, or both. To standardize tracking of medication doses an as needed
order has also been created to be used in conjunction with the infusion order to support this
practice and accurately capture medication administered in the control arm. Patients that are
admitted to the ICU on a continuous propofol infusion will be converted to the midazolam
infusion or intermittent protocol within twenty-four hours or be excluded from the study.
During weekdays this will be performed by the clinical pharmacist; during weekends, this will
be performed by the ICU resident. If a patient must be taken off a midazolam protocol they
will be excluded from the study.

If the patient's birth year ends in an odd number, the order set will open the trial arm.
Here, the ICU resident will be able to order midazolam and fentanyl in a sliding scale
fashion. Doses will be started at the same doses as the infusion medications; for midazolam 1
mg/hr, for fentanyl 25 mcg/hr and titrated to target RASS -1 or CPOT = 0. Dosing may be
modified for creatinine clearance, hemodynamics, and opiate naivety.

Nursing Protocol: Nursing protocol for titrating sedation to RASS and pain to CPOT have been
adopted institutionally. Patient RASS levels and CPOT levels are checked hourly.

Statistical Analysis: Demographics will be reported as aggregate means; if a larger than
anticipated sample size is achieved we will also perform sub-analysis of individual groups
(i.e., trauma vs. general surgical patients vs. neurovascular patients, etc). End points will
be reported in means with a 95% confidence interval and will undergo standard significance
testing (using α and β that are 0.05 and 0.20, respectively.) Continued Inclusion: Each
patient will be assessed on a daily basis by a surgical critical care attending, resident,
and pharmacist to determine appropriateness of his/her sedation regimen. If a patient
continues to require significant additional sedative or narcotic outside the pre-established
protocol, the patient may be withdrawn from the study and switched to a continuous infusion
at the discretion of the attending physician in conjunction with the clinical pharmacist. In
addition, a 24-hour on-call support for nurses and residents will be available to provide
optimal, intermittent doses. At any time the attending critical care physician may remove a
patient from the study at their discretion for any reason should it be required.

Inclusion Criteria:

- Mechanical ventilation in the Surgical ICU.

- Age >18 years old

Exclusion Criteria:

- Use of dexmedetomidine (Precedex®)

- Use of neuromuscular blocking agents

- Use of propofol >24 hours

- Discontinuation of midazolam as sedative (i.e., switching to propofol or
dexmedetomidine)

- Therapeutic hypothermia

- Patients that do not require sedatives/narcotics while intubated (i.e. coma, traumatic
brain injury)

- Pregnancy

- Prisoners

- Patients with target RASS of -3 to -5 (Deep Sedation)