Background

Effective sedation and analgesia are indispensable elements of treating patients in intensive care units (ICU) in order to reduce pain, anxiety, and agitation during mechanical ventilation and when other invasive diagnostic and therapeutic interventions are performed. Current guidelines for analgesia and sedation of patients in ICU favor the use of intravenous forms of sedation. [1] While fentanyl or morphine intravenous infusions are the most common analgesics used in the mechanically ventilated patients, Propofol and midazolam are the most commonly used drugs for sedation of critically ill patients. However, use of benzodiazepines has been shown to prolong the duration of ventilation, and thus delay extubation. These effects occur due to decreased sleep, inducing fatigue and exhaustion and need for prolonged weaning and ventilation. Recently intravenous dexmedetomidine infusion has been shown to be superior to midazolam in reducing the incidence of delirium in the critically ill.

Delirium is one the worst side effects seen due to use of the current drugs infused for sedation. Delirium is a neuropsychiatric syndrome, which is transient and usually reversible. It is defined as a disturbance in attention, awareness, and cognition that develops over a short period of time and fluctuates in severity. [2] It is a very common phenomenon in ICU, yet an under-diagnosed form of organ dysfunction. High-risk populations include elderly and mechanically ventilated ICU patients.[3] Incidence of delirium has been reported to range from 16-89% in hospitalized patients.[4] It is highest in mechanically ventilated patients (80%). [5] Elderly and post-operative patients are most vulnerable. Incidence of post-operative delirium varies from 10% to 70%. [6, 7]

Rationale for use of Inhalational Agents for Sedation

Compared to most intravenous anaesthetics, volatile anaesthetics, such as sevoflurane and isoflurane, offer better control of sedation since they do not accumulate or develop tolerance. Emergence (recovery) times (time required to recover from the sedation effects) of patients sedated by inhalation are therefore shorter and more predictable than after intravenous infusion of sedative agents. The end-tidal tension of a volatile anaesthetic accurately reflects arterial partial pressure, providing a precise indicator of the volatile anaesthetics partial pressure and concentration in the central nervous system.

Possible Physiological Advantages of Isoflurane for Sedation

Volatile anesthetic agents act primarily on the cerebral cortex, depressing the consciousness and have analgesic properties even at low concentrations, while leaving many autonomic functions such as temperature control, blood pressure regulation or respiration, undisturbed.  In comparison with intravenous anaesthetics, they are mainly excreted via the respiratory system, so the liver or kidney only metabolize a minor part.  In humans, the metabolism degrades approximately 0.2 % of isoflurane and 2-5 % of sevoflurane.

Volatile-based sedation may provide superior awakening and extubation times in comparison with current intravenous sedation agents (Propofol and benzodiazepines). Volatile agents may possess important end-organ protective properties mediated via cytoprotective and anti-inflammatory mechanisms. Above all they are cardioprotective and cerebroprotective in nature. [8]

AnaConDa Device –a Means to Aid Precise Delivery of Inhalational Sedation:

Initial attempts at conserving anaesthetic vapors using an open system involved the development of a reflector that incorporated zeolite crystals. However, because of the possibility of zeolite inhalation causing pulmonary toxicity, one proposed solution was to use a charcoal filter instead of a zeolite one.  The principle of the charcoal filter was further developed, leading to the creation of a device for inhalation sedation AnaConDaâ„¢ (Anaesthetic Conserving Device; Sedana Medical, Uppsala, Sweden), which enables administration of sedation in ICU patients with isoflurane and isoflurane. AnaConDaâ„¢ is a device that delivers a safe sedative dose of either isoflurane or sevoflurane to a patient using existing critical care ventilators, common syringe pumps and gas monitors. The device is essentially a small disposable anaesthetic vaporizer and HME filter combined into one airway component. Similar to the HME filter, the device reflects moisture back to the patient, but also reflects 90% of the anaesthetic by adsorbing and releasing the drug using a proprietary carbon filament-reflecting medium. These active lipophilic carbon fibers have the capacity to bind 90% of the expired volatile anaesthetic agent. These are again released with the following inspiratory cycle. This reflection reduces the total amount of anaesthetic needed, reducing the amount that is exhausted or scavenged upon exhalation. The AnaConDaâ„¢ is inserted between the Y-piece of the breathing circuit and the endotracheal tube (ET-tube) and can be used with any type of ICU ventilator. A heated humidifier is therefore not required. It can be used for 24 h of sedation, and fits into current critical care ventilator circuits almost without modifications. [9,10]

Leakage of the anaesthetic into the environment is thus limited and use of the volatile anaesthetic is also more economical and safer for medical personnel. The lost amount of volatile anaesthetic (10%) is replaced by liquid anaesthetic, which is uninterruptedly supplied to the equipment by a standard syringe pump and then through a miniature evaporator rodvaporizer into the breathing gas with which the patient is ventilated.

A sampling port located on the patient side of the device allows the expired volatile agent concentration to be continuously displayed on the gas monitor. Expired gas needs to be actively or passively scavenged at the gas outlet of the ventilator.

Aim: To study the feasibility and safety of administering inhalational sedation using isoflurane through AnaConDaâ„¢ device in the postoperative period.

Primary Outcomes:

1.      Proportion of time spent between Richmond Agitation Sedation Scale scores of either -3 or -4.

Secondary outcomes:

1.      Incidence of post-operative delirium as measured by Confusion Assessment Method(CAM-ICU) [12]

2.      Ease of administration (incidence of and proportion of difficulties in managing the equipment for administration overall and per patient)

3.      Incidence of renal, hepatic, hemodynamic and other adverse effects and others, if any.

Study Design: Prospective open label trial

Sample Size:  A convenience sample size of 50 patients

Inclusion Criteria:

1.      Age 50-80 years

2.      Weight 50-120 kg

3.      Elective post-operative patients anticipated to require sedation between 12 -24 for elective mechanical ventilation.

4.      Hemodynamically stable patients (not requiring more than 0.3 microgram/kg/min of noradrenaline)

5.      Patients willing to participate in the trial by giving written informed consent.

Exclusion Criteria:

1.      Contraindications to use of HME filter during mechanical ventilation, these may include, but not limited to: excessive secretions or pulmonary hemorrhage likely to block the filter, indications for reducing apparatus dead space.

2.      Head trauma and neurosurgical patients or mental obtundation due to any other reason preoperatively.

3.      Patients with raised ICP.

4.      Low GCS (<9).

5.      Pregnant or breast feeding women.

6.      Family or personal history of malignant hyperthermia.

7.      Patients already receiving sedation for more than >6 hours.

Material and Methods:

This study will be conducted in the postoperative Intensive Care Unit of a tertiary referral cancer center after obtaining Institutional Ethics Committee approval and The Clinical Trials Registry- India (CTRI) registration. Fifty adult intubated post-operative patients expected to require sedation for 12- 24 hours will be recruited. Written informed consent will be obtained preoperatively. After connecting the patients the ICU ventilators, and starting an intravenous Fentanyl infusion (0.5-15 microgram/kg/min) for analgesia, patients will be administered inhalational isoflurane via the AnaConDaâ„¢ and the time of initiation of inhalational sedation would be noted. The liquid form of isoflurane would be used via standard ICU syringe pump. An initial bolus of 1ml will be given and an infusion rate of 2-6ml /hour would be chosen, which will be adjusted to meet to sedation goal.

Dose adjustments will be done by steps of 0.1% of end tidal isoflurane guided by RASS scale. Sedation will be evaluated every 10 mins, by attending staff nurse until RASS score of -3 to -4 is reached and then every 2 hours from then on. The following data would be collected.

1.      The infusion rate of isoflurane, number of dose adjustments required and no of boluses of isoflurane administered would be noted.

2.      If the desired RASS score of -3 or -4 is not achieved solely with isoflurane additional boluses of intravenous conventional sedatives would be administered and the amount of sedatives consumed (over the duration of ventilation) would be noted.

3.      The no of episodes of hypotension (defined as Mean Arterial Pressure (MAP) < 70 mmHg in normotensive individuals and up to -10% of the baseline in others) attributed solely to alteration in dose of isoflurane or administration of bolus of isoflurane would be noted.

4.      At the time when the patient is planned for extubation or at the end of 24 hours (whichever is earlier) the administration of isoflurane would be terminated.

5.      The proportion of time spent within RASS score range of -3 or -4 would be noted.

6.      The time for awakening after termination of sedation would be noted. The time from stopping of sedation to time taken to follow simple verbal commands like tongue protrusion, eye opening and closing, hand-grip would be noted every 5 minutes.

7.      Time taken for extubation from the stopping of agent would be noted if the patient ceases to require mechanical ventilation.

8.      At any point during the course of sedation if the RASS score is not between -3 or -4; patients will be assessed by the attending resident in the ICU, for delirium using the CAM-ICU flow sheet. In CAM-ICU assessment if patients were found to have “altered level of consciousness (step 3)” and RASS score assessment was “non-zero” or if patients corresponded to “disorganized thinking group (CAM ICU step 4)” with >1 error the presence of delirium would be confirmed and the score noted. The inhaled sedation bolus will be administered to attain the target RASS range.

9.      The number of episodes of self-extubation or pulling out of catheters or nasogastric tube by the patient if any would be noted. The duration of study would range from 12 - 24 hours from the time of inclusion in the study or till the time of extubation as decided by the treating intensivist, whichever is earlier. Patients who require sedation for more than 24 hours would be discontinued from inhalational sedation and would receive then routine sedation as per our ICU protocol. In such patients we will assess the ability to achieve and maintain the RAAS score in the target range and presence of delirium (CAM-ICU score). In such patients secondary outcomes will not be measured.

1.  If the patients are found to be delirious, they will treated appropriately, as per our standard ICU protocol, which includes administration of intravenous haloperidol in appropriate doses. The total dose of haloperidol required by the patients will be noted.

Statistics: Descriptive statistics will be used to calculate the proportion of time spent by each patient in the adequate sedation range (along with Confidence Intervals). P-trend test will be used for to assess a proportional decrease or increase in need for the inhaled sedative agent. P value < 0.05 will be assumed to be significant.