End Tidal Carbon Dioxide Concentration and Depth of Anesthesia in Children

Carbon Dioxide (CO2) is a by-product of metabolism and is removed from the body when we breathe out. High levels of CO2 can affect the nervous system and cause us to be sleepy or sedated. Research suggests that high levels of CO2 may benefit patients who are asleep under anesthesia, such as by reducing infection rates, nausea, or recovery from anesthesia . CO2 may also reduce pain signals or the medication required to keep patients asleep during anesthesia; this has not been researched in children.

During general anesthesia, anesthesiologists keep patients asleep with anesthetic gases or by giving medications into a vein. These drugs can depress breathing; therefore, an anesthesiologist will control breathing (ventilation) with an artificial airway such as an endotracheal tube. Changes in ventilation can alter the amount of CO2 removed from the body. The anesthesiologist may also monitor a patient's level of consciousness using a 'Depth of Anesthesia Monitor' such as the Bispectral Index (BIS), which analyzes a patient's brain activity and generates a number to tell the anesthesiologist how asleep they are.

The investigator's study will test if different levels of CO2 during intravenous anesthesia are linked with different levels of sedation or sleepiness in children, as measured by BIS. If so, this could reduce the amount of anesthetic medication the child receives. Other benefits may be decreased medication costs, fewer side effects, and a positive environmental impact by using less disposable anesthesia equipment.

Purpose: Carbon dioxide (CO2) is a major end-product of metabolism and can have marked effects on central nervous system function. It can also be easily manipulated during general anesthesia via controlled ventilation. High levels of carbon dioxide (hypercapnia) are associated with sedation and have been shown to produce selective suppression of thermal and ischaemic pain in animals and humans. This effect was attenuated by dexamethasone and naloxone, indicating that stress pathways and endogenous opioids may be implicated. Hypercapnia during anesthesia may have additional benefits, including reduced levels of wound infection due to improved tissue oxygenation reduced incidence of postoperative nausea and vomiting and reduced recovery time from volatile anesthetic.

It is a known phenomenon for high levels of CO2 to be associated with reduced levels of consciousness in humans, known as CO2 narcosis. A 1927 paper described narcosis of animals when breathing 30-40% CO2 in oxygen, with prompt recovery upon removal. The authors described a 'sharp sour taste' and associated hypertension when the same solution was administered to humans. However, few studies investigate the impact of carbon dioxide on anesthetic requirements. An animal study from 1967 demonstrated that very high levels of CO2 (\>95 mmHg) offset halothane requirements in dogs. Most recently, increased carbon dioxide levels during surgery (40 - 45 mmHg) were shown to reduce the Minimal Alveolar Concentration to Blunt Adrenergic Response (skin incision; MAC-BAR) of sevoflurane in adult patients undergoing gastric carcinoma resection.

Total intravenous anesthesia (TIVA), an alternative to inhalational anesthesia, is a commonly used anesthetic technique in the investigator's institution. This is due to its many benefits, including reduced emergence delirium, reduced environmental impact and reduced post-operative nausea and vomiting. Administration can be guided by depth of anesthesia monitoring such as the Bispectral Index (BIS), which measures the patient's level of consciousness derived from electroencephalogram readings. BIS has been shown to help guide propofol dosing in children regardless of whether the TIVA technique was target controlled or a manual infusion regimen, and to correlate well with both modelled and measured propofol levels in children.

The investigator's study aims to determine whether differing levels of CO2 affect the anesthetic depth in anesthetized children, as measured by BIS.

Hypothesis: Hypercarbia is associated with a reduction in BIS readings, in anesthetized children.

Justification: The impact of EtCO2 on BIS has not been studied in children. If discovered, a correlation between the two could significantly change anesthetic practice. It is straightforward to increase EtCO2 levels in anesthetized patients, and if this was found to reduce their anesthetic requirements it could enable lower rates of anesthetic drug administration. This would benefit the patient by exposing them to less medication and fewer associated side effects, as well as benefitting the hospital and wider environment by reducing cost and use of disposable equipment such as ampoules, packaging and syringes.

Objectives: (1) To determine the effect of EtCO2 on the depth of anesthesia in children, as measured by BIS.

(2) Patient movement as detected clinically by the surgical or anesthetic team.

Research Design: The investigators plan to conduct a randomized, prospective, crossover trial. The within-subject design allows patients to act as their own controls. The order in which the EtCO2 levels are tested will be randomized between patients using sealed envelopes. The anesthesiologist in the room will be blinded to the BIS reading but will be informed by a research assistant if it reads persistently high (\>60) for over one minute.

Statistical analysis: Physiological data will be collected in real-time using purpose-built software. Patient demographics and characteristics will be collected by a research assistant. Time-series plots of BIS and EtCO2 for each participant will be made in R (R Foundation for Statistical Computing, Vienna, Austria). Generalized estimating equations (GEE), using the geepack package, will be applied to estimate the effect of changes in target EtCO2 on serial BIS measurements during the anesthesia maintenance phase. Each participant will be considered their own data cluster to provide an appropriate grouping structure for the analysis. An independent correlation structure will be applied, and a robust (sandwich) estimator method will be used to obtain standard errors.

Eligibility Criteria:
Inclusion Criteria:

* Children aged 3 - 11 years undergoing non- or minimally-stimulating elective procedures, defined as anesthesia without skin incision or painful manipulation (e.g., non-invasive imaging, auditory brainstem response testing), middle ear surgery, surgery with effective local or regional anesthesia before surgical incision (e.g dental procedures with local anesthetic infiltration, urology with regional block).
* American Society of Anesthesiologists (ASA) physical status I and II
* TIVA technique appropriate throughout induction and maintenance of anesthesia
* Controlled ventilation via endotracheal tube
* Anticipated surgical time ≥ 90 minutes: to allow time for anesthetic induction and subsequent testing and washout periods at all three EtCO2 levels.

Exclusion Criteria:

* Need for inhalational induction of anesthesia
* Sedative premedication
* Use of ketamine intraoperatively
* Unable to place BIS electrodes due to surgical site or other contraindications (e.g., MRI)
* Allergy to study drugs (propofol, remifentanil, lidocaine)
* Depression of conscious level for any reason
* BMI \<5th or \>95th centile for age
* History of obstructive or central sleep apnea
* Known or suspected raised intracranial pressure
* Recent or historical traumatic brain injury