Which of the following is true regarding thermal support for mice during anesthesia

D Intraoperative Monitoring and Support

Monitoring anesthesia in rodents is often limited to observation of respiratory rate and character, color of the skin and mucus membranes (if the animal is an albino), and response to surgical stimulus. Depth of anesthesia may be estimated by pedal withdrawal response and eye reflexes but is probably most reliably indicated by response to surgical stimulus (Flecknell, 2009). While heart and respiratory rate, as well as oxygen saturation are more easily monitored in larger rodents, such as rats and guinea pigs, pulse oximeter options are now commercially available for use in mice and sensitive enough to be utilized for hypoxia research (Chodzyński et al., 2013). Electrocardiography is primarily used only as a research tool in rodents. Hypothermia will occur with all anesthetic protocols in rodents, and it is therefore important that body temperature is measured, and means of warming the animal are employed. Temperature can be monitored by using small rectal and surface probes. Thermal support utilizing circulating hot-water pads, homeothermic blankets, infrared warming pads, heating lamps, space blanket, or even bubble wraps are recommended. Fluid support in the form of warmed subcutaneous fluids is useful and simple, especially with prolonged procedures. As rodents do not close their eyes while anesthetized, lubrication to prevent corneal drying is an important step for all anesthetic events lasting more than a few minutes. Another undesirable side-effect of anesthesia, particularly with injectable agents, is modest to severe hypoxia and hypercapnia. Moderate hypercapnia can be tolerated by healthy animals for reasonable periods of time but if progressive may be difficult to correct without mechanical ventilation. Hypoxia, on the other hand, is often easily and inexpensively corrected by providing a low flow of oxygen by mask during anesthesia and surgery.

8.4.3 Assessment of Anesthetic Depth

The depth of anesthesia is assessed by testing the response to various stimuli. If voluntary movement results from physical stimuli of the body, the animal is not at the anesthetic level required for surgery. The swallowing reflex manifests as an attempt by the animal to swallow normal salivary secretions. Physical methods utilized for anesthetic depth assessment include the toe pinch, tail pinch, ear pinch, palpebral reflex, and corneal reflex. To use the toe pinch method, the leg is extended and the webbing between the toes is isolated. Using finger nails or atraumatic forceps, the area is firmly pinched. If the leg is retracted or the foot is withdrawn, it is a positive reaction to the stimulus. The tail pinch and ear pinch utilize the same method, but on the tip of the tail or the pinnae of the ear. Any movement of the tail or ears indicates a positive reaction to the stimulation. For assessment of the palpebral reflex, a fingertip is touched to the medial canthus (inner corner) of the eye, and for the corneal reflex, a sterile cotton-tipped applicator is used to gently touch the cornea (eyeball). Blinking or movement of the whiskers is indicative of a positive response. Generally, the animal is not at a surgical plane of anesthesia if there is movement, vocalization, or marked increase in respirations.

Physiological indicators such as heart rate, respiratory rate, blood pressure, mucous membrane color, and capillary refill time can also be used to evaluate depth of anesthesia. General observations are useful to detect changes in the respiratory rate of the animals. However, specialized equipment is required to determine the heart rate or blood pressure. The color of the mucous membranes, color of the eyes, ears, mouth, nose, anus, and to a lesser extent the paws and tail can be observed. All of these areas should be pink, indicating adequate respiration and cardiac function. However, if the animal moves to Stage IV anesthesia, cyanosis of the mucous membranes and surrounding skin will develop. Capillary refill time, the amount of time taken for color to return to an external capillary bed after it has been blanched, is tested by the application of gentle pressure over an area. For example, an applicator stick or a finger can be pressed on the gums, pinnae, or nail beds of the anesthetized animals. It should take no more than 1–2 s for the blanched area to return to its normal pink color. An extended refill time can indicate a reduction in heart rate or strength of cardiac contraction that is caused by the animal being too deeply anesthetized and, possibly, near death.

It is important to use multiple parameters to assess anesthetic depth. Areas tested for a pinch reflex will become desensitized if used repeatedly. Using both physical and physiological parameters provide a complete evaluation of the anesthetized animal. Anesthetic depth should be reassessed every 10–30 min throughout the surgical procedure.

Pharmacokinetics (volatile liquids, gases)

The depth of anaesthesia is correlated with the tension (partial pressure) of anaesthetic drug in brain tissue. This is driven by the development of a series of tension gradients from the high partial pressure delivered to the alveoli and decreasing through the blood to the brain and other tissues. The gradients are dependent on the blood/gas and tissue/gas solubility coefficients, as well as on alveolar ventilation and organ blood flow.

An anaesthetic that has high solubility in blood, i.e. a high blood/gas partition coefficient, will provide a slow induction and adjustment of the depth of anaesthesia. Here, the blood acts as a reservoir (store) for the drug so that it does not enter the brain readily until the blood reservoir is filled. A rapid induction can be obtained by increasing the concentration of drug inhaled initially and by hyperventilating the patient.

Anaesthetics with low solubility in blood, i.e. a low blood/gas partition coefficient (nitrous oxide, desflurane, sevoflurane), provide rapid induction of anaesthesia because the blood reservoir is small and anaesthetic is available to pass into the brain sooner.

During induction of anaesthesia the blood is taking up anaesthetic selectively and rapidly, and the resulting loss of volume in the alveoli leads to a flow of anaesthetic into the lungs that is independent of respiratory activity. When the anaesthetic is discontinued the reverse occurs and it moves from the blood into the alveoli. In the case of nitrous oxide, this can account for as much as 10% of the expired volume and so can significantly lower the alveolar oxygen concentration. Mild hypoxia occurs and lasts for as long as 10 min. Oxygen is given to these patients during the last few minutes of anaesthesia and the early post-anaesthetic period. This phenomenon, diffusion hypoxia, occurs with all gaseous anaesthetics, but is most prominent with gases that are relatively insoluble in blood, for they will diffuse out most rapidly when the drug is no longer inhaled, i.e. just as induction is faster, so is elimination. Nitrous oxide is especially powerful in this respect because it is used at concentrations of up to 70%.

Uptake and distribution

The depth of anesthesia produced by an inhalation anesthetic depends on the concentration of the anesthetic agent in the brain. The speed of induction and the speed of recovery follow the rate at which the concentration of the agent changes in the brain. During induction, the gas must move from the anesthetic apparatus to the pulmonary alveoli, from the alveoli to the blood, and from the blood to the brain. On termination of anesthesia, the inhaled gas moves in the opposite direction across the same interfaces. The principal force governing this movement of anesthetic gas is the diffusion or concentration gradient, and the behavior of the gases as they move from one compartment to another across biologic interfaces is defined by two gas laws. Dalton’s law deals with the partial pressure (or tension) of gases and states that in a gas mixture, the partial pressure of each component gas is directly related to its concentration in the mixture. Henry’s law describes the solubility of gases in liquids and states that the quantity that will dissolve in a liquid is proportional to the partial pressure of that gas in direct contact with the liquid.

The partition coefficient is an expression of the relative solubility of a substance in two immiscible phases. When applied to anesthetic gases, it compares the relative amount of gas dissolved in one phase when one part is present in the other phase. The blood/gas partition coefficient of 1.4 for isoflurane indicates that 1.4 parts of isoflurane are dissolved in blood for every part contained in an equal volume of alveolar air at equilibrium. These relationships are shown schematically in Figure 15-3.

As mentioned earlier, during induction the various compartments of the body are brought into equilibrium regarding the inhaled anesthetic gas. When equilibrium is reached, the tensions of the anesthetic gas in the inspired air, alveolar air, arterial blood, body tissues, and mixed venous blood become equal, but the concentrations vary in concert with the relative solubility of the agent in each compartment. The speed with which equilibrium is achieved is influenced by many variables, and each of these is considered subsequently, particularly regarding how it affects the alveolar concentration.

The alveolar concentration of an inhalation anesthetic is of pivotal importance to the onset of anesthesia. Because the brain is extremely well perfused, the tension of an inhaled anesthetic in the brain closely follows that of the arterial blood, which itself is equilibrated with the alveolar tension as the blood passes through the pulmonary microvasculature. Within broad limits, anything that increases delivery of anesthetic to the alveoli, and increases its alveolar partial pressure, would hasten anesthesia onset, and anything that enhances its removal from the lungs—in other words, anything that increases overall alveolar transfer to the pulmonary circulation, and hence systemic uptake—would reduce its alveolar partial pressure and delay anesthesia onset.

d Rescue

No single therapy can be reliably predicted to effectively treat IOB, especially when it is critical. A major distinction between IOB and severe asthma in awake, self-ventilating patients is the difference in bioavailability of inhaled drugs. Patients with IOB invariably have an airway device (face mask, SLA, or ETT) connected to a breathing system. The great majority of any aerosolized drug is deposited in this device, with only 3% to 9% of drug reaching the lung. This is about 10 times less efficient than administration in self-ventilating patients.99,100 A combination of inhaled and IV drugs may confer additive or synergistic effect, and a number of drug interventions are available for use in an escalating sequence.

As for any scenario, especially an emergency, in which task saturation is a risk, safe drug selection and timing of use are crucially important. The therapeutic rescue options available are listed in the following paragraphs.

Depth of Anesthesia

For assessment of anesthetic depth, BIS or other processed EEG methods are the most commonly used technologies. These hypnotic indices appear to provide clinically useful information. However, their fundamental differences may result in monitor-specific performance, so agreement among these measures during surgical procedures should not be expected. Reported rates of intraoperative awareness during cardiac operations range from 0.2% to 2%, a 10-fold increase in risk compared with the general surgical population. The American Society of Anesthesiologists Practice Advisory on Awareness and Brain Monitoring made the recommendation that the decision to use a brain monitor, including a BIS monitor, should be made on a case-by-case basis and should not be considered standard of care.

Sedation Depth Versus Sedation Risk

Sedation scales and sedation depth monitors attempt to quantify the depth of sedation but do not directly measure the “risk” of sedation. While the depth of sedation is defined by response to stimulation, the important assessment of the child is not the response to stimulation, but the ability to protect and maintain the airway.51,52 In fact, each sedative drug or a particular dose of a drug may provide pain relief but may also obstruct the airway or depress ventilation. For example, propofol is a potent, effective sedative that confers no analgesia but has marked effects on the airway tone and respiratory drive.53 Conversely, dexmedetomidine provides less intense sedation than propofol but modest pain relief with minimal depression of respiration and minimal compromise of airway morphology. In contrast, ketamine produces intense analgesia and decreases the responses to stimulation, but infrequently obstructs the airway or depresses respiratory effort even at very large doses (Table 48.5).54

There are also aspects of the patient that affect risks for airway-related adverse events as much as sedation depth. For instance, a child with obstructive sleep apnea (OSA) or obesity is much more likely to obstruct his or her airway during deep sedation than one who does not have this comorbidity.55 A history of prematurity has been shown to increase the risks associated with sedation throughout childhood and adolescence.56 Furthermore, other comorbidities such as congenital heart disease, airway anomalies, lower respiratory tract disease, and upper respiratory tract infection increase the risk of general anesthesia, and one would expect that they would also increase the risk of sedation, although they have not been studied specifically in this regard. Similarly, the procedure itself can increase the risk for a child. A bronchoscopy or upper gastrointestinal endoscopy carries much greater risks of airway-related events than a noninvasive diagnostic test.57 The environment of the procedure can also increase risk. The MRI scanner (where the observer is remote from the airway during the scan and ferromagnetic objects are forbidden) is a significantly more difficult environment than one where the sedation provider can be situated at the airway and all monitors and rescue equipment are available (as per standard routine). In summary, when assessing the risk of sedation, one must consider the multidimensional aspects of sedation that include the planned level of sedation, existing comorbidities in the child, the procedure to be performed, and the environment in which the procedure will be performed.

The safety of sedation must also focus on appropriate discharge readiness and the subtle differences in recovery from sedation. Adverse events, including deaths, have occurred after premature discharge after procedural sedation.52 These events were most often associated with sedating medications with a prolonged duration of effect such as chloral hydrate (Fig. 48.3).51 With this in mind, a simple “maintenance of wakefulness” score (infants had to stay awake for at least 15 to 20 consecutive minutes in a quiet environment before discharge) ensured that more than 90% of children had returned to baseline levels of consciousness, compared with only 55% of children assessed as “street ready” according to usual hospital discharge criteria.58

Monitoring

The standards for intraoperative anesthetic monitoring have been outlined by the American Society of Anesthesiologists. Monitoring standards are the same regardless of whether the case entails a general anesthetic, regional anesthetic (peripheral nerve block, spinal or epidural), or monitored anesthesia care. The standards according to the ASA include an oxygen analyzer, noninvasive blood pressure cuff, continuous ECG, pulse oximeter, end-tidal carbon dioxide analyzer, precordial or esophageal stethoscope, temperature probe, and a ventilator disconnect alarm. Based on the medical condition of the patient and the surgical procedure, more elaborate and invasive monitoring may be added to these standard monitors, such as a urinary catheter; catheters for measuring intraarterial, central venous, and pulmonary artery pressures; and transesophageal echocardiography. Although there are no strict guidelines dictating which patients should have invasive monitors placed, there have been recommendations set forth for the adult population. These recommendations must be taken in context of the limited data available comparing outcomes, for instance, in patients managed perioperatively with or without pulmonary artery (PA) catheters.20,21 The ASA recommends considering three variables including disease severity, magnitude of the surgical procedure, and practice setting when assessing benefit versus risk of PA catheters.22 Additional information regarding structural and functional issues of the myocardium may be obtained by the use of transesophageal echocardiography (TEE). TEE is used with increasing frequency in the adult population. There are now specific curriculae in cardiac anesthesia fellowships to teach the skills necessary for performance of TEE. The practice has been encouraged by the American Board of Anesthesiology, which recognizes such training and provides the opportunity for credentialing through the completion of a written examination. The strongest indications for perioperative transesophageal echocardiography that are supported by evidence-based medicine include cardiac surgery procedures such as repair of valvular lesions (insufficiency or stenosis) or congenital lesions, assessments and repairs of thoracic aortic aneurysms and dissections, pericardial window procedures, and the repair of hypertrophic obstructive cardiomyopathy.23 For noncardiac surgery, intraoperative transesophageal echocardiography is indicated to evaluate acute, persistent, and life-threatening hemodynamic disturbances in which ventricular function and its determinants are uncertain and which have not responded to treatment, especially when placement of a PA catheter is not feasible.

In addition to standard ASA monitors, there is growing interest in the development and potential use of “depth of anesthesia” monitors. Although controversial, the potential impact of such monitors is highlighted by the results of several trials which demonstrate that intraoperative awareness may occur in anywhere from 0.1% to 0.2% of all patients, with even higher incidences in specific procedures including trauma, cardiac, obstetrical, and emergency surgery. Several manufacturers have marketed or are developing monitors which provide the anesthesia provider with a numerical value against which anesthetic agents are titrated. There are currently five such monitors, including the Bispectral Index (BIS monitor, Aspect Medical, Newton, MA); the Narcotrend (MonitorTechnik, Bad Bramstedt, Germany), which is currently available only in Europe; Patient State Analyzer (PSA 4000, Baxter Healthcare, Deerfield, IL); SNAP (Everest Medical, Minneapolis, MN); and Auditory Evoked Potential Monitor (AEP Monitor, Danmetter Medical). To date, the one that has received the most clinical use is the BIS monitor. The BIS is a modified electroencephalographic monitor that uses a preset algorithm based on intraoperative data obtained from adults to evaluate the electroencephalogram. The BIS number is determined from three primary factors, including the frequency of the electroencephalographic waves, the synchronization of low and high frequency information, and the percentage of time in burst suppression. Part of the simplicity and attraction of the BIS monitor is that the depth of sedation/anesthesia is displayed numerically, ranging from 0 to 100, with 40 to 60 being a suitable level of anesthesia to ensure amnesia and lack of recall. With the use of BIS monitoring, a decreased incidence of awareness has been demonstrated, as well as a decrease in the total amount of anesthetic agent used.24-26 Additional studies have suggested faster recovery times and faster discharge times from the postanesthesia care unit; all of which may translate into reduced perioperative costs.26,27 Although not considered the standard of care as of yet for intraoperative anesthesia care, the ASA does recommend the availability of such monitors whenever general anesthesia is provided. Given the success of such monitors in the perioperative arena, there is ongoing interest in the application of such technology in the ICU and the procedural sedation arena.28-30

Control of Anesthetic Depth

Two feedback responses modulate the depth of anesthesia during inhalational anesthesia: (1) a negative-feedback respiratory response and (2) a positive-feedback cardiovascular response. The feedback responses refer to the relationships between the inspired concentration of anesthetic and depth of anesthesia. After an increase in the inspired concentration, a negative feedback response refers to a decrease in the depth of anesthesia, whereas a positive-feedback system refers to an increase in the depth of anesthesia. Two examples that follow are used to illustrate the importance of these responses in clinical pediatric anesthesia practice.

During spontaneous respirations, as the partial pressure of inhaled anesthetics increases, alveolar ventilation decreases, thereby limiting both the wash-in of anesthetics and the depth of anesthesia achieved (Fig. 6-18A).209 This negative-feedback response is a protective mechanism that permits the safe use of inspired concentrations of inhalational anesthetics that are severalfold greater than MAC (overpressure technique) during spontaneous respirations. Excessive depth of anesthesia cannot normally be achieved during spontaneous respirations (irrespective of the inspired concentrations of anesthetics, even if multiple anesthetics are administered simultaneously), because of the negative-feedback effect such anesthetic concentrations have to depress minute ventilation. As alveolar ventilation decreases and the wash-in of anesthetics slows, the uptake of anesthetic by blood slows and the delivery of anesthetics to the VRG slows. When the partial pressure of anesthetics in the VRG exceeds that in blood, anesthetics move along their partial pressure gradients from the VRG into blood and other tissues, thus decreasing the depth of anesthesia. As the depth of anesthesia decreases, alveolar ventilation again increases and uptake of anesthetic from the alveoli resumes. Thus, spontaneous ventilation protects against an anesthetic overdose by its negative feedback effect on respirations.

In contrast to the negative-feedback effect of spontaneous ventilation, the positive-feedback effect of controlled ventilation relentlessly delivers inhaled anesthetic to the alveoli, increasing FA/FI but at the same time diminishing cardiac output (Fig. 6-18B).209 The decrease in cardiac output limits the uptake of anesthetic from the alveoli, further increasing FA/FI. Hence, as cardiac output decreases, FA/FI increases and the depth of anesthesia increases, thereby further decreasing cardiac output. For a given minute ventilation, the speed at which cardiovascular collapse can occur in a neonate is reflected in part in the maximum MAC-multiples the vaporizers can deliver (Table 6-6). This is a positive-feedback response. This response creates a downward spiral that may result in death if it is not interrupted.

In a model of uptake and distribution, dogs who breathed spontaneously received up to 6% inspired concentrations of halothane209; the anesthetic was tolerated without cardiovascular collapse because the negative feedback response of respiratory depression prevented excessive concentrations of anesthetic from depressing the VRG. In contrast, when ventilation was controlled, cardiovascular collapse occurred at inspired concentrations ≥4% and some dogs succumbed. High concentrations of inhalational anesthetics (i.e., as those used in the overpressure technique) are commonly administered during inhalational inductions either as stepwise increases in inspired concentrations or as a single-breath high concentration. These high concentrations are tolerated provided that spontaneous respiration is maintained. If, however, ventilation is controlled, then cardiovascular collapse becomes a substantive risk. This is of particular concern in neonates and small infants who are more susceptible to the cardiodepressant effects of inhaled agents.194