Anesthesia Pharmacology:  Physics and Anesthesiology

• ¹⁰Special consideration: interaction of nitrous oxide molecules with gases within closed-gas spaces

  • Nitrous oxide is administered at high inspired concentration, and despite relatively limited solubility, significant numbers of nitrous oxide molecules are transferred to the blood and are available to transfer to other compartments.

  • Usually, we think of these of the compartments as tissue compartments, such as the brain; however, some compartments represent "closed gas spaces" and the walls of such compartments can be relatively compliant such as observed in a balloon. 

    • Anatomical examples of such compliant compartments would include the bowel (bowel gas) or pneumothorax.

  • In these examples, and others, it is easy to recognize that nitrous oxide molecules will transport into these compartments, increasing the number of molecules in these compartments, and as a consequence, given compliance noted above, result in a tendency for volume expansion.  

    • Initially, such compartments contain nitrogen from the air and it is a characteristic of nitrogen to have exceedingly limited solubility in blood with a blood: gas partition coefficient about equal to 0.015.  

    • That means that nitrogen molecules "trapped" in these gaseous compartments are not readily removed by the blood.  

    • By contrast, since nitrous oxide can readily transfer across membrane barriers without nitrogen from inside the compartment transferring out proportionally, a volume increase must obtain, [nitrogen is 35 times less blood soluble compared to nitrous oxide]  

    • The extent of volume increase ultimately depends on the alveolar nitrous oxide concentration, since all other compartments at equilibrium would exhibit partial pressure equivalence to that observed in alveolar volume.  

    • Analysis suggests that an alveolar concentration of 50% could cause a doubling of such compliant compartment volumes; furthermore, a higher alveolar nitrous oxide concentration (75%) could even cause a quadrupling of compartment volumes.

  • Clinical correlation: pneumothorax

    • In the presence of pneumothorax, administration of 75% nitrous oxide, could result in a doubling of pneumothorax volume rapidly (10 minutes) with a 300% increase possible within a half-hour.  The significant volume effects might be sufficient to compromise cardiorespiratory function.  Therefore, it is not surprising that nitrous oxide would-be contraindicated in the presence of significant pneumothorax.  By way of review ,chest x-ray of pneumothorax examples are presented below.¹⁶

• ¹⁰Clinical correlation: nitrous oxide and air embolism

  • As noted above, the increase in volume in compliant regions may be fairly rapid.  

    • Unfortunately, the increase in volume may be the more rapid in the presence of air embolism.  

    • The same mechanism which explains an increase in pneumothorax volume following nitrous oxide also applies to an increase in air embolus volume in the presence of nitrous oxide.

  • Experimental studies (animal) indicate that air embolus lethal volume is reduced in cases in which nitrous oxide is present.  This result is explained by the increase in air embolus volume as nitrous oxide molecules transfer into the embolus volume.

  • Clinically, nitrous oxide should be used only with caution in those procedures in which the air embolus might be considered an important risk.  Examples of such procedures include posterior fossa craniotomy and laparoscopy.

  •  A corollary to this analysis is that if air embolism is suspected intraoperatively, nitrous oxide should be discontinued without delay.

   

• ¹⁰Other clinical correlations

  • Expansion of the endotracheal tube cuff, normally filled with air, they also occur following nitrous oxide administration.  The mechanism is the same as described above and can result in a 2X or 3X increase in two-volume.  The consequence may be excessive tracheal mucosal compression and checking to avoid this would be appropriate intraoperative technique.  

  • Endotrol®  The Endotrol® tracheal tube was designed to facilitate intubation of patients where aid is needed in controlling the direction of the tip of the tube.  PMX Medical

  • Emergency Medicine Tube (EMT) For drug administration via ET tubes. Integral injection port delivers medication to distal end of tube, eliminating the need for CPR interruption or disconnection of the tube from ventilation source.  PMX Medical

  • 20Cuffed Murphy tube

  • Even expansion of balloon-tipped catheters occurs (Swan-Ganz catheters would be an example).

• Nitrous oxide and non-or poorly-compliant volumes:  The examples above considered responses of compliant volume walls to increase force exerted by nitrous oxide in combination with other molecules internal to the volume.  However, other sorts of spaces in the body are characterized by much less compliance.  

  • For example, elevation in intraocular pressure can occur following nitrous oxide administration which itself follows intravitreal hexafluoride injection.

    • Explanation:  Sulfur hexafluoride is a liquified gas under pressure which is administered by injection into the vitreous cavity and is used in treatment of uncomplicated retinal detachment by pneumatic retinopexy. 

      • Following intravitreal administration, gas surface tension blocks retinal tears by holding the retina against the choroid allowing retinal pigment epithelial pump to remove sub-retinal fluid which is responsible for retinal breaks.

      • There are several opthalmological-based contraindications; however package-insert warning notes that the use of nitrous oxide must be stopped at least ten minutes prior to gas injection and nitrous oxide should not be used during anesthesia when a gas bubble is in place.

  •  Another consideration focuses on the middle ear which contains a natural gas space. 

    • Following nitrous oxide administration, middle ear pressure increases in the range of 20 mmHg - 50 mmHg may occur and may be sufficient to cause movement of tympanoplastic grafts.

    • ¹⁹"Tympanoplasty implies reconstruction of the tympanic membrane but also deals with pathology within the middle ear cleft, such as chronic infection, cholesteatoma, or an ossicular chain problem.";

    • "Tympanoplasty is usually performed under general endotracheal anesthesia although patients who are reluctant to undergo general anesthesia may be given local anesthesia supplemented with intravenous sedation.

      • Nitrous oxide should be avoided as it can shift the graft position.

      • Muscle relaxants should also be avoided if possible.

      • The postauricular and canal skin are initially injected with 1% lidocaine with 1:100,000 concentration of epinephrine to assist with hemostasis."
        

²¹CO₂ Level Assessment: Capnography

• Capnography is a term that refers to the measurement and display of carbon dioxide concentration in expired and inspired gas. 

  • Sampling occurs at the connector-end of the endotracheal tube, the Y-piece, the face mask or from the nasal cannula.

  • The more reliable sampling is associated with tracheal tube or Y-piece analysis, compared to sampling from the mask or nasal cannula. 

  • The idea is not only the measurement of exhaled CO₂ concentration but also analysis of the waveform. The figure below is that of a normal capnogram; principal characteristics include a CO₂  concentration of zero during inspiration; however, the concentration rises rapidly during expiration with the alveolar plateau being flat or exhibiting a slight upslope. 

    • The highest CO₂   concentration is associated with the termination of exhalation and is referred to as end-tidal CO₂ .

    • The now common use of capnography has been part of the revolution in anesthesia safety, typically permitting rapid assessment of endotracheal intubation by contrast to esophageal intubation.

• The sequence of events leading to CO₂ evolution which results in a normal diagram include the following steps: 

  1. Physiological generation of CO₂

  2. CO₂ transport by the blood to the lungs for exchange

  3. Exhalation of CO₂ by the lungs with subsequent sampling of gas

  4. Working/connected sampling line, detectors, and capnograph

  5. CO₂-free inhalation gas is required to clear the CO₂ present in the sample line due to previous exhalation.

• In practice,CO₂  exhalation over several breaths, sequentially (5-7) is a good indication that adequate blood flow supporting gas exchange is occurring, the ventilating gas from the anesthesia machine is reaching alveolar gas exchange sites and is being exhaled and the capnography system is working adequately. 

  • Abnormal capnograms could indicate a problem somewhere in the sequence noted above.

• ²²"Technology of capnography

  • CO₂ monitors measure the concentration of CO₂ in an air sample.

    • This information can be displayed simply as a number (as in digital CO2 monitors) or in a waveform (known as the capnogram).

    • Capnograms, or CO₂ waveforms, provide the user with a great deal of information about the ventilatory status of a patient.

  • Most CO₂ monitors measure the CO₂ of expired air using infrared absorption techniques (see figure below).

    • The basis of this technique is that CO₂ molecules absorb infrared radiation of very specific wavelengths.

      • Other technologies include the qualitative colorimetric method, the mass spectroscopy method and the Raman capnometer.

        • The colorimetric capnometer is a single use device which can be useful for verification of ETT placement.

        • It consists of a disk coated with a chemical which reacts with CO₂ to produce hydrogen ions producing a color change relative to the resultant pH. Mass spectroscopy ionizes gases and then separates the molecules based on mass and charge.

          • This method is accurate, however mass spectrometers are large and expensive and thus not practical for most applications.

      • Raman spectroscopy is based on the scattering properties of energy after exposure of gas molecules to ultraviolet light.

        • It is an effective method for measurement of CO₂ concentrations, but not as widely used as infrared (IR) capnometry.

  • In the IR technique, the exhaled air from the patient is passed into a "sample cell" which is placed between an IR light source and a detector which is specific for the spectral region absorbed by CO2 molecules. The presence of CO₂ in the cell blocks radiation from the light source. The reference cell contains no CO2 and thus the difference between these two cells can be used to determine CO₂ concentration in the exhaled air.

  • 

  • CO₂ monitors can measure carbon dioxide in one of two ways: mainstream or sidestream.

    • The sidestream CO₂ monitors aspirate gas through tubing to a sample cell inside the device where-as the sample cell in the mainstream variety is placed directly in the airway.

    • The advantage and disadvantage of mainstream sampling systems is that the sensor is directly on the airway.

      • The advantage is fast response time and the disadvantage is exposure and vulnerability to moisture and patient secretions resulting in occlusion of the system.

        • Mainstream sampling systems are primarily used for intubated patients.

          • Conventional high-flow sidestream systems, although designed for use in both intubated and spontaneously breathing patients, have problems with occlusions and with accuracy in pediatric patients especially newborns."

• A main advantage of capnography is the ability to rapidly detect and ultimately avoid the consequences of esophageal intubation. 

  • Therefore, one becomes interested in knowing whether or not there are cases in which esophageal intubation occurs but the capnogram is not "flat".  

    • One example refers to the situation which the individual has ingested soda or has ingested Alka-Seltzer, either of which provides a CO₂ source.

      • This event can cause unusual CO₂ values and waveforms and capnographic evidence of CO₂ would rapidly diminish.(see below) 

      • Another possibility is that CO2 might reach the stomach with improper mask ventilation.

• ²¹The generation of the capnogram is represented in the diagram below.  

  • The capnogram itself represents the CO₂ concentration as measured at theY-piece. 

  • The phases include:

    •  1 (below) Expiration with CO₂ present at theY piece.  Note that the capnogram remains elevated since CO2-containing gas remains at theY piece until the next inspiration cycle begins. and 

    • 2 (below) Inspiration where we note the absence of CO₂ at the Y piece.

• ²¹Suppose that right after endotracheal intubation, the capnogram, instead of indicating appropriate CO₂ concentrations, indicates a value of about 0. 

  • In the interoperative setting then, under time pressure, what would be the possibilities to consider in your analysis?

  • Here are some possibilities:

    • The lack of CO₂ concentration in the capnograph could be due to the lack of pulmonary blood flow, a significant problem secondary to massive pulmonary embolism or cardiac arrest. 

    • Another possibility would be the absence of tidal ventilation, which could be due to a physiological reaction, e.g. severe bronchospasm associated with an asthmatic attack or a problem in the ventilatory circuitry.

    • The legitimacy of a value displayed on any instrument of this type is based on at least two presumptions (1) the sampling line is not compromised and (2) the instrument itself is working in a proper manner.

    • Lastly, the underlying important presumption is that the endotracheal tube is in the trachea; if not, a capnographic result indicating a CO₂ level of 0 would not be unexpected.

  • Diagnosis of the problem in the formulation of a proper response may be assisted by the following considerations: 

    • Verification of the conclusion that initial placement of the endotracheal tube into the trachea is correct.  Therefore in this situation, recertification of the endotracheal tube positioning is important.

    • The possibility of cardiac arrest can be resolved in a number of ways.  For example, if the precordial stethoscope is being utilized, the anesthetist will know immediately if there is an absence of heart sounds.  However, with the increased reliance on indirect means or technologies, checking by direct palpation of the carotid artery for pulse is appropriate; secondarily, verification of appropriate pulse oximetry output would also be reasonable.  The possible presence of severe asthma (causing an absence of tidal ventilation) or cardiac arrest could be easily detected by direct precordial monitoring.

    • As noted above, one possibility in this situation would be the failure of the capnograph.  A quick way to check the functioning of the instrument would be to disconnect the sampling line and then exhale on it.  It should, of course, register a CO₂ reading and if it doesn't the problem has probably been isolated to the instrument. 

    • Under some circumstances, one might be forced to conclude that the endotracheal tube was not positioned properly and did not go through the vocal cords. 

      •  In that case, options include a repeat laryngoscopy or ventilating the patient with a mask following removal of the tracheal tube. 

      • Circumstances that might lead one to this conclusion would take into account that physical examination did not reveal airway obstruction and that the occurrence of a severe acute pulmonary embolism is unlikely. 

        • Given that, if the patient exhibits a pulse and the capnography instrumentation works but the patient is desaturating and becoming cyanotic, and the above conclusion is likely then repeat laryngoscopy or mask ventilation should be initiated.

• ²¹Suppose the capnogram exhibits baseline elevation.  We want to consider possible causes.

  • At high respiratory rates, at least for certain capnography instruments, the baseline may not return to zero.  More of the time, a significantly elevated baseline, which might be about 2 mmHg CO₂, indicates a problem, one consequence of which is that the patient will be inspiring some CO₂.  There are certain explanations with respect to this CO₂ source including:

    • CO₂ absorption is inadequate

    • There is improper functioning of the unidirectional inspiratory or expiratory valve

    • or there has been administration of CO₂ from a CO₂-equipped anesthesia machine -- This administration could be accidental or intentional.

• ²¹Consider the above capnogram examples which illustrate features of elevated CO₂ baselines dependent on causes. 

  • The shaded (black) regions represent areas in which CO₂ is present during inspiration. 

  • In the case in which there is a failure of the expiratory valve or there is inadequate CO₂ absorption, the consequence is that there will be CO₂ gas present mixing with CO₂-free inspiratory gas at the Y-piece.  This mixing results in, assuming all other factors remain constant, in the consistent elevation of the CO₂ concentration in the inspired gas.

  • The second case considers a failure of the unidirectional inspiratory valve the failure of which allows the exhaled CO₂-containing gas to flow backward into the inspiratory limb of the gas path.  A consequence is the addition of previously exhaled CO₂ mixing with CO₂-free gas during inspiration and thus these CO₂ molecules will be detected by the capnograph as the molecules pass the Y-piece.  In this latter case the capnogram will finally exhibit 0 CO₂ following rebreathing of all previously exhaled CO₂;at this point only fresh gas will be present at the Y-piece.

• ²¹Sometimes, equipment problems may be identified by abnormal capnogram waveforms. 

  • For example, abnormal capnograms may be produced if there is a gas leak around a somewhat deflated endotracheal tube cuff. 

  • Furthermore, a partially obstructed or kinked endotracheal tube induces expiratory delay with consequent delay in capnographic waveform rise.

    • Abnormal physiology may be observable in the abnormal capnograms. 

      • Delayed capnographic upslope with the steep alveolar plateau could be caused by asthma and chronic obstructive pulmonary disease (COPD). 

    • Pulmonary embolism or systemic hypotension effectively causing hypoperfusion of the lung retards CO₂ excretion with the consequent reduction in end-tidal CO₂  levels. 

      • The capnogram could have a normal shape despite this attenuation.  

      • ²⁴Note: even if the CO₂ waveform appears stable in his continuous, and although one can reasonably conclude that alveolar ventilation is occurring, it is not possible to conclude that the endotracheal tube is in fact correctly positioned since the tip could be located in a mainstem bronchus.

• Spontaneous respiratory efforts with patient-induced inhalation before mechanical ventilation-induced inhalation can cause a break or "cleft" in the alveolar plateau. 

  • This capnogram feature is clearly clinically useful since it indicates the patient has started to breathe.

²³Capnograms from Kodali. Bhavani Shankar MD, Harvard University

• Factors that may alter the expiratory CO₂ (PECO₂) include changes in ventilation, altered cardiac output, changes in pulmonary blood flow distribution, as well as changes in basic metabolic rate.

  • Capnometry refers to the measurement as well as numeric representation of dynamic CO₂  concentration changes during the inspiratory and expiratory cycles.

  • The capnogram, examples of which are noted above, present a continuous concentration-time display allowing constant CO₂  concentration assessment by sampling at the patient's airway.

  • Capnography would be the continuous monitoring of the capnogram.  As noted earlier, the capnogram can be divided into four phases.

• ²⁴The first phase (A - B) is the first expiratory stage and gas sampled during this phase represents anatomical dead space and would typically not contain CO₂. 

  • CO₂-containing gas will be present at the sampling site beginning at point B. 

  • A result of CO₂  appearance is the rapid increase in CO₂ concentration which in the representation above is B-C. 

  • The upstroke slope depends on ventilation evenness and alveolar emptying. 

  • The next phase is C - D which is referred to as the alveolar plateau or expiratory plateau. 

    • During this phase of the capnogram, sampling to determine CO₂ concentration is performed. Point D is referred to as the end-tidal CO₂ (ETCO₂).  Alveolar CO₂ (PACO₂) is best estimated by ETCO₂.

    • With the next inspiratory cycle, fresh gas entrainment occurs and therefore a rapid reduction in CO₂ concentration would be noted (D - E) above. 

    • In the absence of conditions favoring rebreathing, the baseline would be flat and the CO₂ concentration approaches 0.

• ²⁴Although the general value of capnography has been previously described in terms of identifying the occurrence of non-endotracheal intubation, a more complete utilization of capnographic information depends on appreciating relationships between arterial CO₂ (PaCO₂), alveolar CO₂ (PACO₂) and ETCO₂ or end-tidal CO₂. Assumptions about capnographic interpretation in normal cases include the following: 

  • (1) That CO₂ diffuses easily across the alveolar -capillary membranes

  • (2) That there is an absence of measurement sampling errors and 

  • (3) The presence of  conditions exist that result in good ventilation/perfusion matching (as opposed to mismatching).  

  • Under these circumstances, changes in ETCO₂  reasonably reflect changes in PACO₂. In the ideal mathematical model representation of the process, ETCO₂  PaCO₂  PACO₂ .  For the case in which the difference in PaCO₂ and PACO₂  i.e.(PaCO₂ -PACO₂ ) is small and constant over time then capnography does provide a reasonable, continuous assessment of ventilation using a method that has the advantage of being noninvasive.  In terms of what reasonable ETCO₂ -PACO₂  differences might be, in the normal general anesthetic protocol, this gradient is about 5-10 mmHg.  

    • One factor that may cause an increase in the ETCO₂ -PACO₂  difference would be significant ventilation/perfusion mismatching ( ) or technical difficulties with gas sampling.

    • Ventilation-perfusion anomalies would be a common cause of higher PaCO₂ -PACO₂ gradients. 

  • Patient factors that can influence the ETCO₂ monitoring accuracy by increasing the PaCO₂ - ETCO₂ difference include "shallow tidal breaths, prolongation of the expiratory phase of ventilation, or uneven alveolar emptying."  

• ²⁴An extreme case of ventilation perfusion mismatching, i.e.mismatching, occurs when adequate alveolar ventilation is combined with an absence of blood flow in that region (dead space ventilation). 

  • Since perfused alveoli are the only alveoli participating in gas exchange, nonperfused alveoli would have a PACO₂  of 0. 

  • The end-tidal CO₂ (ETCO₂) reflects an average across the alveoli, including both perfused and unperfused fractions.

  • If significant dead space ventilation is present, the ETCO₂ will be decreased and an increased PACO₂ -ETCO₂  will be observed. 

    • This condition, an increased PACO₂ - ETCO₂  gradient, might be expected to occur in some clinical settings such as following embolisms [thrombus, fat, air, amniotic fluid], hypo-perfusion states associated with reduced pulmonary blood flow, as well as in COPD. 

    • On the other hand, clinical circumstances associated with increased pulmonary shunting -- the circumstance of perfusion without ventilation -- minimal changes in the PACO₂ - ETCO₂  gradient are noted.

• ²⁴Factors that can induce a change in end-tidal CO₂ (ETCO₂  ):

  • Increases in ETCO₂  

    • Changes in CO₂ production:

      • Increasing metabolic rate due to:

        1. Hyperthermia

        2. Sepsis

        3. Malignant hyperthermia

        4. Hyperthyroidism

        5. Shivering

    • Changes in CO₂ elimination:

      • Hypoventilation

      • Rebreathing

  • Decreases in ETCO₂  

    • Changes in CO₂ production:

      • Decreasing metabolic rate due to:

        1. Hypothermia

        2. Hypothyroidism

    • Changes in CO₂ elimination:

      • Hyperventilation

      • Hypoperfusion

      • Pulmonary embolism

•  ²⁵Effects of Asthma on Capnographic signatures

  • Bronchospasm often causes a reduction in ventilation without a proportional reduction in pulmonary blood flow through the affection volume. 

    • This condition defines an increase in ventilation/perfusion mismatching, recognizing that even in an optimal case ventilation will not be precisely matched with perfusion. In the diagram below, note the 2 alveoli, A & B and note that "B" shows a constriction in the terminal bronchiole.

    • This diagram emphasizes that the capnographic waveform represents a summation across local alveolar capnograms.  Poorly ventilated alveoli (B-type in the diagram) empty their gas content later--an idea called "sequential emptying of parallel units with decreasing VA/Q."  This effect, at the level of capnography, is manifest as a recording delay with possible widening and deformation of the capnogram.

   

• Additional capnograms (²³ Capnograms from Kodali. Bhavani Shankar MD, Harvard University) illustrating the following clinical or equipment signatures:

  • Exhausted soda lime (example 1)

  • Exhausted soda lime (example 2)

  • Dilution of CO₂ by Fresh Gas Flow (FGF)

  • Acute Reduction in Cardiac Output

  • Pulmonary Embolism

  • Leaks in Sampling Tube (one example)

Citations

• ¹⁰Eger II, E.I., "Uptake and Distribution" in Anesthesia 5th edition vol. 1 (Miller, R.D. editor; Cucchiara, R.F., Miller, Jr., E.D., Reves, J.G., Roizen, M.F. and Savarese, J.J., consulting editors) Churchill Livingstone, Philadelphia, 2000, pp 74-95.

• ¹¹Eger, II, E.I., "Concentration and Second Gas Effects" in Anesthetic Uptake and Action, The Williams & Wilkins Company, Baltimore, Maryland, Chapter 6, pp 113-121, 1974

• ¹²Eger, II, E.I., "Ventilation, Circulation and Uptake" in Anesthetic Uptake and Action, The Williams & Wilkins Company, Baltimore, Maryland, Chapter 7, p. 131, 1974.

• ¹³Color illustrations and design: from Lecture 8. Lung Dynamics by M. Ludwig, McGill University (http://www.mmi.mcgill.ca/Unit2/Ludwig/lect21ventilationperfusion.htm)

• ¹⁴Eiger, E II, Severinghaus. JW:  Effect of uneven pulmonary distribution o fblood and gas on induction with inhalation anesthetics.  Anesthesiology 25:  620-626, 1964.

• ¹⁵Stoelting,.R.K., Longnecker, D.E. Effects of right-to-left shunt on rate of increase in arterial anesthetic concentration.  Anesthesiology 6: 352-356, 1972.

• ¹⁶Diagrammatic representation of pneumothorax: http://bio.bio.rpi.edu/.../Lectures/ L17NEWPVent/L17hpneumo.html

• ¹⁷Chest Teaching File, Wayne State University

• ¹⁸Tension pneumothorax, Michael L. Richardson, M.D., University of Washington

• ¹⁹T Katzenmeyer, K, Friedman, N, Quinn Jr., F.B.Tympanoplasty,  Grand Rounds Presentation, UTMB, Dept. of Otolaryngology; June 9, 1999  (http://www.utmb.edu/otoref/Grnds/Tplasty-9906/Tplasty-9906.htm)

• ²⁰Ko, JCH, "Airway Management and Ventilation, http://www.cvm.okstate.edu/courses/vmed5412/Lect22.asp

• ²¹Goldman, J.M., "Capnography" in Anesthesia Secrets, 2nd Edition, James Duke, ed, Hanley and Belfus, Inc, Philadelphia, pp 122-125,  2000

• ²²Capnography Society (http://www.capnography.net/techno.html)

• ²³Example Capnograms from Kodali. Bhavani Shankar MD, Harvard University (http://www.capnography.com/What/what.htm#),used with permission

• ²⁴Murphy, G.S. and Vender, J.S. "Monitoring the Anesthetized Patient" in Clinical Anesthesia (4/e), edited by Paul G. Barash, Bruce F. Cullen and Robert K. Stoelting, Lippincott Williams & Wilkins, pp 668-673, Philadelphia, 2001

• ²⁵Capnography research in asthma (http://capno.chez.tiscali.fr/)