EASTWOOD et al.  1have contributed an article to this issue addressing the upper airway at various levels of propofol anesthesia. Ventilatory depressant properties of anesthetic agents can be characterized by their effects on resting carbon dioxide concentrations and the ability to alter the normal ventilatory response to hypoxia and hypercapnia.2However, in most clinical situations, the presence of hypercapnia as a result of ventilatory decline is not harmful, especially during administration of supplemental oxygen.3In fact, the most serious complication that results from the administration of agents that depress consciousness is upper airway obstruction because, if undetected or inadequately treated, it rapidly results in hypoxemia.4 

Several decades ago, researchers studying obstructive sleep apnea syndrome developed a model to measure upper airway collapsibility during sleep.5By considering the cartilage-free upper airway as a classic Starling resistor, the pressure within or contiguous with the airway can be artificially altered, and by measuring corresponding peak flows during conditions of flow limitation, a critical pharyngeal closing pressure (Pcrit) is derived.6Pcrit reproducibly describes the inherent collapsibility of a subject’s airway and has been used to measure the impact of an intervention such as weight loss,7uvulopalatopharyngoplasty,8or administration of continuous positive airway pressure.9 

The Pcrit measurement has been used previously to characterize upper airway collapsibility in sedated10and anesthetized11patients. However, in this issue of the Journal, Eastwood et al.  1take this methodology to a new and more clinically meaningful level by demonstrating the dose–response relation between the depth of propofol sedation and Pcrit. The dose response for upper airway collapse is one of several important components that describe the safety of a sedative agent (i.e. , therapeutic margin) and may determine the choice of sedatives by practitioners without training in general anesthesia.

I believe there are two perspectives to consider when interpreting this data. The first is the actual Pcrit values obtained and the ability to compare these values against those obtained with other anesthetics or sedatives at the same depth of unconsciousness. The range of Pcrit values reported for propofol is between those reported for isoflurane11and midazolam,10indicating that its relative propensity to preserve upper airway patency (i.e. , safety) is greater than for isoflurane but less than for midazolam. That is, at similar depths of sedation, propofol is more likely to cause upper airway obstruction than midazolam. This underscores the recent American Association of Nurse Anesthetists–American Society of Anesthesiologists joint statement cautioning that use of propofol for sedation should be restricted to practitioners with training in general anesthesia.*I do not believe I would be taking great risk of criticism by stating that when it comes to upper airway obstruction, propofol is not a typical sedative!

The second perspective is the percent change in Pcrit relative to the change in level of unconsciousness. For Eastwood’s group as a whole, the mean Pcrit increased from −0.3 mmHg at the lowest propofol plasma concentration studied (2.5 μg/ml) to +1.4 mmHg at the highest concentration studied (6.0 μg/ml). Although statistically significant, this is hardly a clinically relevant difference and is less than the span of pressures seen within one respiratory cycle in most anesthetized adults. As a reference, remember that this lower concentration of propofol is associated with a wide range of states of consciousness, from awake to deeply sedated, and the higher concentration of propofol is usually associated with a state of deep sedation.12This relative change in Pcrit between a span of sedative states may serve as a marker of an agent’s safety. Future investigations with additional anesthetic and sedative agents will reveal these types of differences.

An important limitation of the measurement of upper airway collapsibility in sedated or anesthetized patients is the lack of a consistent and reliable pharmacodynamic indicator of the depth of unconsciousness. In our study on the effect of midazolam on Pcrit, we used a standardized sedation score.10Eastwood et al.  used target plasma concentrations of propofol and Bispectral Index scores, which exhibited reasonable consistency but poor precision. The comparison of Pcrit values between different agents must rely on a standardized level of unconsciousness so that one is comparing “apples with apples.”

Another limitation of this methodology is the subjective identification of flow-limited breaths, which indicate upper airway narrowing. To date, investigators using the Pcrit method have identified flow-limited breaths by their characteristic flow wave appearance consisting of a flattened plateau during inspiration. More objective, mathematically based methods that use inspiratory flow and airway pressure values have recently been described13and may prove more consistent in future trials.

The use of the genioglossus electromyography also deserves comment. Sleep apnea researchers believe that a major factor contributing to the loss of pharyngeal patency in patients with obstructive sleep apnea is the dysfunction of certain patency reflexes, such as the negative-pressure reflex. The negative-pressure reflex describes the activation of pharyngeal dilator muscles in response to the application of pharyngeal negative pressure. This has been most widely studied in the genioglossus muscle because the body of the muscle is easily accessible to electromyographic needles.14Contraction of the genioglossus causes extrusion of the tongue, and alleviation of upper airway obstruction at the level of the oropharynx. However, magnetic resonance imaging studies have demonstrated that upper airway obstruction during sedation with propofol also occurs at the level of the soft palate and epiglottis.15,16Therefore, reflex activation of the genioglossus during the application of negative pressure likely serves as a surrogate for other pharyngeal dilator muscles at distant locations within the upper airway. Nevertheless, the effect of a sedative or anesthetic agent on the negative-pressure reflex may prove useful as a measure of safety in future studies.

The effects of standardized levels of anesthetic and sedative agents on upper airway patency are an important step in advancing safety for nonintubated, sedated patients. Sleep apnea researchers have extensively investigated a myriad of factors that affect upper airway collapsibility.17In comparison, upper airway studies during sedation or general anesthesia are in their infancy, and we should follow their leads.

University of Pennsylvania School of Medicine and The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania. litmanr@email.chop.edu

Eastwood PR, Platt PR, Shepherd K, Maddison K, Hillman DR: Collapsibility of the upper airway at different levels of propofol anesthesia. Anesthesiology 2005; 103:470–7
Ward DS, Temp JA: Neuropharmacology of the control of ventilation, Anesthesia: Biologic Foundations. Edited by Yaksh TL, Lynch C, Zapol WM, Maze M, Biebuyck JF, Saidman LJ. Philadelphia, Lippincott–Raven, 1998, pp 1367–94Yaksh TL, Lynch C, Zapol WM, Maze M, Biebuyck JF, Saidman LJ
Akca O, Doufas AG, Morioka N, Iscoe S, Fisher J, Sessler DI: Hypercapnia improves tissue oxygenation. Anesthesiology 2002; 97:801–6
Nunn JF: Oxygen, Applied Respiratory Physiology, 4th edition. Oxford, Butterworth-Heinemann, 1993, pp 247–305
Suratt PM, Wilhoit SC, Cooper K: Induction of airway collapse with subatmospheric pressure in awake patients with sleep apnea. J Appl Physiol 1984; 57:140–6
Smith PL, Wise RA, Gold AR, Schwartz AR, Permutt S: Upper airway pressure flow relationships in obstructive sleep apnea. J Appl Physiol 1988; 64:789–95
Schwartz AR, Gold AR, Schubert N, Stryzak A, Wise RA, Permutt S, Smith PL: Effect of weight loss on upper airway collapsibility in obstructive sleep apnea. Am Rev Respir Dis 1991; 144:494–8
Schwartz AR, Schubert N, Rothman W, Godley F, Marsh B, Eisele D, Nadeau J, Permutt L, Gleadhill I, Smith PL: Effect of uvulopalatopharyngoplasty on upper airway collapsibility in obstructive sleep apnea. Am Rev Respir Dis 1992; 145:527–32
Schwartz AR, Smith PL, Wise RA, Bankman I, Permutt S: Effect of positive nasal pressure on upper airway pressure-flow relationships. J Appl Physiol 1989; 66:1626–34
Litman RS, Hayes JL, Basco MG, Schwartz AR, Bailey PL, Ward DS: Use of dynamic negative airway pressure (DNAP) to assess sedative-induced upper airway obstruction. Anesthesiology 2002; 96:342–5
Eastwood PR, Szollosi I, Platt PR, Hillman DR: Collapsibility of the upper airway during anesthesia with isoflurane. Anesthesiology 2002; 97:786–93
Glass PS, Bloom M, Kearse L, Rosow C, Sebel P, Manberg P: Bispectral analysis measures sedation and memory effects of propofol, midazolam, isoflurane, and alfentanil in healthy volunteers. Anesthesiology 1997; 86:836–47
Mansour KF, Rowley JA, Badr MS: Noninvasive determination of upper airway resistance and flow limitation. J Appl Physiol 2004; 97:1840–8
Horner RL, Innes JA, Morrell MJ, Shea SA, Guz A: The effect of sleep on reflex genioglossus muscle activation by stimuli of negative airway pressure in humans. J Physiol 1994; 476:141–51
Litman RS, Weissend EE, Shrier DA, Ward DS: Morphologic changes in the upper airway of children during awakening from propofol administration. Anesthesiology 2002; 96:607–11
Mathru M, Esch O, Lang J, Herbert ME, Chalijub G, Goodacre B, van Sonnenberg E: Magnetic resonance imaging of the upper airway. Anesthesiology 1996; 84:273–9
Veasey SC: Molecular and physiologic basis of obstructive sleep apnea. Clin Chest Med 2003; 24:179–93