Key Point

Most cases of sleep apnea have elements of both obstructive and central sleep apnea.

DENVER—Traditionally, sleep-disordered breathing has been viewed as two distinct disorders: obstructive sleep apnea and central sleep apnea. Now evidence obtained from recent experimental as well as clinical studies challenges this view and suggests that most cases of sleep apnea have elements of both disorders.¹

The classic picture of inadequate breathing is perhaps best described by the adage “Either a patient can’t breathe or won’t breathe.” Patients who could not breathe while sleeping were classified as having obstructive sleep apnea, which was thought to be due to narrowing or collapse of the pharynx. Patients in the “won’t breathe” category were said to have central sleep apnea, which was attributed to ventilatory instability.

For years, this view of sleep apnea—as type 1 and type 2, each with its own distinct pathophysiology—represented the “gospel” for treating patients who presented with sleep-disordered breathing, said John E. Remmers, MD, Professor of Internal Medicine and of Physiology and Biophysics at the University of Calgary, Alberta. The distinction can be made using polysomnography, but Dr. Remmers wondered if it is really meaningful. What, one must ask, is wrong with this picture?

“First of all it’s simplistic—life isn’t that simple: black and white, one or the other,” Dr. Remmers observed. “This categorization of apneas approaches the truth only in extreme cases. Most cases of sleep apnea or sleep-disordered breathing have both obstructive and instability factors at play.”

For instance, chemical feedback, which characterizes central sleep apnea, contributes to obstructive sleep apnea. Conversely, pharyngeal instability—the hallmark of obstructive sleep apnea—contributes to Cheyne-Stokes respiration. “So our gospel may be a little tarnished,” remarked Dr. Remmers at the 19th Annual Meeting of the Associated Professional Sleep Societies.

LIMITED VERSUS BLOCKADE

To understand how the characteristic factors of one type of sleep apnea contribute to the other, one must first be familiar with the features that define each type. Dr. Remmers focused on the distinctions within sleep apnea types in order to illustrate how the defining factors of each cross over into the other.

To begin, obstructive sleep apnea comes in two “flavors,” according to Dr. Remmers: There is the apnea marked by high upper-airway resistance, where the patient has inspiratory flow limitation; and there is the apnea associated with recurrent pharyngeal occlusion, which is characterized by the complete blockade of airflow.

Dr. Remmers showed a video of a patient with high upper-airway resistance. “This individual is struggling to breathe, to say the least, and this is the common disorder that we’ve now come to appreciate,” he said. “Let me tell you what this is not: This is not a sphincter contraction of muscles that’s closing the airway. The airway is being closed by negative intraluminal pressure.

“Airflow during inspiration is limited so that no matter how hard the individual tries to breathe in, the airflow is fixed at a low value. This is the behavior of the critical closing of a choke point, so to speak.”

He cited the work of Dr. Magdy Younes on increased and decreased airflow in patients receiving nasal continuous positive airway pressure as driving the field at this time. It also serves as illustration of the crossover of characteristic factors that Dr. Remmers emphasized.

“Even independent of an arousal occurring, or before an arousal occurs, one has an increase in flow, because during inspiratory flow limitation, ventilation is completely regulated by the activity of the dilator muscles of the pharynx,” Dr. Remmers explained. “That we have a response in most individuals of greater than baseline indicates there’s a chemical feedback onto the upper airway muscles occurring during a period of hypopnea that regulates flow. It is the chemical feedback onto the pharyngeal dilators that determines the expression, ultimately, of the sleep-disordered breathing.”

With respect to recurrent pharyngeal occlusion, he played a video showing the inside of a patient’s pharynx during the ventilatory phase of breathing, and narrated, “There’s an effort … an effort … no breathing … now a little breathing … then we’ll have an opening.… There’s the ventilatory phase—a pretty horrible story from the inside of the pharynx,” he observed. “Now complete obstruction … closure … closure.… So this is obstructive sleep apnea in its purest form: recurrent occlusion of the pharyngeal airway.”

“It’s important to realize that in this situation the pump muscles—the thoracic inspiratory muscles—no longer determine how much airflow you take in. Rather, it’s the outward pull of the dilators opening the pharynx that determine that. Clearly, we have here a neuromuscular component that we need to deal with, but we also have an anatomic component.”

NEURAL VERSUS ANATOMIC

Recognition of both neuromuscular and anatomic components in recurrent pharyngeal occlusion has led to one further distinction within the pathophysiology of obstructive sleep apnea: the neural hypothesis versus the anatomic hypothesis. In the neural hypothesis, patients with sleep apnea have subnormal genioglossal activity during sleep; the anatomic version postulates that persons with apnea have a structurally narrowed pharyngeal airway. “Either one might be key, and obviously we can have combinations,” he said.

Dr. Remmers presented data from studies that tested the anatomic hypothesis by successfully excluding neuromuscular influences. Investigators achieved this by studying the passive pharynx with the help of general anesthesia and complete paralysis. They were also able to compare airway pressure in patients with sleep apnea with that in matched controls. Research that Dr. Remmers conducted with Shiroh Isono, MD, has helped lead to several conclusions about the anatomic hypothesis.

First, patients with obstructive sleep apnea have decreased maximal pharyngeal area and increased closing airway pressure compared to matched controls. Second, structural changes of the passive pharynx constitute a plausible pathogenic factor in obstructive sleep apnea. “We certainly haven’t established that that is the case, but it’s plausible, at least,” Dr. Remmers observed. “Finally, the interaction of anatomic and neuromuscular factors probably determines the ultimate expression of sleep-disordered breathing in any individual patient.”

Research conducted by White and colleagues examining the neural hypothesis served to illustrate what Dr. Remmers finds to be one of the “phenomenal behaviors in human biology.” In a study comparing the behavior of patients while they were awake and during REM and non-REM sleep, the investigators applied negative suction pressure in an attempt to close the pharynx.² But what happens in the patient who is awake? Dr. Remmers then asked.

“The airway doesn’t close,” he said. “In fact, immediately there’s recruitment of the genioglossus, which promotes a patent airway. “While awake, you won’t allow your pharynx to close, except to swallow. [But] look what happens during sleep: Apply the same challenge to the airway, and we have no response. The genioglossus doesn’t find out about the challenge to the airway. Control is lost.”

This behavior is called the proprioceptive reflex. Mechanical receptors in the pharynx or larynx stimulate the flow of afferents up to the brain, and they in turn reflexly activate the increased genioglossal activity when the patient is awake and cause no response to occur when the patient is asleep.

Dr. Remmers pointed to a study that compared genioglossus electromyographic activity in awake patients with obstructive sleep apnea versus matched controls. “What you see is that the genioglossus is greater in the patients with obstructive sleep apnea. They certainly don’t have lazy tongues—in fact, they have hyperactive tongues,” he said. “Why would that be? Well, I think it does go together with the structural narrowing that we saw in the passive pharynx, so that when we put the passive and active pharynx together, we see that the activity while awake must be greater in order to maintain a patent pharynx. While asleep, that compensation is either lost or greatly reduced, leaving the pharynx susceptible to critical narrowing or closure,” Dr. Remmers concluded. “In other words, the difference between a normal [person] and an apneic [patient] is this underlying structural narrowing.”

—Fred Balzac

Reference
1. Remmers JE. Sleepless or breathless: the human conundrum. Presented at: annual meeting of the Associated Professional Sleep Societies; June 20, 2005; Denver, Colorado.
2. Katz ES, White DP. Genioglossus activity during sleep in normal control subjects and children with obstructive sleep apnea. 2004. Am J Respir Crit Care Med. 2004; 170:553-560.

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