Panel 2

Gas Exchange

For adequate sound transmission and prevention of pathology, the total gas pressure in the ME must approach ambient. It has been suggested that 3 routes of gas exchange control ME pressure: bolus gas exchange during periodic opening of the ET^34-39 (reviewed elsewhere); transtympanic membrane gas exchange, which has recently been dismissed for the normal and abnormal atrophic, sclerotic TM^40,41; and gas exchange/production by the ME mucosa and MACS.^42,43 However, the last can be questioned given that a number of early studies showed that the CO₂, O₂, and H₂O partial pressures in the ME approximate those of blood, but that of N₂ is much greater. Because diffusion drives gas exchange been blood and the ME, the mechanism responsible for the higher N₂ concentration, if real, must involve active transport.

Of note is the fact the MACS is significantly smaller in ears with a past history of disease, but it is unclear if this results from a genetically programmed small mastoid or an effect of disease on the MACS growth, although the latter is better supported.^44,45 For example, Sade and colleagues ⁴⁴ reported smaller MACS in ears with recurrent AOM, and Csakanyi et al, ⁴⁵ in a cross-sectional study of infants, children, and adolescents with and without ear disease, found that the diseased groups had significantly smaller MACS.

The geometry of the MACS has been studied using CT scans, and over a wide range of volumes, the left-right MACS surface area and volumes were linearly related; that is, the surface area is a linear function of volume, and the surface area/volume ratio is independent of volume.^46,47 Identical results were reported for MACS during growth and development. ⁴⁵ This geometry does not support the hypothesis that the normal MACS serves as a gas transfer reserve. While a number of studies showed preferential areas of ME gas reserve or changes in the mucosal thickness during pathology, these effects can be expected only to increase or decrease the rate of transmucosal gas exchange^48,49 but will not solve the problem of the partial-pressure difference between blood and ME. Similarly, in a set of studies of questionable design, the transmucosal rate of all physiological gas was reported to be perfusion limited, ⁵⁰ but these results were not replicated in other experiments ⁵¹ and again do not affect the passive ME to blood exchange properties of ME mucosa.

One model to explain the effect of a smaller MACS volume on OM depends on both the ET and MACS gas transfers and proposes that a larger MACS reduces the frequency and efficacy of ET openings during transient obstruction of that structure; experimental data supporting this explanation have been published.^52,53

However, once an effusion develops, its persistence may be controlled by physiological processes associated with fluid balance. Using a physiologic sodium chloride solution, Li and colleagues ⁵⁴ quantified ME fluid volume changes in the rat model and then modulated these rates using amiloride (sodium channel anagonist), gluconate (chloride substitute), and a chloride channel blocker. Petrova and colleagues ⁵⁵ employed solutions of various osmolarities, in the context of an obstructed ET in guinea pigs, to demonstrate fluid absorption (hypotonic) and production (hypertonic) through the ME mucosa. They also demonstrated an effect of noise exposure on fluid resorption.

Anatomy

Although less frequently than in the past, human temporal bone ET specimens continue to be studied. For example, Ozturk and colleagues ⁵⁶ compared mucosal folds of the ET lumen of children and adults, concluding that children have more folds than adults and that they might function as “microturbinates” for protection and clearance. Doyle and Swarts ⁵⁷ studied the vector relationships between the ET, tensor veli palatine muscle, and the cranial base in skulls of children and adults. They reported sexual dimorphism and that the significant differences between children and adults could account for the observed poorer ET function in children.

Despite the extensive knowledge gained from studying the ET anatomy of cadaveric specimens, the focus of anatomical studies has shifted to noninvasive imaging of living subjects. Oshima and colleagues ⁵⁸ employed MRI to compare the cartilage morphology of normal subjects to those with patulous ETs. They confirmed its hook-shaped configuration but found diverse morphologies uncorrelated to the ET physiologic status. ⁵⁸ Another MRI study based on 35 human cadaveric heads showed that Ostmann’s fat pad was the only anatomic structure evidencing age-dependent changes, decreasing in size with advancing age. ⁵⁹ In a study using CT scanning and multiplanar reconstruction of children and adults, Takasaki and colleagues ⁶⁰ showed that the angle and length of the ET is more horizontal and shorter in infants. Using this same method, Yoshioka and coworkers ⁶¹ compared the ET of children with adults and showed that the ET lengthens with age and that the angle between the osseous and cartilaginous ET was more acute in children, as documented originally in histopathological temporal bone specimens. Most recently, this group employed a 320-row CT scanner and sophisticated postprocessing to capture ET dilation and torus tubarius movements during swallowing. ⁶² Bergin and coworkers ⁶³ reviewed 200 CT scans to assess the distance between the ET and the internal carotid artery and reported a decrease with age and that aberrant carotid arteries are closer to the ET; thus, CT scanning, with contrast, prior to skull-base surgery is recommended. ⁶³

Physiology

Sonotubometry continues to be refined and used as a noninvasive test of ET function. Using an updated sonotubometry instrument, van der Avoort and colleagues ⁶⁴ reported that 82% of 61 healthy children had ET openings on at least 1 of 2 testing opportunities, and those results were highly correlated between sessions (Spearman r = 0.89). In a subsequent study, ³³ children with otitis media with effusion (OME) and poor ET function, tested before and 1 and 3 weeks after TT insertion resolved to the control group levels. ⁶⁵ Among the technical refinements proposed and tested was the use of “perfect sequences” as the probe tone. Using that modification, all 40 ETs (20 subjects) of otologically healthy adults and 35 of 40 pathological ears (32 subjects) had ET openings. ⁶⁶ Handzel and colleagues ⁶⁷ employed simultaneous sonotubometry and nasopharyngeal (NP) endoscopy to evaluate ET function in a cohort of 18 healthy adults; one-third were unable to dilate their ET. The other two-thirds successfully dilated their ETs on 75% of their attempts, and the dilations averaged 440 ± 240 milliseconds in duration. There was 100% congruence between swallowing and yawning as methods for dilation. ⁶⁷

From Korea, Shim and coworkers ⁶⁸ compared the maximum osseous ET cross-sectional area from coronal temporal bone CT images of 80 (80 ears) patients with chronic OM to those of 50 (100 ears) controls. Chronic OM subjects with poor outcomes, evaluated 1 year after ME surgery, had smaller cross-sectional areas than the subjects with normal otoscopy and type A tympanograms and the controls. ⁶⁸ Mathew and colleagues ⁶⁹ used dynamic slow-motion video endoscopy and a detailed classification scheme to visually evaluate ET function in a prospective, case-controlled study. They reported that the protocol was a useful tool for diagnosing ET dysfunction, especially, for example, patulous ET.

Neural control of ET function remains a lacuna. Since the ET innervation studies of Eden and Gannon^70,71 20 years ago, only a few studies have been performed examining the neural control of ME aeration. Following unilateral sectioning of the Jacobson nerve and sham surgery contralaterally in rabbits, Ceylan and colleagues ⁷² found significantly more retraction pockets, ME effusion, and goblet cells in the experimental ears. These differences were attributed to disruption of tympanic glomus cells, which function as ME chemoreceptors. Songu and colleagues ⁷³ attempted to discriminate between baroreceptor and mechanoreceptor control mechanisms for middle ear pressure (MEP) using 95 (95 ears) volunteers. They topically anesthetized ME and ET baroreceptors and mechanoreceptors in various combinations and assessed ET function using the Toynbee or Williams test. Anesthesia of the baroreceptors of the tympanic plexus elicited more frequent ET dysfunction, in contrast to the low frequency found in subjects with blockade of TM mechanoreceptors. ⁷³

Pathophysiology

In 2 articles, Bluestone and colleagues offered an evolutionary biological perspective on OM. Specifically, they posited that OM is a side effect of morphological adaptations in the midface for speech and/or diet, which modify ET morphology and secondarily reduce the efficiency of the ET/NP muscles with respect to ME pressure equilibration.^37,74

Recently, an analogous situation has been identified in dogs. Primary secretory OM is the term veterinarians use to describe chronic OM with effusion in canines. It has been reported to occur almost exclusively in short-faced canines, and its prevalence in the Cavalier King Charles spaniel breed is estimated at about 40%. ⁷⁵ The effusion is mucoid and fills the entire ME. Diagnosis is either by microscopic examination, CT scanning, or MRI and has been confirmed at the time of myringotomy. Myringotomy and tympanostomy tube placement has been recommended for treatment. ⁷⁶ Artificial selection of this breed has, until recently, focused on producing a shortened front-to-back diameter of the skull, a result of premature fusion of the coronal sutures. These breeds are characterized as brachyephalic and neotenic (retention of juvenile characteristics into adulthood). ⁷⁷ Bluestone and Swarts ⁷⁴ have speculated that the Cavalier King Charles is a natural animal model, induced by artificial selection for those breed characteristics, which secondarily elicit chronic OM with effusion due to ET dysfunction. ⁷⁴

Poe and Pyykko ⁷⁸ quantified endoscopically visible NP orifice movements in healthy subjects with OME or with patulous ETs. They found that the lateral excursion of the anterolateral wall of the ET lumen was less in the two groups with ET dysfunction in comparison with healthy individuals. ⁷⁸ In a longitudinal study of ET function in 3-year-old children with either chronic OME or recurrent AOM, tested within 3 months of tympanostomy tube placement with the forced response test (FRT), passive resistance and one measure of active function were higher in the rAOM group. ⁷⁹ Ghadiali and colleagues, ⁸⁰ using an FEM, reported that the timing and magnitude of the forces produced by the tensor and levator veli palatini muscles simulate the ET resistance patterns found during swallowing in the FRT. ⁸⁰ From the same team, again using an FEM of cleft palate infant ET function, they found that the tensor veli palatini muscle force was directly proportional to and mucosal/cartilage compliance was indirectly proportional to ET dilation. ET function was independent of hamular position and the magnitude of levator veli palatini muscle force. ³⁶

The role of gastroesophageal reflux in the pathogenesis of ET dysfunction and OM continues to be a subject of investigation. Pepsin, identified in the ME in several human studies, ⁸¹ correlated with reflux episodes documented by dual-probe pH monitoring, ⁸² although one study ⁸³ found a lower prevalence than previously reported. Sudhoff et al ⁸⁴ found India ink, a tracer, in the larynx, ET, and ME of guinea pigs in response to gastric pressure when the lower esophageal sphincter was relaxed using Aquo-trinitrosan. From Turkey, Yazici and coworkers ⁸⁵ found that rats whose NP was exposed to gastroesophageal reflux demonstrated ET mucosal histopathological changes consistent with ET dysfunction that induces OM. Further studies using animal models suggested that it is the acid pH, not the pepsin, that initiates Muc5b ⁸⁶ upregulation and that Helicobacter pylori whole-cell protein extracts can elicit cytokines and an ME inflammatory response. ⁸⁷

Other NP inflammatory stimuli continue to receive attention with respect to ET dysfunction and its associated OM. The role of allergic rhinitis in the pathogenesis of ET dysfunction was investigated in a comparison of 123 children with allergic rhinitis to 141 control subjects; significant differences in ET function, total eosinophils, and serum and ME effusion IgE concentrations were not evident. ⁸⁸ However, in a rat model of allergen-induced allergic rhinitis, Ebert and colleagues ⁸⁹ reported that immune modulatory oligonucleotides prevented nasal allergen-induced ET dysfunction. The pathological effect of cigarette smoke on the ET has been demonstrated in the rat. Kong and colleagues ⁹⁰ exposed rats to cigarette smoke, which resulted in ET histologic changes including goblet cell proliferation and excessive mucus secretion. The protective effect of pulmonary surfactant on ET cilia was documented by Ma and his colleagues ⁹¹ in a guinea pig model of pneumococcal-induced OM using auditory brain stem response and histopathology.

Coldlike illnesses (CLI), documented by daily tympanometry and symptom diary, corroborated by in-home visits, identified 566 CLI episodes in 169 children over the course of 7 months (16% CLI/child burden), with MEE resulting as a complication in 37% of the episodes. ⁹² Using the same methodology, daily tympanometry and symptom diary, 249 children from 123 families were evaluated to ascertain whether constitutional ET function could be abstracted from that data. The investigators found that mapping of MEP standard deviation on average MEP allows interpretations of ET function. ⁹³

Patulous ET

The patulous ET continues to be a commonly heard patient complaint; thus, it is a concern of clinicians and scientists. There have been several reports of the patulous ET co-occurring with a variety of diseases and disorders. Two reports identified this condition in patients with amyotrophic lateral sclerosis,^94,95 in 2 patients following bariatric surgery,^96,97 associated with hemodialysis, ⁹⁸ in spontaneous intracranial hypotension syndrome,^99,100 and as a complication of anorexia nervosa. ¹⁰¹

A variety of treatments have been recommended. Poe ¹⁰² found that the insertion of a submucosal cartilage graft at the NP end of the ET restored the normal convexity to the ET wall and provided relatively long-term relief in 14 patients. Although the condition is thought to be rare in children, it was diagnosed in a 4-year-old child with a history of chronic unilateral tympanostomy tube otorrhea. It was successfully managed by the endoscopic transoral injection of calcium hydroxylapitite. ¹⁰³ Another strategy for treating the symptoms of a patulous ET, without manipulating the ET, was a simple mass loading of the TM with Blu Tack, a claylike, nontoxic substance. This technique successfully improved the symptoms of 14 patients. ¹⁰⁴ In another apparently new method of treatment, Olthoff and colleagues ¹⁰⁵ injected botulinum toxin into the ET in 1 patient with long-standing symptoms; the problem was relieved for 9 months. Another method, used by Takano and coworkers, ¹⁰⁶ involved ligating the NP end of the ET of patients with intractable symptoms, which produced relief in some but not all of the patients.

Medical Treatments

There is increasing evidence that surfactants may be efficacious in the treatment of OM and ET dysfunction. As noted above, Ma et al ⁹¹ demonstrated a protective effect of porcine phospholipid given by intratympanic injection into guinea pigs with established OME induced by heat-killed pneumococci. Surfactant-treated animals demonstrated a significantly faster recovery of ME and ET cilia and resolution of effusion versus the placebo treatment. Johnson et al ¹⁰⁷ found that an aerosolized surfactant, synthetic preparation of dipalmitoylphosphatidylcholine in a 200:1 ratio with cholesterol palmitate, introduced as a nasal spray into gerbils with induced OME significantly reduced time to resolution of the effusion relative to the placebo. In addition, they found that combining surfactant with phenylephrine significantly prolonged the time to effusion resolution, hypothesizing that the decongestant-drying effect inhibits surfactant distribution, which is dependent on wet surfaces. Thus, the common clinical practice of treating ET dysfunction with decongestants may be counterproductive.

In a cohort of 8 Navy divers, Duplessis and colleagues ¹⁰⁸ assessed the effects of oxymetazoline, acetylcysteine, pseudoephedrine, and pulmonary surfactant on ET function as measured by the 9-step test and sonotubometry prior to and after simulated dives in a water tank within a hyperbaric chamber. ET function was degraded by repeated dives when the treatment was the saline placebo. The active treatments all produced decreases in ET opening pressure on the post dive tests, but only those elicited by oxymetazoline were significant. ¹⁰⁸

Delivering medications to the ME through the ET has been proposed, and a novel endoscopic approach was introduced by Todt et al. ¹⁰⁹ Under local anesthesia, supine and with the head turned laterally and dependently, a 1.6-mm-diameter flexible endoscope was passed into the NP orifice of the ET, and topical nasal decongestant was injected through the working channel. The fluid was observed by otoscopy in the ME cavity.

Surgical Treatments

Eustachian tuboplasty to debulk soft tissue or cartilage from the posteromedial wall of the cartilaginous ET lumen was first performed in 1997 ¹¹⁰ ; modifications of the techniques have been reported recently. Metson and colleagues ¹¹¹ performed a prospective study on 20 adult patients with ET dysfunction in which Eustachian tuboplasty using a microdebrider technique was performed concurrently with nasal sinus surgery. Seventy percent of the patients showed significant improvement; the failures correlated with elevated tissue eosinophil count and advanced sinus CT stage. There were no complications. The study was limited by a lack of a control group and possible confounding effects due to simultaneous surgical treatments (sinus and tuboplasty). These results were consistent with earlier reports of Eustachian tuboplasty in which failures are associated with advanced mucosal disease or ongoing inflammatory disease.

A follow-up study of a cohort of patients who underwent diode or Argon laser Eustachian tuboplasty was reported by Poe et al. ¹¹² Of the original 13 adults with long-term refractory OME who had undergone tuboplasty, 8 were reevaluated 2 years after surgery; of these, 3 were free of OME. Failures correlated with the presence of laryngopharyngeal reflux and allergic disease, supporting the role of mucosal inflammation for ET dysfunction and the etiology of OME. Sedlmaier et al ¹¹³ performed diode laser Eustachian tuboplasties in 38 adult patients via a transnasal approach primarily using local anesthesia for a variety of indications including chronic OM with TM perforation, OME, chronic atelectasis, and difficulty during flying or scuba diving. Outcome measures included opening pressures, in those with perforations; the Valsalva maneuver; and tympanograms. Sixty-four percent showed improved tubal function, similar to earlier reports, and the results remained stable over the 1-year follow-up period. ¹¹³ Caffier and colleagues, ¹¹⁴ using the same testing and treatment protocols, reported that laser ET surgery of the hyperplastic mucosa of the epipharyngeal dorsal ostium was successful in 62% of 31 adults who had been enrolled for chronic ET dysfunction.

A novel technique for laser Eustachian tuboplasty, introduced by Yañez et al, ¹¹⁵ employed a KTP laser to create vertical full-thickness cross-hatches through the luminal mucosa into the cartilage. The goal was to weaken the spring of the medial cartilaginous lamina within the torus tubarius, expanding the diameter of the lumen. Debulking of mucosa other than within the cross-hatches was not performed, but a substantial amount of mucosa was debulked in the course of creating the cross-hatches. Patients were adults with unspecified ET dysfunction, symptoms of ear blockage, and abnormal tympanograms. Thirty-five ETs of 25 patients were treated under general anesthesia; improvement as evaluated by tympanometry was reported in 92% over a mean 15-month follow-up. There were no complications. ¹¹⁵ The early results from Eustachian tuboplasty to debulk the tissues of the posteromedial luminal wall of the ET suggest that the procedure may improve tubal function and that the benefits can be durable.

A new approach for Eustachian tuboplasty using a balloon catheter for dilation of the tubal lumen was introduced in 2010. Ockermann and colleagues worked with a manufacturer to develop a balloon catheter designed for dilation of the bony and cartilaginous portions of the ET. The catheter was evaluated in a cadaver study^116,117 and subsequently employed on 13 ETs of 8 patients (age range, 21-81 years) having nonspecified manifestations of ET dysfunction. ¹¹² The outcome measure, a nonvalidated score, was the sum of the subjective perception of tubal opening as a consequence of swallows or Valsalva maneuvers and tubal opening as assessed by tubomanometry. There were no complications and no temporal bone fractures seen on postoperative CT scans. ET function scores increased significantly from baseline and continued to improve throughout the follow-up 8-week period. Weaknesses of this study include no clear of definition of ET dysfunction, lack of description of preoperative or postoperative findings, and a short duration of follow-up. In addition, because the study attempted to dilate the ET osseous portion, there was an unacceptable increased risk of injury to the internal carotid artery.^118-120

Dilation of the cartilaginous ET using sinuplasty balloons was first investigated in a cadaver study, ¹²¹ and a pilot study was then performed unilaterally in 11 adult patients with refractory OME (>5 years). ¹²² Under general anesthesia, sinuplasty balloons (6 or 7 mm × 16 mm) were passed transnasally with endoscopic guidance into the cartilaginous ET, where they were inflated for 1 minute to a maximum of 12 atmospheres. There were no significant complications. Outcome measures included tympanograms for intact TMs, Valsalva maneuvers, and a nonvalidated ET mucosal inflammation severity score. After the procedure, all 11 patients successfully changed their ME pressure using the Valsalva maneuver, but by 6 months, that number decreased to 7. OME, atelectasis, and ET pathology severity scores all improved. The study was limited by lack of a control group and lack of objective tubal function testing in patients with a TM perforation.

Progress on 2007 Short- and Medium-Term Goals

In this section, we outline the progress that has been made since the last conference on the short-term goals (STG # indicates the short-term goal from the 2007 report).

Significant progress has been made in a number of areas identified in the previous report. Pathways of ME gas exchange have received focused attention, including TM permeability to the physiologic gases both in its normal and pathologic state and mucosal gas exchange via both isopressure and isovolume experiments, although much less information has been developed concerning bolus ET dilatory pressure equilibration (STG 5, 12). Several estimates of ME and mastoid volume and surface area, with respect to age and OM history, have been developed, although the capillary architecture has not been elucidated (STG 19). ET anatomy, physiology, and modeling continued as a focus of development. That focus has shifted from histopathologic studies to studies employing noninvasive imaging techniques, including endoscopy, CT, MRI, and optical coherence (STG 3). Previously obtained histology specimens have been used as the substrate for ET FEM to identify the structures, specifically the lateral membraneous wall compliance and tensor veli palatini muscle force, which are significant for effective tubal dilation and ME-NP pressure equilibration. These FEMs have been applied to the analysis of cleft palate ET dynamics as well as to the physiology of subjects with persistent OM (STG 4). In the face of persistent ET dysfunction into adulthood, new surgical methods, including mucosal debulking, cartilage cross-hatching, and balloon tuboplasty, have been developed and piloted (STG 3). The role of viruses in the pathogenesis has also received significant effort, including refinement of monitoring methodologies, assessment of NP inflammatory status, and the temporal dynamics of the infection within families (STG 10). Significant efforts have been made to ascertain the relationship of gastroesophageal reflux disease to OM, including the prevalence of ME pepsin concentrations, identification of the causal inflammatory component of refluxant, and quantifying the causal link between episodes for gastroesophageal reflux and OM (STG 11). Lastly, the pathogenesis of the patulous ET and potential management options were extensively explored (STG 13).

Some progress was reported on a series of short-term goals. Two reports examined ME fluid homeostasis via manipulation of the osmolarity and by targeting the sodium and chloride receptors of the epithelial cells (STG 6). Efforts continue on the goal of delineating the neural control of ET function, during this study period focusing primarily on the afferent branch of the pathway (STG 14). Initial efforts to discriminate between ET function in subjects with rAOM and those with OME showed significant differences in passive resistance and active function, supporting differences in their pathogenesis (STG 16).

No studies were reported for 3 short-term goals. No progress has been made on the anatomy and function of the ET lymphatic system over the past 10 years (STG 1), so the committee recommends this goal be eliminated. Further characterization of the ET histopathology of special populations with a high incidence of OM, such as aborigines of Australia and specific Native American groups, did not advance in the intervening time (STG 2). In addition, no studies examining the impact of normal and pathologic ME pressures and gas composition on biofilm formation, or the converse, were performed (STG 18).

Future Directions