Enflurane

ABSTRACT. Background: Aspiration pneumonia remains a significant and often devastating problem in critically ill patients. It is unclear whether aspiration pneumonia occurs because of problems in the handling of oropharyngeal secretions or if the reflux of gastric contents is the major etiological factor. Additionally, the obvious breakdown of upper aerodigestive protective mechanisms in the critically ill patient population is largely unstudied. Finally, the impact and contribution of tubes, both endotracheal and nasoenteral, on aspiration pneumonia is unclear. Methods: A Medline literature search on scientific and review articles concerning the normal physiology of the aerodigestive tract and factors that compromised normal physiology was undertaken. Readings were supplemented by expert outside opinion from researchers in these fields and from the combined expertise from a multidisciplinary panel of experts assembled at a

recent summit on aspiration pneumonia. Results: Changes in the normal physiology of the aerodigestive tract are vast and varied and dependent on the response to injury, iatrogenic interventions, and the use of nasoenteral and endotracheal tubes. The effects on gastric and esophageal motility are likely dynamic and represent an ongoing but changing risk of reflux for the patient. Nasoenteral and endotracheal tubes likely compromise upper aerodigestive protective mechanisms. Conclusions: More research is needed on the functioning of the aerodigestive protective mechanisms in critically ill patients. Understanding of the dynamic changes in gastrointestinal motility will also be an important factor to decrease the incidence of aspiration pneumonia in this patient population. (Journal of Parenteral and Enteral Nutrition 26:59-518, 2002)

PHYSIOLOGIC PRINCIPLES

The respiratory and gastrointestinal tracts are tremendously complex systems that play many roles that are vital to the survival of the organism. The lungs are not only the site of gas exchange between the organism and its environment, but also a potential portal of entry for inspired antigens and allergens; it must serve in a defensive posture. The barrier to an inhalant challenge is maintained through resident immune cells, mucous production, ciliary action, and the cough reflex. Also in place are protective mechanisms from endogenous challenges, such as oral secretions or gastrointestinal refluxant.

The gastrointestinal tract is essential for nutrient assimilation and waste disposal. Similar to the lungs, it is a portal of entry from the environment, and as such, also has a resident immune presence. Another mechanism by which the gastrointestinal tract accomplishes both its digestive and protective function is through a complex system of interrelated visceral and sphincteric muscular contractions. The gastrointestinal system is further influenced by central nervous system input, gut peptides, hormones, cytokines, and other immune cell secretogogues.

These complex systems have adapted over time to benefit the host. However, evolutionary pressure has not yet accounted for present day intensive care units (ICUs). Significant perturbations in this intricate system can occur in severely ill patients when tubes are placed into the lung or across sphincters, when various drugs are used, when other organ systems fail, or when the severity of the initial insult and concomitant inflammatory response causes teleologically advantageous responses to contribute to the demise of the host.

This article will review the normal physiology and the threats to that normal function commonly seen in severely ill patients that may contribute to aspiration pneumonia.

OROPHARYNGEAL VERSUS GASTRIC REFLUX: NORMAL AND ABNORMAL PHYSIOLOGY

Oropharyngeal Physiology: Normal Versus Compromised Function

Swallowing is a complex activity that simultaneously transports nutrients from the oral cavity to the stomach while preventing aspiration into the respiratory tract.1 Swallowing is controlled by central neural networks that are able to initiate coordinated muscle activity independent of, although potentially modifiable by, sensory feedback.1 There seems to be two levels of central control of swallowing, one at the brainstem and the other in the cerebral cortex.2 The basic act of swallowing is primarily a brainstem function.

Premotor neurons, localized in the medulla, organize the sequential activity of peripheral swallowing motor neurons. Because of their connections to multiple areas in the brainstem and other areas of the central nervous system, the swallowing premotor neurons provide a potential junction for the integration of swallow-related activities with airway protective reflexes. Superimposed on this primary function, multiple areas of the cerebral cortex seem to modulate the act of swallowing.

With volitional swallowing, these cortical areas may contribute aspects such as intent, planning, and possibly urge to the act of swallowing. Although not yet fully defined, the functional importance of this multifocal cortical involvement in swallowing is clinically evidenced by the development of swallowing disorders after injury to a wide range of cortical regions not directly related to the sensory/motor aspect of swallowing.2

Reflex or pharyngeal swallows are nonsuppressible and occur in healthy controls despite an intention to avoid swallowing.3 These swallows seem to be a more basic brainstem function. However, they too receive cortical input, although more limited than volitional swallows, particularly from the sensory/motor cortex.2

This cortical input may explain why patients with brain injury, without detectable brain stem involvement, can exhibit a deficit in pharyngeal swallowing.

The vagal nerve seems to be an important afferent arm to this neural network, providing information from more distal visceral activity that may impact on the proximal aerodigestive system.1

Volitional swallowing is comprised of an oral, pharyngeal, and esophageal phase. During the oral phase, the fluid or solid bolus is readied and propelled backward from the tongue. About the time the bolus reaches the posterior portion of the tongue, the pharyngeal response is triggered.4 The pharyngeal response is important in airway protection and involves the coordinated activation of several muscles that collectively serve to close the nasopharynx and larynx, relax the upper esophageal sphincter (UES), and finally bring about propulsion of the bolus and pharyngeal clearance. The esophageal phase involves the movement of the bolus from the cervical esophagus to the stomach by esophageal peristalsis.

In addition to the protective mechanisms involved during volitional swallowing, there are additional airway protective mechanisms that guard the respiratory system against oral spillage/secretions and retrograde challenges from the gastrointestinal tract. These mechanisms can be divided into 2 groups: (1) basal mechanisms that are constantly maintained without need for stimulation such as the lower esophageal sphincter (LES) and the UES and (2) response mechanisms that become activated on stimulation. The stimulus for the activation of this latter mechanism is usually distention of the esophagus or pharyngeal stimulation.6 The first of these response mechanisms is the esophagoglottal closure reflex, which brings about a brief closure reaction of the vocal cords in response to mechanical stretch of the esophagus. Pharyngeal swallows are pharyngeal clearing events that are initiated by either direct or retrograde pharyngeal stimulation. Although different from primary swallow because of the absence of lingual peristalsis and transfer of the oral bolus into the pharynx, they do result in glottal closure, thus sealing off the airway and protecting against aspiration. The volume of fluid needed to trigger this reflex in the elderly is greater than in the young and may contribute to aspiration in that population. The third mechanism is the pharyngo-UES contractile reflex that results in increased UES tone with pharyngeal stimulation from retrograde gastric contents. Such a reflex is believed to limit the further insult to the pharynx after initial stimulation.6 The final reflex is the pharyngoglottal adduction reflex, which brings about brief closure of the vocal cords with pharyngeal stimulation. The volume needed to trigger this reflex is significantly less than that needed to trigger pharyngeal swallows, requiring about the same volume stimulus for initiation as the pharyngo-UES reflex. As with pharyngeal swallows, the volume of fluid needed to trigger this reflex is much greater in the elderly.3

Patients in intensive care units are at increased risk for aspiration. Situations that seem to predispose these patients to aspiration from an oropharyngeal perspective include a depressed level of consciousness, drugs, and intubation both with nasoenteric tubes and endotracheal tubes.

Although not formally studied, mental status depression may interfere with swallowing mechanisms and more importantly with airway protective reflexes, possibly through disruption of the coordination between cortical and brainstem swallowing pathways.

The effects of anesthetic agents have not been evaluated extensively as a risk factor for aspiration beyond their ability to depress mental status, but there are a few studies addressing this issue. Some anesthetic agents seem to change the relationship between swallowing and the respiratory cycle. In normal patients, approximately 80% of swallows occur during expiration. In a study by Nishino and Hiraga 7 of intubated patients without assisted breathing and recovering from general anesthesia (enflurane and nitrous oxide), there was an equal probability of a swallow occurring during inspiration or expiration. Although the authors postulated that the coordination between swallowing and respiration might be lost and therefore predispose the patient to aspiration, this was not seen. Thus, the clinical implications of this finding are unknown.7

A recent study looked at the effects of propofol, isoflurane, and sevoflurane on pharyngeal function and airway protection at subhypnotic concentrations. During the evaluation, normal volunteers were given 1 of 3 anesthetic agents. The study subjects underwent evaluation of the deglutination both manometrically and fluoroscopically after receiving a contrast bolus to swallow. The authors demonstrated that subhypnotic concentrations of all 3 agents caused a significant increase in the incidence of pharyngeal dysfunction.

Pharyngeal dysfunction was manifest as either an inability to retain the bolus of contrast in the mouth with premature leakage of contrast medium into the pharynx, penetration of contrast medium to the laryngeal vestibule, or retention of contrast medium in the pharynx after completion of swallowing. The greatest increase in pharyngeal dysfunction from baseline was seen in the high-dose propofol group (8% to 58%, p

A clear predisposing factor for aspiration in the ICU is patients who have undergone endotracheal intubation or tracheostomy. Both procedures can impede laryngeal elevation and closure. Occasionally an inflated cuff can impinge on the esophagus, causing a partial obstruction with subsequent overflow of secretions into the hypopharynx.ll Elpern et al 12 performed videofluoroscopic swallowing studies in 83 ventilatordependent tracheostomized patients and found an incidence of aspiration of 50%. The authors concluded that aspiration was quite common in this patient popula tion, particularly during the pharyngeal phase of swallowing.

Finally, a nasoenteral tube is a protean feature in severely ill patients. One reported role in reflux/ aspiration is by the physical passage of this tube through both the upper and the lower esophageal sphincter with consequent compromise of the integrity of those sphincters. If the tube itself was responsible for the compromise in the function of these sphincters, then it should follow that a larger tube will cause more sphincteric dysfunction than a smaller tube. This reasonable hypothesis was not supported, at least in adults, in a recent study by Ferrer et al.13 They determined that gastroesophageal reflux and microaspiration of gastric contents was not influenced by the size of the tube.

Another method of compromising esophageal sphincter integrity is by inducing transient loss of tone in that sphincter. Patterson et al 4 demonstrated that in opossums, subthreshold pharyngeal stimulation, which did not result in esophageal peristalsis, could nevertheless result in lower esophageal sphincter relaxations. Mital et all15 looked at the number of transient LES relaxations with and without a pharyngeal tube in place.

The motility catheter that measured LES tone was introduced through a gastrostomy tube. They found a significant increase in the number of LES relaxations when a pharyngeal tube was in place compared with when it was absent, suggesting that a tube across the pharynx may predispose to reflux episodes.

The clinical implication is that pharyngeal stimulation by a nasoenteric tube may result in enhanced compromise of the lower esophageal sphincter, which could predispose the patient to reflux events, and as such, enhance the possibility of an aspiration event. A reasonable way to evaluate this risk would be to compare reflux events in patients fed by nasoenteral tube versus those whose enteral access is a gastrostomy tube. However, there are scant data in the literature on this issue. Gastrostomy tubes do not seem to be completely protective against gastroesophageal reflux because these events continue to be a significant problem after tube placement. 16,17 However, there are data in both the adult and pediatric literature that suggest postgastrostomy tube reflux is associated with preexisting reflux disease.l7-is However, given the multitude and varied medical problems in patients needing enteral access and the inherent bias associated with the decision to place either a nasoenteral tube or a gastrostomy tube, it is unknown if enteral feeding provided through a gastrostomy tube truly decreases risk of reflux compared with a nasoenteral tube. However, even if a reflux episode should occur, airway protective mechanisms should be in place to limit aspiration.

An insightful alternative mechanism that was recently hypothesized involves disruption of these protective mechanisms. Chronic stimulation of the phar ynx by the nasoenteral tybe may result in a desensitization of this important mediator of airway protection (R. Shaker, personal communication). Although the effect of a nasoenteral tube on pharygeal reflexes has not been studied, there are data supporting disruption of this reflex in pateints intubated for greater than 24 hours. De Larminat et al20 assessed swallowing latency using an electromyogram in recently extubated patients and at days 1,2, and 7 postextubation. They compared these results with nonintubated controls. It should be noted that both groups had a nasogastic tube in place at the time of evaluation. The study demonstrated that ICU patients intubated for greater than 24 hours has severe but transsient dysfunction of the swallowing reflex after exbutation.

Cough. Cough is an important mechanism that allows for clearance of foreign material and secretions from the upper airway. It is also a defense strategy used to prevent aspiration of food and fluid.21 The cough reflex is comprised of an afferent limb, central control, and an efferent limb. The epithelium of the larynx, trachea, and larger bronchi contain sensory nerves that are responsible for triggering the cough.

Receptors in the larynx and trachea are extremely sensitive to mechanical stimuli such as the presence of food and fluid, whereas those in the bronchi are more chemosensitive and thus are more sensitive to noxious gases and fumes. The presence of inflammatory mediators such as bradykinin can further sensitize air-way receptors and cause hyperreactivity.21 Although both mechanical and chemical receptors become less sensitive when subjected to continuous stimulation, the mechanical receptors adapt more rapidly. This is evident in patients with prolonged endotracheal intubation.22 Perhaps it is this accommodation to chronic stimulation that depresses the cough reflex in the intubated patients, thereby diminishing an important defense mechanism against aspiration. The afferent arm of the cough reflex is predominantly mediated through the vagus nerve, although other afferent nerves may also play a role. Various clinical and laboratory studies identify the brainstem as the central site of the cough reflex, although a discrete cough has not been characterized, and it is likely that it is diffusely localized near but separate from the respiratory center in the medulla. 21,22

Opiates inhibit the cough reflex when given centrally, most likely through a direct effect on the cough center. The effects of opiates are not secondary to sedation, because drugs that have equal sedative effects are not antitussive.

The afferent impulses are transmitted to the respiratory musculature through the phrenic and other spinal motor neurons and to the larynx through the recurrent laryngeal branches of the vagi.22 Vagal afferents also mediate bronchial smooth muscle constriction by narrowing the airways and thus increasing velocity of not antitussive.22

Because the effectiveness of cough in clearing airway secretions is at least partially dependent on expiratory flow velocities, factors that weaken respiratory muscles or change mechanics also weaken the cough reflex as a defense mechanism.

Mucociliary clearance. If fluid or particulate matter breach the upper pharyngeal and airway defenses, the epithelial cells lining the respiratory tree have another method of defense. These lining cells are equipped with cilia with an overlying airway surface liquid. The surface liquid is comprised of at least two layers: an overlying mucous layer and a periciliary liquid layer. The mucous layer is made up of mucin macromolecules, which function to bind and trap inhaled particles for clearance from the lung. The periciliary liquid layer provides a medium in which the cilia can beat rapidly and shields the epithelial cell from the overlying mucous layer.23 Particles trapped in the mucous layer are transported proximately in the respiratory tree, ultimately to be cleared through cough.

Airspace defense mechanisms. The lungs also have an intrinsic defense mechanism against aspiration of acid from the stomach. Recent studies suggest that the exchange of bicarbonate in the serum with chloride in the airspaces is responsible for much of the buffering observed in lungs exposed to acid. Several channels and transporters including the cystic fibrosis transmembrane conductance regulator may play a role in neutralizing airspace acid.24

Role of Gastroesophageal Reflux

Gastroesophageal reflux is a common event in both healthy subjects and hospitalized patients. However, protective mechanisms exist to limit the extent and severity of this event. Once reflux has occurred, up to 90% of refluxed volume can be cleared by 1 or 2 peristaltic sequences.25

This sequence can either be primary, swallow-initiated peristalsis, or secondary peristalsis, which involves the genesis of a non-swallow, initiated contraction wave above the level of esophageal body distention. This contraction wave will consequently strip the refluxed bolus back into the stomach. In addition to the physical clearance of the refluxed material, bicarbonate laden salivation increases to bring the esophageal pH back to baseline in a stepwise fashion. This process is known as esophageal clearance time.

The esophagus also exhibits baseline tone. This tone has been postulated to help restrict retrograde flow of material up the esophagus during a reflux event. In normal subjects, reflux either produces no change in tone or an increase in esophageal tone, whereas in patients with reflux disease, reflux episodes usually eliminate tone. Although not fully determined, it is possible that patterns of tonic change in response to reflux events may contribute to more proximal extent of the refluxant or a higher prevalence of reflux during tone of the lower esophageal sphincter (TLESRs). In this experimental setting, esophageal tone was abolished on exposure to amyl nitrate, a precursor of nitric oxide (NO). The esophageal response to NO may have significance in ICU patients as discussed below.

Distention of the fundus of the stomach has been associated with transient decreases in TLESRs in healthy subjects. These TLESRs are associated with reflux events. Therefore, factors that influence gastric emptying, particularly proximal gastric emptying, may predispose the patients in the ICUs to reflux events, thereby potentially increasing the risk for aspiration.

Hyperglycemia, commonly seen in the ICU also influences esophageal motility. In healthy volunteers, marked hyperglycemia (blood glucose approximately 270 mg/dL) decreased lower esophageal sphincter pressure and the velocity of esophageal peristalsis, but increased the duration of peristaltic waves when compared with euglycemia. In addition, the number of TLESRs was increased during hyperglycemia.27

Although there are no specific data on the effects of sepsis on esophageal peristalsis or LES function, there are data on the effect of NO on this organ. Sepsis has been reported to increase NO and as such, its potential effects on esophageal physiology through this mechanism may be pertinent. TLESRs are centrally mediated and are stimulated, in part, by gastric distention.

In a recent study by Hirsch et al, NO was found to play a role in the reflex arc mediating TLESRs triggered by gastric distention. They demonstrated that an inhibitor of NO synthesis, NG-monomethyl-L-arginine (L-NMMA), prevented the increase in TLESRs triggered by gastric distention. Of note, L-NMMA did not affect basal LES pressure or swallow-induced LES relaxation. Also of interest, L-NMMA increased contraction amplitude in the distal esophagus and decreased latency time between the pharyngeal signal and the onset of contractions in the proximal esophagus. This compound also increased peristaltic velocity in the proximal esophagus.28 A similar, but more intense, response was seen with infusion of an NO scavenger. In this study, there also was inhibition of TLESRs, but there were aberrations in esophageal peristalsis, including swallow-induced simultaneous contractions, increases in the velocity of antegrade esophageal peristalsis, retrograde peristalsis, and increases in the contractile activity of the esophagus.

Again these results clearly implicate a role for NO in esophageal peristalsis and LES relaxation. Thus, at least experimentally, sepsis has been associated with an increase in inducible nitric oxide synthase and as such, an increase in NO. Although specific data addressing this relationship is not available, it is possible that the "septic induced" increase in NO may result in greater fundic relaxation, increased propensity to LESRs, and lowered esophageal contraction amplitude. This "NO effect" might not only predispose the critically ill patient to reflux but also compromise cleaning efficacy of a reflux event. In addition, a delay in the latency period between the pharyngeal signal and proximal esophageal contractions could potentially predispose the patient to oropharyngeal aspiration.

Hirsch et al 0 looked at the inhibition of TLESRs with L-NMMA while simultaneously looking at gastric emptying. They reported that the dose of L-NMMA used in their study caused an inhibition, although not a complete abolition of meal-induced TLESRs. There was no effect on basal gastric tone or inhibition of meal-induced relaxation. Because of these findings, the authors concluded that the effect is on the "neurocircuitry-mediated triggering of TLESRs." However, these researchers did note (although no data were shown) that on doubling the dose of L-NMMA, there was an increase in basal gastric tone and an inhibition of meal-initiated fundic relaxation. There was no obvious effect on gastric emptying, although authors postulated that the possible increase in fundic tone may have been offset by an increase in pyloric tone. Additionally, the authors used a solid rather than a liquid meal.

ROLE OF GASTRIC EMPTYING

Normal Gastric Emptying of Liquids

The entire stomach plays an important role in the handling of liquids. The proximal stomach can accommodate to the volume of the ingested fluid load through a process called "receptive relaxation." The fundus also serves in a reservoir capacity, gradually propelling the liquid to the distal stomach and eventually the small bowel. The difference in tone between the proximal stomach and duodenum creates a pressure gradient, which is instrumental in the movement of liquids from the stomach into the small bowel. However, other factors are also important in the handling of liquids by the stomach. The rate of emptying of fluid from the stomach depends on both the pressure exerted on the fluid mass by the proximal stomach and the variations in flow resistance in the distal stomach. Contractile activity of the antrum can also expel fluids independent of proximal tone and pressure. A positive correlation between antral motor events and the rate of liquid emptying has been observed.31 It is therefore possible that proximal gastric tone governs the volume of the fluid volume bolus that is then propagated by antral contractions. Additionally, tonic and localized increases in phasic pressure generated by the pylorus provide an important braking mechanism, which results in decreased gastric outflow.31,32 The vagus nerve is instrumental in regulating both proximal gastric and pyloric tone and moderating antral contraction waves.33 Although pyloric motility is primarily under neural regulation, humeral signals may modulate the waves.33 Although pyloric motility is primarily under neural regulation, humeral signals may modulate the and contractility also contribute to the liquid emptying from the stomach. Specifically, both a delay in clearance of duodenal contents or increased duodenal tone will delay gastric outflow.34

Changes in Gastric Motility in Critical Illness

Drugs. Propofol is becoming more commonly used in ICU patients because of ease in titration of effective dose and rapid recovery. However, there are studies that suggest an effect on visceral smooth muscle. One study in health volunteers demonstrated no adverse effects on gastric emptying, but a minimal, probably clinically insignificant, lengthening of oral cecal transit time.35 A second in vitro study, looking at clinically relevant higher dose and prolonged exposure, demonstrated an inhibitive effective on spontaneous muscle contractions and a concentration-dependent depression of stimulated muscle contractions in gastric fundal and descending colon muscle strips obtained from patients undergoing resection of cancers in those respective areas.36

Propofol has a relaxing effect on visceral smooth muscle that seems to be clinically insignificant in healthy subjects. In the ICU setting, where multiple factors affect gastric emptying, this agent may contribute to delayed gastrointestinal motility.

Dopamine in a low-dose infusion is commonly used in ICU patients for impending or manifest renal insufficiency. Dopamine is also used to improve intestinal perfusion. In a study in healthy volunteers, low-dose dopamine induced a dose-related reduction in gastric tone.37 Food ingestion causes a similar reduction in tone, but in this latter setting, it is usually followed by increased tone. This "receptive relaxation" response to food is caused through activity in nonadrenergic, noncholinergic vagal efferent fibers, and dopamine has been proposed as a candidate neurotransmitter in gastric relaxation.37

In another study on healthy volunteers by Levein et al,38 continuous infusion of moderate dose dopamine (5 Rg/kg per minute) resulted in significant decreases in gastric emptying and orocecal transit time. Dopamine does not cross the blood-brain barrier, and therefore, its effects on the gastrointestinal system are believed to be peripheral.

Because dopamine infusion decreases proximal gastric tone and therefore the pressure gradient between the fundus and duodenum, there may be potential for compromise of gastric emptying of liquids. However, this is not the only effect of dopamine on gastric emptying. In a recent study by Dive et a139 in ICU patients, low-dose dopamine (4 [Lg/kg per minute) decreased contractions in the gastric antrum and induced phase III motor activity in the duodenum. These effects were seen in both the fasting and the fed state. The authors concluded that low-dose dopamine adversely affects gastroduodenal motility in mechanically ventilated critically ill patients.

Acid suppressive agents. There is some suggestion that gastric emptying is impacted by acid suppression.

There have been some theories suggesting that such suppression would delay gastric emptying, whereas others point out a reason for an increase in emptying.

Those who favor a delay in gastric emptying point to less acid hydrolysis with a resultant delay in trituration and hence a delay in emptying of solids. Similarly, acid suppression leads to the release of gastrin, a peptide known to inhibit gastric emptying. Conversely, others have pointed out that alkalinized gastric contents would empty faster as duodenal acid receptors that delay gastric emptying would not be activated.

Still others have pointed to the cholinergic (prokinetic) properties of some of the H2 blockers such as ranitidine and nizatidine.40 In a study by Parkman et al,40 gastric emptying of a solid meal was assessed after acid suppression with ranitidine (positive cholinergic properties), famotidine (minimal cholinergic properties), and omeprazole. All 3 drugs resulted in delayed gastric emptying of a solid meal while simultaneously increasing antral contractility. It is unclear whether acid suppression would have a similar effect on the gastric emptying of a liquid meal.

Opioids. Opioids are used extensively in hospital practice for the treatment of pain. A study in critically ill patients reported that morphine was prescribed to 35% of these patients.41 One of the major problems with their use is the associated gastrointestinal side effects. The exact mechanism behind these effects is unknown, but both a central and peripheral mechanism have been proposed. The iL-opioid receptor is responsible for both analgesia and motility disorders.

One of the mechanisms of dysmotility is through the ability of opioids to initiate migrating motor complexes (MMCs). MMCs are cyclically occurring motor patterns that are seen in the fasting state. There are 4 repeating phases to this electrical activity, with phase III having associated propagative motor activity. Phase III of the MMC begins in the stomach and is propagated to the cecum, and as such, is believed to serve a "clearing function" for the proximal gut. Motilin is believed to be the initiator of phase III of the MMC. It has been shown that morphine can initiate phase III of the MMC in dogs.42 However, the patterns of MMCs initiated by opioids are somewhat different then the usual motilin-- initiated MMC. Specifically, the opioid-initiated complex, which begins in the duodenum, preceded rather than occurred simultaneously with gastric MMC.43 Morphine also initiated phase III activity in fed dogs, approximately 20 minutes after a meal.

Similar induction of "abnormal" phase III motor activity has been demonstrated in healthy human volunteers. The pattern of duodenal activity suggested morphine stimulated multiple levels of the duodenum spontaneously and that the contractions induced were more prolonged in duration.44 Overall, longitudinal propulsive peristalsis is reduced, whereas contractility and sphincter tone is increased.45

Murphy et a146 studied the effect of morphine on gastric emptying using epigastric bioimpedance or acetaminophen absorption test and found that morphine quadrupled the time that the stomach emptied one-half of its contents compared with controls. They also demonstrated an attenuation of the gastric slowing effects of morphine with the use of the peripheral opioid antagonist, methylnaltrexone. The authors suggested that this study implicates peripheral opioid receptors as playing a large role in regard to gastric emptying abnormalities because methylnaltrexone is unable to penetrate the blood-brain barrier.

It seems that peripheral opioid receptors exert more of an influence on gut motility, whereas central receptors are associated more with analgesia. It would be clinically beneficial to have an agent that would preferentially bind to central receptors. Naloxone is an opioid antagonist that enters the central nervous system (CNS), and as such, reverses analgesia and thus is not a good candidate for reversal of the opioid effects on the bowel. Quaternary derivatives of the narcotic antagonists are poorly lipid soluble and do not penetrate the CNS. Therefore, they do not antagonize the central effects of morphine or precipitate withdrawal.

Methylnaltrexate (MNTX) is highly selective for the periphery. In preliminary studies, MNIX used as adjunctive therapy to opioids has demonstrated efficacy in reducing the delay in orocecal transit time without sacrificing the analgesic properties of this narcotic.47

HYPERGLYCEMIA

The impact of hyperglycemia on the gastrointestinal system was first appreciated in long-standing diabetes where the occurrence of dysmotility had been attributed to visceral neuropathy. Recently, however, abnormalities in gut motility, in the setting of hyperglycemia, have been appreciated in diabetic patients without obvious neuropathies and in normal controls.

This disordered motility is seen throughout the gastrointestinal tract and occurs both in the face of frank hyperglycemia and perturbations in blood glucose levels within the normal range.

With regard to gastric emptying, hyperglycemia retards emptying in diabetic patients with autonomic neuropathy, in diabetic patients without neuropathy, and in normal controls compared with euglycemics.

Hyperglycemia also attenuates the prokinetic effect of IV erythromycin on gastric emptying in both diabetic patients and healthy controls. These same effects of impaired emptying and attenuation of prokinetic drug effect have been reported in hyperglycemia within the physiologic range.4

Fraser et a149 measured gastric motility and myoelectric patterns in normal healthy volunteers who were rendered hyperglycemic through infusion of IV glucose. They demonstrated that under these circumstances, hyperglycemia stimulates localized pyloric contractions. They also reconfirmed the potent suppressive effect of hyperglycemia on antral motility.

Finally, they showed that duodenal phase III-like activity can be stimulated by hyperglycemia. The obvious implication of the increased pyloric resistance and decreased antral contractions is the retardation of gastric emptying.

Again in normal volunteers, generated blood glucose levels of approximately 175 mg/dL inhibited postprandial phasic antral motor activity (which will retard emptying of solids and liquids), whereas at higher levels (approximately 230 mg/dL), there was an increase in abnormal electrical activity resulting in a marked increase in tachygastric and arrhythmic (noneffective) electrical activity. The authors speculated that at lower levels of hyperglycemia, there was inhibition of spike potentials that induce antral contractions, whereas at higher levels of hyperglycemia, there may be disruption of the pacemaker that controls their frequency and directionality.50

Physiologic hyperglycemia may also play a role in delay of gastric emptying though a synergistic effect on cholecystokinin (CCK). Endogenously administered CCK analog, CCK-8, demonstrated a significantly enhanced basal pyloric pressure at a blood glucose level of 128 mg/dL compared with 72 mg/dL. This effect is seen when CCK is stimulated by intestinal nutrients.51 Because pyloric tone is a major determinant of transpyloric flow, elevated blood glucose, even within the normal range, may retard enteral feeding through CCK-mediated pathways.

RENAL FAILURE

The majority of the available studies in the literature evaluating the effect of renal disease on bowel motility are in patients with chronic renal insufficiency that may not be directly extrapolatable to patients with renal disease in acute illness. One reason for the caution in expanding the results to an ICU population is the presence of visceral neuropathy in a significant portion of patients with chronic renal failure. Dumitrascu et a152 evaluated gastric emptying in patients with chronic renal failure and demonstrated that patients with parasympathetic and sympathetic neuropathy had delayed antral filling and emptying of a semisolid meal, those with only parasympathetic neuropathy had normal emptying, and those with neither had increased emptying. The authors explained the rapid emptying in the latter group by decreased compliance of the fundus by congestion.52 Although studies differ, for the most part, patients on chronic dialysis have liquid emptying that is essentially normal as determined by radionuclide scans. Uremic patients not on dialysis have normal or delayed gastric emptying times.53

However, there is some reason to believe that renal insufficiency, aside from neuropathy, may influence gastric emptying. Gastric motility is regulated by gastric myoelectrical activity, and abnormal gastric myoelectrical activity has been associated with gastric motility disorders. The rationale for the gastrointestinal dysfunction in renal failure is the effect of uremia on myoelectrical conduction and the increased plasma levels of gastrointestinal hormones that may modify gastric and small intestinal motility (gastrin CCK, motilin, etc).54 To further evaluate some of these issues, Lefebvre et al 154 studied gastrointestinal myoelectric activity and motility in dogs with a surgically induced 66% decrease in renal function. They found that these animals displayed alterations in gastrointestinal electrical activity. However, they failed to find changes in transit times of the proximal gut, and the demonstrated decrease in the oroanal transit time was largely explained by a decrease in colonic transit time.

Gastric emptying was not significantly affected.

In conclusion, chronic renal failure is associated with a high degree of dyspeptic symptoms and gastric emptying abnormalities. These abnormalities are significantly but not totally explained by associated neuropathy. There are few studies available evaluating the acute effects of renal insufficiency on gastric motility.

In the few experimental studies that are available, uremia seems to cause disordered myoelectrical activity, but the clinical corollary, namely significantly delayed gastric emptying, has not been convincingly demonstrated.

SEPSIS

In animal studies by Cullen et al,55 dogs given a single dose of E. coli lipopolysaccharide experienced delayed gastric emptying of a liquid meal for 2 days.

There was no change in the levels of CCK or peptide YY (PYY) levels during endotoxemia, indicating that endotoxemia has little effect on the production of these peptides. Similarly, there was no decrease in splanchnic blood flow to account for the gastric emptying abnormalities. The authors do note that pancreatic polypeptide levels increased 5 to 10 times over baseline. They insinuated from this finding that vagal stimulation was decreased during endotoxemia.

Cullen et al" again added to our understanding of endotoxin-induced motility aberrations, this time looking at the myoelectric pattern in dogs after a single dose of endotoxin. These researchers found that a single sublethal dose of endotoxin abolishes the interdigestive and digestive small intestinal action potentials.

These effects were temporary, with normal myoelectrical patterns returning on post-toxin day 3. The authors speculated that this may explain the ileus seen in sepsis. These same authors in a similar experiment attempted to further define the mediator of the effect on gut myoelectrical activity and found vasoactive intestinal peptide (VIP) to be elevated on the first day after endotoxin injection. The level of N0^sub 2^/NO^sub 3^ increased on postendotoxin day 2. The authors speculated that there may be 2 mechanisms at work, with the immediate postendotoxin ileus caused by VIP, whereas the later suppression may be caused by NO.57

In the rat model, lipopolysaccharides (LPS) have been shown to increase iNOS, which in turn produces NO. Experiments suggest that the maximal induction of iNOS takes approximately 3 to 6 hours. Takakura et al,5' evaluating gastric emptying after LPS exposure in rats, found depression of gastric emptying after exposure; however, this abnormality was delayed for 3 to 6 hours, paralleling the induction of iNOS. Additionally, an inhibitor of iNOS dampened the effect of delayed gastric emptying in LPS rats but not control animals, suggesting a role for NO. However, because reversal of the motility abnormalities were not complete (despite what was believed to be maximal effectiveness by the inhibitor), the authors suggested that other mediators, such as the autonomic nervous system, eicosanoids, platelet-activating factor, and CCK, may also play a role.58

CHANGES IN GUT PEPTIDES

Gastrointestinal hormone is released from the L-cells of the gut in the postprandial period. It exerts a glucose-dependent insulinotropic effect on pancreatic B-cells and lowers glucagon release. Glucagon-like peptide-1 (GLP-1) substantially retards gastric emptying of liquids and solids, which may be involved in the glucose-lowering effect of this peptide. In healthy volunteers, in the interdigestive state, GLP-1 greatly inhibited antroduodenal contractility by a reduction of contraction frequencies and amplitudes. Specifically, it abolished antral wave propagation in the interdigestive state and stimulated tonic and phasic motility of the pylorus.59 In a recent study by Schirra et al,59 GLP-1 was found to (1) relax the fundus in a dosedependent fashion, (2) reduce phasic volume events, and (3) increase gastric compliance. Thus, exogenous GLP-1 reduces driving forces and stimulates breaking mechanisms of gastric outflow.59 GLP-1 is rapidly cleaved to an inactive form by an exopeptidase dipeptidyl peptidase IV (DPIV), but it is also nonenzymatically cleared by several organs such as the kidney, which is considered an important clearance site.so GLP-1 also seems to be an anorexic-inducing agent when injected into cerebral ventricles in animals. Preliminary data also show that peripheral administration of GLP-1 and its agonist exendin-4 clearly reduce appetite and food intake after peripheral administration in normal or diabetic human subjects. Proglucagon-derived peptides are increased in a broad variety of intestinal diseases that affect the integrity of the mucosal epithelium or after surgical resection of the bowel.60 GLP-2 is released in response to gut injury and also has a role in delaying gastric emptying.

Visceral stress information reaches the caudal brainstem through the vagal and glossopharyngeal nerves and then is relayed to the paraventricular nucleus (PVN) through direct and indirect neural pathways.

Most of these pathways are catecholaminergic, but a relatively small amount of noncatecholaminergic neurons located in the caudal nucleus of the solitary tract (NST) and reticular formation also project directly to the PVN. These neurons coexpress several neuropeptides including GLP-1. In an experimental study by Rinaman,61 intraperitoneal injection of lipopolysaccharide to rats results in activation of GLP-1-positive neurons. Although not specifically addressed in this study, it is possible that centrally released GLP-1 may play a role in vagally mediated gut motility.

CONCLUSION

Gastrointestinal motility in the critically ill patient is influenced by a number of inflammatory and iatrogenic factors. The impact of these factors likely has a dynamic effect on esophageal, gastric, and small bowel motility. However, despite a changing propensity for both gastric reflux and penetration of oropharyngeal secretions, a profound breakdown of upper aerodigestive-protective reflexes likely has to occur before a clinically significant aspiration pneumonia is realized.

Further understanding of the impact of these factors on gut motility and in-depth study of these protective reflexes in the critically ill population will be instrumental in decreasing the risk of aspiration pneumonia in these patients.

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Mark T. DeMeo, MD*; and Keith Bruninga, MD

From the Department of Medicine, Division of Gastroenterology and Nutrition, Rush University Medical Center, Chicago, Illinois

Correspondence: Mark T. DeMeo, MD, Division of Gastroenterology and Nutrition, Rush University Medical Center, Chicago, IL 606123824. Electronic mail may be sent to mark_t_demeo@rush.edu. *Co-Director, North American Summit on Aspiration in the Critically III Patient.

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